Table of Contents
Preamble
4
Key Revisions
5
Chapter 1. Summary of the Guidelines
7
Chapter 2. Clinical Diagnosis of Atherosclerosis
12
Chapter 3. Comprehensive Risk Assessment
14
3-1. Risk Factor Assessment
14
3-2. Disease Concept and Diagnostic Criteria for Metabolic Syndrome
27
Chapter 4. Comprehensive Risk Management
29
4-1. Absolute Risk of Atherosclerotic Cardiovascular Diseases (ASCVD) and Lipid-Management
Targets
29
4-2. Lifestyle Modification
34
4-3. Drug Therapy
47
4-4. Managing Major High-Risk Conditions
59
4-5. Implementation of Comprehensive Risk Assessment and Management
66
Chapter 5. Familial Hypercholesterolemia
75
Chapter 6. Other Types of Primary Dyslipidemias
80
Chapter 7. Elderly
83
Chapter 8. Women
86
Chapter 9. Children
90
References
92
Appendix 1: Physical Activity Guidelines for Health Promotion 2013
137
Appendix 2: Exercise Guidelines for Health Promotion 2006
138
Appendix 3: Method for Achilles Tendon Radiography
139
Preamble
Every 5 years, the JAS publishes guidelines for the treatment of dyslipidemia and
atherosclerosis. To date, this society has released four such guidelines. Since 2007,
the JAS has included objectives that consider all the risk factors for atherosclerotic
cardiovascular diseases (ASCVD) and has accordingly been publishing manuals, such
as the “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases.” Because
guidelines should be based on evidence of diagnoses and treatments that have already
been validated, regular revisions are necessary to administer medical care of high
quality.
Apart from age, gender, and family history, for which clinical intervention is not
possible, the major risk factors for ASCVD include diabetes, hypertension, smoking,
and dyslipidemia. Dyslipidemia is a huge risk factor for coronary artery disease (CAD),
a form of ASCVD, and in the current set of guidelines, we will be dealing with CAD
as the main disease of interest. Nevertheless, other risk factors also ought to be
thoroughly managed as part of the efforts for preventing ASCVD.
In 1987, a consensus conference on hyperlipidemia was held at the JAS, and reference
values for diagnosing hyperlipidemia were proposed. Although the reference values
were established when there was a lack of evidence in Japan, it was an unprecedented
proposal that provided the clinical limits of lipids for the prevention of ASCVD.
In 1988, the evidence-based National Cholesterol Program (NCEP) was announced in the
United States, and since then, the reference values have undergone several revisions.
At that time, there was a strong momentum for the creation of a set of Japan-specific
guidelines; therefore, the “Guidelines for Diagnosis and Treatment of Hyperlipidemia”
were established in 1997. Following the publication of epidemiological studies, such
as the Hisayama study, and observational studies, such as J-LIT, we gradually gathered
sufficient evidence in our country. Subsequently, the “Guidelines for Diagnosis and
Treatment of Atherosclerotic Cardiovascular Diseases”, which took risk factors into
consideration, were established in 2002.
The “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2007” were
later published in 2007. A change of terms from “hyperlipidemia” to “dyslipidemia”
and replacement of total cholesterol with LDL cholesterol (LDL-C) as the major risk
factor were features of this guideline. Establishing LDL-C as the major risk factor
has led to an even more direct approach toward managing the risk factors for ASCVD.
Furthermore, raising the topic on the importance of measures against metabolic syndrome
and smoking, which have gained considerable attention, serves as a reminder to pay
attention also to measures for the prevention of ASCVD in our daily lives. For healthy
individuals, the risk of ASCVD has traditionally been assessed through the relative
risk; however, this was replaced by the use of absolute risk in the guidelines released
in 2012. This change resulted in a higher awareness of the importance of combined
risk factors. Considering the need to comprehensively manage the wide range of atherosclerotic
risks, we have compiled information on the “Comprehensive Management of Atherosclerotic
Cardiovascular Diseases” and have created charts, which incorporate the guidelines
of various scientific societies.
We have striven to include more updated information in the current revision; hence,
you will find several newly introduced Clinical Questions (CQs), which are the mainstream
of recent guidelines.
Shizuya Yamashita
President, the Japan Atherosclerosis Society
Key Revisions
1.
CQs and Systematic Review (SR)
In the subsections on dyslipidemia in the assessment of risk factors, absolute risk
of ASCVD, lipid management targets as well as drug therapy and diet therapy in improving
lifestyle habits, we created CQs and performed an SR based on the MINDS method. For
our SR, we essentially chose the literature published before the end of 2015.
2.
Calculation of Absolute Risk
Following the 2012 version, the assessment of risk has been performed using the absolute
risk calculation described in this set of guidelines. The NIPPON DATA80, which was
used to calculate the absolute risk in the 2012 version, was the result of baseline
surveys conducted when statins were not available. It is suited to the observation
of the natural course of disease, and the data are highly useful; however, using death
instead of disease onset as the outcome and the absence of information on LDL-C and
HDL-C are major issues, in addition to some others. SR indicated that the Suita study,
which used CAD as its outcome, is most suitable for risk calculation in this set of
guidelines. We believe that the determination of the incidence rate of CAD instead
of the overall risk assessment has enabled a clearer demonstration of the importance
of each risk.
3.
Addition of High-Risk Conditions
In view of the plan to compile an extensive list of risks for atherosclerosis, we
included hyperuricemia and sleep apnea syndrome (SAS) as conditions to be considered.
Although these conditions may contribute to atherosclerotic lesions to different extents,
it is necessary to consider them from the perspective of comprehensive management.
4.
Stricter LDL-C Control in High-Risk Conditions for Secondary Prevention
For the secondary prevention of high-risk conditions, such as familial hypercholesterolemia
(FH) and acute coronary syndrome (ACS), we proposed an even stricter LDL-C control
level than the current LDL-C control level of < 100 mg/dL.
5.
Elaborating on FH
In conjunction with the launch of new drugs, the addition of pediatric FH as an indication
for statins, and so on, we have provided a detailed description of the diagnosis and
treatment of FH. To facilitate easy comprehension, we have used a flow chart for describing
the treatment methods.
6.
Evidence Levels and Recommendation Levels
Similar to the previous guidelines, we have included statements at the beginning of
each section. The evidence levels and recommendation levels have also been provided
(Tables below).
The evidence levels are separately presented as evidence from therapeutic interventions
and that from epidemiological studies. The evidence in Japan was regarded as the core
of the evidence levels; however, please note that important data from various other
countries may have been used wherever the data from Japan was insufficient.
Classification of Evidence Levels in Relation to Treatment and Diagnosis
1+
High-quality RCT* and their MA/SR
1
Other RCT* and their MA/SR
2
Prospective cohort studies, their MA/SR, and (pre-determined) RCT sub-analysis
3
Non-randomized comparative studies, before–after comparative studies, and retrospective
cohort studies, case–control studies, their MA/SR, and RCT post hoc sub-analysis
4
Cross-sectional studies and case series
RCT: Randomized controlled trial, MA: Meta-analysis, SR: Systematic review
*
A high-quality RCT is defined as a study that (1) involves a large number of subjects
(high statistical power), (2) is double-blinded and independently assessed, (3) has
a high follow-up rate (low drop-out rate) and few of protocol deviations, (4) includes
a clear method for random allocation, etc.
Classification of Evidence Levels of Epidemiological Studies
E-Ⅰa:
Meta-analysis of cohort studies
E-Ⅰb:
Cohort studies
E-Ⅱ:
Case-control studies and cross-sectional studies
E-Ⅲ:
Descriptive studies (case series)
Recommendation Levels
A
Strong recommendation
B
Weak recommendation
Recommendations made according to consensus are indicated by the word “consensus.”
Conflict of Interest
In accordance with the “COI Management Guidelines for Clinical Research” established
by the Japan Association of Medical Sciences' COI committee, a conflict of interest
(COI) statement has been obtained from each member of the committee involved in drafting
the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. The
names of the enterprises disclosed in the COI statement are provided below. The applicable
period is January 01, 2013, to December 31, 2015.
Amgen Astellas BioPharma K.K., Astellas Pharma Inc., AstraZeneca plc, Abbott Japan
Co., Ltd., Izumisano city, Eisai Co., Ltd., Aegerion Pharmaceuticals, Inc., MSD K.K.,
Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Omron Healthcare Co.,
Ltd., Curves Japan Co., Ltd., Kaizuka city, Kaneka Medix Corp., Kissei Pharmaceutical
Co., Ltd. Kyowa Hakko Kirin Co., Ltd., Kyowa Medex Co., Ltd., Kirin Company, Limited,
Quintiles Transnational Japan, GlaxoSmithKline K.K., Kowa Company, Ltd., Kowa Pharmaceutical
Co., Ltd., Signpost Corporation, Sanofi K.K., Sanwa Chemistry Co., Ltd, Sanwa Kagaku
Kenkyusho Co., Ltd., JCR Pharmaceuicals Co., Ltd., Shionogi & Co., Ltd. Skylight Biotech,
Inc. Zuyou Co., Ltd., Daiichi Sankyo Company, Limited., Taisho Pharmaceutical Co.,
Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.,
Takeda Pharmaceutical Company Limited., Mitsubishi Tanabe Pharma Corporation, Chugai
Pharmaceutical Co., Ltd., Teijin Home Healthcare Limited., Teijin Pharma Limited.,
Terumo Corporation, Tomiyama Scientific Industry Co., Ltd., Eli Lilly Japan K.K.,
Japan Blood Product Organization, Nippon Boehringer Ingelheim Co., Ltd., Medtronic
Japan Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Bayer Yakuhin, Ltd.,
Biogen Idec, Inc., PPD Japan, K.K., Lake Biwa Consortium of Health and Welfare, Pfizer
Japan Inc., Philips Respironics GK, Fukuda Denshi Co., Ltd. Bristol-Myers Squibb Company,
Boston Scientific Corporation Japan, Maruha Nichiro Corporation, Meiji Seika Pharma
Co., Ltd., Medical Review Co., Ltd., Merck & Co., Mochida Pharmaceutical Co., Ltd.,
Rinku General Medical Center, ResMed Inc.
Chapter 1.
Summary of the Guidelines
1.
Clinical Diagnosis of Atherosclerosis
To prevent ASCVD, it is essential to identify the presence of atherosclerotic lesions
and understand their severity before the clinical symptoms appear. The risk factors
need to be managed and treated, with consideration for the prevention of progression
and regression of such lesions. Therefore, it is necessary to diagnose the extent
to which atherosclerosis has progressed.
Angiography, intravascular ultrasound, and invasive diagnostic methods involving a
vascular endoscope are occasionally used for diagnosis in patients who present symptoms
and for the secondary prevention of ASCVD. Conversely, non-invasive methods are mainly
used for assessing atherosclerosis for the primary prevention of ASCVD in patients
who do not present with any symptoms. These non-invasive methods of assessment are
generally classified into either morphological examinations [ultrasound, multi-detector
computed tomography (MDCT), and magnetic resonance imaging/magnetic resonance angiography
(MRI/MRA)] or vascular function tests [ankle–brachial index (ABI), brachial–ankle
pulse wave velocity (baPWV), cardio–ankle vascular index (CAVI), and flow-mediated
vasodilation (FMD)]. We anticipate that carotid intima–media thickness (IMT)/plaque,
ABI, baPWV, CAVI, and FMD will be useful means for predicting the future risks of
ASCVD. In addition, MDCT is a simple and highly specific examination method, which
can easily detect coronary lesions. Each patient should be assessed using one or a
combination of methods as applicable to his or her condition.
2.
Comprehensive Risk Assessment and Management
1)
Risk Assessment and Management
Assessing each risk factor for atherosclerosis and managing the factors that can be
resolved through interventions are important for preventing ASCVD. Evidence from numerous
epidemiological studies has revealed many risk factors for atherosclerosis. They include
dyslipidemia, smoking, hypertension, diabetes, chronic kidney disease (CKD), aging,
male sex, family history of CAD, history of CAD, non-cardiogenic cerebral infarction,
peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), hyperuricemia, and
SAS as well as metabolic syndromes that are caused by the accumulation of visceral
fats and insulin resistance. Led by The Japanese Society of Internal Medicine, 11
scientific societies and The Japanese Association of Medical Science/Japan Medical
Association published the “Comprehensive Risk Management Chart for the Prevention
of Cerebro- and Cardiovascular Diseases” in 2015 as a comprehensive set of guidelines
for the prevention of ASCVD. The methods of assessment and management were thoroughly
explained in six steps in the guidelines, which covered topics from screening (based
on the rationale behind the chart) to drug therapy.
2)
Diagnostic Criteria and Management Standards for Dyslipidemia
The incidence of CAD is high when the LDL-C or triglyceride (TG) levels are high or
when the HDL-C level is low. The diagnostic criteria for dyslipidemia are established
in this set of guidelines (
Table 1
) with regard to preventive screening for ASCVD.
Table 1.
Diagnostic Criteria for Dyslipidemia (Blood Collected from Patients in Fasting State)*
LDL-C
≥ 140 mg/dL
Hyper-LDL cholesterolemia
120–139 mg/d
Borderline hyper-LDL cholesterolemia**
HDL-C
< 40 mg/dL
Hypo-HDL cholesterolemia
TG
≥ 150 mg/dL
Hypertriglyceridemia
Non-HDL cholesterol
≥ 170 mg/dL
Hyper-non-HDL cholesterolemia
150–169 mg/dL
Borderline hyper-non-HDL cholesterolemia**
*
“Fasting state” is defined as fasting for at least 10 h. However, consumption of liquids
with no calories, such as water and tea without milk or sugar, is allowed.
**
If screening shows borderline hyper-LDL cholesterolemia and borderline hyper-non-HDL
cholesterolemia, investigate whether a high-risk condition is present and consider
the need for treatment.
LDL-C is derived using the Friedewald formula (TC.HDL-C.TG/5) or through a direct
method.
Non-HDL-C (TC.HDL-C) or a direct method is used if the TG level is 400 mg/dL and greater
or if postprandial blood is collected. However, if hypertriglyceridemia is absent
during screening, the risk shall be assessed with the consideration that the difference
from LDL-C can possibly turn out to be smaller than + 30 mg/dL.
When employing this set of diagnostic criteria, the basis is to measure the total
cholesterol (TC), TG, and HDL-C levels using blood collected in a fasting state and
subsequently calculating the LDL-C using the Friedewald formula (LDL-C=TC–HDL-C–TG/5).
However, this formula cannot be applied if the TG level is 400 mg/dL and greater,
or when using postprandial blood. In such cases, non-HDL-C ( = TC– HDL-C) shall be
used. The accuracy of the LDL-C direct measurement method has improved over time,
and it can therefore be used in place of the Friedewald formula.
In the 2012 version of the guidelines, for primary prevention, patients are stratified
based on the absolute risk, and we had established management standards for dyslipidemia,
which catered to the stratification. We followed the same plan while formulating the
current guidelines and searched for methods of assessment according to absolute risk.
Specifically, we formulated the CQ, “Does an assessment method that predicts the incidence
of or death due to ASCVD in the Japanese exist?”, and performed an SR. Although nine
studies were selected by SR, we eventually chose the Suita study because (1) LDL-C
and HDL-C were both included as predictive indicators, (2) the LDL-C levels were categorized
in detail, (3) stroke was not included as an endpoint, and (4) the outcome was set
as event onset instead of death. We performed the stratification based on the Suita
score (
Fig. 1
). As shown in
Fig. 2
, due to the complexity of calculating the Suita score, we created an application
for categorization so that this method can be easily applied in our daily medical
practice (http://www.j-athero.org/publications/gl2017_app.html). In addition, we created
a chart describing the stratification by gender, age, and number of risk factors (
Fig. 3
). Categorization based on
Fig. 2
and that based on
Fig. 1
have been verified through simulation and found to be almost consistent.
Fig. 1.
Flowchart Using the Suita Score to Establish LDL-C Management Targets, from the Perspective
of CAD Prevention
• The Suita score is calculated based on Fig. 2.
• Note: For patients diagnosed with FH and those diagnosed with familial type Ⅲ hyperlipidemia,
do not use this chart and refer to Chapter 5 (Familial Hypercholesterolemia) and Chapter
6 (Other Types of Primary Dyslipidemias), respectively.
Fig. 2.
Model for Predicting CAD Onset Using the Suita Score
* Ex-smokers should be regarded as nonsmokers. Note that the risk of CAD decreases
by almost half 1 year after smoking cessation and drops to the same level as in nonsmokers
after 15 years of smoking cessation.
** The current values are used even if the patient is currently undergoing treatment
or not. However, counsel the patient while keeping in mind that patients undergoing
treatment for hypertension have a higher risk of CAD than those who have the same
blood pressure value without undergoing treatment.
Fig. 3.
Flowchart for Establishing LDL-C Management Targets from the Perspective of CAD Prevention
(Simplified Version Using Risk Factors)
The lipid management targets that catered to this categorization are shown in
Table 2
. For primary prevention, the administration of drug therapy should generally be considered
after lifestyle modifications have been made for a certain period and when the effects
have been ascertained. The management targets are challenging goals by utmost effort
for patients with low or moderate risk. A 20–30% decrease in LDL-C also indicates
a reduction in the risk of CAD by 30%; hence, we decided that a reduction of 20–30%
in LDL-C levels can be considered another target for such patients. For secondary
prevention, it is advisable to initiate drug therapy, with the management targets
shown in
Table 2
as the goal, along with lifestyle modifications.
Table 2.
Lipid Management Targets for Patients with Different Risk Category
*
For patients who are also suffering from high-risk conditions, such as FH, ACS, and
diabetes complicated by other high-risk conditions shown in
Table 3b
, stricter LDL-C control should be considered, with a level of < 70 mg/dL as the target.
Although non-drug therapy is used as a standard means for achieving the management
target in primary prevention, drug therapy should be considered for patients with
low risk if the LDL-C level is ≥ 180 mg/dL. The possibility of FH should also be considered
(refer to Chapter 5).
Achieving the LDL-C management target should be the first goal, and reaching the non-HDL-C
management target should be the next goal after the first goal has been achieved.
Managing the TG and HDL-C levels is important during this process.
These values are challenging goals by utmost effort; a 20%–30% reduction in LDL-C
levels for primary prevention (low or moderate risk) and a decrease of ≥ 50% for secondary
prevention are also possible targets.
For elderly patients (aged ≥ 75 years), refer to Chapter 7.
3)
Lifestyle Modification
As previously mentioned, lifestyle modification is required for both primary prevention
and secondary prevention patients. The cessation of smoking is important for preventing
atherosclerosis, and controlling the energy intake to reduce obesity would lead to
improvements not just in obesity but also in other risk factors. Although a limited
number of studies have followed the onset of ASCVD as an endpoint, diet therapy based
mainly on the Japanese dietary pattern contributes to decrease risk factors, including
improvement of lipid metabolism. In terms of exercise therapy, epidemiological studies
have shown that the amount of exercise and level of physical fitness are negatively
correlated with CVD, indicating the importance of appropriate exercise.
4)
Drug Therapy
Given that statin therapy has been shown to be beneficial for prevention of ASCVD
not just overseas but also in Japan, we believe that it is appropriate to consider
statins as the first medication of choice for controlling LDL-C levels. In high-risk
primary prevention patients, the management target for LDL-C should be < 120 mg/dL.
On the other hand, for secondary prevention, aggressive treatment with the aim of
lowering LDL-C level at least < 100 mg/dL should be initiated immediately after the
disease onset; furthermore, an even lower target value should be considered when patients
are complicated with other high risk clinical conditions. The application, effectiveness,
and safety of oral hypolipidemic agents other than statins have already been validated;
thus, before prescribing them, clinicians should always pay attention to the indications
as well as clinical status of contraindication and careful administration. Ezetimibe,
PCSK9 inhibitors, and EPA are the medications that have been proven to be effective
for the prevention of ASCVD when used in combination with statins. When prescribing
hypolipidemic agents, efforts should be made to improve adherence for medication because
good adherence has proven to lead to better efficacy for prevention of ASCVD.
The effects on plasma lipids' levels of each agent are listed in
Table 4
. Taking into account of the importance for prevention of ASCVD as well as the attainability
of the target level for each lipid through drug therapy, we set the order of intervention
starting with LDL-C, followed by non HDL-C and TG. In the main chapter of “Drug Therapy”,
we also referred to the significance or meaning of management for hypertriglyceridemia.
Table 4.
Classification of Medications Used to Treat Dyslipidemia According to Their Efficacy
Category
LDL-C
NonHDL-C
TG
HDL-C
Major drug name
Statin
↓↓∼ ↓↓↓
↓↓∼ ↓↓↓
↓
-∼↑
Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, Pitavastatin, Rosuvastatin
Intestinal cholesterol transporter inhibitor (Cholesterol absorption inhibitor)
↓↓
↓↓
↓
↑
Ezetimibe
Anion exchange resin
↓↓
↓↓
↑
↑
Colestimide, Cholestyramine
Probucol
↓
↓
–
↓↓
Probucol
PCSK9 inhibitor
↓↓↓↓
↓↓↓↓
↓∼↓↓
–∼↑
Evolocumab, Alirocumab
MTP inhibitor*
↓↓↓
↓↓↓
↓↓↓
↓
Lomitapide
Fibrate
↑∼↓
↓
↓↓↓
↑↑
Bezafibrate, Fenofibrate, Clinofibrate, Clofibrate
Selective peroxisome proliferator-activated receptor α modulator (SPPARMα)
↑∼↓
↓
↓↓↓
↑↑
Pemafibrate
Nicotinic acid derivative
↓
↓
↓↓
↑
Niceritrol, Nicomol, Tocopheryl Nicotinate
N-3 polyunsaturated fatty acid
–
–
↓
–
Ethyl icosapentate, Omega-3-acid ethyl ester
*
Applicable only to patients with homozygous FH
↓↓↓↓: ≤ – 50% ↓↓↓: −50∼30% ↓↓: −20∼30% ↓: −10∼ −20%
↑: 10∼20% ↑↑: 20∼30% –: −10∼10%
5)
Major High-Risk Conditions
A history of CAD, diabetes, and cerebrovascular diseases are observed in patients
requiring more active treatment due to unsatisfactory disease management, the presence
of complications, and overlapping risk factors. Therefore, we created a special subsection
in this set of guidelines to provide detailed explanations on cases requiring enhanced
management.
3.
Primary Dyslipidemias
FH is a hereditary disease, and its heterozygote exists in 1 of 200–500 individuals.
FH poses a high risk of CAD and is frequently encountered by general practitioners.
Because the rate of diagnosis in Japan is still low, there is a need to accurately
diagnose and treat this condition by assessing the family history, tendon xanthoma,
and LDL-C levels, which are part of the diagnostic criteria for FH. In this set of
guidelines, we will discuss the guiding principles for treating FH during pregnancy
and childbirth and in children. In addition to the treatment methods involving LDL
apheresis, we have included explanations on the types of primary dyslipidemia other
than FH. Patients who are suspected to be suffering from any of these diseases should
be referred to specialists for further assessment.
4.
The Elderly, Women, and Children
In the elderly persons 65–74 years of age, a high LDL-C level is an important risk
factor for CAD, and the effect of statin therapy on CAD prevention and primary prevention
of non-cardiogenic cerebral infarction is promising. Meanwhile, because the effect
of statin therapy on primary prevention in the elderly persons ≥ 75 years of age is
not evident, the objective is to manage cases individually, according to the decisions
of the attending physician. The treatment for women is basically lifestyle modification,
but for secondary prevention patients and patients with FH or at a high risk of CAD,
drug therapy shall be considered. It is also important for children to maintain the
intake of proper meals and continue with exercise therapy. Similar to adults, the
management of secondary dyslipidemia in children should focus on treating the primary
disease. It should be kept in mind that the diagnostic criteria for pediatric cases
of dyslipidemia, including FH, are different from those for adult cases.
Chapter 2.
Clinical Diagnosis of ASCVD
From the perspective of preventing ASCVD, it is important to identify the presence
of arteriosclerosis and atherosclerotic lesions and understand its severity before
clinical symptoms appear. The management and treatment of risk factors with the prevention
of progression or even regression taken into consideration is essential. Invasive
diagnostic methods, such as angiography, are necessary in the secondary prevention
of ASCVD. However, noninvasive methods are mainly used in primary prevention to assess
arteriosclerosis and atherosclerosis. In this section, we will be discussing the methods
for assessing arteriosclerosis and atherosclerosis.
1.
Morphological Examinations
1)
Ultrasonography
Ultrasonography is a widely used noninvasive imaging method. Lesions in the peripheral
arteries, such as the carotid arteries, and arteries in the lower extremities, can
be assessed using an ultrasound machine that comes with a high-frequency linear probe
of ≥ 7 MHz.
The Japan Society of Ultrasonics in Medicine and The Japan Academy of Neurosonology
recommend using ultrasonography as a standard method to measure the intima–media thickness
(IMT), plaques (localized protruding lesions of ≥ 1.1 mm), stenosis and such for assessing
the degree of arteriosclerosis, particularly in the carotid arteries
1–3). IMT is assessed as the thickness adjusted by age
4). It is also used to reflect the degree of systemic arteriosclerosis or as an alternative
assessment factor for predicting the risk of co-existence or onset of ASCVD (e.g.,
CAD, PAD, cerebrovascular diseases, etc.)
5–8). Although the presence of plaque has a stronger significance in disease prediction
compared to the IMT, a high IMT value in cases where plaques are not detected is the
underlying pathogenetic mechanism for the development of plaques. With reference to
the Mannheim consensus, it is also necessary to assess the properties of plaques that
have a maximum IMT of > 1.5 mm
3, 9), and assessment is especially important for some plaques that can possibly lead
to cerebral embolism (e.g., echolucent plaques, ulcers, mobile lesions, and lipid-rich
plaques). If short-axis scanning shows a buildup of plaque in ≥ 50% of the vascular
lumen, then the degree of stenosis needs to be assessed. When the stenosis is significant
(i.e., ≥ 70%), in addition to active medical treatment, carotid endarterectomy or
carotid artery stenting should also be considered.
Performing the assessment to determine the properties of the plaques and the percentage
of stenosis in the same way as it is done in the carotid arteries is likewise important
for arteries in the lower extremities
10). Furthermore, confirming the presence of collateral circulation, the patterns
of blood flow waveforms and the below-knee transit time of vessel flow (TVF) would
make it possible to estimate where the stenotic portions are
11).
Ultrasonography is also a useful method for diagnosing atherosclerotic renal artery
stenosis in the renal arteries
12, 13).
2)
Computed Tomography (CT)
CT is a method of examination that can diagnose arteriosclerosis in a short amount
of time. It can also determine whether aneurysm is present by measuring the size of
the artery. Furthermore, as the degree of calcification, fats, and fiber content can
be estimated to some extent based on the CT number, it is an excellent means for confirming
the presence of calcified lesions in the aorta and peripheral arteries. Multidetector
CT (MDCT) offers superior imaging speed and spatial resolution, and by injecting a
contrast medium through the peripheral veins, it enables the visualization of diseases
in all the arteries and coronary arteries. It is commonly used to screen for CAD.
It has excellent specificity
14–17), and organic coronary stenosis can almost be ruled out if no abnormalities
are detected using this technique.
3)
Magnetic Resonance Imaging/Angiography (MRI/MRA)
MRI is especially useful for detecting lesions in the brain, which include ischemic
changes and cerebral infarction. MRA provides an excellent means for visualizing stenosis
and obstructive lesions in the intracranial arteries, carotid arteries, aorta, renal
arteries and other blood vessels. Nowadays, non-contrast enhanced MRA is sometimes
used in place of angiography. The properties of the plaques can also be assessed using
MRI plaque imaging.
4)
Catheterization
To date, angiography using a catheter remains as one of the main methods for diagnosing
arterial stenosis despite being an invasive examination. Stenotic portions are assessed
on the basis of the percentage of stenosis, which is calculated using the luminal
diameter of normal-appearing portions and stenotic portions. However, limitations
such as eccentric plaques and compensatory remodeling hinder the accurate determination
of plaque volume. Meanwhile, intravascular ultrasound (IVUS), optical coherence tomography
(OCT) and the vascular endoscope are some other methods that provide an excellent
assessment of the plaque volume as well as the properties of the plaques.
2.
Vascular Function Tests
18)
1)
Ankle–Brachial Index (ABI) and Toe–Brachial Index (TBI)
ABI is the ratio of the blood pressure (BP) in the brachial artery to the BP at the
ankle joint. This ratio is an indicator of narrowing of the central major arteries
from the ankle joint or the presence of obstructive lesions and the degree of compensation
by collateral circulation. Methods of measurement include the Doppler technique and
the oscilloscope. The Korotkoff sounds should be verified when measuring the BP in
the extremities using a sphygmomanometer and a stethoscope. On the other hand, the
oscillometric method is employed when performing automated measurement using an automated
sphygmomanometer or specialized equipment. Although the correlation between both methods
is generally good, the precision of the oscillometric method is low when used in cases
of critical limb ischemia. If the ABI is ≤ 0.9, then the presence of obstructive lesions
in the lower extremities should be suspected
19, 20). TBI is the ratio of the BP in the brachial artery to the blood pressure at
the toes. Measuring both the ABI and TBI allows us to gauge the peripheral artery
obstructive lesions distal than ankle joints. The reference TBI value is ≥ 0.7, and
the presence of obstructive lesions in the arteries of the lower extremities should
be suspected if the resulting value is ≤ 0.6. It is necessary to note that diabetes
patients and patients undergoing dialysis are prone to calcification in the walls
of arteries below the knee, and hence, there are cases in which the ABI cannot be
accurately measured.
2)
Brachial-Ankle Pulse-Wave Velocity (baPWV)
The pulse-wave velocity (PWV) produced by cardiac output reflects the stiffness of
arteries
21). It can be easily determined by measuring the pulse waves in the extremities using
a specialized device. However, it is necessary to note that the PWV is an indicator
of arterial stiffness and does not necessarily reflect atherosclerosis. The PWV is
the speed at which the aortic vibration (i.e., pulse wave) generated by the beating
of the heart is transmitted to the peripheral artery. It is proportionate to the stiffness
and thickness of the arterial walls. The carotid-femoral PWV (cfPWV) and baPWV are
the two forms of PWV measurement. baPWV is currently being used in clinical practice
in Japan. For baPWV, influences during BP measurement must be taken note of.
Aging
22), hypertension
23), diabetes
24), and pulse rate
22) are CVD risk factors that have been reported to cause increased baPWV, and they
show a good correlation with the Framingham Risk Score. A baPWV of 1,400 cm/sec corresponds
to the moderate risk level in the Framingham Risk Score.
3)
Stiffness Parameter β and Cardio-ankle Vascular Index (CAVI)
Stiffness parameter β is an index that represents the localized intrinsic stiffness
of the arterial walls. Arterial elasticity is hardly affected by BP, and stiffness
parameter β has been designed as an index of arterial elasticity that is corrected
using BP during measurement. It is calculated using the formula ln (Ps/Pd)/[(Ds-Dd)/Dd],
with BP and changes in carotid artery caliber as the variables
25). Additionally, it has been reported that stiffness parameter β is correlated with
carotid atherosclerosis
26, 27).
The CAVI is an index that represents the elasticity of the entire artery, from its
aortic root to the ankle, and it is derived by applying the concept of the stiffness
parameter β to the long arteries. A feature of CAVI is its nondependence on BP during
measurement
28). The CAVI increases with age
28), and patients with cerebral infarction, CVD
29), chronic kidney disease (CKD), and vasculitis have high CAVI values. It is also
increased in patients who suffer from hypertension, diabetes, metabolic syndromes,
sleep apnea syndrome (SAS), smoking, stress caused by disasters, etc., but at the
same time, it has been reported that the CAVI improves with treatment of these contributing
factors
25). Prospective surveys on cardiovascular events have revealed that a high CAVI value
is associated with a high frequency of cardiovascular events
30).
In addition to these, the central BP is also an index that reflects vascular function.
4)
Vascular Endothelial Function
Reactive hyperemia following a 5-minute avascularization in the forearm and certain
drugs such as acetylcholine cause a vascular endothelium-dependent increase in blood
flow, and vascular endothelial function is assessed by measuring the resulting increase
in arterial diameter and blood flow. The first method of assessment is strain-gauge
plethysmography, which measures the changes in circumference of the extremities as
the arterial pulse is produced. The second method is flow-mediated dilatation (FMD),
in which the changes in diameter of arteries in the upper arm are measured by ultrasonography.
FMD is a test that assesses the extent of brachial artery dilation caused by reactive
hyperemia after 5 minutes of forearm ischemia. The formula used for calculation is
FMD (%) = (diameter of the most dilated blood vessel - resting blood vessel diameter)/resting
blood vessel diameter × 100. The normal FMD value is ≥ 6–7%, and a malfunction in
the endothelial cells results in poor production of nitric oxide (NO), which in turn
lowers the amount of FMD. FMD starts decreasing from early stages of arteriosclerosis
31, 32), and it is therefore useful for the initial assessment of ASCVD.
3.
Predicting the Risk for ASCVD by Assessing Arterial Walls
It has been reported that IMT/plaque of carotid artery, ABI, baPWV, CAVI, FMD, and
such are independent predictive factors of future risk for ASCVD. However, reports
of other countries have revealed that adding the result of IMT measurement does not
increase the ability of risk prediction by the Framingham Risk Score
33). Although there are reports on the significance of noninvasive arterial wall assessment
in Japan
34), there is still a lack of sufficient evidence. Recent reports by Japan have shown
that
35) when data from a meta-analysis that integrated personal-level data of 14,673 Japanese
was used, the addition of baPWV to the classic risk factors increased the ability
to predict the risk for CVD. These reports have particularly demonstrated the usefulness
of baPWV in risk prediction for low-risk groups. In addition, it is suggested that
a baPWV > 1,800 cm/s is a risk that is equivalent to the high-risk conditions
18, 21). However, baPWV that reflects a high risk may possibly be different in the
target group, and further accumulation of data would be advantageous. To indicate
the abnormal findings of these indices except ABI in the risk categories in this set
of guidelines, which will lead to stricter management, more evidence needs to be built.
Chapter 3.
Comprehensive Risk Assessment
1.
Risk Factor Assessment
1)
Dyslipidemia
CQ1. Is LDL-C a predictor of the ASCVD incidence and mortality in the Japanese people?
Elevated LDL-C predicts the CAD incidence and mortality in the future. Among the types
of stroke, LDL-C has been shown to be positively related to cerebral infarction and
negatively related to hemorrhagic stroke, but in regard to the Japanese, the evidence
cannot be considered adequate. (Evidence level: E-1b)
Many epidemiological studies have been conducted in Europe and America, including
the Framingham Study in the US. Similar to the results of these studies, the increase
in hazard ratio for the CAD incidence and mortality following an elevation in LDL-C
has been validated in cohort studies involving the Japanese
36–40). It was shown in the Circulatory Risk in Communities Study (CIRCS) that in
comparison with the LDL-C < 80 mg/dL group, the risk was increased by 1.4 times in
the 80–99 mg/dL group, 1.7 times in the 100–119 mg/dL group, 2.2 times in the 120–139
mg/dL group, and 2.8 times in the ≥ 140 mg/dL group
37). The results have therefore made it clear that the risk of CAD incidence also
increases by two times or more in the Japanese if the LDL-C level is ≥ 140 mg/dL.
As for deaths from CAD, gender differences were observed in regard to risk, and a
significant increase was seen only in men
38).
An elevated LDL-C level also increased the risk for cerebral thrombosis (except lacunar
infarction) among the subtypes of ischemic stroke
36). However, on the contrary, it has been reported that there was a negative relationship
between hemorrhagic stroke (primarily intracerebral hemorrhage) and a decrease in
hazard ratio in the groups with high LDL-C levels
40).
Interventions for hypercholesterolemia, including lifestyle modifications, have been
clearly shown to significantly suppress CAD events according to the Western studies.
Large-scale clinical studies conducted in Japan have also reported similar results
41–44), in which it was evident that the occurrence of CAD in the Japanese subjects
decreased as a result of treating the hyper-LDL cholesterolemia. Furthermore, it has
not been observed in these studies that decreasing the LDL-C level adds to the risk
for intracerebral hemorrhage.
Overlapping risk factors also increase the incidence and mortality rates of CAD in
the Japanese
45, 46). It has been shown that even with the same degree of hypertension, the addition
of hyper-LDL cholesterolemia contributes to an increased risk for cardiovascular diseases
47).
Considering all the points mentioned above, in this set of guidelines, we have set
LDL-C ≥ 140 mg/dL as the screening reference value for the Japanese. Furthermore,
we have set a range of 120–139 mg/dL as the borderline level for which the effects
of overlapping risk factors should be carefully assessed.
CQ2. Is total cholesterol (TC) a predictor of the ASCVD incidence and mortality in
the Japanese people?
Elevated TC predicts the CAD incidence and mortality in the future. Regarding stroke,
it has been shown that TC is positively related to cerebral infarction and negatively
related to hemorrhagic stroke, a result that many studies have in common. TC therefore
predicts the occurrence of and death from stroke. (Evidence level: E-1a)
Similar to the above mention about LDL-C, a number of cohort studies conducted in
Japan have reported an increase in the incidence and mortality rates of CAD following
an elevation in TC level
48–54). A 24-year follow-up in NIPPON DATA80 showed that the hazard ratio for CAD
death was 1.55 times higher in the TC ≥ 220 mg/dL group than in the TC < 220 mg/dL
group, and the population attributable fraction (PAF) was 18.2%
54). When the TC level was ≥ 240 mg/dL, even though the hazard ratio further increased
to 1.79 times, the PAF dropped to 11.9%. The association between TC and the incidence/mortality
rate of CAD is almost linear, but a statistically significant increase in risk with
TC levels around 220 mg/dL has been observed in many studies. Although a relationship
between TC and risk of CAD death was seen in both the men and women, some reports
have stated that this relation is attenuated in elderly individuals who are ≥ 65 years
old
55).
Regarding stroke, the association between TC and hazard ratio differed because of
cerebral infarction and hemorrhagic stroke (primarily intracerebral hemorrhage). For
hemorrhagic strokes, in contrast with the increase in risk of occurrence at low TC
levels
55–57), an increased risk because of high TC levels was observed in ischemic stroke,
as with in CAD
58, 59).
The synergy between BP and TC in regard to CAD death was demonstrated in the EPOCH-JAPAN
study
60). When a systolic BP of ≥ 160 mmHg overlaps with TC levels of ≥ 220 mg/dL, the
adjusted hazard ratio for CAD death increased to 4.4 times that of the group with
BPs < 120 mmHg and TC levels < 180 mg/dL. On the other hand, there was a smaller number
of deaths caused by intracerebral hemorrhage in the group with TC levels of ≥ 220
mg/dL even when the BP readings were within the normal range.
CQ3. Is non-HDL-C a predictor of the ASCVD incidence and mortality in the Japanese
people?
Elevation of non-HDL-C predicts the CAD incidence and mortality in the future. But
at the same time, there are reports stating that an association does not exist in
regard to stroke. (Evidence level: E-1b)
As non-HDL-C includes all arteriosclerosis-causing lipoproteins, such as remnant lipoproteins,
there are views that claim its relatively superior ability in predicting the CAD incidence
in comparison with LDL-C
61, 62). The association between non-HDL-C and CAD has been reported in the results
of many epidemiological surveys conducted in Japan
51, 63–70). As with LDL-C, non-HDL-C was similarly associated with the occurrence
of myocardial infarction (MI), and they both had the same ability to predict MI
64). On the other hand, non-HDL-C surpasses TC in the ability to predict the occurrence
of MI
51). On the basis of analyses performed using data obtained from men, or both men
and women, there have been reports stating that the risk of and death from CAD and
MI increase when the non-HDL-C levels are approximately ≥ 140 mg/dL
67, 71, 72). In all of these studies, the risk of onset and risk of death were evidently
increased when non-HDL-C levels were ≥ 170–180 mg/dL or more, but there was no fixed
trend observed in the women
51, 64, 71, 73).
Meanwhile, studies concerning the association between non-HDL-C and stroke have reported
varying results. There are reports saying that the association is unclear
51, 67), and there are also those that revealed an increase in risk when non-HDL-C
levels were low
70). In reports of studies that reviewed the effect of hypertriglyceridemia on the
ability of non-HDL-C to predict MI
65), an obvious increase in risk for MI was seen in the presence of hypertriglyceridemia
(TG ≥ 150 mg/dL) and non-HDL-C levels of ≥ 190 mg/dL. Similar to the US, the non-HDL-C
levels of Japanese individuals with dyslipidemia was shown to be +30 mg/dL that of
LDL-C
74, 75).
On the basis of the results above, we concluded that non-HDL-C is possibly a useful
indicator for predicting the risk of CAD incidence and mortality. Therefore, in this
set of guidelines, the screening reference value for non-HDL-C has been set at ≥ 170
mg/dL. Furthermore, we have set a range of 150–169 mg/dL as the borderline level for
which the effects of overlapping risk factors should be carefully assessed.
CQ4. Is HDL-C a predictor of the ASCVD incidence and mortality in the Japanese people?
A decrease in HDL-C level predicts the CAD and ischemic stroke incidence and mortality
in the future. (Evidence level: E-1b)
A low HDL-C level is a risk for developing CAD and ischemic stroke. On the contrary,
the risk decreases when HDL-C levels are high
39, 53, 76–79). A 9.6-year observational period in NIPPON DATA90 showed that HDL-C
was significantly inversely correlated with all deaths as well as stroke-related deaths
80). It has been revealed in regional and occupational cohort studies that the risk
for CAD increases when HDL-C levels are < 40 mg/dL
46, 53, 78, 79). Likewise, in the J-LIT study that involved a cohort of simvastatin
users, the relative risk was 1.3 times higher in the < 40 mg/dL group than in the
40–49 mg/dL group in primary prevention
81). In addition, the relative risk was higher at 1.6 times in secondary prevention
82). Studies conducted in 23 countries in Asia and Oceania, including Japan, have
shown that a decreased HDL-C level alone also becomes a risk factor for CAD when both
the LDL-C and TG levels are within the normal range, and this is especially so in
Asia
83). However, there have also been reports from large-scale cohort studies involving
only the Japanese that low levels of HDL-C by itself does not constitute a risk for
CAD
84).
Considering the above findings, we have defined a HDL-C level of < 40 mg/dL in these
guidelines as the screening reference value for hypo-HDL cholesterolemia. Women generally
have a higher HDL-C level than men
46, 80, 85). However, there is still insufficient evidence on the association between
the discrepancy in HDL-C levels because of gender differences and CAD in each gender
78). Therefore, in these guidelines, we have set the reference value for women to
be the same as men.
CQ5. Is triglyceride (TG) a predictor of the ASCVD incidence and mortality in the
Japanese people?
An increase in TG level, whether fasting or nonfasting, predicts the CAD and ischemic
stroke incidence and mortality in the future. (Evidence level: E-1b)
There have been numerous reports on the association between a high TG level and the
risk for CAD not just in Europe and the US
86), but also in Asia, Oceania
87) and even in Japan
46, 78, 88–91). Despite a normal range of HDL-C, the association between TG and CAD
was still observed in several of these studies
86–89). Subsequent to the Framingham Study, hypertriglyceridemia is currently defined
as a TG level of ≥ 150 mg/dL (fasting) in the US
92). Although TG is traditionally tested with blood collected in a fasting state,
some reports have stated that its ability to predict the risk for cardiovascular events
is higher using blood collected in a nonfasting state
91). It has been shown in epidemiological surveys in Japan that the occurrence of
CAD increases when fasting TG levels of are ≥ 150 mg/dL
46, 90). These surveys have also shown that a nonfasting TG level of ≥ 165 mg/dL adds
to the risk for MI, exercise-induced angina, sudden death
88) or ischemic CVD
91). Furthermore, there have been many reports on hypertriglyceridemia being a risk
factor for ischemic stroke, though the association is weaker than that with CAD
46, 65, 87, 93–95).
Considering the above findings, hypertriglyceridemia has been defined as a TG level
of ≥ 150 mg/dL in these guidelines. However, hypertriglyceridemia often comes with
other important implications, such as an increase in the amount of remnant lipoproteins
or small dense LDL and the co-existence of hypo-HDL cholesterolemia. It could also
be a finding of metabolic syndrome, and hence, other factors accompanying an elevated
TG level should also be thoroughly considered.
Diagnostic Criteria for Dyslipidemia
As mentioned in CQ1 to CQ5, the positive correlation between a higher incidence rate
of CAD and high levels of LDL-C, TC, non-HDL-C and TG, or low levels of HDL-C, has
been shown not just in epidemiological surveys conducted in Europe and the US but
also in Japan. Among the different types of stroke, the association with cerebral
infarction has been found to be almost similar to that with CAD. However, for hemorrhagic
stroke (primarily intracerebral hemorrhage), the incidence and mortality rates are
instead higher at low LDL-C and TC levels. At present, the absolute risk of CAD (incidence
and mortality rate) in Japan is very much lower than that in the Western countries
96). However, there have been reports and such revealing that the LDL-C and TC levels
of the Japanese have been on the rise because of recent westernization of lifestyle
habits. As a result of this change, the TC levels of the Japanese have already reached
the levels in the US, or even higher
97). These reports have also pointed out the increasing incidence rate of CAD in some
regions in Japan
98, 99), and this is why the management of dyslipidemia is of importance. In these
guidelines, we have therefore established the diagnostic criteria for dyslipidemia
with a focus on preventing the development of CAD. The diagnostic criteria are shown
in
Table 1
.
The sequence of diagnosis is to first measure the TC, TG and HDL-C levels in a fasting
state in the morning and subsequently calculating the LDL-C level using the Friedewald
formula (LDL-C = TC–HDL-C–TG/5). However, measurement using the direct method is also
allowed. Even though problems with the accuracy of the direct method have been pointed
out
100), there have recently been the discontinuation of sales and production, improvement
and revision of standard pricing of reagents that were found to be mediocre over time.
As a result of the improved performance of reagents, the validity of LDL-C measurement
within daily clinical practice has been substantiated
101). However, most of the studies providing evidence relating to the treatment of
hyper-LDL cholesterolemia have used the Friedewald formula to determine LDL-C levels.
It should be noted that the diagnostic criteria, treatment targets and such are based
on the Friedewald formula. Non-HDL-C or the direct method of LDL-C measurement is
used when the patient is in a nonfasting state or when the TG level is ≥ 400 mg/dL.
However, the accuracy of the direct method and the non-HDL-C calculation cannot be
guaranteed when the TG level is ≥ 1000 mg/dL
101) and ≥ 600 mg/dL, respectively. Other methods of assessment should be considered
in such cases.
2)
Smoking
[Statement]
Smoking is a risk factor for CAD, stroke, abdominal aortic aneurysm and peripheral
artery disease (PAD). (Evidence level: E-1a)
Passive smoking is a risk factor for CAD and stroke. (Evidence level: E-1a)
Smoking has been reported to be a risk factor for CAD and stroke in a number of sources,
such as cohort studies conducted overseas and in Japan, as well as their meta-analyses.
Compared to nonsmokers, smokers face a higher risk for CAD and stroke, and there is
a dose-response relationship in this association
102). In addition, there has been no data showing that low-tar, low-nicotine tobacco
decreases the risk for these diseases. The risk increases even when the number of
cigarettes smoked per day is less than five
102). Reviews in Japan alone have shown that smoking has been consistently reported
in many cohort studies
103–111) to be a risk factor. Compared to lifetime nonsmokers, the relative risk for
developing CAD and death from it was 2.15 times higher for those who smoke ≤ 20 cigarettes
a day and 3.28 times for those who smoke > 20 sticks in a meta-analysis. Furthermore,
the relative risk of getting stroke and stroke-related death was 1.41 times higher
for those who smoke ≤ 20 cigarettes a day and 1.56 times for those who exceed 20 sticks
112). Other than that, a metaanalysis of cohort studies in Japan have shown that for
abdominal aortic aneurysm(AAA), the relative risk is 3.89 times higher for men and
4.30 times for women
113). The dose–response relationship has also been made apparent in the analysis.
The association with PAD has also been shown in cohort studies, including the Framingham
Study. Even in cross-sectional studies conducted in Japan, the proportion of PAD,
as determined using the ABI, was shown to be 3.7 times higher in current smokers (4.2
times for those with ≥ 45 pack-years) and 3.7 times in ex-smokers. The dose–response
relationship has similarly been demonstrated in these studies
114).
On the other hand, for passive smokers, it has been revealed in a meta-analysis that
the relative risks for CAD and stroke are 1.31
115) and 1.25
116), respectively.
Smoking increases the risk for developing type 2 diabetes to 1.4 times
117), and the risk for metabolic syndrome increases in accordance with the number
of cigarettes smoked
118). A meta-analysis has shown that smokers have lower HDL-C levels and higher LDL-C
and TG levels, and the dose-response relationship has again been observed
119). Smoking by itself is not just a risk factor for ASCVD. It also increases the
risk for diabetes, dyslipidemia and metabolic syndrome, in turn contributing to an
added risk for ASCVD.
Recently, new forms of tobacco (heat-not-burn tobacco products and electronic cigarettes,
etc) that differ from the conventional combustion cigarette have been in circulation.
As these new forms of tobacco have only been in circulation for a short period of
time, their effects on health, such as the risk for ASCVD and related death, cannot
be determined at this point of time. Nonetheless, although heat-not-burn tobacco products
do not contain substances that are produced by combustion, users still inhale and
exhale the aerosol generated by heating the tobacco leaves and additives, including
nicotine
120). Moreover, from the fact that various carcinogens have been reported to be found
in the aerosol, regardless of whether electronic cigarettes contain nicotine
121), the use of any of them has a possibility of adversely affecting health.
3)
Hypertension
[Statement]
Blood pressures that exceed the optimal reading (i.e., systolic BP (SBP) < 120 mmHg
and diastolic BP (DBP) < 80 mmHg) increase the risk for developing CVD, stroke, MI,
CKD, etc. (Evidence level: E-1a)
Hypertension is an important risk factor for cerebro- and CVD, such as cerebrovascular
disease and CAD, as well as heart failure, CKD and many more. Hypertension at middle
age also increases the risk for dementia when one reaches old age
122). In the results of EPOCH-JAPAN, a meta-analysis of 10 domestic cohort studies
(70,000 men and women in total), the hazard ratio for cerebro- and cardiovascular
disease-related death increases progressively with an elevation of BP levels that
exceed the optimal level (< 120/80 mmHg). This association was stronger in the middle-aged
adults than in the elderly
123).
The estimation by EPOCH-JAPAN showed a death rate of 50% from all forms of cerebro-
and CVD, 52% from stroke and 59% from CAD. They were all assessed to be caused by
high BPs that exceed the optimum level. Among all deaths from these causes, subjects
with grade-I hypertension made up the highest proportion
123). A comparison between subjects with hypertension and those without hypertension
in the lipid intervention study J-LIT showed that the relative risk for CAD in primary
prevention subjects was 2.05 times higher in women and 2.15 times in men
124).
The basis for diagnosing hypertension is usually the BP reading measured at the outpatient
clinic. However, it has been reported that BP measurements at home and 24-hour ambulatory
BP monitoring (ABPM) can predict the incidence of cardiovascular events better than
in-clinic BP measurements. In The Japanese Society of Hypertension's Guidelines for
the Management of Hypertension 2014 (JSH 2014), it has been explicitly stated that
if the diagnosis made with in-clinic BP readings differs from that with home BP readings,
BP-lowering effects should be determined and diagnosis should preferably be made on
the basis of the BP measured at home
122). The reference value for hypertension differs for in-clinic BP, 24-hour ABP and
home BP. In-clinic BP readings of ≥ 140/90 mmHg, home BP readings of ≥ 135/85 mmHg
and ABP readings of ≥ 130/80 mmHg shall be managed as hypertension
122).
4)
Diabetes Mellitus (DM)
[Statement]
DM is a strong risk factor for ASCVD. (Evidence level: E-1a)
DM is an important risk factor for ASCVD
125, 126). In NIPPON-DATA80, diabetic patients showed significantly higher risk of
2.8 times for death from CAD than non-diabetic subjects
127). The Hisayama study reported that the incidence rate of CAD and cerebral infarction
in diabetic patients were both high after adjusting multiple factors, such as gender
and age. In this study, the incidence rate of CAD was 5.0/1,000 person-years for diabetic
patients and 1.6/1,000 person-years for subjects with normal glucose tolerance (NGT).
Similarly, the incidence rate of cerebral infarction was 6.5/1,000 person-years in
diabetic subjects, that significantly higher than the 1.9/1,000 personyears in subjects
with NGT
128). The CIRCS study also showed that the incidence rate of cerebral infarction for
diabetic patients was higher at 1.9 times in men and 2.2 times in women as compared
to non-diabetics
129). Although the absolute risk of CAD among Japanese diabetic patients is thought
to be 30–70% compared to that of diabetic Europeans and Americans
130, 131), the difference has been closing in the near future.
Silent myocardial ischemia often coexists in diabetic patients, and this may result
in delayed diagnosis
132). Features of coronary lesions in diabetic patients include (1) multiple-vessel
disease, (2) highly complicated and diffuse
133, 134) and (3) multiple calcified lesions
135).
As for cerebral infarction, the JPHC study has shown that lacunar infarction, atherothrombotic
infarction and thromboembolic infarction occur more often in diabetic patients than
non-diabetic subjects
136).
Furthermore, prognosis of CAD in diabetic patients is worse than in non-diabetic subjects
137–139), and also have a higher risk for recurrence of cerebral infarction
140, 141). The risk for PAD is as much as three to four times higher in diabetic patients
142), and this risk increases by 26% with every 1% increase in the HbA1c level
143).
The risk of CVD begins to increase since impaired glucose tolerance (IGT) state
144). In the Hisayama study, the incidence rate of CAD in patients with IGT is 1.9
times higher than that of subjects with NGT, even though it was lower than the level
of 2.6 times in diabetics
128). The incidence rate of cerebral infarction increased significantly following
the HbA1c level was ≥ 5.5–6.4%
145). The JPHC study showed that the risk for CAD was 1.65 times higher in the borderline
glucose tolerance group and 3.05 times higher in the diabetic group as compared to
subjects with NGT, indicating the risk increases before the incidence of diabetes
146). The two hours glucose level post glucose load was more strongly associated with
the risk for CAD than the fasting level in subjects with IGT
147, 148). These suggest that the significance of postprandial glucose level as a
risk factor of atherosclerosis.
Women generally have a lower risk for CAD than men. But in diabetic patients, it has
been reported that the increase in relative risk of CAD was higher in women than men,
resulting in reduced gender differences
149, 150). It has also reported that compared to male subjects with NGT male diabetic
patients increased the risk of CAD by 17 times higher at ages 31–40 years, and by
2 to 3 times higher at ages 41 to 61 years, which suggests that the impact of diabetes
on CAD was markedly greater in younger men compared with men in middle age
151).
Thus, prevention of ASCVD in addition to microvascular disease is quite important
issue even in Japanese diabetic subjects
152).
5)
Chronic Kidney Disease (CKD)
[Statement]
CKD is a high-risk condition for ASCVD. (Evidence level: E-1a)
In the Evidence-based Clinical Practice Guideline for CKD 2013 published by the Japanese
Society of Nephrology
153), CKD is defined as continuously having for ≥ 3 months, (1) an obvious renal damage
based on abnormalities in urine, diagnostic images, blood, and pathology; the presence
of proteinuria of ≥ 0.15 g/gCr (albuminuria of ≥ 30 mg/gCr) is especially important,
and/or (2) a glomerular filtration rate (GFR) of < 60 mL/min/1.73 m2. An estimated
GFR (eGFR) is used for GFR. CKD is not merely a highrisk condition for end-stage kidney
disease but also for ASCVD. As the risk of these composite outcomes differs greatly
depending on the cause, GFR and amount of proteinuria (albuminuria), the severity
of CKD is classified (CGA classification)
153, 154) using these three primary factors. It has been estimated that 13% adults
in Japan have CKD
155), and screening for CKD is therefore an important element in the comprehensive
risk management for ASCVD.
In the screening for CKD
156), urinary protein and urinary occult blood are assessed by a qualitative urine
test, and eGFR is determined by measuring serum creatinine levels. Whenever necessary,
the degree of proteinuria is further determined quantitatively using the casual spot
urinary protein-to-creatinine ratio. If a patient is identified with CKD, even when
he/she is in the group for primary prevention of ASCVD, stricter control of risk factors,
including dyslipidemia, is recommended as a high-risk patient.
CKD may include conditions for which diagnosis by kidney biopsy is preferable so as
to treat for remission, conditions requiring urgent treatment (immune suppression
therapy with corticosteroids, immune suppressants, molecular-targeted agents, or in
combination), and also conditions that may need specialized medical care with renal
replacement therapy such as renal transplantation and dialysis. The Japanese Society
of Nephrology recommends the following criteria for referral to nephrologists: (1)
advanced proteinuria (urinary protein-to-creatinine ratio of ≥ 0.50 g/gCr or ≥ 2+
by dipstick test), (2) both urinary protein and urinary blood are positive (≥ 1 +
by dipstick test) and (3) eGFR < 45 mL/min/1.73 m2
154).
Traditional risk factors, such as BP, lipids and carbohydrate metabolism, are exacerbated
in CKD. On top of that, non-traditional risk factors, such as abnormal phosphate-calcium
metabolism play roles in advanced stages of CKD, and the relative contributions of
certain risk factors for ASCVD are altered. According to a large-scale cohort study
in Canada
157), the association between LDL-C and ASCVD is lower when eGFR is lower, and the
association was no longer significant when eGFR was < 15 mL/min/1.73 m
2
. This finding is consistent with the results of randomized controlled trials revealing
that the use of statin did not decrease the risk for ASCVD significantly in dialysis
patients
158, 159), suggesting the importance of implementing effective measures on patients
with earlier stages of CKD.
6)
Aging and Gender Differences
[Statement]
Aging is the strongest risk factor for ASCVD, such as CAD and cerebrovascular disease.
(Evidence level: E-1b)
Women have a lower risk for MI and MI-related death than men, but the gender difference
decreases with aging. (Evidence level: E-2)
The risk for ASCVD, such as MI, and death from it increases as one moves up to the
next age category. In terms of absolute risk, aging enhances the risk for ASCVD and
death from it much more than any other risk factors
160–162).
Women have a lower risk for MI and MI-related death than men. In a survey conducted
in Takashima town, Shiga Prefecture from 1999 to 2001, the age-adjusted incidence
rate of acute MI (100,000 person-years) was 35.7 for women, and this was one-third
the figure of 100.7 for men
163). Furthermore, according to the vital statistics of 2014, the (approximate) rate
of mortality due to ischemic heart disease in a target population of 100,000 is 49.8
for men and 36.6 for women. The mortality rates (target population of 100,000) according
to age are as follows: 2.6 for men and 0.6 for women in the 30s, 11.0 for men and
2.3 for women in the 40s, 30.2 for men and 6.6 for women in the 50s, 66.5 for men
and 17.3 for women in the 60s, 131.9 for men and 60.3 for women in the 70s, 334.9
for men and 209.5 for women in the 80s, 675.6 for men and 460.2 for women in the 90s,
and last but not least, 787.5 for men and 549.0 for women in the ≥ 100s. The mortality
rate of ischemic heart disease was lower in the women than men in all age groups.
However, the mortality rate of ischemic heart disease for women starts increasing
when they reach the 60s. Women in the 70s have a mortality rate that is almost the
same as men in the 60s, which goes to show that the risk for ASCVD is not low for
elderly women
164). There was almost no difference between the mortality rates of cerebral infarction
for men and women (target population of 100,000), which were 25.4 and 28.8, respectively.
The mortality rates (target population of 100,000) according to age are: 0.2 for men
and 0.1 for women in the 30s, 0.9 for men and 0.4 for women in the 40s, 3.6 for men
and 1.1 for women in the 50s, 15.9 for men and 4.7 for women in the 60s, 61.9 for
men and 24.9 for women in the 70s, 242.3 for men and 156.2 for women in the 80s, 662.7
for men and 605.3 for women in the 90s, and lastly, 1125.0 for men and 1182.4 for
women in the ≥ 100s. Up to the 90s age group, the mortality rate of cerebral infarction
was lower in women than men.
7)
Family History of CAD
[Statement]
A family history of CAD is a risk factor for developing CAD. (Evidence level: E-1b)
It has been reported in the Western countries since 1970s that a family history of
CAD is a risk factor for the disease itself
165–172). A family history of CAD, especially in first-degree close relatives (parents,
children, brothers and sisters), and a family history of premature CAD (age of incidence:
< 55 years for men and < 65 years for women) are strong risk factors for CAD.
It was reported in the Framingham Study that if at least one parent has CAD, the age-adjusted
odds ratio for the risk of developing CAD is 2.6 for men and 2.3 for women. After
adjusting all the variables in the multivariate analysis, the ratios were 2.0 and
1.7 for men and women, respectively
168). The J-LIT study in Japan has shown that a family history of CAD increases the
relative risk of developing CAD by three times
173). The recent CREDO-Kyoto study has also reported that a family history of CAD
contributes to the occurrence of major cardiovascular events at a young age
174).
Traditional risk factors (high LDL-C, low HDL-C, hypertension, diabetes, and smoking)
are associated with genetic predisposition and are influenced by habits within the
family. In other words, a family history of CAD is considered to also include genetic
and environmental risk factors, a fact that is already known. There has been attention
on other risk factors that should be considered, such as Lp (a), small dense LDL and
homocysteine, which are all genetically regulated. However, it is assumed that unknown
genetic factors play a role
170) as family history remains a strong risk factor even after adjusting all the traditional
risk factors in multivariate analyses
80, 166–168, 175, 176).
Therefore, most studies relating to family history have concluded that a family history
of CAD is an independent risk factor for CAD. Individuals with a family history of
premature CAD (age of incidence: < 55 years for men and < 65 years for women) should
particularly be considered to be at high risk for CAD.
8)
History of CAD
[Statement]
A history of CAD poses a higher risk compared to primary prevention. (Evidence level:
E-1b)
It is evident in epidemiological studies and intervention trials conducted in the
Western countries that the incidence rate of cardiovascular events is higher in patients
with CAD than in primary prevention patients
177–179). Similar results have also been reported in studies in Japan. The MEGA study,
a primary prevention trial involving the use of statin
41), showed that the incidence rate of cardiovascular events for the group that underwent
diet therapy was 2.1/1,000 person-years. In the J-LIT study, the incidence rate in
primary prevention patients was 0.9/1,000 person-years
180) and 4.5/1,000 person-years in CAD patients
173). In JELIS, primary prevention patients had an incidence rate of 1.6/1,000 person-years
while the rate was 6.8/1,000 person-years in patients with CAD
181). In addition, the incidence rate of cardiovascular events was ≥ 15/1,000 person-years
in the JCAD
182) and CREDO-Kyoto studies
183), which are registry studies involving patients with CAD.
9)
Noncardiogenic Cerebral Infarction
[Statement]
A history of noncardiogenic cerebral infarction is a high-risk condition for cerebrovascular
disease and CAD. (Evidence level: E-1b)
Patients with a history of cerebrovascular disease are known to be a high-risk group
for CAD. In Japan, there has been reports revealing that the 1-year incidence rate
for patients with a history of stroke is 0.40–0.45% (4.0–4.5 people/1,000 person-years)
184, 185). Patients in Japan who have a history of stroke are considered to be at
a high risk for developing CAD, especially those with noncardiogenic cerebral infarction
originating from arteriosclerotic lesions.
In addition, findings of arteriosclerosis in the carotid arteries are an independent
risk factor for CVD
6, 8). It has been reported that an increase in the intima-media thickness (IMT) of
common carotid arteries is particularly a significant predictive factor in cerebral
infarction and CAD
186–188). However, it was reported in the results of a meta-analysis that both CVD
and stroke were not seen to be significantly correlated with the progress of IMT
189).
On the other hand, it has been reported that the incidence rate of cerebrovascular
disease is higher than the recurrence rate of CAD in patients with a history of CAD.
Moreover, the risk of developing cerebrovascular disease is also higher than the risk
of CAD in those with a history of PAD
184). Therefore, a history of cerebrovascular disease is something that should be
taken note of.
10)
Peripheral Artery Disease (PAD)
i)
Lower extremity PAD
[Statement]
PAD causes CAD and cerebrovascular disease to occur easily at high incidence rates.
(Evidence level: E-1b)
Although “ASO” has traditionally been used in Japan to refer to PAD, the term used
in these guidelines is “PAD”
190). It mainly refers to diseases based on stenosis and obstructive lesions in the
arteries of the lower extremities due to atherosclerosis. Coldness in the lower extremities,
intermittent claudication, ulcers, and necrosis are some of the symptoms observed
in PAD. In Europe and America, it has been clearly demonstrated in epidemiological
studies that PAD patients are more prone to developing other forms of ASCVD, such
as CAD and cerebrovascular disease. Similar reports have also been surfacing in Japan
recently.
In the Hisayama study, in which ordinary citizens were involved, 2,954 subjects who
were ≥ 40 years old and did not suffer from CVD were followed up for an average of
7.1 years. The results showed that the risk for developing CAD was 4.13 times higher
in subjects who had an ABI of ≤ 0.9 than those who had a normal ABI
191). The CIRCS study was another study that involved ordinary citizens, in which
939 subjects who were 60–74 years old and did not suffer from CVD were followed up
for an average of 9.3 years. The results have likewise showed that subjects with an
ABI of ≤ 0.9 had a higher risk of 2.04 times for developing CAD than those with an
ABI of ≥ 1.1, and the risk for developing cerebrovascular disease was also higher
at 3.39 times
192). The REACH Registry, a prospective cohort study, had 5,193 Japanese entered by
2004. Among them, the incidence of CVD within 1 year was studied in 603 individuals
who were suffering from coexisting PAD. The resulting incidence rates were generally
high - 1.25% for all deaths, 0.55% for cardiovascular death, 0.77% for nonfatal MI,
and 1.56% for nonfatal stroke
184). A prospective observational study was conducted on 557 patients with PAD by
Shigematsu et al. It was observed in the study that the three-year incidence rate
was 6.3% for cardiovascular death, 11.3% for heart disease, 7.0% for cerebrovascular
disease and 16.9% for events in the lower extremities
193).
As mentioned above, other forms of ASCVD, such as CAD and cerebrovascular disease,
easily occur in PAD patients at high incidence rates, and this has also been clearly
shown in Japan. Therefore, when encountering a PAD patient, a careful full body examination
is necessary to check for the presence of ASCVD.
ii)
Abdominal Aortic Aneurysm (AAA)
[Statement]
Atherosclerotic disease often coexists in patients with AAA. (Evidence level: E-2)
High LDL-C
194), high TC
195), hypertension
196), and smoking are the factors that contribute to the development of AAA, and this
is a commonality with ASCVD. A survey conducted by Akai et al. on 374 Japanese patients
with AAA showed that hypertension contributed to the increase in diameter of the aneurysms.
However, the association of its increased size with a history of ASCVD or TC was ruled
out
197). Hollier et al. studied the long-term prognosis of 1,087 patients who had undergone
open surgical repair for AAA. Among the causes of death, they reported that cardiovascular-related
causes made up 37% and MI made up 22%
198). However, they were unable to obtain any results showing that AAA is a risk factor
of ASCVD. There are currently no papers relating to studies on the long-term prognosis
of patients with AAA in Japan. Nonetheless, in a study where preoperative coronary
angiography was performed on 94 patients with AAA who were to undergo elective surgery
for, 45.7% of them were found to having coexisting CAD
199). In a separate study, ATP-loading myocardial single-photon emission computed
tomography (SPECT) was performed on 788 Japanese patients, including 500 patients
with AAA who had no history of CAD, 183 patients with PAD and 105 patients with both
AAA and PAD. As a result, myocardial ischemia was seen in 37% the patients with AAA,
55% patients with PAD and 77% patients with both
200). From these results, even though there are no longitudinal studies demonstrating
AAA as a risk factor for ASCVD, there are some cross-sectional studies showing the
association between AAA and ASCVD. Therefore, it is recommended to screen for ASCVD
in patients with AAA.
iii)
Atherosclerotic Renal Artery Stenosis
[Statement]
Atherosclerotic Renal Artery Stenosis Is a High-risk Condition for ASCVD. (Evidence
Level: E-2)
Ninety five percent of renal artery stenosis (RAS) is caused by arteriosclerosis and
it coexists with other forms of ASCVD at a high rate. RAS is a progressive condition,
and individuals with RAS have a tendency for worsened renal function. However, there
is also an added risk for cardiovascular complications at the same time
201, 202). There has been a report stating that upon examining the renal arteries
during cardiac catheterization as a screening test, 30% patients who went through
the procedure were found to be having RAS
203), and that the survival rate decreases with higher degrees of RAS
204). However, there are currently no relevant detailed reports or reports from cross-sectional
studies. Even though coronary artery lesions are found at high rates when RAS is present
and RAS is an important high-risk condition in CVD, there is insufficient evidence
showing that it is a direct primary risk factor for ASCVD.
11)
Other Diseases to Be Considered
i)
Hyperuricemia
[Statement]
Hyperuricemia can be regarded as a risk factor for ASCVD. (Evidence level: E2)
The Guideline for the Management of Hyperuricemia and Gout (Second Edition) released
by the Japanese Society of Gout and Nucleic Acid Metabolism was revised in 2010. In
the revised guideline, it was mentioned that serum uric acid levels (1) can be regarded
as an independent predictive factor for the development of hypertension, and (2) it
can possibly be a predictive factor for the risk of incipient stroke and recurrence,
as well as for the re-hospitalization and prognosis caused by heart failure. At the
same time, it was mentioned in the guideline that conflicting reports on whether serum
uric acid level is an independent risk factor for CVD have been produced
205).
According to subsequent reports, including a meta-analysis, it has been revealed that
uric acid level is an independent risk factor for the development of hypertension,
stroke, and coronary events
206–208). Uric acid levels was also reported as an independent risk factor for cerebro-
and cardiovascular death in EPOCH-JAPAN, in which 13 cohort studies in Japan were
summarized
209).
On the other hand, there is still a lack of evidence from interventional studies on
whether uric acid-lowering treatments contribute to the suppression of ASCVD and the
improvement of prognosis, and this remains a question to be answered. Nonetheless,
a meta-analysis of interventional studies has shown that uric acid-lowering treatment
using allopurinol lowers BP
210). In a study involving elderly patients with hypertension, the group that received
allopurinol was compared to the propensity score-matched control group. The results
showed that the suppressive effect on the incidence of stroke and coronary events
(acute MI and ACS) was especially seen when high doses of allopurinol were administered
211).
ii)
Sleep Apnea Syndrome (SAS)
[Statement]
Obstructive sleep apnea is an independent risk factor for ASCVD. (Evidence level:
E-1b)
Abnormal breathing pattern (occurrence of apnea and hypopnea) and ventilatory failure
during sleep are two characteristics of SAS, a representative condition of sleep-disordered
breathing (SDB) which presents various symptoms. SAS is divided into obstructive sleep
apnea (OSA), which is based on obstruction of the respiratory tract, and central sleep
apnea (CSA), which is caused by an absence of respiratory drive from the respiratory
center. Among the two types of SAS, CSA is relatively less common. Although it is
regarded in the field of circulatory system to be a condition that brings about heart
failure, OSA is on the other hand, seen as a common disease that is closely related
to lifestyle habits and is strongly associated with ASCVD. It is possible that OSA
causes arteriosclerosis to progress through various mechanisms.
A meta-regression analysis has clearly shown that patients with OSA have lower endothelial
function than those without OSA, in addition to increased stiffness of the blood vessels
and high-sensitivity C-reactive protein level
212). It has also been evident in a meta-analysis that OSA is an independent risk
factor for intima–media thickening
213). Many cohort studies and prospective studies involving large numbers of patients
have confirmed that OSA poses a risk for developing type 2 diabetes
214). It has also been substantiated in these studies that OSA increases the rate
of new future occurrences of hypertension
215). We can hence see from these results that OSA directly or indirectly contributes
to the incidence and progression of ASCVD.
A comparison between subjects with severe OSA and the control group in prospective
observational studies has revealed a significant increase in the occurrence of both
fatal and nonfatal cardiovascular events in the group with severe OSA
216, 217). Therefore, it is advisable to treat OSA as one of the risk factors for
ASCVD and carry out screening accordingly. Regardless of whether an underlying heart
disease is present, active screening is especially recommended for patients who are
noticed to be experiencing two or more of the following: excessive daytime sleepiness
or a choking sensation during sleep, asthma, repeatedly waking up from sleep, feels
unrefreshed when waking up, feels tired during the day and lacks concentration
218). Continuous positive airway pressure (CPAP) is an effective therapy for patients
who are diagnosed with severe OSA. However, the effect of CPAP on primary or secondary
prevention of CVD has not proven yet in recent RCTs
219, 220).
12)
Other Risk Factors and Markers to Be Considered
[Statement]
Hyper-Lp(a)-lipoproteinemia is a risk factor for ASCVD. (Evidence level: E-1a)
Measuring the level of malondialdehyde-modified LDL (MDA-LDL) is useful for prognostic
prediction of the incidence of CAD in diabetic patients who have a history of CAD.
(Evidence level: E-1b)
Hyper-remnant-lipoproteinemia is a risk factor for ASCVD. (Evidence level: E-1b)
Postprandial hyperlipidemia is a risk factor for CAD. (Evidence level: E-1b)
A high small dense LDL level is a risk factor for ASCVD. (Evidence level: E-1a)
A high apolipoprotein B (apo B) level is a risk factor for ASCVD. (Evidence level:
E-1a)
The TC/HDL-C ratio, non-HDL-C/HDL-C ratio, LDL-C/HDL-C ratio, and apo B/AI ratio are
markers for ASCVD. (Evidence level: E-1a)
High levels of fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are markers
for ASCVD. (Evidence level: E-1a)
It is necessary to take note that these factors include genuine risk factors that
contribute to the progression of ASCVD, but at the same time, there may also be factors
within that are very likely to be markers for ASCVD.
Risk factors or markers for ASCVD that should be considered are proposed separately
from the risk factors established in the preceding sections.
i)
Lp(a)
Lp(a) is an independent risk factor for CAD and stroke. When the size of apolipoprotein
(a) [apo(a)] is small, the concentration of Lp(a) is high, and there is a high risk
of CVD. Single-nucleotide polymorphisms have been revealed in genes that reflect this
correlation
221–228). There have been some hypotheses regarding the mechanism through which Lp(a)
causes ASCVD. One hypothesis is that apo(a) protein is highly homologous to plasminogen
222, 227), and it interferes with the actions of plasminogen, thereby promoting thrombus
formation
228, 229). It has also been suggested that apo(a) protein preferentially binds to
oxidized phospholipids, which influence the risk for CAD
230, 231); furthermore, it has been suggested that apo(a) is easily anchored to the
arterial walls
232, 233). High Lp(a) concentrations are found in patients with FH, and it is presumed
that hyper-Lp (a)-lipoproteinemia further increases the risk for CVD in patients with
FH
222).
ii)
MDA-LDL
MDA-LDL is a form of oxidized LDLs, which are lipoproteins produced through the oxidative
modification of lipids, such as phospholipids, and apolipoproteins when LDL is subjected
to oxidative stress
234, 235). MDA-LDL is involved in a wide range of processes of atherosclerosis, such
as the damaging of endothelial cells, acceleration of monocyte penetration into the
vascular walls, and formation of foam cells
235). MDALDL is useful for prognostic prediction of the incidence of CAD and the recurrence
of stenosis after percutaneous coronary intervention (PCI) in diabetic patients with
a history of CAD
236). In patients with stable angina who were receiving lipid-lowering treatment,
the risk for cardiovascular events after treatment using a drug-eluting stent has
been shown to increase by 1.14 times with every 10 U/L elevation in MDALDL levels
237).
iii)
Remnant Lipoprotein
Remnant lipoprotein is an intermediate lipoprotein that is produced during the process
in which chylomicrons and very low-density lipoproteins (VLDL) are metabolized. Remnant
lipoproteins deposit themselves in the vascular intima, causing the progression of
atherosclerosis
238). Patients with MI have a high risk for cardiovascular events when the remnant
lipoprotein level is high. In addition, hyper-remnant-lipoproteinemia is an independent
risk factor even when LDL-C is maintained at < 100 mg/dL
239, 240). Studies have shown that the measurement of remnant lipoprotein levels is
useful for risk assessment in secondary prevention for patients with ACS who have
undergone coronary interventions and are taking statins. Its usefulness has also been
demonstrated in the assessment of risk for ASCVD in primary and secondary prevention
for patients with coexisting type 2 diabetes and CKD
241, 242). In addition, hyper-remnant-lipoproteinemia can explain part of the residual
risk of allcause mortality in patients with CAD
243). Some of the conditions in which the amount of remnant lipoprotein increases
include familial combined hyperlipidemia, familial type Ⅲ hyperlipidemia, DM, and
metabolic syndrome.
iv)
Postprandial Hyperlipidemia
Zilversmit et al. proposed that the increase in the postprandial levels of remnant
lipoprotein after meals can cause atherosclerosis. Considerable evidence has been
accumulated thereafter, and this hypothesis has therefore been established as the
disease concept
238, 243–245). Epidemiological studies in Japan have also demonstrated that a high
nonfasting TG level adds to the risk of CAD. Overall, every 1 mmol/L increase in TG
levels increases the relative risk of CAD by 1.34 times (men, 1.29 times; women, 1.42
times)
88). The risk starts increasing when the nonfasting TG level reaches 115 mg/dL, and
at ≥ 167 mg/dL, the risk increases by ≥ 3 times. The result remains the same even
with correction using HDL-C
88). In the sub-analysis of MRFIT, the nonfasting TG level was as useful as, or even
more useful than, the fasting TG level for the risk for CAD; a nonfasting TG level
of ≥ 200 mg/dL indicates a high risk
246). The diagnostic criteria for hypertriglyceridemia in a nonfasting state have
recently been gaining attention, especially in Europe and America
247, 248). In addition, measurement of the amount of apolipoprotein B-48 in a fasting
state is expected to be useful as a screening marker for postprandial hyperlipidemia
249).
v)
Small Dense LDL
Among all the LDL particles, small dense LDL particles
250, 251) have a high density. The association between the levels of small dense LDL
and CAD has been reported in numerous sources
251–256), and its relationship with PAD and aneurysms has also been demonstrated
257
,
258). In addition, small dense LDL is more strongly associated with the risk for CAD
259), the severity of coronary atherosclerosis
256, 260), and the incidence of ASCVD in secondary prevention
261) than is LDL-C among Japanese populations. There have been several hypotheses
regarding the mechanism of small dense LDL as a strong atherogenic factor. One hypothesis
is that small dense LDL is easily oxidized
262) and processed in pathways other than that of the LDL receptor
263). Small dense LDL is also easily incorporated into the arterial wall
264), where it binds readily to the matrix
265), and this is another proposed mechanism. Small dense LDL is closely associated
with hypertriglyceridemia and hypo-HDL cholesterolemia
259
,
266). In addition, its levels are increased in conditions such as type 2 DM, metabolic
syndrome, and insulin resistance
259, 267).
vi)
Apo B
Apo B (apo B-100) is an apolipoprotein found in atherosclerosis-causing lipoprotein
particles, such as LDL and remnant lipoprotein. As each lipoprotein particle contains
one apo B molecule, the apo B value is proportionate to the number of these lipoprotein
particles. According to a meta-analysis of epidemiological studies, apo B is a stronger
risk factor for cardiovascular events than are LDL-C and HDL-C
268, 269). The Framingham Study has revealed that apo B improves the risk assessment
for CAD more than do LDL-C and non-HDL-C
270). A meta-analysis of studies using statins has clearly shown that compared to
a reduction in LDL-C and non-HDL-C levels, a reduction in the amount of apo B has
a stronger association with the decrease in the risk of CAD
271). Another meta-analysis has demonstrated that measurement of the amount of apo
B, in addition to LDL-C and non-HDL-C, improves risk prediction
272).
vii)
Ratios of Lipids and Apolipoproteins
The levels of lipids, such as LDL-C and HDL-C, are commonly considered as risk factors.
However, rather than the levels of these lipids and apolipoproteins, the ratio of
different cholesterols and the ratio of different apolipoproteins contained in each
lipoprotein are risk factors for ASCVD. These ratios are namely the TC/HDL-C ratio,
non-HDL-C/HDL-C ratio, LDL-C/HDL-C ratio, and apo B/AI ratio
268, 273–275). Nonetheless, these data are mostly the results of studies in various
Western countries; therefore, the current management targets to be achieved in Japan
should be the absolute values of each lipid. In Chinese diabetic patients, the TC/HDL-C,
non-HDL-C/HDL-C, LDL-C/HDL-C, and apo B/AI ratios were involved in the spread of coronary
lesions. The apo B/AI ratio, in particular, was strongly involved in the coronary
atherosclerosis; however, the significance disappeared after adjustment for confounding
factors
276). Studies conducted in Japan have reported that the TC/HDL-C ratio is significantly
associated with coronary artery calcification, even after correction for the confounding
factors
277).
viii)
Inflammatory Markers (C-reactive Protein and Pentraxin-3)
C-reactive protein (CRP) is an acute-phase protein that is used as an inflammatory
marker. It has been already revealed that chronic inflammation of the blood vessels
is an important factor for the progression of atherosclerosis. However, in recent
years, high-sensitive CRP (hs-CRP) has been reported as a possible risk factor for
ASCVD
278, 279). There are reports in Japan stating that a significant association was seen
between hs-CRP and stroke (especially cerebral infarction and lacunar infarction)
280). hs-CRP has also been associated with the onset risk of MI and stroke, of which
the association is particularly strong in MI
281). Conversely, in a study on the genotype related to CRP concentration in the blood
and the frequency of CAD, there was no association between the concentration of CRP
and the frequency of CAD
282). This result suggests that the concentration of CRP is probably not a cause of
ASCVD but instead reflects the extent to which atherosclerosis has progressed. Pentraxin
(PTX)-3 belongs to the same pentraxin family of proteins as CRP. Unlike CRP, which
is found in the liver, PTX-3 is specifically expressed in the endothelial cells, smooth
muscle cells, and WBCs. Recent reports have suggested that the association of CRP
and PTX-3 in coronary artery plaques in pathological autopsies shows that both CRP
and PTX-3 reflect unstable plaques. However, the distributions of CRP and PTX-3 in
the plaques are not the same, and there is a possibility that they play different
roles. There have also been reports on the PTX-3-lowering effect of statins. PTX-3
is expected to serve as a specific marker reflecting CVD in the future
283–286).
ix)
Homocysteine
The elevation of homocysteine concentration in the blood has been reported to be a
risk factor not just for CAD but also for stroke and PAD
287–289). In a study involving elderly individuals who were aged ≥ 85 years and had
no history of cardiovascular disease, a high homocysteine concentration in the blood
increased the relative risk for MI
290). Furthermore, analyses in the recent years have suggested that homocysteine is
a stronger marker than is CRP
291). However, therapies for lowering the concentration of homocysteine through vitamin
supplementation did not result in the suppression of events
292, 293). Furthermore, it has also been reported that there is no association between
ASCVD and hereditary genetic mutations that cause an increase in homocysteine levels
294). In a meta-analysis related to the risk for CAD at a young age, the effect of
homocysteine was not seen in all subjects. However, in the group with homocysteine
levels of ≥ 15 µmol/L or in Asians with a 677C→T mutation in the methylenetetrahydrofolate
reductase gene, a significant increase in risk was observed
295). The background for this finding has been suggested to be the relatively lower
intake of folic acid by Asians than that by other races, and this implies a need to
study hyperhomocysteinemia as an independent risk factor in Japan. The various genetic
polymorphisms affecting homocysteine concentration have been evaluated in studies
that involved individuals of European descent, using genome-wide association study.
The results revealed that the concentration of homocysteine did not contribute to
the risk for CAD in the Caucasians
296).
x)
Blood Coagulation and Fibrinolytic Factors
Fibrinogen is an independent risk factor for cardiovascular disease
297–299). The conclusion of an integrated analysis of 52 prospective studies was that
both CRP and fibrinogen are risk factors for primary cardiovascular disease
278). By contrast, some recent reports on the association of CRP and fibrinogen with
mean IMT and coronary artery calcium score in the Japanese, Japanese–American, and
Caucasian populations have stated that a significant association was not seen in any
of the races after adjustment for multiple variables (age, SBP, LDL-C, HDL-C, fasting
glucose level, smoking, and alcohol consumption) or for age and BMI
300, 301). PAI-1 is a fibrinolytic factor secreted by the endothelial cells, and its
activity increases in the acute phase of acute MI. Sakamoto et al. have shown that
although its activity was decreased at the time of discharge at approximately 1 month
later, the levels were still higher in patients with acute MI than in the control
group
302). Reports have demonstrated that PAI-1 is associated with ASCVD and metabolic
syndrome, which involves an accumulation of visceral fats and insulin resistance
303). The risk may possibly increase further depending on the genotypes that exist
for PAI-1
304, 305).
2.
Disease Concept and Diagnostic Criteria for Metabolic Syndrome
[Statement]
Metabolic syndrome is a condition that poses a high risk for the development of cardiovascular
disease (Evidence level: E-1b).
Japanese eating habits and dietary components have clearly changed in recent years
306). Lifestyles that include overnutrition and physical inactivity are threatening
to increase the incidence of CAD and stroke. Among the conditions underlying the development
of ASCVD, particular importance is ascribed to a cluster of multiple risk factors,
including hyperglycemia, dyslipidemia, and elevated blood pressure, which are closely
related to lifestyle. This pathologic condition used to be called “Syndrome X,”
307), “the deadly quartet”
308), “visceral fat syndrome”
309), or “insulin resistance syndrome”
310) but those terms were unified as “metabolic syndrome”
311) in 1999. Metabolic syndrome is recognized as a condition in which the risk factors
of atherosclerosis cluster on the basis of obesity, particularly visceral fat accumulation,
due to overnutrition and physical inactivity
312, 313). The dysregulated secretion of adipose tissue-derived bioactive molecules
(adipocytokines), which accompanies the accumulation of visceral fat tissue, is important
for the development of metabolic syndrome and related cardiovascular diseases.
1)
Importance of Risk Factor Accumulation
The Group of ‘The Research for the Association between Host Origin and Atherosclerotic
Diseases under the Preventive Measure for Work-related Diseases of the Japanese Ministry
of Labour’ performed a case-control study in approximately 120,000 office workers
314, 315). The records of annual medical health checkups performed 10 years prior
to the onset of CAD were reviewed. The surveys revealed that BMI, BP, fasting blood
glucose, and serum lipids levels were significantly higher in cases compared with
those in controls for the evaluated 10-year period, even though these abnormalities
were mild or moderate. The NIPPON DATA80 epidemiological study also showed that the
relative risk of death due to CAD and stroke increased with the number of combined
risk factors
314–317) [
Fig. 4
: Relationship between the number of concurrent risk factors and death due to CAD
and stroke (NIPPON DATA80: 1980–1994)]. These results clearly indicate the importance
of a cluster of multiple risk factors in the development of CAD in Japan, even if
the severity of each risk factor is mild. According to a survey of middle-aged and
elderly Japanese, the frequency of having multiple risk factors were high in subjects
with visceral fat accumulation
318). The Japan Society for the Study of Obesity proposed a definition of “obesity
disease” based on susceptibility to the clustering of obesity-associated risk factors
319, 320). The fat distribution in CAD patients revealed that approximately half of
the patients had excess visceral fat accumulation
321). A 10-year follow-up study of middleaged and elderly Japanese-American men revealed
that approximately 30% of subjects developed CAD and that the accumulation of visceral
fat, hypertension, and hyperglycemia were important risk factors
322).
Fig. 4.
Relationship between the number of concurrent risk factors and death due to CAD and
stroke (NIPPON DATA80: 1980–1994)
316
Risk factors: Obesity, hypertension, hyperglycemia, hypercholesterolemia
Conditions, such as metabolic syndrome, that involve the clustering of multiple risk
factors have been shown to increase the risk of cardiovascular diseases in epidemiological
studies
323–326) and meta-analyses
327), as well as in CIRCS study78), the Tanno and Sobetsu study
328) and the Hisayama study
317). (
Fig. 5
: Relationship between the number of concurrent risk factors and incidences of CAD
and cerebral infarction
317)). Concerning the secondary prevention of CAD, it was also reported that the presence
of metabolic syndrome increased the incidence of subsequent cardiac events. Accordingly,
metabolic syndrome is positioned as an important high risk pathologic condition for
CAD
312).
Fig. 5.
Rerationship between the number of concurrent risk factors and incidences of CAD and
cerebral infarction
317
Components of metabolic syndrome: Obesity, impaired glucose tolerance, lipidosis,
hyperttention, hyperinsulinemia
After adjustment for age, 5-year (1988–1993) follow-up of 1097 men and women aged
≥ 60 years in Hisayama-cho
2)
Diagnostic Criteria for Metabolic Syndrome
The definition of metabolic syndrome in Japan, which is characterized by the accumulation
of visceral fat accompanied by the concurrence of multiple risk factors including
elevated blood pressure, dyslipidemia, and hyperglycemia, was established in 2005
(
Table 5
). Diagnostic Criteria for Metabolic Syndrome in Japan
312)). In the diagnostic criteria, waist circumference is used as an index of visceral
fat accumulation for practical convenience, and individuals with metabolic syndrome
are defined as those having visceral fat accumulation demonstrated by increased waist
circumference and 2 or more risk factors
312). The International Diabetes Federation also published similar diagnostic criteria
313). However, European and American scientific societies issued a joint declaration
later proposing that an individual with three out of the five risk factors - visceral
obesity, hypertriglyceridemia, hypo-HDL cholesterolemia, high BP reading, and high
glucose level - can be diagnosed as metabolic syndrome
329). Visceral fat accumulation was not considered a necessary condition in this criteria.
Table 5.
Japanese diagnostic criteria for metabolic syndrome
Visceral fat accumulation
Waist circumference
Men ≥ 85 cm
Women ≥ 90 cm
(The values for both men and women correspond to visceral fat ≥. 100 cm2).
Two or more of the items mentioned below in addition to the above
Hypertriglyceridemia
≥ 150 mg/dL
and/or
Hypo-HDL cholesterolemia
< 40 mg/dL
for both men and women
Systolic blood pressure
≥ 130 mmHg
and/or
Diastolic blood pressure
≥ 85 nnHg
Fasting hyperglycemia
≥ 110 mg/dL
Measurement of visceral fat by methods such as CT scanning is recommended.
The waist circumference is measured at the umbilical level in the standing position
during light breathing. If the umbilicus is displaced due to marked fat accumulation,
measurement is performed at the level of the midpoint between the lower costal margin
and iliac crest.
If a diagnosis of metabolic syndrome has been made, a glucose tolerance test is recommended,
but it is not essential for the diagnosis.
If the examinee is undergoing drug treatments for hypertriglyceridemia, hypo-HDL-cholesterolemia,
hypertension, and/or diabetes mellitus, each item is considered to be positive.
(Evaluation Committee on Diagnostic Criteria for Meabolic Syndrome: Internal Medicine,
2005; 94: 794–809, in Japanese)
The criteria for waist circumference in Japan were determined by the absolute visceral
fat area (VFA) of 100 cm
2
. According to a recent large-scale cross-sectional study conducted in Japan on visceral
fat area and accumulated risk factors, the average number of obesity-related cardiovascular
risk factors (dyslipidemia, high blood pressure, and high blood glucose) was more
than 1.0 at 100 cm2 for visceral fat area in both men and women
330). It is obvious that the Japanese criteria of waist circumference is based on
scientific evidence. On the other hand, Western criteria of waist circumferences are
merely based on the value corresponding to the obesity criteria in each country.
Visceral fat accumulation is required for the diagnostic criteria in Japan, and the
aim is to solve the integration of risk factors through the interventions to reduce
visceral fat. Since 2008, the measurement of waist circumference has been made compulsory
in specific medical examinations and occupational health examinations, with the intent
to prevent diabetes and atherosclerotic cardiovascular disease based on the concept
of metabolic syndrome.
Chapter 4.
Comprehensive Risk Management
1.
Absolute Risk of Atherosclerotic Cardiovascular Disease (ASCVD) and Lipid-Management
Targets
CQ 6. Are there any assessment tool for predicting the ASCVD incidence and mortality
in the Japanese people?
There are several assessment tool that predict the absolute risk of ASCVD in the Japanese
population. Hypertension, diabetes, and smoking are regarded as predictive factor
for ASCVD. In addition, total cholesterol (TC), LDL cholesterol (LDL-C) and HDL cholesterol
(HDL-C) are predictive indicators in the assessment tool that predicts the coronary
artery disease (CAD) incidence and/or mortality. (Evidence level: E-1b)
Relative risk is usually used to indicate the risk of future ASCVD incidence and/or
mortality. Recently, methods of assessing the actual incidence rate in individuals,
otherwise referred to as absolute risk, have been developed and are being used in
clinical guidelines in various countries. These include the Framingham Score
331) in the USA and the SCORE Risk Assessment Charts in Europe
332). The 2013 American College of Cardiology/American Heart Association (ACC/AHA)
guidelines include a new pooled cohort ASCVD risk equation to assess absolute risk
333). Not like the Framingham Score which predicts only CAD incidence, this model
predicts cerebro-cardiovascular disease incidence including stroke and CAD within
10 years.
The NIPPON DATA80 Risk Chart
161) was used in the 2012 Japanese Atherosclerosis Society (JAS) Guidelines for Prevention
of Atherosclerotic Cardiovascular Diseases to estimate absolute risk. The management
target is set after categorizing the target individuals (patients) according to 10-year
CAD mortality. An understanding of absolute risk is important for managing ASCVD risk
factors, implementing effective preventive strategies, and establishing the priority
of future treatments. We performed a systematic review to answer CQ1: “Are there any
assessment tool that predict the ASCVD incidence and mortality in the Japanese?” The
Japanese population in this review included adults with no history of ASCVD. It did
not include individuals treated for secondary prevention or studies only consisted
of patients with dyslipidemia. Nine articles published between January 01, 1990 and
September 30, 2016
161, 162, 334–340) were selected for this review and are summarized in
Table 6
.
Table 6.
Tools for Predicting the Absolute Risk of ASCVD On the Basis of Cohort Studies Conducted
in Japan
Name of cohort
Method of risk assessment
Period of risk assessment
Risk factors used for assessment
Outcome (event to be predicted)
(Communiy-based cohort)
NIPPON DATA80 (CAD)
161)
Risk assessment chart
10 years
(Gender-specific tables), age, TC, smoking, SBP and random blood glucose
CAD mortality
NIPPON DATA80 (all forms of CVD)
161)
Risk assessment chart
10 years
(Gender-specific tables), age, TC, smoking, SBP and random blood glucose
all forms of CVD mortality (including stroke risk assessment chart)
Hisayama Study
334)
Scoring table
10 years
Gender, age, LDL-C, HDL-C, diabetes, SBP and smoking
MI incidence, sudden cardiac death, coronary revascularization and stroke incidence
JMS cohort (MI)
335)
Risk assessment chart
10 years
(Gender-specific tables), age, TC, SBP, smoking (for men only) and diabetes (for women
only)
MI incidence
JMS cohort (stroke)
336)
Risk assessment chart
10 years
(Gender-specific tables), age, SBP, smoking and diabetes
Stroke incidence
JALS-ECC
337)
Scoring table
5 years
Gender, age, TC (or non-HDL-C), HDL-C, hypertension (grades 1 and 2), smoking and
diabetes
MI incidence
Ibaraki cohort
338)
Website
5–15 years
Gender, age, body weight, SBP, HDL-C, TG, AST, blood glucose level (including status
of treatment), blood withdrawal conditions, smoking and alcohol consumption
Death due to each cause (stroke, cancer, ischemic heart disease, all forms of CVD
and total death)
JPHC
339)
Scoring table
10 years
Age, gender, smoking (gender-specific scoring), BMI (25–30 and ≥ 30), BP (scoring
by whether the patient is taking antihypertensive drug; The Japanese Society of Hypertensionfs
criteria are adopted in the classification) and diabetes
Stroke incidence
Suita study
162)
Scoring table
10 years
Age, gender, smoking, diabetes, BP classification (The Japanese Society of Hypertensionfs
standards are adopted in the classification; however, grade II hypertension and above
are one category), TC or LDL-C, HDL-C and CKD
CAD incidence (MI, sudden cardiac death, coronary revascularization)
JPHC (cohort II)
340)
Scoring table
10 years
Age (logarithmic value), gender, smoking, whether the patient is taking any antihypertensive
drug, presence of diabetes, SBP (logarithmic value), HDL-C (logarithmic value), non-HDL-C
(logarithmic value, only for CAD)
Incidence of CAD (MI + sudden cardiac death) or cerebral infarction
1)
Establishing Absolute Risk
In this guideline revision, we reviewed the continued use of the NIPPON DATA80 risk
chart for death due to CAD that had been adopted in the 2012 guidelines. The NIPPON
DATA80 had various advantages, including the fact that groups were selected from all
over Japan by random sampling, the chart was based on a baseline survey conducted
before statins were available and its high suitability for the observation of the
natural course of disease, making it very useful for the assessment of absolute risk.
However, some aspects of NIPPON DATA80 are problematic such as (1) the fact that its
predicted outcome is death and not CAD incidence, (2) the fact that it does not include
information on LDL-C or HDL-C and (3) the fact that the baseline year is 1980, and
when this baseline hazard is applied to more recent cohort populations, the estimated
mortality of the high-risk group is higher than the actual measured mortality of recent
populations
341).
Like the NIPPON DATA80 survey, the Ibaraki Prefectural Health Study used death as
the outcome. The other seven articles selected for review used disease incidence as
the outcome. Stroke was the outcome in two articles; MI in two; and CAD, combined
CAD and stroke, and CAD or cerebral infarction in one article each. Hardly any cohort
studies conducted in Japan have demonstrated that dyslipidemia was a risk factor for
stroke
342), and hypercholesterolemia (e.g., TC or non-HDL-C) was not included as a risk
factor in any of the assessment tool in which the outcome was stroke or cerebral infarction.
In addition, absolute risk was assessed over 5 years in two of the reviewed articles
and 10 years in the other seven. Furthermore, only two articles included both MI and
coronary intervention as the outcomes, which also included both LDL-C and HDL-C as
predictive indicators, i.e., important risk factors for establishing the management
targets for dyslipidemia. Accordingly, we concluded that the Hisayama score
334) and the Suita score
162) include the most suitable criteria for assessment of absolute risk relevant to
the primary prevention of ASCVD in Japanese adults by managing dyslipidemia. The biggest
difference between these risk assessment tools is the fact that the Suita score considers
only CAD (MI, PCI, coronary artery bypass, and sudden cardiac death), whereas the
Hisayama score considers a combined outcome of CAD, with diagnostic criteria nearly
the same as the Suita score, and stroke. In both scores, the fasting LDL-C value is
calculated using the Friedewald formula. Stroke comprises a large proportion of the
cases of cerebro- and cardiovascular disease in Japan. The ratio of stroke to CAD
in the Hisayama study was approximately 2: 1; however, among stroke cases, the percentage
of atherothrombotic cerebrovascular disease in which LDL-C was a risk factor is approximately
20%
36). Therefore, it is difficult to determine detailed risk by LDL-C level with the
Hisayama score, as it uses a combined outcome. The Suita score permits detailed risk
assessment by specific dyslipidemia values because it includes five LDL-C level criteria
in contrast to the Hisayama score, which includes two levels.
2)
Management of Dyslipidemia Using Absolute Risk
The 2013 ACC/AHA guidelines
343) recommended avoiding setting an LDL-C control target and using statins to treat
four groups of patients for whom they are considered beneficial. The JAS position
on those guidelines, published as a press release in February 2014, is that having
a management target is advisable in clinical practice in Japan from the viewpoint
of patient adherence. Many practicing clinicians use management targets as treatment
references, and our view is that their use should be continued. The 2016 European
Guidelines for the Management of Dyslipidemias published in August 2016 continue to
require the use of a management target
344). We have also included management targets in the management of ASCVD with absolute
risk in this revision of the guidelines.
As the threshold of each risk grade cannot be determined statistically by using the
absolute risk, the criteria were based on clinical consensus and social conventions.
In the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) Ⅲ
guidelines of the USA, a ≥ 20% 10-year risk of incidence of fatal CAD and nonfatal
MI based on the Framingham Score was considered high risk. However, this cannot be
used in Japan because ASCVD types and incidence rates of ASCVD differ from those in
the USA. The aforementioned 2013 ACC/AHA Guidelines, based on novel pooled risk calculations,
recommend statins for anyone with a predicted 10-year incidence of cerebro- and cardiovascular
disease (CAD and stroke) of ≥ 7.5%
333) which, however, is a rough indication to select the patients to for statin therapy.
We have not accumulated enough evidence from clinical studies in Japan to establish
a similar reference for selecting patients for statin therapy. Our society's guidelines
must maintain continuity and consistency with the risk categorization used in our
guidelines before. Management targets for dyslipidemia are also provided in the 2015
Comprehensive Risk Management Chart for the Prevention of Cerebrovascular and Cardiovascular
Diseases jointly published by 13 academic societies, including JAS and the Japanese
Society of Internal Medicine
156). We considered these recent changes in existing recommendations when creating
this set of guidelines and established risk categories and lipid-management targets.
3)
CAD Risk Categories
In the 2012 version of our guidelines, the NIPPON DATA80 risk chart was the basis
for categorizing absolute risk. While the chart detail allows to determine detailed
individual risk, it is complex in appearance. The guidelines published in 2007, were
simple and convenient to use, but risk categorization depended on a number of risk
factors other than LDL-C. Application of the 2007 guidelines results in lack of association
with absolute risk because of the huge influence of age and sex. The effect of age
is especially substantial. This means that the estimated absolute risk is low in young
people even with multiple risk factors and high in older individuals even with few
risk factors. Therefore, reference material 2 of the 2012 guidelines (http://www.j-athero.org/publications/gl2012_114.pdf)
notes that the number of risk factors can be used in estimates of absolute risk if
sex and age taken into account. Accordingly, we presented two types of flowchart for
determining the lipid-management target; one uses an absolute risk calculation by
the Suita score and the other uses the number of risk factors, consistent with the
Comprehensive Risk Management Chart for the Prevention of Cerebrovascular and Cardiovascular
Diseases 2015.
Fig. 1
shows the flowchart using the absolute risk derived from the Suita score. When screening
for dyslipidemia, whether patients are candidates for secondary prevention is first
confirmed. Next, whether these patients have a high-risk condition such as diabetes
(not including impaired glucose tolerance), CKD, non-cardiogenic cerebral infarction,
or PAD is evaluated. The Suita score calculation is performed in patients with none
of these conditions. Diabetes and CKD are included in the original Suita score; but
they are not used in calculating the score here as they would already have been treated
as high-risk conditions. If the patient has a family history of premature CAD, i.e.,
first-degree relatives with incidence before 55 years of age for men or 65 years of
age for women, or impaired glucose tolerance, it is assumed that they have a risk
equivalent to smoking or low HDL-C; five points is added to the Suita score. The predictive
model for CAD incidence based on the Suita score is shown in
Fig. 2
.
In terms of the probability of CAD incidence, apart from the lowest risk category
(≤ 35), the minimum value of score range is shown as an integer in each risk category
in the original article of the Suita score. In this guideline, ranges (smallest score-highest
score) and the median of risk scores are shown in each category. For consistency with
the absolute risk assessment by NIPPON DATA80 used in the 2012 guidelines, the absolute
risk of CAD is classified by scores ≤ 40 as low (a 10-year probability of CAD incidence
of < 2%), 41–55 as moderate (2–8%), or ≥ 56 as high (≥ 9%). Committee members have
confirmed that the distribution of low risk, moderate risk, and high risk individuals
in two different populations is almost identical to the distribution of categories
Ⅰ, Ⅱ, and Ⅲ calculated by the NIPPON DATA80 as in the 2012 guidelines.
On the other hand, determination of the risk for each sex and age group (i.e., age
40–59 and 60–74 years) is easily achieved with the Comprehensive Risk Management Chart
for the Prevention of Cerebrovascular and Cardiovascular Diseases 2015. Using that
categorization, we estimated the actual absolute risk of CAD using the Suita score
(i.e., the LDL model). We made a few changes to make the evaluation easier. We adopted
the Suita score age groups of 45–54 years in place of 40–59 years and 65–69 years
in place of 60–74 years. Smoking, hypertension, and low HDL-C were added as risk factors.
We used the median Suita hypertension scores of grade 1 and ≥ grade 2, and we increased
the number of points awarded to the low HDL-C category (< 40 mg/dL) compared with
the 40–59 mg/dL category. All were awarded five points. An LDL-C level of ≥ 180 mg/dL
has always indicated a high risk for CAD, and may also suggest the presence of familial
hypercholesterolemia (FH). Therefore, these guidelines clearly recommend drug therapy
for patients with an LDL-C level ≥ 180 mg/dL regardless of the number of other risk
factors. A flowchart of the recommended LDL-C management target based on the number
of risk factors is shown in
Fig. 3
. The flowchart conforms to the low-risk, moderate-risk, and high-risk criteria of
the simplified Comprehensive Risk Management Chart for the Prevention of Cerebrovascular
and Cardiovascular Diseases 2015. However, if the estimation is performed on the basis
of the Suita score, the distribution is 39–41 points for the low-risk, 42–56 points
for the moderate-risk, and 49–71 points for the high-risk groups. Overlapping of groups
is unavoidable, but considered acceptable in this simplified method. In addition,
a family history of premature CAD, which is absent in the Suita score, and impaired
glucose tolerance are considered to carry the same level of risk as the other factors
included in the assessment method and are therefore also counted as risk factors.
A management target that corresponds to the respective risk level, from low to high,
is identified and compared with the actual lipid level. If the target has not been
achieved, the aim of lowering is set.
As the risk of CAD changes with age and risk factor status, the management category
should be reassessed at least once per year according to the most recent test findings.
In addition, the risk scores have been basically created assuming that they apply
to patients with risk factors, including dyslipidemia, that are not being treated.
Two scores from the Japan Health Center Study took into account patients with or without
antihypertensive drugs for blood pressure control
339, 340). However, no risk scores that consider whether the patient is taking any
medicines for control of dyslipidemia or diabetes are available in Japan, the USA,
or Europe. The currently available risk scoring tools can be used even if the patient
is on medication, but the actual risks of cerebro- and cardiovascular diseases differ
in patients with or without antihypertensive drug treatment. Usually patients whose
blood pressure cannot be controlled by lifestyle modification are medicated and their
risk of cerebro-and cardiovascular diseases are lowered by medication. However, as
their blood pressure are assumed to remained high for long time before medicated,
it is difficult to lower their risk to the same level of those who are not medicated.
If they both have the same blood pressure, then the patient on medication is at a
higher risk
345). It should be kept in mind that the actual risk of disease in patients on medication
may be higher than the risk indicated by the prediction score.
The incidence of CAD differs in the various regions and populations in Japan, and
is higher in cities than in rural areas
98), and employees of large companies have an extremely low incidence rate of MI compared
to the general population
346). The NIPPON DATA80 outcome was the number of deaths in populations that were
selected by stratified random sampling from all regions of Japan and should be representative
of the general population. There are doubts as to whether the absolute risk assessed
using the Suita score is also representative of the general population of Japan. The
incidence of CAD is likely to be higher in the Suita study than in other regional
cohort studies and it differs from many other regional cohort studies in the use of
coronary intervention as one of outcomes. Consequently, the estimated absolute risk
for CAD may be much higher than in other regional cohort studies. In Japan, the Hisayama
score is the only other method in which coronary intervention is also assessed as
an outcome, and coronary intervention is not used for an outcome in the scoring system
of the 2013 ACC/AHA Guidelines in the USA
333).
4)
Management Targets for Dyslipidemia from the Perspective of Preventing CAD
The category-specific dyslipidemia management targets are shown in
Table 2
. For primary prevention, drug therapy should be considered after lifestyle modifications
have been applied for 3–6 months and when the effects have been ascertained. However,
for patients in any of the risk categories, including the low-risk category, if the
LDL-C level remains at ≥ 180 mg/dL, then the addition of drug therapy and lifestyle
modifications can both be considered. The validity of an LDL-C management target has
been partially confirmed by the systematic review data (see Chapter 4, CQ17). The
management targets for high-risk category is < 120 mg/dL, and for the the low-risk
and moderate-risk groups are the same as in the previous guidelines, i.e., < 160 mg/dL
and < 140 mg/dL, respectively. Achieving these management targets is challenging.
The results of a meta-analysis of randomized controlled trials involving the use of
statins revealed that a 20–30% decrease in LDL-C level lowers the risk for CAD by
approximately 30%
347, 348). Considering long-term effects and safety, a reduction rate of 20–30% in
the LDL-C level can also be used as a target for the low-risk and moderate-risk groups.
However, this management target cannot be applied to patients with FH or familial
type Ⅲ hyperlipidemia. As patients with FH are difficult to treat, and their risk
of CAD in the future is extremely high, it is recommended that these patients be referred
to a specialist (see Chapter 5, Familial Hypercholesterolemia and Capter6, Other Types
of Primary Dyslipidemias).
This set of guidelines was developed for use in adults aged < 75 years of age. The
advantages and disadvantages of lipid management in patients aged < 40 years of age
are at the discretion of the attending physician; however, if lipid management is
to be carried out, then the Suita score absolute risk for 35–44 years of age group
is used.
As patients with a history of CAD most likely require more aggressive treatment for
secondary prevention, they are managed differently than patients in need of primary
prevention. The LDL-C management target for secondary prevention should be set at
a lower value than for primary prevention. Large clinical studies conducted in Western
countries have shown that lowering the mean pretreatment LDL-C level decreases the
risk of recurrence and total mortality of CAD and it is also effective in decreasing
stroke incidence. Observational studies and clinical trials conducted in Japan found
that the decrease in frequency of recurrence was proportional to the decrease in LDL-C
level until it reached a level of 100 mg/dL. Consequently, by means of drug therapy
together with lifestyle modification, the LDL-C management target for secondary prevention
shall be at < 100 mg/dL; however, if a level of < 100 mg/dL is difficult to achieve,
the target shall be a 50% reduction in the LDL-C level.
As in the previous guidelines, during secondary prevention, if non-cardiogenic cerebral
infarction, PAD, CKD, or metabolic syndrome are also present or if the patient has
multiple risk factors or is still smoking, it is advisable to make it mandatory to
achieve an LDL-C level of < 100 mg/dL considering the higher risk. Some reports in
Japan have also indicated the usefulness of controlling the LDL-C level to < 70 mg/dL
for a regressive effect on coronary plaques in patients complicated with ACS or diabetes
mellitus. In view of the extremely high risk of CAD with FH, if the patient's condition
is complicated with FH or ACS, then it would be appropriate to consider stricter lipid
management with a target LDL-C level of < 70 mg/dL and a non-HDL-C level of < 100
mg/dL during secondary prevention. In addition, because diabetic patients who are
complicated with conditions shown in
Table 3b
had a high risk for recurrence of CAD, their management target should be set as that
of ACS or FH (see Chapter 4.4-1 ‘History of CAD’ for details).
Table 3.
Patient Conditions that Require Stricter Management in Secondary Prevention
a
Familial hypercholesterolemia (FH)
Acute coronary syndrome (ACS)
Diabetes mellitus (DM)
b
Noncardiogenic cerebral infarction
Peripheral artery disease (PAD)
Chronic kidney disease (CKD)
Metabolic syndrome
Overlap of major risk factors
Smoking
Although management targets for each lipid of concern in dyslipidemia have been established,
the primary objective should be the achievement of the LDL-C management target. The
non-HDL-C targets can be reviewed when the LDL-C target has been achieved. NCEP-ATP
III guidelines recommend a non-HDL-C target 30 mg/dL higher than that of LDL-C, similar
to the guidelines in Japan
74, 75). We thus include a non-HDL-C management target that is 30 mg/dL higher than
the LDL-C target in this set of guidelines. If the TG level is ≥ 400 mg/dL, or if
blood is collected after a meal, then the non-HDL-C target shall be used for the initial
management of dyslipidemia instead of the LDL-C target. If non-HDL-C levels are used
for screening in the general population, then it should also be noted that the difference
between the non-HDL-C and LDL-C levels would be < 30 mg/dL, at approximately 20 mg/dL
349, 350). As in the previous guidelines, a TG level of < 150 mg/dL and an HDL-C level
of ≥ 40 mg/dL are the recommended targets for both primary and secondary prevention.
Even if the LDL-C management target has been achieved, a high non-HDL-C level may
be accompanied by hypertriglyceridemia, and management of this condition is important.
Few available medications are effective for increasing low HDL-C, and some reports
have found that CAD risk is low if a low HDL level is not accompanied by other lipid
abnormalities
351). On the basis of this evidence, the approach for managing HDL-C, should basically
involve lifestyle modification after management of LDL-C, non-HDL-C and TG levels.
2.
Lifestyle Modification
1)
Overview of Lifestyle Modification
ASCVD is developed by various environmental factors such as excessive total energy
intake and insufficient physical activity in addition to genetic predisposition. Many
epidemiological studies in Japan and other countries have revealed that excessive
intake of cholesterol and animal fats (saturated fatty acids) results in increased
serum LDL-C levels. Excessive total energy intake and insufficient physical activity
are the primary causes of metabolic syndrome, inducing the accumulation of visceral
fat, abnormal glucose metabolism, elevated blood pressure and increased triglyceride
levels, and decreased HDL-C levels. These lifestyle abnormalities result in ASCVD
such as myocardial infarction. Therefore, the basic management to prevent ASCVD is
the adoption of lifestyle changes such as smoking cessation and avoiding passive smoking,
achieving and maintaining an appropriate body weight by re-evaluating total energy
intake and physical activity, adhering to traditional Japanese dietary pattern with
a low salt content, refraining from excessive alcohol intake, and performing aerobic
exercise for at least 30 minutes per day. It is recommended that medical practitioners
take improvements in patient lifestyle and ASCVD risk factors into account.
Table 7.
Lifestyle Modifications for ASCVD prevention
• Stop smoking and avoid passive smoking
• Pay attention to excessive total energy intake and insufficient physical exercise,
and maintain an appropriate body weight
• Refrain from the consumption of large amounts of fatty meat, animal fat, eggs, and
processed foods with fructose
• Increase the intake of fish, green and yellow vegetables, seaweed, soy products,
and unrefined grains
• Moderately consume fruits with low carbohydrate content
• Avoid excessive alcohol consumption
• Perform moderate- or high-intensity aerobic exercise for a target of at least 30
minutes a day
Table 8.
Dietary Advice for Prevention of ASCVD
• Total energy intake (kcal/day) is generally calculated as body weight [kg, (height
in meter)2 × 22] × physical activity (25–30 for light, 30–35 for normal, and ≥ 35
for strenuous activity)
• Limit fat intake to 20–25%, saturated fatty acids intake between 4.5% ≤ and < 7%
of total energy intake, and cholesterol intake to < 200 mg/day
• Increase the intake of n-3 polyunsaturated fatty acids
• Refrain from consuming industrial trans fatty acids
• Limit carbohydrate intake to 50–60% of total energy intake and increase dietary
fiber intake
• Keep salt intake to < 6 g/day
• Limit alcohol consumption to ≤ 25 g/day
2)
Smoking Cessation
[Statement]
For primary and secondary prevention of ASCVD, one should stop smoking and avoid passive
smoking. (Evidence level: 2, recommendation level: A)
Smoking is an independent risk factor for ASCVD, and regardless a history of ASCVD,
smoking cessation decreases the development and subsequent progression of ASCVD, and
the risk of death due to ASCVD. The effects of smoking are not dependent on age or
gender
102). In ASCVD patients, the benefits of smoking cessation are apparent soon after
quitting, and the longer the duration of abstinence from smoking, the greater is the
decrease of risk
107). As decreasing the number of cigarettes smoked or switching to low-nicotine or
low-tar tobacco does not lead to a reduction in risk, cessation is a must for primary
and secondary prevention of ASCVD. All smokers should be encouraged to quit regardless
of age. Passive smoking also increases CAD and stroke risk
115, 116), and it is also important to advise patients to avoiding secondhand smoke
exposure. A meta-analysis found that in other countries, the implementation of smokefree
legislation decreased the number of cases of ACS and stroke
352).
For all patients, the first step is to determine whether they have a history of smoking
or passive smoking
156). The rate of successful smoking cessation increases by 1.7 times if physicians
advise their patients to quit smoking, compared with not doing so
353). The “5A approach,” i.e., Ask, Advise, Assess, Assist, and Arrange can be effective
in such cases in a short time
354). As with other drug dependencies, symptoms of nicotine withdrawal appear soon
after quitting, and that makes it difficult for many smokers to quit. In Japan, when
both medical facilities and patients satisfy certain requirements, health insurance
coverage is applied for smoking cessation treatment for 12 weeks
355). The 2016 medical fee revision expanded coverage to qualifying minors. The use
of effective drugs to treat nicotine-dependence (e.g., nicotine patches, nicotine
gum, and varenicline)
356, 357) combined with counseling for psychological dependence increase the success
rate of smoking cessation.
While the long-term benefits of smoking cessation are evident, a recent meta-analysis
reported a 4–5 kg increase in body weight 1 year after quitting smoking, with the
increase quite pronounced within the first 3 months after cessation
358). Short-term worsening of blood glucose and lipid levels may be observed during
that interval, but improvement in insulin resistance
117), increase in HDL-C
359) and reduction in oxidized LDL
360) have been reported regardless of weight gain. Although the expectation of weight
gain hinders the start of smoking cessation and causes resumption of smoking, it is
suggested that discontinuing smoking surpasses the disadvantages caused by weight
gain and reduce the risk of CVD
361). Patients must be made aware of the benefits of quitting smoking and given support
to discontinue smoking during the process.
3)
Management of Obesity and Metabolic Syndrome
[Statement]
For the management of obesity and metabolic syndrome, lifestyle modification is essential
for the reduction of body weight and visceral fat. (Evidence level: 2, recommendation
level: A)
To achieve and maintain an ideal body weight and optimal waist circumference are important
targets for lifestyle modification. Obesity, especially excess visceral fat accumulation,
is considered to be an independent risk factor for CVD and promotes atherosclerosis
directly or indirectly via dyslipidemia, impaired glucose tolerance, hypertension
and the dysregulated production of adipocytokine
362–365). Therefore, it is important to achieve lifestyle modification through dietary
management and exercise.
i)
Obesity Disease
Obesity disease is an obesity with complications that require medical treatment of
weight loss for the improvement. The status of body weight is evaluated based on the
body mass index, BMI (body weight (kg)/[height(m)]2). In Japan, the ideal body weight
is defined to be a BMI of 22, which has the lowest morbidity, and a BMI ≥ 25 is diagnosed
as obesity
366). However, the obesity is not immediately categorized as a disease. If obesity
is complicated by or associated with health problems that require weight loss for
the improvement, or associated with visceral fat accumulation likely accompanied by
health problems, it is diagnosed as the obesity disease
367). For screening of obesity disease in daily clinical practice, a waist circumference
at the umbilical level of ≥ 85 cm for men and ≥ 90 cm for women is used as the criteria
of visceral fat accumulation
368). Patients with suspected visceral fat accumulation should be evaluated by abdominal
CT, and those with a visceral fat area of ≥ 100 cm
2
at umbilical level are diagnosed as visceral obesity, which is common to metabolic
syndrome. The reduction of visceral fat is expected to normalize the multiple abnormalities
in plasma lipids, glucose and blood pressure caused by obesity
312).
ii)
Metabolic Syndrome
Metabolic syndrome is a condition with excessive accumulation of visceral fat complicated
by anomalies of hyperglycemia, dyslipidemia and elevated blood pressure, even though
the criterion for obesity (BMI ≥ 25) is not met. Metabolic syndrome is significant
because it is a high risk of ASCVD even if the levels of hyperglycemia, dyslipidemia
and elevated blood pressure are relatively mild
323–327). The difference between the diagnostic criteria in Japan and the joint statement
by Western academic societies
329) is whether they are based on visceral fat accumulation or not. It is generally
accepted that ASCVD risk is high in conditions with coincident hyperglycemia, hypertension
and dyslipidemia without visceral fat accumulation, but multiple treatments are required
in such patients, and weight loss is not likely to be effective for the improvement
of multiple risk factors. For the management of metabolic syndrome with excess visceral
fat accumulation, however, the benefits of lifestyle modification and behavioral therapy
are evident.
iii)
Treatments for Obesity and Metabolic Syndrome
The target body weight in the treatment of obese patients should not immediately be
set as a BMI of < 25. Rapid weight loss resulting from extensive calorie restriction
may lead to rapid rebound weight gain. Weight reduction by diet and exercise therapy
is expected to provide relatively rapid improvement in moderate abnormalities of plasma
lipids, glucose and blood pressure caused by obesity, even if the BMI is within the
range of obesity
369). Even if medications are needed to treat coexisting diabetes, dyslipidemia, and
hypertension, it is necessary that both medical staffs and patients realize the risk
reduction through measuring body weight and assessing waist circumference.
Accordingly, it is important to achieve ≥ 3% reduction body weight or waist circumference
over 3–6 months and to review the patient's accomplishments over time
320, 323, 370).
iv)
Relationship of Hyper-LDL Cholesterolemia with Metabolic Syndrome
Hyper-LDL cholesterolemia is a major risk factor for ASCVD, and its management protocol
has been established. Metabolic syndrome has been proposed as a high-risk condition
for ASCVD independent of hyper-LDL cholesterolemia. Therefore, the diagnostic criteria
of metabolic syndrome include no criterion concerning the LDL-C level. However, subjects
with metabolic syndrome sometimes have elevated plasma LDL-C levels. The combination
of metabolic syndrome and hyper-LDL-cholesterolemia will further increase the risk
of ASCVD, a comprehensive approach for both risk factor control are necessary in such
cases.
4)
Diet Therapy
CQ7: Is limiting total energy intake and maintaining an appropriate body weight effective
in preventing ASCVD?
Limiting total energy intake and maintaining an appropriate body weight is effective
in improving serum lipid levels. (Evidence level: 1, recommendation level: A)
Although there is no direct evidence showing that limiting total energy intake and
maintaining an appropriate body weight suppresses ASCVD, improvement in serum lipid
levels by lifestyle modification including body weight reduction in response to diet
therapy may prevent ASCVD. (Recommendation level: A)
There is no direct evidence that diet alone, by decreasing the total energy intake,
suppresses ASCVD. However, lifestyle modification including body weight reduction
has positive effects on ASCVD risk factors including serum lipid levels, which may
in turn suppress ASCVD.
There is no clear evidence of setting total energy intake to improve serum lipid levels.
Rather, the total energy intake should be optimized on the basis of an ideal body
weight and the amount of daily activity. The total energy intake (kcal/day) can be
calculated as ideal body weight (kg) x physical activity (25–30 min for light activity,
30–35 for normal activity, and ≥ 35 for strenuous activity)
371). In Japan, active support of lifestyle modification resulted in a weight loss
of ≥ 3% in obese individuals within 1 year, could reduce LDL-C, TG, uric acid, and
blood pressure levels, improve blood glucose control, and increase HDL-C levels significantly
320, 372).
An RCT comparing an energy-restrictive diet with an energy-restrictive diet+exercise
in overweight postmenopausal women found decreases in body weight and amount of body
fat; decreased TG, TC, LDL-C, and the LDL-C/HDL-C ratio; and a decrease in SBP in
both groups
373).
Another RCT compared the effects of lifestyle modification, including total energy
intake of 1,300 kcal/day (lowered fat intake to 25% of total energy intake and saturated
fat intake to 7% of total energy intake, and lowered to 100 mg/day cholesterol) and
1,000–1,500 kcal/week of physical activity for an average of 54 months in premenopausal
women. Although 35% of the women had become postmenopausal during the intervention
period, the increases of LDL-C, TG, and blood glucose levels in the intervention group
were significantly less than in the assessment-only group. Body weight and waist circumferences
in the intervention group also decreased significantly
374). A meta-analysis of RCTs revealed that lifestyle and weight-loss intervention
including diet in overweight and obese adults with type 2 diabetes resulted in a reduction
of TC, LDL-C, and TG as well as an increase in HDL-C level in the subjects that achieved
a weight loss of > 5% over 1 year
375).
Therefore, maintaining an appropriate body weight is effective in improving serum
lipid levels, and it is possible to prevent ASCVD by improving serum lipid levels.
However, in such a case as sarcopenia and malnutrition in the elderly, caution should
be exercised when decreasing the total energy intake, and the appropriate ratio and
intake of nutrients should be considered.
CQ8: Is limiting the percentage of energy derived from fat in the appropriate total
energy intake effective in preventing ASCVD?
Limiting the percentage of energy derived from fat in the total appropriate energy
intake is effective in improving serum lipid levels. (Evidence level: 1, recommendation
level: B)
Although there is no direct evidence showing that limiting the percentage of energy
derived from fat in the total appropriate energy intake suppresses ASCVD, lifestyle
modifications including weight loss and modified and/or decreased fat intake may prevent
ASCVD. (Recommendation level: A)
There is no direct evidence showing that reduction of the percentage of energy derived
from fat decreases ASCVD. However, many trials comparing low-fat* and low-carbohydrate
meals in the appropriate total energy intake have been performed to reveal these effects
on weight loss as the primary outcome and on ASCVD risk factors as the second outcomes
in obese subjects with BMI more than 25 kg/m2.
A meta-analysis of RCTs comparing ≥ 1 year outcomes of high-fat (> 30% of total energy
intake) and low-fat diets in obese subjects with BMI > 25 kg/m2, found significant
reductions of TC and LDL-C levels following a low-fat diets compared with high-fat
diets. The TG levels were lower and the HDL-C levels were higher following a high-fat
diet. The differences in TC and LDL-C levels observed in the two groups were abolished
when total energy intake was restricted. A high carbohydrate intake was associated
with an increase in the TG levels
376). Another meta-analysis of RCTs compared the effects of balanced diets (fat to
25–35% of total energy intake, and carbohydrate to 45–65% of total energy intake)
with low-carbohydrate (< 45% of total energy intake) diets under restricting total
energy intake in obese subjects with BMI ≥ 26 kg/m
2
. This analysis found no differences in body weight or ASCVD risk factors (serum lipids,
blood pressure, and fasting blood glucose) at 3–6 months and 1–2 years
377). Another meta-analysis of RCTs that compared low-fat and low-carbohydrate diets
found that the 6-month weight loss was greater in participants with an extremely low-carbohydrate
diet containing ≤ 20 g or < 30 g/day of carbohydrates, compared with a low-fat diet
with meals containing fat to ≤ 25–30% of total energy intake. However, the difference
in body weight was no longer significant at 1 year. TG decreased and HDL-C increased
in the low-carbohydrate diet group; TC and LDL-C were lower in the low-fat diet than
in the low-carbohydrate diet group
378). In another RCT, obese participants with BMI of 25 to 40 kg/m2 were divided into
four energy-restricted diet groups that had different percentages of energy of protein
in total energy intake (15–25%), fat (20–40%), and carbohydrate (35–65%) for two years.
There were no significant differences in the body weights and waist circumferences
among four groups after 2 years, and the body weights remained decreased in subjects
who were able to continue the diet therapy for 2 years in all groups. In this study,
the largest decrease in LDL-C levels was observed in the low-fat diet, TG also decreased
regardless of the diet, and the largest increase in HDL-C occurred in those with the
low-carbohydrate diet
379). A meta-analysis of RCTs comparing high-protein and low-protein diets for ≥ 12
months found improved fasting insulin levels in the high-protein diet compared with
the low-protein diet, but there were no differences in body weight, serum lipid levels
or blood glucose levels
380).
Thus, limiting the percentage of energy derived from fat in total energy intake in
a diet with appropriate total energy intake improves blood lipid levels, which in
turn may help prevent ASCVD. A metaanalysis of RCTs that evaluated diet therapy in
which the fat content was modified and/or decreased did not find significant effects
on total mortality or mortality due to ASCVD. However, modified and/or decreased fat
intake decreased CVD events by 14% in men with high or moderate risk of CVD who continued
the therapy for at least 2 years
381).
No findings contradict the setting of the percentage of energy derived from fat of
total energy intake at 20–25% and the percentage of energy derived from carbohydrate
at 50–60%, which have been the recommendations for some time based on the appropriate
total energy intake according to the current situation in Japan and various conditions.
Most importantly, limiting the percentage of energy derived from fat is effective
in lowering blood LDL-C levels. For managing hypertriglyceridemia and low HDL-C, it
is recommended to intake a somewhat low percentage of energy derived from carbohydrate
in consideration of complications such as obesity, diabetes, and hypertension.
CQ9: Is reduction of the intake of saturated fatty acids (SFA) or substituting with
monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) effective
in preventing ASCVD?
In an appropriate total energy intake, reduction of the amount of SFA or substituting
with PUFA is effective in improving serum lipid levels, and in preventing CAD. (Evidence
level: 1+, recommendation level: A)
Serum lipid levels are expected to improve by substituting SFA with MUFA. (Evidence
level: 1, recommendation level: A)
Considerable reduction in SFA intake may be associated with the incidence of cerebral
hemorrhage. (Evidence level: 2)
A meta-analysis of RCTs did not find significant decreases in overall mortality or
CVD mortality associated with a reduction of SFA intake for ≥ 2 years, but did find
a 17% decrease in CVD events. Substitution of SFA with PUFA resulted in a 27% reduction,
but the effect of substitution of SFA with MUFA was unclear
382). Greater reduction in SFA intake reduced CVD events, and increases in PUFA and
MUFA intake were protective of CVD events. Other meta-analysis of RCTs also found
that consuming PUFA in place of SFA reduced CAD events
383). Some meta-analyses of cohort studies have reported an association of SFA intake
and the incidence of CVD events, but others have denied its involvement
384–390). The effects of substituting SFA with carbohydrate or protein is unclear
382).
Cohort studies in American women and Japanese population have shown that cerebral
hemorrhage increased when the intake of animal fat and protein was low
391, 392). The Japan Collaborative Cohort (JACC) Study found an inverse association
between SFA intake and mortality from total stroke, cerebral hemorrhage, and ischemic
stroke
393). The Japan Public Health Center (JPHC) study found inverse associations between
SFA intake and cerebral hemorrhage and ischemic stroke, and positive association between
SFA intake and myocardial infarction
394).
The effect of reduction in SFA intake on serum lipid levels has been investigated
in RCTs, and a metaanalysis revealed an association with decreases in TC and LDL-C
with no significant effects on HDL-C and TG levels
382). Other meta-analysis have also found decreases in TC and LDL-C levels, but the
effect of decreased SFA intake on HDL-C is less clear, and many reports have not found
significant changes in TG levels
395–401). NIPPON DATA90 also found that SFA intake is positively associated with TC
and LDL-C levels
402), and in the INTERLIPID Study, a dietary increase in the PUFA/SFA ratio was associated
with decreases of the TC and LDL-C but not the TG and HDL-C levels
403). A meta-analysis including the above-mentioned RCTs reported that the reduction
in CVD events was clearer in subgroup with greater reduction in saturated fats, and
that degree of reduction in CVD events was strongly related to degree of reduction
of serum TC level, and there was a modest suggestion of greater increase in PUFA and
MUFA
382). Substitution of 9.5–9.6% of total energy intake of dietary SFA with either MUFA
or n-6 PUFA significantly decreased both TC and LDL-C levels in RCT among subjects
with moderate risk of CVD
397).
The available evidence shows that reduction of SFA in an appropriate total energy
intake or substitution of SFA with PUFA improves serum lipid levels and prevents CAD.
Substitution of SFA with MUFA also helps to improve serum lipid levels. Considerable
reduction in SFA intake may also be associated with increased risk of cerebral hemorrhage.
The evidence is not strong enough to establish a recommended SFA intake. However,
taking account of the intake at which the incidence of cerebral hemorrhage increases
and the current average intake in Japan, no findings contradict the setting of SFA
intake between 4.5% ≤ and < 7% of total energy intake for the patients with dyslipidemia.
CQ10: Is increasing the intake of n-3 PUFA effective in preventing ASCVD?
Increasing the intake of n-3 PUFA is effective in decreasing the TG level. (Evidence
level: 1, recommendation level: A)
Increasing the intake of n-3 PUFA may lead to suppression of CAD. (Evidence level:
2, recommendation level: A)
A meta-analysis of RCTs found that increased intake of n-3 PUFA (fish oil and α-linolenic
acid) resulted in a significant reduction of vascular death (i.e., death due to MI,
stroke, and sudden death), but there was no overall effect on composite CVD events
or on total mortality
404). Participants in the JPHC cohort study with a higher fish consumption had a lower
incidence of nonfatal CAD
405), and CVD mortality was low in JACC Study and NIPPON DATA80 participants with
high fish consumption
406, 407). However, the effect of fish consumption on CVD was not clear in cohort
studies conducted in Western countries
408–414). A meta-analysis of cohort studies did not find a decrease in combined CVD
events, but did report a reduction in overall mortality, CVD death, fatal MI and sudden
death with increasing the intake of n-3 PUFA
415). Another meta-analysis of cohort studies reported a decrease in sudden cardiac
death and a trend to a decrease of fatal CAD in subjects who consumed ≥ 250 mg/day
n-3 PUFA, compared with those who consumed < 250 mg/day
416). A similar analysis reported a significant reduction of CVD events in subjects
with a high intake of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and
EPA+DHA +docosapentaenoic acid (DPA)
415, 417). Thus, it is expected that CAD would be decreased in populations with a
diet high in fish, which contain EPA and DHA.
Meta-analyses of RCTs including both healthy participants and those with dyslipidemia
have shown that increased intake of fish oil resulted in decreased TG levels
415, 418–420). It has also been shown to decrease postprandial elevation of TG levels
421). Adding fish meals to energy-restricted diets for obese patients with hypertension,
improved blood glucose, fasting insulin level, and oral glucose tolerance test results
in addition to decreasing TG level
422). Increasing n-3 PUFA intake is thus effective in decreasing TG levels. Although
meta-analysis of cohort studies have shown that there was an inverse association (not
significant) between intake of α-linolenic acid and CAD in men
423) and non-significant association of α-linolenic acid with low incidence of CVD
424), the association of α-linolenic acid with ASCVD has not been confirmed by well-controlled
RCTs
425).
CQ11: Is increasing the intake of n-6 PUFA effective in preventing ASCVD?
In an appropriate total energy intake, increasing the intake of n-6 PUFA may improve
serum lipid levels. (Evidence level: 1, recommendation level: A)
It is not clear whether increasing the intake of n-6 PUFA prevents ASCVD. (Evidence
level: 1)
Many meta-analysis of RCTs to analyze the effects of increasing the intake of n-6
PUFA has been reported. A significant 27% reduction of CVD events was observed in
a meta-analysis of RCTs that evaluated the effects of substituting SFA with PUFA
382), and in another analysis, substitution of dietary SFA of 5% of total energy intake
with n-6 PUFA resulted in a 19% reduction in CAD events
383). However, other meta-analysis of RCTs and cohort studies did not find that increasing
the intake of n-6 PUFA was associated with a reduction of CAD
426). Other cohort study of US also found no association with CVD for n-6 PUFA
417). After publication of these reports, a negative correlation of the concentration
of linoleic acid in the blood and both overall and CAD mortality was reported in the
cohort study of the elderly
427), and an analysis of cohort studies found that CAD events were 15% lower in patients
with a high compared with low linoleic acid intake, and CAD mortality was 21% lower
428). The preventive effect of an increasing the intake of n-6 PUFA on ASCVD incidence
is thus unclear.
Regarding the effect on serum lipid levels, substitution of dietary SFA of 9.5–9.6%
of total energy intake with n-6 PUFA significantly decreased both TC and LDL-C levels
in RCT among subjects with moderate risk of CVD
397), and a diet with n-6 PUFA as 19% of the total energy intake in the form of corn
oil decreased TC, LDL-C, and TG levels in patients with dyslipidemia
400). Thus, increasing the intake of n-6 PUFA may improve serum lipid levels.
CQ12: Is increasing MUFA intake effective in preventing ASCVD?
In an appropriate total energy intake, increasing the intake of MUFA may improve serum
lipid levels. (Evidence level: 1, recommendation level: A)
It is not clear whether increasing the intake of MUFA prevents ASCVD. (Evidence level:
1)
Evidence from RCTs indicates that substituting SFA with MUFA had no effect on overall
mortality, CVD events, or the incidence of myocardial infarction, stoke, and coronary
death
382). The PREDIMED trial found that a Mediterranean diet supplemented with olive oil
or nuts, decreased the incidence of CVD events compared with a controlled diet
429). However, a meta-analysis of cohort studies reported that the association of
dietary MUFA with CVD events and CVD death was inconsistent
386). Another meta-analysis of cohort studies reported that increasing the intake
of olive oil among MUFA seems to be negatively correlated with overall and CVD mortality,
CVD events, and stroke incidence
430).
In patients with dyslipidemia, a diet high in MUFA was shown to decrease TC, LDL-C,
and HDL-C levels compared with a diet high in SFA
431), and the substitution of SFA with MUFA has been shown to decrease TC, LDL-C,
and HDL-C
432) or TC and LDL-C levels
397). However, the addition of MUFA to the American Heart Association (AHA) STEP 1
Diet, increasing from 30.1% to 37.8% of total energy intake, resulted in no significant
improvement of serum lipid levels
433). A comparison of high-SFA (stearic acid), high-MUFA (oleic acid) and high-PUFA
(linoleic acid) diets of approximately 38% of total energy intake in healthy individuals
found no significant differences in serum lipid levels
434). A metaanalysis of RCTs reported that substitution of carbohydrate with MUFA
decreased TC and LDL-C levels non-significantly, and decreased TG level significantly
and increased HDL-C level significantly. However, the lowering effect on LDL-C level
was less pronounced than after substitution of carbohydrate with the same amount of
PUFA
435). Other RCT has reported improvements in body weight, body fat mass, and systolic
and diastolic blood pressure with diets in which the MUFA > 12% of total energy intake,
compared with ≤ 12%, but significant effects on the serum lipid levels have not been
confirmed
436). Meta-analysis of RCT to analyze the effect of substitution of SFA with MUFA
also did not have significant effect on serum lipid levels
382). The current evidence thus shows that increasing MUFA intake may improve serum
lipid levels, but that this effect may disappear with excessive intake.
CQ13. Is reducing the intake of trans fatty acids effective in preventing ASCVD?
Reducing the intake of trans fatty acids is effective in preventing ASCVD. (Evidence
level: 2, recommendation level: B)
Trans fatty acids are constituents of naturally occurring foods such as beef, mutton,
milk, and dairy products, and may also be industrially produced (hydrogenation) or
refinement (deodorization or high-heat processing) of fat. Trans fatty acids produced
by hydrogenation are contained in hard margarine, fatty spreads, and vegetable shortening,
deep-fried food and confectionery made using these products. Trans fatty acids are
also contained in refined vegetable oils such as salad oil.
Industrially produced trans fatty acids increase LDL-C
437–441) and lipoprotein (a) [Lp(a)] which is a lipoprotein that promotes atherosclerosis
437, 442, 443) and decrease HDL-C
439, 442, 444), compared with other fatty acids, whereas the effect on TG is inconsistent
440–442). Cohort studies and their meta-analyses provide concordant evidence that
the intake of trans fatty acids is associated with CAD
384, 438, 445–448). No significant relationship with ischemic stroke has been observed
447). A cross-sectional study reported high blood concentration of elaidic acid, an
industrial trans fatty acid, in Japanese patients with metabolic syndrome or young
Japanese patients with CAD
449). Currently, there is no consensus on whether naturally occurring trans fatty
acids should be regarded in the same way as industrially produced ones
439, 444, 445, 450, 451).
A meta-analysis of RCTs comparing the effects of vegetable oils containing industrially
produced trans fatty acids with oils substituted with other fatty acids reported that
TC, LDL-C, and TG levels were significantly decreased, and the HDL-C level significantly
increased, when trans fatty acids were substituted with MUFA or PUFA
448). A meta-analysis of cohort studies in the same article found that substitution
of trans fatty acids with SFA, MUFA or PUFA has decreased CAD risk
448).
The average daily trans fatty acid intake of the Japanese is 0.92–0.96 g, or 0.44–0.47%
of the total energy intake
452), which is lower than the < 1% target recommended by the World Health Organization
453, 454). Caution is required as intake may exceed the average value if one consumes
an imbalanced diet with an excessive amount of confectionery and high-fat foods. Trans
fatty acids should be cut back on to prevent CAD.
CQ14: Is restricting cholesterol intake effective in preventing ASCVD?
Decreasing cholesterol intake to < 200 mg/day can result in a lower LDL-C level for
patients with hyper-LDL cholesterolemia. (Evidence level: 1, recommendation level:
A)
Restricting the intake of cholesterol may prevent ASCVD in patients with hyper-LDL
cholesterolemia. (Recommendation level: A)
Among cohort studies, the Seven Countries Study and the Honolulu Heart Program reported
that cholesterol intake was associated with CAD mortality in men
384, 455). Whereas, the Framingham Study did not find any significant relationships
between cholesterol intake and the prevalence of CAD or CADrelated death in men
456). Cholesterol intake was not also significantly associated with death due to CAD
in both men and women in the Strong Heart Study
457). In the Framingham Study, TC and LDL-C levels were significantly and positively
associated with SFA but not cholesterol intake
458). However, an RCT found that a high-cholesterol diet (600 mg/day) did significantly
increase LDL-C levels more than a low-cholesterol diet (200 mg/day)
459). Cholesterol in the same dietary concentrations produced a larger increase in
LDL-C levels when combined with SFAs than with PUFAs
460). A meta-analysis of RCTs and cohort studies reported that increasing the cholesterol
intake increased TC, LDL-C and HDL-C levels, and increases of LDL-C were no longer
statistically significant when intervention doses exceeded 900 mg/day
461).
Restriction of energy of fat to 30% of total energy intake, energy of SFA to 10% of
total energy intake, and cholesterol intake to < 250 mg/day in the AHA Step 1 diet
has been shown to significantly decrease TC levels
433). Similar RCTs reported significant reductions in TC, LDL-C, and HDL-C levels
with the AHA Step 1 diet with cholesterol to < 300 mg/day
462, 463) or the Step 2 diet, with fat to 30% of total energy intake, SFA to 7%, and
cholesterol to < 75 mg/1,000 kcal/day plus lifestyle modification
464). A diet intervention containing SFA to 8% of total energy intake and cholesterol
to < 200 mg/day also decreased LDL-C levels
465). Many RCTs studying the effects of varying types and amounts of fatty acids on
serum lipid levels do take the amount of cholesterol into account by restricting cholesterol
intake to 200–300 mg/day.
Cholesterol-containing meals also contain SFA, the cholesterol absorption differs
greatly from person to person, and serum cholesterol levels are regulated by the synthesis
in the liver. Consequently, the effects of cholesterol intake on serum lipid levels
vary among individuals
466, 467), and have also been demonstrated in intervention studies
459, 468–472). For example, although hens' eggs are high in cholesterol content, the
relationship between egg consumption and serum lipid levels is variable in both healthy
individuals and in patients with dyslipidemia
469–471, 473–482). Meta-analysis of clinical studies demonstrated that TC, LDL-C,
and HDL-C levels have been shown to increase with the dietary consumption of egg yolks
483). The average daily intake of cholesterol in the Japanese ≥ 20 years of age was
estimated as 340 mg in men and 290 mg in women from the 2015 National Health and Nutrition
Survey. In diabetic subjects, some cohort studies and a meta-analysis of these have
found that CVD, especially the incidence of or death due to CAD, was increased with
a high intake of hens' eggs
484–488).
Although it is difficult to establish a limit of cholesterol intake for patients with
hyper-LDL cholesterolemia, an intake of cholesterol to < 200 mg/day and of SFA to
< 7% of total energy intake may decrease the LDL-C level, and the improvement of serum
lipid levels may prevent ASCVD. Individuals who do not have serum high-LDL cholesterol
levels should also refrain from excessive intake of cholesterol, because excessive
intake may elevate their LDL-C levels in future.
CQ15: Can increasing the intake of vegetables be recommended for ASCVD prevention?
Consumption of vegetables may decrease the risk for CAD and stroke. (Evidence level:
2, recommendation level: A)
Consumption of green and yellow vegetables may decrease stroke risk. (Evidence level:
2, recommendation level: A)
Meta-analyses of cohort studies have shown that overall mortality, death due to CVD
489), and risks of CVD
490) and CAD
491, 492) decrease when vegetable intake is high. Before 2004, an association between
stroke and the vegetable consumption had not been demonstrated
493
,
494), but a recent study reported that stroke risk was 14% lower in a group with the
highest vegetable intake than in a group with the lowest intake. The association was
strongest for the intake of leafy vegetables
495). Cruciferous, green and yellow vegetables may have preventive effects on stroke
496).
Cohort studies in Japan reported the reduced mortality risk due to CVD in men and
women who consumed vegetables in large amounts
497) and in women who consumed more vegetables dishes
498). In one study, stroke mortality rate has been shown to be low in with frequent
consumption of green and yellow vegetables
499), however this was not shown in another study
500).
Very few RCTs have evaluated the effects of increased vegetable intake. Adding 350
g of Okinawan vegetables, such as bitter gourd, green papaya, and gynura bicolor,
for 2 weeks had no effect on the serum lipid levels in healthy young women
501, 502).
The consumption of vegetables including green and yellow vegetables may be useful
for preventing ASCVD incidence. However, as pickled vegetables habitually consumed
in Japan have a significant influence on the salt intake
503, 504), the intake of a vegetable dish containing reduced-salt content should be
recommended.
CQ16: Can increasing the intake of seaweed be recommended for ASCVD prevention?
Consumption of seaweed may be useful for preventing ASCVD. (Evidence level: 2, recommendation
level: B)
Japan is one of the few countries in the world in which seaweed is regularly consumed.
The consumption of seaweed has been routinely recommended in energy-restricted diets
in Japan as it provides little energy
505), and is rich in viscous fibers and minerals such as potassium, calcium, magnesium,
iron, zinc, and iodine.
In recent years, much attention has been focused on the health effects of the sulfated
polysaccharides and carotenoids contained in seaweed.
Although, very few studies have focused on the benefits of seaweed consumption, a
cohort study in Japan reported that a high frequency of seaweed consumption was associated
with decreased all-cause mortality in both men and women, as well as decreased risk
of death due to cerebrovascular disease in women, but no association with CAD was
found
506). No studies have investigated the association between the dietary consumption
of seaweed and cardiovascular risk factors. At present, information on the effectiveness
of seaweed consumption to prevent ASCVD incidence is insufficient.
Incidentally, as seaweed contains a high concentration of iodine, and some kinds of
seaweed contain a high amounts of arsenic, it is necessary to avoid excessive consumption
of seaweed
507).
CQ17: Can increasing the intake of fruit be recommended for ASCVD prevention?
Consumption of fruit may decrease the risk for CAD and stroke; moderate consumption
of fruit with low sugar content is recommended. (Evidence level: 2, recommendation
level: A)
Meta-analyses of cohort studies have shown that the regular intake of fruit decreases
overall and CVD mortality
489) and CAD
492, 508), stroke
493), and type 2 diabetes risk
509), and the association is especially strong with the regular intake of citrus fruits
495, 496), apples, and pears
495).
In Japan, cohort studies have revealed that as the amount or frequency of fruit consumption
increases, the risk of mortality due to CVD
497) and stroke
497, 499, 500) lowers. A high frequency of citrus fruit consumption is related to
a reduction in overall mortality
500), CVD mortality
500), and CVD incidence
510), and an increased amount of citrus fruit consumption is associated with a lower
risk of CVD
511). Furthermore, increased fruit intake was reported to decrease the prevalence
of hypertension
512). Some RCTs have reported the effects of consuming additional fruit with low sugar
content on serum lipid parameters. The addition of grapefruit or oroblanco to the
diet resulted in small decreases in the level of LDL-C and TGs
513, 514), however, the addition of kiwifruit and berries increased the levels of
HDL-C
515, 516).
The meta-analysis of RCTs showed that the consumption of fruit juice could decrease
diastolic blood pressure, but did not influence blood cholesterol level
517). However, the sweetie juice supplemented diet decreased levels of LDL-C and TGs
518) and daily consumption of a high amount (750 mL) of orange juice increased TG
levels by 30% and HDL-C levels by 21%
519), in an RCT study on patients with high TC levels. It should be noted that the
effects of fruit consumption on ASCVD risk factors differ according to the variety
and quantity of fruit.
The evidence shows that increasing the intake of citrus fruits or fruits with low
sugar content reduces stroke and CAD risk, but excessive fruit consumption may lead
to increased TG concentration.
CQ18: Can decreasing the intake of processed foods containing fructose be recommended
for ASCVD prevention?
Consuming large amounts of processed foods containing fructose may increase ASCVD
risk; reducing the intake of such foods is recommended. (Evidence level: 3, recommendation
level: B)
Decreasing the intake of fructose in processed food may decrease the TG concentration.
(Evidence level: 3, recommendation level: B)
Fruit and honey contain natural fructose. Its sweetness is stronger than that of sugar
and increases when chilled. Because of its potent sweetness, fructose, sucrose which
is a disaccharide containing glucose and fructose, and isomerized sugars (high-fructose
corn syrup), are used as sweeteners in soft drinks, milk beverages, and ice sweets
such as sherbet and gelato. Consuming large quantities of fructose in processed foods
has been considered to increase CAD risk through excess energy intake, obesity, increased
TG level, worsened insulin resistance, and the incidence of type 2 diabetes.
The results of cohort studies that investigated the association of sugar-sweetened
beverage consumption with CVD and stroke risk are inconsistent
520, 521). In the JPHC cohort study in Japan, soft drink was positively associated
with the risk of ischemic stroke in women, but the risk tended to be lower in men
522).
A meta-analysis of RCTs that studied the effects of sugars containing fructose in
healthy and obese participants and type 2 diabetes patients reported significant increases
in TG levels when 18–35% energy derived from fructose was added to the control diet.
No difference was found between the control and fructose diets in isocaloric trials
523). Another metaanalysis of RCTs on healthy and obese subjects found an association
of fructose with elevated TG levels and blood pressure as well as decreased HDL-C
levels, but the significance disappeared when studies that lead to the highest effect
on the heterogeneity test were excluded
524). The effects of fructose on the risk factors for ASCVD were not observed in other
RCTs
525, 526).
As demonstrated above, evidence on the direct effects of a high intake of processed
foods containing fructose on ASCVD is lacking, however, it is necessary to note that
this would be the cause of excessive energy intake.
CQ19: Can the consumption of soy and soy products be recommended for ASCVD prevention?
Consuming soy and soy products is recommended because they may decrease CAD and stroke
risk. (Evidence level: 2, recommendation level: A)
Investigations of the association of ASCVD with soy consumption are limited to cohort
studies in Japan, where soy and soy products are habitually consumed. The JPHC study
reported that the risk of cerebral infarction and MI in women who consumed soy ≥ 5
times/week was lower by 36% and 45%, respectively, compared to the corresponding risk
in women who consumed soy 0–2 times/week
527). A study in a cohort with a very high prevalence of hypertension did not find
the same association
528).
The association of soy products that are consumed as food, such as soy milk, soybeans,
kinako (toasted soybean flour), tofu, fermented soybeans and cookies with ASCVD risk
factors, has been evaluated in RCTs. Some reported a decrease in TC or LDL-C levels
529–541), and others have not reported such a decrease
542–553). Differences in the subjects, type and quantity of food products, and the
intervention period make it difficult to compare studies. In a Japanese RCT, decrease
in TC levels was observed in premenopausal women with a diet supplemented with soy
milk
554). Some studies have reported decrease in blood pressure associated with soy consumption
555, 556), whereas others have not reported such a decrease
540, 544–546, 557). A meta-analysis of studies evaluating consumption of isolated
soy protein reported a reduction of LDL-C levels in individuals with high TC levels
558). The consumption of soy or soy products may play a part in decreasing CAD and
stroke risk.
CQ20: Can meals following the Japanese dietary pattern (The Japan Diet) be recommended
for ASCVD prevention?
A low-salt Japanese dietary pattern with reduced fat on meat and animal fats such
as beef tallow, lard, and butter and the consumption of a combination with soy, fish,
vegetables, seaweed, mushrooms, fruits, and unpolished grains are recommended for
ASCVD prevention. (Recommendation level: A)
Daily meal preparation involves combining a variety of food items. It is therefore
useful to evaluate the effects of meals on the incidence of diseases and their risk
factors, taking into account the combination of food items consumed (dietary pattern)
and not just the individual nutrients
559).
Epidemiological findings of the Seven Countries Study obtained in the 1960s and 1970s
revealed that the CAD mortality rate in Japan was extremely low compared with that
in Northern Europe and the USA. The notable diet in Japan was very small amounts of
meat, fats and oils, and dairy products with large amounts of rice, soy, and fish
560). Other than polished rice, barley and slightly polished rice were consumed in
Japan up to the 1960s
561). Domestic cohort studies with baseline data up to the 1990s showed a low CVD
mortality rate patients with dietary pattern containing high percentages of soy, fish,
vegetables, seaweed, mushrooms and fruits
562, 563). The mortality rate due to overall and CVD were approximately 20% lower
with a Japanese-style dietary pattern with salt reduction
564). However, the CVD mortality rate was higher if the dietary pattern contained
of high percentages of meat, butter, and high-fat dairy products
562–564).
As described above, the consumption of food items that constitute the Japanese dietary
pattern has been reported to decrease ASCVD risk. Furthermore, a meta-analysis of
cohort studies conducted in Northern Europe, the USA, and China found that the consumption
of unrefined grains resulted in a lower risk of CAD
565).
Therefore, the traditional Japanese dietary pattern in which fat on meat and animal
fats such as beef tallow, lard, and butter, are avoided, and barley, millet and unpolished
grains are consumed in combination with soy, fish, vegetables, seaweed, mushrooms,
and fruits, is believed to contribute to preventing ASCVD
566).
The high salt content of a Japanese diet, with an average salt intake of 10.0 g/day
567) is of concern. As excessive salt intake leads to increased blood pressure and
promotes atherosclerosis, a target intake of < 6 g/day is thus recommended
122). In addition, although moderate alcohol intake may have preventive effects in
terms of CAD risk, it should be noted that excessive alcohol intake causes high blood
pressure and hypertriglyceridemia
568).
Diet to Improve Risk Factors
Diet modification is essential for the treatment of dyslipidemia and ASCVD. Based
on “the Japan diet” with a lower salt content, it is important to instruct the patients'
diet in consideration of eating behavior, condition, and lifestyle. Timely evaluations
of the effects are needed to modify their diet appropriately.
•
Hyper-LDL Cholesterolemia and Diet
Intake of SFAs, cholesterol and trans fatty acids, which increase the LDL-C level,
should be decreased with the appropriate management of total energy intake. Replace
SFAs with MUFAs or PUFAs, reduce intake of SFA to < 7% of energy, and cholesterol
to < 200 mg a day. Specifically, reduce intake of high fatty meat and/or animal fats
(beef tallow, lard, butter), milk, offals, and eggs. The consumption of vegetables,
including green and yellow vegetables, and soy or soy products is recommended.
•
Hypertriglyceridemia and Diet
Patients should achieve and maintain a desirable body weight. Lower intake of carbohydrates,
and avoide excessive consumption of alcohol. Excessive consumption of fruits and fructose-containing
processed foods should be avoided as they may contribute to an increase in TG level.
The intake of n-3 PUFA should also be increased. In patients with hyperchylomicronemia,
the total amount of dietary fats should be redused (≤ 15% of energy); the use of medium-chain
fatty acids
569, 570).
•
Low HDL-C and Diet
Patients should maintain an ideal body weight or consider a total energy intake to
help achieve it. The percentage of energy derived from carbohydrates should be slightly
decreased, and the amount of trans fatty acids should be decreased.
•
Metabolic Syndrome and Diet
The total energy intake should be optimized on the basis of the ideal body weight
and the amount of daily activity. Patients should aim to decrease their body weight
or waist circumference by ≥ 3% within 3–6 months
320), rapid weight loss should be avoided. The percentage of energy derived from carbohydrates
should be slightly decreased while consuming enough protein to help prevent a reduction
of muscle mass
320). Preparing meals with foods with a low glycemic index and a low glycemic load
lower the risk ASCVD incidence
571–574). Concomitant exercise therapy is effective for improving obesity, serum lipid
levels, and blood pressure
373, 575).
•
Hypertension and Diet
Salt intake should be restricted, with positive consumption of vegetables and fruits.
It should work toward sodium restriction and potassium sufficiency, which promote
the urinary excretion of sodium. It is recommended to treat obesity, maintain an ideal
body weight, refrain from the consumption of cholesterol and SFAs, and positively
consume fish (fish oil). The excessive consumption of alcohol should be avoided as
it increases blood pressure.
•
Diabetes Mellitus and Diet
Improving obesity is the most important lifestyle component for controlling type 2
diabetes. Total energy intake should be adequate for individual physical activity
(energy consumption), and whenever possible, it should be divided equally into three
daily meals i.e., breakfast, lunch, and dinner. Food should be chewed well and consumed
without rushing. Keep in mind that sugars should not be overly consumed, and should
comprise < 60% of the energy intake. There should not be an excess or insufficient
intake of any nutrients. Patients should increase dietary fiber. Eating the vegetables
first during meals suppresses the elevation of postprandial blood glucose, which can
help in decreasing body weight
576). The dietary percentages of energy from SFAs and PUFAs should be ≤ 7% and ≤ 10%,
respectively.
5)
Exercise Therapy
[Statement]
Habitual physical activity and aerobic exercise are effective for ASCVD prevention.
(Evidence level: 1, recommendation level: A)
Lack of physical activity is associated with increased body fat (obesity), dyslipidemia,
metabolic syndrome, hypertension, diabetes/impaired glucose tolerance, vascular endothelial
dysfunction, and decreased physical fitness. It is also a risk factor for ASCVD such
as CAD and cerebrovascular disease
577–587). Increased sedentary behavior, defined as “any waking behavior with an energy
expenditure of 1.5 metabolic equivalents (METs) or less in a sitting or reclining
posture” may be a risk factor for various health outcomes independent of physical
activity
588–590).
Increasing physical activity maintains or adds to physical fitness, improves serum
lipid levels, decreases blood pressure, increases insulin sensitivity and glucose
tolerance, improves vascular endothelial function, and decreases thrombosis risk
591–593). It also decreases mental stress and slows the decline in cognitive function
594
,
595). The amount of daily physical activity, leisure time physical activity and physical
fitness level have been found to be negatively correlated with morality due to cerebrovascular
disease and cancer, as well as all-cause mortality in studies conducted worldwide
596–606) and cohort studies in Japan
577).
Exercise therapy includes both aerobic and resistance (muscle) exercise. Aerobic exercise
is effective in improving lipid metabolism
607–615). The effects of aerobic exercise (walking, brisk walking, supervised or nonsupervised
training) compared with nonexercising controls on LDL-C, TG, and HDL-C levels have
been extensively studied. However, study results are difficult to compare because
of differences in subjects, exercise intensity and duration, and pre-intervention
lipid levels. Among 8 reports of systematic review and metaanalysis of RCTs with comparison
of exercise and non-exercise control including Japanese participants and were published
after 2,000, significant decreases in LDL-C and TG levels were reported in two articles,
respectively. Six reported a significant increase in HDL-C levels, which was the most
frequently observed effect of exercise on serum lipids
577, 607–613). A meta-analysis of 25 RCTs that compared aerobic exercise for training
periods of at least 15 minutes for ≥ 8 weeks with nonexercise control reported that
exercise therapy significantly increased the HDL-C levels
612). The increase in HDL-C was positively correlation with the duration of exercise,
and exercising for ≥ 121 minutes/week significantly increased the levels. A meta-analysis
of four RCTs conducted in Japan comparing the effects of low to moderate-intensity
aerobic exercise for 10 weeks to 24 months with nonexercise therapy found that exercise
significantly increased the HDL-C levels
577).
Table 9
shows simplified guidelines for exercise therapy. Efforts should be made to increase
daily physical activity and to incorporate exercises suited to individual lifestyles.
Increasing aerobic exercise is the primarily goal, and brisk walking or slow jogging
are recommended. Moderate-intensity exercise (e.g., walking at normal speed) is effective
and safe and can be performed for extended periods without strain. The increase in
blood pressure during moderate exercise is modest, and blood lactate does not accumulate.
The aim is to exercise for at least 30 minutes a day at least three times a week,
daily if possible. For the elderly with a muscle wasting, aerobic exercise combined
with mild resistance training is useful. Bench-stepping exercises, which can be performed
indoors, are recommended
577). In 2013, the Ministry of Health, Labor and Welfare of Japan published “Japanese
official physical activity guidelines for health promotion (Active Guide)”
616) (see Appendices 1 and 2). To prevent lifestyle-related diseases, starting with
“Plus 10,” be active for an additional 10 min every day” helps to achieve the ultimate
aim of 60 minutes of activity per day for adults and 40 minutes per day for the elderly.
Table 9.
Guidelines for Exercise Therapy
Type
Implement with an emphasis on aerobic exercises such as walking, brisk walking, swimming,
aerobic dance, slow jogging, cycling, and bench-stepping
Intensity
Aim for a moderate intensity* or above
Frequency and duration
Aim to exercise for at least 30 min per day at least 3 days a week
Others
Walk or perform other, similar activities frequently and at times other than during
exercise therapy and avoid a sedentary lifestyle as much as possible
*
Moderate intensity means as follows:
An exercise intensity equivalent to walking at normal speed (= walking)
In terms of METs (a unit that expresses the intensity of exercise as the equivalent
number of times the resting metabolism), it is typically 3 METs (walking) but it differs
according to individual physical fitness
The perceived exertion during exercise corresponds to 11–13 on the Borg scale, i.e.,
fairly light to somewhat hard)
The Borg Scale
Scale
Perceived
20
19
Very, very hard
18
17
Very hard
16
15
Hard
14
13
Somewhat hard
12
11
Fairly light
10
9
Very light
8
7
Very, very light
6
(Borg GA: Med Sci Sports Exerc. 1973; 5: 90–93)
Note that unaccustomed exercises carry a risk of musculoskeletal disorders, and in
addition to bone and joint injury, strenuous exercise may add to the risk of sudden
death and MI in patients with CVD
617, 618). This should be taken into careful consideration, and when exercise therapy
is performed, underlying ASCVD and bone and joint diseases should be taken into account.
It is necessary to choose exercises and physical activities that are adapted to individual
physical fitness, exercise history, and the current status of physical activity.
3.
Drug Therapy
1)
Drug Therapy
CQ21. Can the evidence on ASCVD prevention in Western countries be applied in Japan?
It has been proven that the effects of LDL-C-lowering therapy using statins to decrease
the relative risk of ASCVD incidence are observed regardless of race and absolute
risk. (Evidence level 1+, recommendation level A)
Although the absolute risk of CAD is lower in the Japanese population than in Western
countries, the relative risk of LDL-C and CAD is similar. The MEGA study
41), a large-scale clinical trial conducted in Japan, confirmed the effectiveness
of LDL-C-lowering therapy using statins to prevent cardiovascular events in Japanese
patients with hypercholesterolemia. Epidemiology studies, however, have not found
a significant correlation of serum cholesterol level and the incidence of noncardiogenic
cerebral infarction
38, 57, 64, 337). LDL-C is also a risk factor for atherothrombotic cerebral infarction
36), and the effectiveness of statins to decrease the incidence of atherothrombotic
cerebral infarction was confirmed in a Japanese population by the J-STARS study
619). The effectiveness of statins for preventing the first occurrence and recurrence
of stroke in Japanese populations was confirmed in a sub-analysis of the MEGA study
620, 621) and in the JELIS study
622).
Meta-analyses conducted by the Cholesterol Treatment Trialists' Collaboration on large-scale
clinical trials using statins confirmed that a decrease in the incidence of cardiovascular
events was proportionate to the decrease in LDL-C level, regardless of pretreatment
LDL-C level and individual absolute risk
177–179, 348). The HOPE-3 study was a large international study with 21 participating
countries, including some in the Asian region, and it evaluated primary prevention
in populations with a risk that was equivalent to high risk in Japan. It has been
proven by the study that LDL-C-lowering therapy using statins exhibits suppressive
effects on cardiovascular events regardless of race
623).
2)
Indications for Drug Therapy
CQ22. Is an LDL-C management target of < 120 mg/dL appropriate for high-risk category
of primary prevention?
The LDL-C level for high-risk patients in primary prevention should be controlled
at a target of < 120 mg/dL. (Evidence level 2, recommendation level B)
The APPROACH-J study was a prospective Japanese study that investigated the 2-year
incidence rate of cardiovascular events for high-risk patients in primary prevention
who had recently started statin therapy. The risk of CAD incidence plateaued at LDL-C
levels ≤ 119 mg/dL, which demonstrates the importance of maintaining an LDL-C level
of < 120 mg/dL
624). The importance of the comprehensive management of overlapping complicating risk
factors in addition to LDL-C, such as smoking, hypertension, and diabetes, was affirmed
in this study. Furthermore, for diabetes patients, who are a high-risk group in primary
prevention, a sub-analysis of the J-LIT study results found that keeping the LDL-C
level < 120 mg/dL was useful for preventing CAD incidence
625). The HOPE-3 study was a randomized comparative intervention trial of statins
for primary prevention in populations with characteristics corresponding to high risk
in Japan. Significant reduction of cardiovascular events was seen in the statin-treated
group that maintained LDL-C levels of < 120 mg/dL. The average pretreatment LDL-C
level of both study groups was approximately 128 mg/dL
623). Thus, controlling the LDL-C level at a target of < 120 mg/dL for high-risk populations
in primary prevention appears to be appropriate. However, despite recent efforts to
increase the awareness of and familiarity with guidelines, it has been reported that
the achievement of the LDL-C management target by high-risk patients with type 2 diabetes,
noncardiogenic cerebral infarction, or PAD is still not adequate in Japanese clinical
practice
626, 627).
CQ23. When should drug therapy be initiated for hyper-LDL cholesterolemia?
For high-risk patients in primary prevention, if lifestyle modification is not likely
to be effective, the combined use of drug therapy should be considered as soon as
possible. (Evidence level 3, recommendation level A)
It has been proven that initiating aggressive LDL-C-lowering therapy at an early stage
after disease incidence is effective for secondary prevention. (Evidence level 1+,
recommendation level A)
In addition to plasma LDL-C level, physicians prescribing drug therapy in primary
prevention should also be aware of other patient characteristics, including smoking
habits, the presence of hypertension, diabetes, CKD, a family history of premature
CAD or other ASCVD, such as noncardiogenic cerebral infarction, PAD or carotid atherosclerosis.
An assessment of individual risk should include this information when drug therapy
is considered for patients with high absolute risk. The long-term follow-up of large
clinical trials of statins that were conducted in the 1990s, such as the West of Scotland
Coronary Prevention Study (WOSCOPS) and the Heart Protection Study (HPS)
628, 629) confirmed that early initiation of LDLC-lowering therapy regardless of the
plasma LDL-C level was useful for the long-term prevention of cardiovascular events
and all-cause mortality in high-risk patients. No increases in new-incidence cancer
or non-CVD deaths were observed, which reconfirms the safety of long-term LDL-C-lowering
therapy using statins.
Lifetime cumulative LDL-C and the threshold for CAD incidence are recent concepts.
Aggressive LDL-C-lowering therapy is recommended as early as possible for patients
with familial hypercholesterolemia who present with hyper-LDL cholesterolemia at a
young age followed by developing the premature CAD. Cardiovascular events may occur
sooner than expected in patients with usual hyper-LDL cholesterolemia because of the
accumulation of LDL-C that is promoted by complicating atherosclerosis risk factors.
A Mendelian randomization analysis found that the risk of cardiovascular events was
extremely low in patients with hypo-LDL cholesterolemia that was caused by gene mutations
630). There is a need to consider LDL-C-lowering therapy as soon as possible for hyper-LDL
cholesterolemic patients with high absolute risk. Long-term observational included
in large clinical trials found that the early initiation of LDLC-lowering therapy
decreased lifetime cumulative LDL-C, which may have made it possible to decrease the
occurrence of cardiovascular events.
Low-risk patients without additional risk factors, young individuals, and premenopausal
women are at low absolute risk. Even if the LDL-C management target is not achieved,
it is possible that the progress may be observed with lifestyle modification only.
Drug therapy should be considered on the basis of the importance of the existing risks
only if strict lifestyle guidance does not improve lifestyle habits and does not achieve
the management target.
CQ24. Can an LDL-C management target be set for preventing occurrence of ASCVD for
secondary prevention in patients with a history of CAD?
In secondary prevention, the LDL-C control target should be at a level of < 100 mg/dL.
However, if it is difficult to achieve an LDL-C level < 100 mg/dL, the alternative
target would be to decrease the level by ≥ 50%. (Evidence level 3, recommendation
level A)
Clinical trials have confirmed that the effects of statins on the reduction of cardiovascular
events can improved by administering statins with more potent LDL-C-lowering effects
177, 631). However, there are no lipid intervention studies that have set an LDL-C
management target. Therefore, when LDL-C-lowering therapy is given to prevent cardiovascular
events, the question of whether to “treat to target” or to use a potent statin without
setting a target value i.e., “fire and forget” is under debate. Currently, it is necessary
to consider the results of epidemiological studies and cohort studies to choose the
LDL-C management target. In a long-term Japanese observational study of secondary
prevention, the incidence of cardiovascular events was significantly decreased in
patients whose LDL-C levels were controlled at < 100 mg/dL
632). In the CREDO-Kyoto Registry Cohort-2, the 3-year incidence of cardiovascular
events in patients treated with potent and standard statins were compared. Patients
underwent analysis stratified by LDL-C management level
633). The incidence of cardiovascular events was significantly lower with the potent
statin than with the standard statin. In addition, in patients with LDL-C levels ≥
120 mg/dL, the risk of the incidence of cardiovascular events was 1.74 times greater
than in patients with LDL-C levels of 80–99 mg/dL, which was a significant difference.
A significant difference in the risk of cardiovascular events was not seen when the
LDL-C level was < 80 mg/dL. The mean LDL-C levels that were analyzed by the strength
of statin were 92 mg/dL in patients treated with potent statins and 101 mg/dL in patients
with standard statins, respectively. The study outcome supports the benefits of controlling
the LDL-C level at < 100 mg/dL rather than basing the treatment on the strength of
statin. It has been reported that the risk of cardiovascular events increased in patients
with the escape phenomenon (i.e., re-elevation in LDL-C level of ≥ 10% after a reduction)
following the start of statin treatment
634). However, patients with the escape phenomenon had an LDL-C level of 106 mg/dL;
whereas the comparison group had an LDL-C level of 90 mg/dL. In addition to the choosing
the strength of the statin, regular blood testing to monitor the LDL-C level is recommended.
A recent survey in Japan, found that 65% patients with ACS, and 55% for other secondary
prevention patients, achieved an LDL-C management target of < 100 mg/dL. Thus, LDL-C
management with lipid-lowering therapy for secondary prevention in Japan is still
not satisfactory
626). A meta-analysis of international trials reported that the risk for ASCVD was
significantly decreased in patients with an LDL-C reduction of ≥ 50%, regardless of
the LDL-C level achieved
635). To prevent ASCVD in cases where it is difficult to control the LDL-C at < 100
mg/dL, lipid management with the aim of lowering pretreatment LDL-C by 50% or more
is recommended
177, 631, 633, 635).
CQ25. Is risk stratification possible in secondary prevention? In addition, is it
possible to set an LDL-C management target?
Even in secondary prevention, the risk for cardiovascular events is high if FH, ACS,
DM, noncardiogenic cerebral infarction, PAD, CKD, and metabolic syndrome are present,
or if there is an overlap in the major risk factors and the presence of smoking. Stricter
LDL-C management is therefore necessary. (Evidence level 3, recommendation level B)
Even in secondary prevention, the incidence of cardiovascular events is clearly high
if FH, ACS, DM, noncardiogenic cerebral infarction, PAD, CKD, and metabolic syndrome
are also present, or if there is an overlap of the major risk factors or continued
smoking (
Table 3
) (refer to Chapter 3, 1–8: History of CAD). After the results of IMPROVE-IT
636) and clinical trials using PCSK9 inhibitors
637–639) conducted in recent years, the clinical significance of maintaining the LDL-C
level at < 70 mg/dL is garnering attention in secondary prevention complicated with
high-risk conditions
640).
In Japan, only a few interventional studies have been conducted using cardiovascular
events as the endpoint for secondary prevention. Therefore, results from interventional
studies involving patients with ACS who underwent IVUS as a surrogate endpoint have
instead been reported. The results of one metaanalysis revealed that the rate of change
in plaque (atheroma) volume [percent atheroma volume (PAV)] correlates significantly
with cardiovascular event risk
641). The results of ESTABLISH
642), JAPAN-ACS
643), the ZEUS study
644), and PRECISE-IVUS
645) have shown that in cases stratified into a high-risk category even in secondary
prevention, such as ACS or ACS complicated by DM, controlling the LDL-C at a target
level of < 70 mg/dL is useful for plaque regression. A meta-analysis of clinical trials
that combined primary and secondary prevention has revealed a linear relationship
between the LDL-C level following statin treatment and the suppressive effects of
statins on cardiovascular events. A review performed outside of Japan reported that
larger suppressive effects on cardiovascular events can be achieved by maintaining
the LDL-C level at < 50 mg/dL
646). We consider these findings to be supportive of the hypothesis of “lower is better.”
As FH puts the patient at extremely high risk for CAD, it is likely that the risk
in primary prevention is equivalent to that in secondary prevention. Therefore, in
secondary prevention complicated with FH or ACS, stricter LDL-C management to achieve
a level < 70 mg/dL can be considered appropriate. The secondary prevention for DM
patients complicated with conditions described in
Table 3b
, should also be treated based on the target level of FH or ACS, as they are considered
to be at high risk of recurrence of CAD. In cases where the target cannot be achieved
with monotherapy using statins, the combined use of medications such as ezetimibe
should be considered.
CQ26. If the LDL-C management target has been achieved, should lipid management be
carried out using the non-HDL-C level as an indicator?
If the TG level is high even when the LDL-C management target has been achieved, lipid
management should be carried out using the non-HDL-C level as the target. (Evidence
level 3, recommendation level B)
Undoubtedly, the LDL-C level is the most important target in lipid management. However,
in managing dyslipidemia expressed by hypertriglyceridemia, the non-HDL-C level is
more useful than the LDL-C level. This has been reported in a number of studies
177–179, 623, 624, 626, 627, 647). The standard non-HDL-C level is defined as a value
30 mg/dL higher than LDL-C in NCEP-ATP Ⅲ. Studies from Japan have shown similar findings
74, 75). Even when the LDL-C management target has been achieved, if hypertriglyceridemia
is present, the non-HDL-C level should be the secondary target for lipid management
aimed at preventing ASCVD. However, if the patient's TG level is ≥ 400 mg/dL or if
blood sample is postprandial period, then the non-HDL-C level should be used initially
instead of the LDL-C level. We hope that additional evidence will be gathered from
interventional studies using the non-HDL-C level as a marker.
Q1. Is therapeutic intervention for hypertriglyceridemia effective in suppressing
the incidence of ASCVD?
There is insufficient evidence regarding the preventive effect of drug therapy for
hypertriglyceridemia upon the incidence of ASCVD. However, keeping in mind that patients
with a marked increase in fasting triglyceride levels face the risk of acute pancreatitis,
it is important that we consider the concurrent administration of fibrates or other
drugs with dietary advice, such as limiting the amount of fat intake and abstinence
from alcohol. (Recommendation level: B)
As yet, no RCT has reported an effect on the incidence of ASCVD after conducting drug
therapy targeted only at patients with hypertriglyceridemia. However, there are reports
of RCTs using TG-lowering nicotinic acid derivatives and fibrates on patients with
dyslipidemia, and some have shown a preventive effect on the incidence of ASCVD. The
first of such RCTs is the Helsinki Heart Study, a large clinical study involving patients
with hypertriglyceridemia
648). In this study, gemfibrozil significantly suppressed the incidence of CAD by
34% in middle-aged men in primary prevention; these men had non-HDL-C levels of 200
mg/dL or higher. Subsequent to the Helsinki Heart Study, there were the FIELD
649) and ACCORD
650) studies, both conducted with fenofibrate. With respect to primary endpoints of
these studies, although the effectiveness of fenofibrate was not demonstrated, a meta-analysis
in primary prevention using fibrates revealed that deaths from cerebrovascular and
cardiovascular diseases, non-fatal myocardial infarction, and non-fatal stroke significantly
decreased by 16%
651). These deaths were also reported to significantly decrease by 12% in secondary
prevention
652). Meanwhile, the co-administration of a nicotinic acid derivative (niacin) and
statin to increase HDL-C levels did not have a suppressive effect on cardiovascular
events in the AIM-HIGH
653) and HPS2-THRIVE
654) studies.
Therefore, we cannot confirm that drugs for hypertriglyceridemia, such as fibrates
and nicotinic acid derivatives, have a preventive effect on ASCVD. Nonetheless, TGs
have been demonstrated to be correlated with acute pancreatitis
655). In addition, we should consider the risk of acute pancreatitis in patients with
markedly increased fasting TG levels (500 mg/dL or higher) and consider the concurrent
administration of fibrates or other drugs with dietary advice.
3)
Characteristics and Criteria for Selecting the Various Drugs
Q2. Have the indications, efficacy, and safety been established for drugs used to
treat dyslipidemia?
The indications, efficacy, and safety of statins, ezetimibe, the anion-exchange resins,
probucol, fibrates, n3-PUFAs, and nicotinic acid derivatives for treating dyslipidemia
have been established. Although the indications and efficacy of PCSK9 inhibitors have
been established, the safety of long-term administration has not been validated.
Table 4
shows the classification of drugs used to treat dyslipidemia according to efficacy.
These are drugs for which the effects have been ascertained through double-blind studies
completed in Japan. There is a need to select safe and effective medications based
on understanding of the characteristics of various drugs, while taking into account
any complicating diseases, drug interactions, etc. The characteristics of various
drugs used to treat dyslipidemia are described below.
i)
HMG-CoA Reductase Inhibitors (Statins): Pravastatin, Simvastatin, Fluvastatin, Atorvastatin,
Pitavastatin, and Rosuvastatin
Statins are indicated for cases of dyslipidemia with a high LDL-C level. They are
currently one of the most effective medications for lowering the LDL-C level and have
been so because their effects on FH were shown
656). Statins competitively inhibit HMG-CoA reductase, which is a rate-limiting enzyme
of cholesterol synthesis, in turn suppressing cholesterol biosynthesis
657). The subsequent activation of SREBP2 promotes LDL receptor synthesis and results
in a reduction in the blood LDL-C level
658). The range of the LDL-C-lowering effect is 20%–50%. Although a reduction in cholesterol
biosynthesis in the liver also results in a decrease in the TG level through simultaneous
suppression of very low-density lipoprotein (VLDL) synthesis and secretion
659), the decrease ranges from approximately 10%–20%. Myopathy-like symptoms, such
as hepatic disorders, an increased creatine kinase (CK) level, and muscular weakness,
have been reported as adverse reactions to statins. Rhabdomyolysis, characterized
by an increased myoglobin level in the blood and urine, has also been reported, though
this complication is very rare. Rhabdomyolysis risk increases with the combined use
of statins with fibrates, nicotinic acid derivatives, cyclosporine, or erythromycin,
etc. Immune-mediated necrotizing myopathy, characterized by muscle fiber necrosis
without infiltration of inflammatory cells on histological examination and the positivity
for anti-HMG-CoA reductase antibodies on serological examination, has also been reported
even in Japan
660, 661). The symptoms which are characterized by muscle weakness predominantly in
proximal muscle and marked muscle pain with an increased CK level, persist even after
stopping administration of oral statins, and there have been cases in which symptoms
progress rapidly. Administration of oral statins should therefore be stopped immediately
if myopathy-like symptoms appear and the patient's condition should be monitored closely.
Moreover, there have been reports on suspected teratogenicity in pregnant patients
who incidentally took statins during early pregnancy
662); therefore, at present, it appears that statins must not be used in women who
are pregnant, possibly pregnant, trying to conceive, or lactating. Pitavastatin (1–2
mg) has been approved for pediatric FH in patients aged ≥ 10 years.
ii)
Intestinal Cholesterol Transporter Inhibitor (Cholesterol Absorption Inhibitor): Ezetimibe
Ezetimibe inhibits a small intestine cholesterol transporter (NPC1L1) that exists
in the small intestinal mucosa and controls the absorption of cholesterol derived
from diet and bile in the small intestine, thereby exerting a blood cholesterol-lowering
effect
663). Unlike resins, this drug is absorbed into the body. After passing through the
intestinal circulatory system, approximately 78% of it is excreted in the feces. Because
this drug selectively inhibits cholesterol absorption, it does not affect the absorption
of fat-soluble vitamins, such as vitamins A and D. The usual oral dose (10 mg/day)
decreases the LDL-C level by approximately 18%. Similar to resins, it enhances cholesterol
synthesis in the liver. Therefore, the combined use of ezetimibe with statins is ideal
and provides a synergistic effect: combination therapy with 10 mg of ezetimibe and
a statin at the usual dose decreases the LDL-C level by approximately 35–50%
664–666), which is equivalent to the effects achieved using a maximum statin dose
alone. A meta-analysis of large-scale clinical trials involving combination therapy
with ezetimibe and statins in patients with high-risk conditions such as FH, ACS,
and PAD, confirmed the safety of combination therapy and cardiovascular event suppression
resulting from its LDL-C-lowering effects
667). It also increased the HDL-C level by 8–9% while decreasing the TG level by 20–30%.
Although gastrointestinal symptoms were found to be common adverse reactions, there
were no significant differences compared to a placebo. Similar to statins, myopathylike
symptoms such as an increased CK level and muscle weakness, have been reported. These
effects are rare, and there are no reports indicating that the combined use with statins
intensifies adverse reactions. It has recently been reported that vitamin K absorption
in the intestines is mediated by NPC1L1; therefore, it is necessary to note that the
action of ezetimibe combination therapy in patients who take oral warfarin may be
intensified
668).
iii)
Anion-Exchange Resins (Resins): Colestimide and Cholestyramine
Resins are indicated for dyslipidemia with a high LDL-C level (type Ⅱa). Although
the first-line drugs of choice for hyper-LDL cholesterolemia are statins, resins may
be the first-line drugs for patients who cannot tolerate statins because of adverse
reactions, and for women who require drug therapy while pregnant or possibly pregnant.
The greatest merit of resin therapy lies in combination therapy with statins.
Cholestyramine is the first medication that was proven through large-scale clinical
trials to have suppressive effects on CAD incidence
669, 670). Resin adsorbs bile acids in the intestines and inhibits intestinal circulation
of bile acid via reabsorption, thereby promoting catabolism from cholesterol to bile
acids. It is believed that this catabolism leads to decreased sterol pools in the
body and an enhanced synthesis of LDL receptors in the liver, resulting in a decreased
LDL-C level in the blood
671). However, HMG-CoA reductase activity in the liver may simultaneously increase,
enhancing cholesterol biosynthesis. Combining these drugs with statins, which are
HMG-CoA reductase inhibitors, is therefore extremely logical. In contrast, bile acids
act as ligands for the nuclear receptor FXR and are involved in regulating TG metabolism
by controlling SREBP1c expression and enhancing lipoprotein lipase (LPL) activity.
Resin administration results in a decreased LDL-C level, as well as VLDL synthesis
and an increased blood TG level because of bile acid absorption. Adverse drug reactions
primarily include gastrointestinal symptoms, such as constipation and abdominal bloating;
however, no serious adverse reactions have been observed so far because these drugs
are nonabsorbable. It has been pointed out that resins adsorb concomitant drugs, such
as statins, digitalis, warfarin, thiazide diuretics, and thyroid gland preparations.
Therefore, when these medications are concomitantly used, instructions to take them
at intervals must be provided. Furthermore, as they may also inhibit the absorption
of fat-soluble vitamins (A, D, E, and K) and folic acid, vitamin supplementation should
be considered during long-term resin administration.
iv)
Probucol
Probucol is indicated for dyslipidemia with a high LDL-C level (type Ⅱa). This drug
is characterized by its ability to cause xanthoma regression. In addition to decreasing
the LDL-C level, this drug also decreases the HDL-C level.
LDL-C level reduction resulting from probucol is 15–25%. The mechanism underlying
this decrease is thought to involve enhanced LDL catabolism, particularly the promotion
of cholesterol excretion into bile. On the other hand, the mechanism underlying the
decrease in the HDL-C level is thought to involve the suppression of ABCA1, a membrane
protein essential for HDL production. Other possible mechanisms include enhanced activity
of cholesterol ester transfer proteins (CETPs) and of SR-BI, an HDL receptor. From
the viewpoint of cell biology
672, 673), immunohistology
674, 675) and other factors, it has become clear that LDL oxidation is an important
aspect of the pathogenic mechanism of atherosclerosis. As probucol is made up of two
butylated hydroxytoluene (BHT) antioxidants and is fat-soluble, it is taken up by
lipoproteins and exerts potent antioxidant effects. Clinically, the suppressive effects
on post-percutaneous transluminal coronary angioplasty (PTCA) restenosis
676, 677), carotid artery IMT progression, and cardiovascular events
678) have been reported from RCTs, albeit small-scales ones. Moreover, a cohort study
has also revealed secondary-prevention effects of probucol in patients with heterozygous
FH
679). In PQRST, however, suppressive effects on atherosclerosis progression in the
femoral arteries could not be achieved with probucol administration in addition to
diet therapy and cholestyramine treatment
680). In any case, because no large-scale clinical studies have been conducted, probucol
use is limited to certain situations such as combination therapy with statins or in
monotherapy in patients who cannot tolerate statins. Other than gastrointestinal symptoms,
hepatic disorders, and rashes, adverse drug reactions include QT prolongation and
torsades de pointes on electrocardiograms.
v)
PCSK9 Inhibitors (Human Anti-PCSK9 Monoclonal Antibodies): Evolocumab and Alirocumab
PCSK9 inhibitors are currently indicated for FH or patients with hypercholesterolemia
who have a high risk for cardiovascular events and do not benefit sufficiently from
even at the maximum tolerated dose statins.
These drugs bind specifically to and inhibit the actions of the PCSK9 (proprotein
convertase subtilisin/kexin type 9) protein, which is involved in the degradation
of LDL receptors in the liver. In doing so, it increases the recycling of LDL receptors,
thereby showing a blood LDL-C-lowering effect
681). Although increasing the synthesis of LDL receptors, statins, which inhibit cholesterol
synthesis in the liver and activate SREBP2, simultaneously increase PCSK9 synthesis.
Therefore, it is reasonable to use statins in combination with PCSK9 inhibitors. Their
LDL-C-lowering effect is the strongest among all the existing medications. In a phase-3
study involving subjects with a high risk for cardiovascular events including those
with heterozygous FH, administrating PCSK9 inhibitor once every two weeks decreased
LDL-C levels by 70–75% with combination oral statins
682, 683). These inhibitors also decrease the Lp(a) level, on which statins do not
show a lowering effect. PCSK9 inhibitors decrease TG levels by 20–25% and increases
HDL-C levels by 10–15%.
As these medications are injected subcutaneously, the main adverse drug reaction reported
is a reaction at the injection site, whereas others include nasopharyngitis and gastroenteritis.
No reports have stated that the combined use with statins intensifies the adverse
reactions in individuals with hepatic or musculoskeletal disorders. Although adverse
events caused by low LDL-C levels have not been reported, the long-term efficacy and
safety of PCSK9 inhibitors should be monitored carefully.
vi)
MTP Inhibitor: Lomitapide
Lomitapide is currently the only microsomal triglyceride transfer protein (MTP) inhibitor
approved in Europe, America, and Japan. The inhibition of MTP decreases VLDL production,
which in turn causes decreased LDL-C and TG levels. Even in patients with homozygous
FH (HoHF) for whom other drug therapies show no effect, lomitapide decreases the LDL-C
level by approximately 50%. However, major adverse drug reactions include accumulation
of fat in the liver, abdominal pain, and diarrhea. As a result of these major adverse
drug reactions, its long-term safety needs to be studied further in the future. The
indication for lomitapide in Japan is limited to patients with hoFH.
Four weeks following commencement of a low-fat diet and administration of lomitapide
in patients with hoFH, the blood LDL-C level and apo-B level decreased by 50.9% and
55.6%, respectively (average pretreatment LDL-C level: 615 mg/dL)
684). During lomitapide treatment, the AST and ALT levels were found to be significantly
elevated, as was the liver fat content. However, these levels returned to normal in
all patients 14 weeks after treatment cessation. Furthermore, a dose-dependent decrease
in the LDL-C and apo-B levels was observed following lomitapide monotherapy or combination
therapy with ezetimibe, in conjunction with a low-fat diet in 85 patients with high
TC (average pretreatment LDL-C level: 170 mg/dL)
685). The maximum lomitapide dose alone decreases the LDL-C level by 30% and the apo-B
level by 24% from pretreatment levels. In contrast, the combination with ezetimibe
showed decreases of 46% and 37%, respectively.
vii)
Fibrates: Bezafibrate, Fenofibrate, Clinofibrate and Clofibrate
Fibrates are the most effective medications for hypertriglyceridemia. Fibrates are
particularly effective for type Ⅲ hyperlipidemia because they enhance the catabolism
of remnant lipoproteins. They are also highly effective in increasing the HDL-C level.
Their primary mechanism of action is the activation of PPARα, a nuclear receptor,
through binding of fibrates as ligands
686, 687). This results in (1) enhanced β-oxidation of fatty acids and decreased TG
production in the liver; (2) increased LPL production; (3) decreased Apo C-Ⅲ production
and enhanced LPL activity, which lead to the promotion of TG degradation and catabolism
from VLDL to LDL; and (4) increased production of Apo A-Ⅰ and A-Ⅱ. As a result, the
TG level decreases and the HDL-C level increases. Bezafibrate has a TG-lowering effect
of 30–40%, a TC-lowering effect of approximately 10%, and an HDL-C-increasing effect
of 35–45%. Fenofibrate is characterized by its long half-life, and exerts a uric acid-lowering
effect in addition to its effect on lipids. The main adverse drug reaction is rhabdomyolysis,
which is likely to occur in patients with renal dysfunction, so caution should be
taken.
viii)
SPPARMα: Pemafibrate
Selective peroxisome proliferator-activated receptor α modulators (SPPARMα) (pemafibrate
already approved in Japan) are considered to be safer than conventional fibrates in
combination with statins because they have few drug interactions with the statins
currently used in Japan and are not renally excreted.
ix)
Nicotinic Acid Derivatives: Niceritrol, Nicomol, and Tocopheryl Nicotinate
Nicotinic acid derivatives are indicated for hyper-LDL cholesterolemia, hypertriglyceridemia,
and dyslipidemia accompanied by increased remnant lipoproteins.
The mechanism of action of these drugs involves the suppression of hormone-sensitive
lipase activation, in turn inhibiting lipolysis in peripheral fat tissue and decreasing
the influx of free fatty acids into the liver. This results in lipoprotein synthesis
suppression in the liver. Furthermore, nicotinic acid derivatives exert HDL-C-increasing
effects by suppressing apolipoprotein A-1 catabolism. Nicotinic acid monotherapy (3.0
g/day) causes a decrease in the TG level by 26%
688). Nicotinic acid derivatives also have Lp(a)-lowering effects
689–691). The main adverse drug reactions include itching and facial flushing because
of peripheral vasodilation. Moreover, as nicotinic acid derivative use may exacerbate
insulin resistance, these drugs must be administered carefully in patients with DM.
x)
N-3 Polyunsaturated Fatty Acids (PUFAs): Ethyl Icosapentate and Omega-3-Acid-Ethyl
Ester
PUFAs are indicated for dyslipidemia accompanied by an increased TG level, particularly
for type Ⅱb and type Ⅳ hyperlipidemia. EPA and DHA suppress VLDL synthesis in the
liver, thereby decreasing the TG level and exerting a slight HDL-C-increasing effect.
The results of epidemiological studies and secondary-prevention studies have previously
demonstrated that the consumption of fish oil and n-3 PUFA helps prevent cardiovascular
events. The JELIS study
692) conducted in Japan found that the addition of EPA to statins showed a significant
preventive effect on major cardiovascular events compared to statin monotherapy. This
indicates the efficacy of EPA in preventing cardiovascular events. However, recent
large-scale clinical studies involving high-risk patients with both myocardial infarction
and type 2 diabetes were unable to demonstrate that n-3 PUFA administration had suppressive
effect on cardiovascular events
693, 694). In addition to their effects on lipids, EPA and DHA are expected to have
antiplatelet and anti-inflammatory effects in ASCVD prevention. Other than gastrointestinal
symptoms, such as diarrhea, the main adverse drug reaction is bleeding diathesis.
4)
Combination Therapy
CQ27. Does combination therapy using statin and other cholesterol-lowering drugs (ezetimibe,
anion-exchange resin, probucol, and PCSK9 inhibitor) prevent ASCVD incidence?
Combination therapy using statin and ezetimibe prevents ASCVD incidence in patients
with ACS. (Evidence level 1+, recommendation level: B).
Combination therapy using statin and PCSK9 inhibitor prevents ASCVD incidence in patients
with a history of myocardial infarction, nonhemorrhagic stroke, or PAD. (Evidence
level 1+, recommendation level: B).
The IMPROVE-IT study
636) which enrolled ACS subjects (secondary prevention) with controlled LDL-C levels
(50–100 mg/dL) under simvastatin treatment, revealed a significantly lower ASCVD incidence
in the group for which ezetimibe was added on to simvastatin treatment. This study
also revealed that the relationship between the reduced LDL-C value and the event
inhibition rate attained with the addition of ezetimibe was similar to that observed
in previous statin studies. The FOURIER study
639) was a study which enrolled high-risk subjects (patients with a history of myocardial
infarction, nonhemorrhagic stroke, or PAD) with an LDL-C level of ≥ 70 mg/dL or a
non-HDL-C level of ≥ 100 mg/dL under statin treatment, and examined add-on effect
of PCSK9 inhibitor to the statin; this study showed that the combined use of PCSK9
inhibitors with statins suppressed ASCVD incidence. There are no large-scale RCTs
which examined the effect of the combined use of statin with anion-exchange resin
or probucol in preventing ASCVD.
The SHARP study
695), although the design of which does not fit into this “CQ22”, showed that combination
therapy using statin and ezetimibe in patients with CKD (including those for both
primary prevention and secondary prevention) suppressed ASCVD incidence compared to
placebo.
CQ28. For patients with dyslipidemia complicated by hypertriglyceridemia or low HDL-C,
would fibrate, nicotinic acid derivative or n-3 PUFA possess beneficial effect in
suppressing ASCVD incidence when used in combination with statin?
Combination therapy using ethyl icosapentate (EPA) preparation or fibrate with statin
is effective in suppressing ASCVD incidence. (Evidence level 2, recommendation level
B).
Although no clinical studies have investigated the efficacy of combination therapy
as a primary endpoint in subjects with the dyslipidemia profile assumed in this CQ,
some clinical studies have investigated it in a sub-analysis.
In a sub-analysis of JELIS study
696) which enrolled subjects with hypercholesterolemia, it was shown that EPA administration
added-on to statins prevented coronary event incidence for patients in primary prevention
whose TG and HDL-C levels were ≥ 151 mg/dL and < 40 mg/dL, respectively. The ACCORD-LIPID
study, which was conducted in North America, involved type 2 diabetes subjects (primary
prevention and secondary prevention). Its subanalysis suggested that fibrate administration
in addition to statins could prevent ASCVD incidence in groups with a TG level of
≥ 204 mg/dL and an HDL-C level of < 34 mg/dL
697).
The AIM-HIGH study
698), which examined the effect of nicotinic acid derivative (NA) added-on to statin
in the subjects with low HDL-C and hypertriglyceridemia together with ASCVD history,
did not show suppressive effects of NA on ASCVD incidence. The sub-analysis of the
HPS2-THRIVE study
699), which included subjects with HDL-C levels < 34.8 mg/dL or TG levels ≥ 151 mg/dL
and a ASCVD history, also could not show beneficial effect of NA added to statin.
However, there would be some pitfalls for these two studies. Statin dose as well as
the prescription rate of ezetimibe for the control group in the AIM-HIGH study was
higher than the NA group. Regarding HPS2-THRIVE, the subjects were those who had already
attained an average LDL-C level of 63 mg/dL, and the sample size for the sub-analysis
was small (19.1% with an HDL-C level < 38.4 mg/dL and 25.6% with a TG level ≥ 151
mg/dL).
5)
Follow-Up of Drug Therapy
Q3. Do we need to perform blood test regularly after initiating drug therapy?
It is advisable to perform regular blood testing after initiating drug therapy. Test
items should be chosen upon consideration of the medications administered and the
patient's background. (Recommendation level B).
Following drug therapy initiation, symptoms associated with adverse drug reactions
should be monitored, and it is also advisable to perform regular blood testing two
to three times within the first 6 months and once every 3–6 months thereafter. The
blood test results will allow for the review of drug effects, dose adjustment, confirmation
of adverse reactions and lifestyle guidance. The tests to be performed in addition
to lipid tests should be selected taking the patient's background and the medications
used into consideration; these tests include liver function tests (AST, ALT, and γGT),
muscle enzyme tests (CK), renal function tests (BUN and Cre) and blood glucose-related
tests (HbA1c and blood glucose level). Because it is usually very rare to detect serious
complications in a timely manner from regular tests, there have been reports insisting
that testings before drug administration and upon the appearance of symptoms are sufficient.
However, regular blood testing is likely to help build a good patient-physician relationship
and inhibit cardiovascular events because of better drug adherence.
Adverse reactions caused by statins (rhabdomyolysis, liver failure, etc.) are extremely
rare if statins are not used in combination with fibrates and other drugs which affect
statin metabolism. In a meta-analysis of 21 RCTs
700) and in another meta-analysis of 30 RCTs
701), the incidence rate of muscles-related adverse reactions with statin use was
not found to be significantly different from that with a placebo. Furthermore, although
the doses are much different from those in Japan, it has been suggested that a high
statin dose, old age, small physical build, and female gender are risk factors for
adverse reactions in Western countries
702–705). It is also shown that adverse reaction develops often within 6 months after
starting the medication
706, 707). Post-marketing surveys in Japan have shown the same trend. We also have
to keep in mind that if the liver enzyme and muscle enzyme levels are found to be
elevated or abnormal, causes other than statins (such as an increase in the liver
enzymes and muscle enzymes because of fatty liver and exercise, respectively) must
be excluded
704). Moreover, although it has been suggested that the risk for diabetes increases
with statin use by 9–13%, meta-analyses of large-scale RCTs suggest that incidence
frequency is low (approximately one to two cases per 1,000 patients per year)
708–710). Furthermore, it has been suggested that diabetes incidence increases in
individuals already at a high risk for diabetes (e.g., the elderly, those with metabolic
syndrome and impaired glucose tolerance)
708, 711). There have been three confirmed cases of diabetic ketoacidosis or hyperosmolar
hyperglycemic nonketotic syndrome in Japan for all statins; however, two of the cases
were already under diabetes treatment, and the remaining case would have been slowly
progressive type 1 diabetes.
Elevation in creatinine levels resulting from fibrates administration is usually mild
and reversible; however, in some cases, creatinine levels may become abnormally high,
thus we always need pay attention. When administering nicotinic acid derivatives (NA),
an increase in the blood glucose level and the development of diabetes from metabolic
syndrome should be taken into account; however, these conditions can be treated and
avoided with appropriate therapy and attention. Caution should be taken when using
fibrates and NA in combination with statins as this can easily bring about liver and
muscle adverse effects
712).
6)
Combination Therapy with Other Agents to Prevent Atherosclerosis
Q4. Does statin use in combination with drugs metabolized by CYP increase the incidence
rate of adverse reactions?
Because many cases of rhabdomyolysis caused by the combined use of hydrophobic statins
and CYP-metabolized drugs have been reported, it is advisable to pay thorough attention
to the adverse reactions that appear when using these drugs concomitantly. (Evidence
level 4, recommendation level A).
Xenobiotic substances, such as statins, are metabolized in the liver by the cytochrome
(CYP) P450 protein. Among the statins, many hydrophobic statins are CYP substrates,
such as CYP3A4 and CYP2C9. Such statins are metabolized by CYP and subsequently excreted.
Pravastatin is a hydrophilic statin that is barely metabolized by CYP, whereas rosuvastatin
is slightly metabolized by CYP2C9.
Drugs such as antifungal agents (fluconazole, itraconazole, etc.), macrolide antibiotics
(erythromycin, clarithromycin, etc.) and protease inhibitors used to treat HIV are
known to be CYP substrates. Drugs used in the fields of cardiovascular medicine and
metabolism, namely calcium antagonists, warfarin, nateglinide, and glimepiride, are
also CYP substrates. The use of these drugs in combination with statins may cause
adverse events because of the intensified effects and increased drug levels in the
blood. Some macrolide antibiotics, antifungal agents, protease inhibitors, and bergamottin
contained in grapefruit juice, exert an inhibitory effect on CYP, and using them in
combination with statins may increase statin levels in the blood. It has also been
recently shown that the combined use of statins with CYP-inducing drugs, such as rifampicin
and barbiturates, may decrease the effects of statins. Statins and the main metabolic
and cardiovascular drugs metabolized by CYP are shown in
Table 10
.
Table 10.
Statins and Cardiovascular and Metabolic Drugs Metabolized by CYP
CYP
Statin(s) metabolized
Cardiovascular and metabolic drug(s) metabolized
CYP3A4
Atorvastatin Simvastatin
Calcium antagonists (diltiazem, verapamil, nifedipine, amlodipine, cilnidipine, azelnidipine,
and benidipine), warfarin, and repaglinide*
CYP2C9
Fluvastatin Rosuvastatin
Angiotensin receptor blockers (ARB) (losartan, valsartan, candesartan, Irbesartan,
and azilsartan), warfarin, glinides (nateglinide and mitiglinide), and glimepiride
*
Repaglinide is mainly metabolized by CYP2C8, but CYP3A4 is also sometimes involved.
It has been reported that the AUC of the blood statin levels increases when they are
used in combination with drugs that are CYP substrates
713). However, a search for reports published between 1990 and the present did not
produce any that have investigated whether the adverse reactions intensify with this
drug combination. Nonetheless, many cases of rhabdomyolysis resulting from statin
use in combination with CYP substrates have been reported
714). Although it involved only a small number of patients, one report from overseas
revealed that the combined use of atorvastatin and ezetimibe in patients who were
undergoing anticoagulation therapy for atrial fibrillation had their doses stabilized
in approximately 3 months and did not experience an increase in the incidence of complications
such as hemorrhage
715) These findings were demonstrated despite the need to slightly decrease anticoagulant
dose in the treatment group.
In addition to CYP, hypolipidemic agents are also influenced by transporters such
as the breast cancer resistance proteins, organic anion transporter protein B1 (OATP1B1),
organic anion-transporting poly-peptide-C (OATP-C), and P-glycoprotein. Even for rosuvastatin,
a water-soluble statin, coadministration with cyclosporine is contraindicated as concomitant
use increases rosuvastatin levels in the blood. This is because transporters of hepatocytes,
such as the breast cancer resistance proteins and OATP1B1, are thought to be inhibited
by cyclosporine, thereby causing a decrease in drug uptake by the hepatocytes.
Q5. Is the use of compound drugs in hyperlipidemia therapy effective in improving
serum lipid levels and preventing the incidence of atherosclerotic cerebrovascular
and cardiovascular diseases?
Although the use of compound drugs has been reported to increase the adherence to
medication compared to prescribing each drug separately, there are no reports of compound
drugs being more effective in preventing ASCVD incidence or at changing the serum
lipid levels. (Recommendation level: B).
Many compound drugs are being used in the metabolic and cardiovascular drug categories
to decrease the burden of taking medicines for the elderly and to improve adherence.
In addition to those made up of multiple hypertensive agents or hypolipidemic agents,
compound drugs containing hypolipidemic agents and other drugs are also available.
For example, a compound drug made up of atorvastatin and amlodipine, a calcium antagonist,
is being used in Japan. In other countries, compound drugs consisting of statins and
DPP4 inhibitors are also being used. The use of compound drugs not only enhances patient
QOL but also adherence to medication, which may lead to improved serum lipid levels
and decrease CVD incidence. A report overseas found that a calcium antagonist–statin
compound drug significantly improved serum lipid levels and better controlled blood
pressure compared to placebo
716). However, there are no reports of comparisons between the administration of a
compound drug and the administration of the various drugs separately. In regard to
CVD incidence, there are similarly no reports in which the effects of prescribing
a compound drug were compared to those of drugs prescribed separately.
It has been reported that compound drugs improve patient adherence to medication compared
to prescribing the drugs separately
717). The maintenance of adherence is greatest when a single medication is added for
patients who take only one drug orally
718). Although the preventive effects on CVD have not been shown, the use of compound
drugs is likely beneficial considering Japan's currently aging society, improvement
of adherence, patient convenience, and healthcare economics.
7)
Adherence
Q6. What are the factors that affect adherence?
Adherence to hypolipidemic agents is low in individuals aged < 50 years, ≥ 70 years,
women, and low-income earners. Adherence is high in patients who have a CVD history.
It has been suggested that frequent lipid testing, low copayment, and the use of generic
drugs are associated with an increase in adherence.
As with other therapeutic agents, adherence decreases as the number of doses per day
increases. (Evidence level: 2)
Meta-analyses conducted overseas have demonstrated that adherence to oral statins
differs according to factors, including age, gender, income, and whether other treatments
are being implemented for comorbid disease. Women and low-income earners have been
shown to have low adherence rates. In individuals aged < 50 years or ≥ 70 years, the
adherence was low, with a “U-shaped” distribution. Secondary-prevention patients who
have a CAD history showed high adherence, whereas primary-prevention patients showed
low adherence. There have been many reports indicating that adherence is also high
in patients receiving treatment for hypertension or diabetes. The frequency of lipid
testing and low cost to the patient has also been shown to be associated with good
adherence
719). In addition, there are differences in adherence between drugs. It is known that
the adherence to anionexchange resins is particularly low, whereas the adherence to
fibrates, omega-3-acid-ethyl esters, and nicotinic acid derivatives is lower than
that to statins
720).
Lipid level improvement and CVD prevention are not likely to occur if the patient
does not actually take the drugs prescribed. The adherence to medication is high in
clinical studies and trials because of strict dosing management by study coordinators,
but adherence is lower in actual clinical practice (Table 11), and high discontinuation
rates have been reported overseas.
Table 11.
Adherence to Statins Reported Outside of Japan
719)
Name of Country
Sample Size
Adherence Rate
Reference
United States
19,422
1 year: 30% 2 years: 20% 3 years: 25%
728)
United Kingdom
6,262
1 year: 66% 5 years: 75% 10 years: 68%
729)
United States
4,776
6 months: 80% 1 year: 74% 2 years: 65% 3 years: 61%
730)
United States
34,501
3 months: 79% 6 month: 56% 1 years: 50% 10 years: 42%
731)
Adherence Rate: PDC [No. of prescription days/observation period × 100 (%)]
Adherence is associated with the preventive effects of CVD. In a retrospective cohort
study on statins conducted overseas, the 4–5-year mortality rate in the group that
had a high ≥ 90%) adherence rate was 45% lower than the group with a low (< 10%) adherence
rate
721). Likewise, in Japan's JELIS study, the group of secondary prevention patients
who achieved an adherence rate of 80% had significantly fewer primary endpoints consisting
of sudden cardiac death and fatal/nonfatal myocardial infarction compared to the group
that did not
722).
To improve drug adherence, guidance on lifestyle modification, such as diet and exercise
therapy, should be provided to individuals who have low adherence, namely women, young
individuals, the elderly, and primary prevention patients. Moreover, medical professionals
must make an effort thoroughly explain the association between dyslipidemia and CVD
incidence to patients, as well as aid patient understanding of the purpose of their
treatment. It is advisable for other members of the medical team, such as nurses and
pharmacists, to also provide regular explanations to patients regarding the importance
of taking their medicine. In a recent comparative study, the study group that met
with a pharmacist regularly had a lower discontinuation rate than the group that did
not
723). Discontinuation often occurs 1–2 years after treatment initiation; however,
the discontinuation rate is known to decrease after that
724). For this reason, to prevent discontinuation, it is particularly important to
repeatedly explain the need for treatment to patients in the 1–2 years after treatment
initiation. Regular lipid testing has also been reported to help increase adherence
719).
It is known that the adherence to medication decreases when the number of daily doses
increases
725, 726). Therefore, when writing prescriptions, physicians should try to keep the
number of doses as low as possible. In addition, the timing of medication doses (e.g.
before or after meals) should not be confusing for the patient. The use of compound
drugs has been known to increase adherence compared to prescribing drugs separately
717); hence, the use of compound drugs should be considered for patients who require
multiple drugs. A low copayment for the drugs is also associated with adherence. A
cohort study conducted in the United States compared patients who were prescribed
name-brand statins to those prescribed generic statins. It was found that patients
who were prescribed generic statins not only had better adherence rates than those
who were prescribed name-brand statins but also fewer composite endpoints such as
hospitalization because of ACS and stroke, and all-cause mortality
727).
4.
Managing Major High-Risk Conditions
1)
History of CAD
[Statement]
Even in secondary prevention, the risk for cardiovascular events is high if FH, ACS,
DM, noncardiogenic cerebral infarction, PAD, CKD, and metabolic syndrome are present,
or if there is an overlap in the major risk factors and the presence of smoking. (Evidence
level: Ep-Ib)
In secondary prevention in patients with a history of CAD, the LDL-C control target
should be at a level of < 100 mg/dL. As the risk of ASCVD incidence is high in patients
with FH or ACS, stricter LDL-C management to achieve a level < 70 mg/dL should be
considered. The secondary prevention for DM patients complicated with conditions described
in
Table 3b
, should also be treated based on the target level of FH or ACS, as they are considered
to be at high risk of recurrence of CAD.
i)
Familial Hypercholesterolemia (FH)
It has been reported that the cumulative LDL-C (total LDL-C from the time of birth)
plays a role in cardiovascular incidence
732). In addition, observational studies have reported that LDL-C-lowering therapy
using statins decreases cardiovascular event risk
733), and delays the age of incidence of these events
734). From an ethical viewpoint, it is difficult to conduct randomized comparative
studies involving secondary prevention patients with FH. However, based on the findings
that patients with early-incidence CAD have are more likely to have FH
735, 736), and that FH patients have a higher risk of CAD recurrence than non-FH patients
737), it is recommended that the LDL-C level be controlled at a stricter level (as
much as possible to LDL-C < 70 mg/dL) in FH patients
738).
ii)
Acute Coronary Syndrome (ACS)
Patients who have experienced ACS have a higher risk of recurrence for cardiovascular
events than patients with stable CAD. The OACIS-LIPID study in Japan investigated
the effect of early administration of statins on suppressing cardiovascular events
in patients with acute myocardial infarction
739). The study showed an incidence rate of 40/1,000 person-years for all-cause mortality
and nonfatal myocardial infarction in the group that underwent lipid-lowering therapy
using drugs other than statins. However, at 30/1,000 person-years, the incidence rate
of cardiovascular events was also remarkably high in the group that received statins.
In the PACIFIC study
740), which was a multicenter observational registry study on ACS, the incidence rate
of fatal and nonfatal myocardial infarction was high, at 35/1,000 person-years, despite
approximatively 80% subjects being administered statins.
Meanwhile, it has been reported that providing LDL-C-lowering therapy at an early
stage following ACS incidence is effective in suppressing cardiovascular events
741), and that stricter LDL-C-lowering therapy suppresses cardiovascular events significantly
more than conventional LDL-C-lowering therapy
742). Regarding the LDL-C management target, the IMPROVE-IT
636) study revealed that lowering the LDL-C level to 53.6 mg/dL using statin–ezetimibe
combination therapy suppressed cardiovascular events by 6.4% more than the group that
had their LDL-C level controlled at 69.5 mg/dL with statins only. In meta-analyses
of RCTs in which statins were administered within 14 days after ACS, cardiovascular
events shown to be significantly suppressed after ≥ 2 years
743). However, these preventive effects were not able to be proven in a shorter observational
period of 4 months
744).
The effectiveness of early LDL-C-lowering therapy for patients with ACS has been studied
in Japan by observing the coronary plaques using intravascular ultrasound (IVUS).
In the ESTABLISH study
642), strict LDL-C-lowering therapy was administered early after ACS. The therapy
decreased the average LDL-C level to 70 mg/dL after 6 months, which resulted in a
13.1% decrease in plaque volume. Moreover, it was reported that the change in plaque
volume showed a significant positive correlation with the post-treatment LDL-C level
and the rate of decrease in the LDL-C level. Additional cases were added and follow-up
surveys (completed an average of 4.2 years later) were conducted in the same study.
The results of the follow-up surveys revealed that starting a strict LDL-C-lowering
therapy at an early stage significantly suppressed cardiovascular events
745). In JAPAN-ACS
643), it was similarly demonstrated that the early initiation of a strict LDL-C-lowering
therapy using statins for patients with ACS suppresses plaque progression. However,
no significant relationship was demonstrated between the rate of decrease in the LDL-C
levels, or in the post-treatment LDL-C level and the rate of plaque regression. It
was reported in the recent PRECISE-IVUS study that decreasing the LDL-C level to <
70 mg/dL using a combination of statin and ezetimibe resulted in a marked plaque volume
regression in patients with ACS, compared to those who were treated with statins only
645). In recent years, the development of vascular imaging techniques other than IVUS
has made it possible to assess the characteristics of plaques, and the association
of these characteristics with clinical events is also being studied
746–748).
iii)
Diabetes Mellitus (DM)
For patients with a myocardial infarction history, it has been reported that the risk
of recurrence of cardiovascular events increases with the presence of diabetes
137, 749–751). Epidemiological studies in Japan involving subjects with CAD have also
revealed that diabetic patients have a high risk for all-cause mortality and cardiovascular
events
138, 182, 752). Likewise, in the analysis of the J-LIT study on patients with CAD,
it was shown that the presence of diabetes causes the relative risk for cardiovascular
events to increase by approximately 2.5-fold
173).
According to a meta-analysis by the Cholesterol Treatment Trialists' (CTT) Collaboration,
the effects of LDL-C-lowering therapy using statins on cardiovascular event are equal
regardless of whether the patient had diabetes
751). In the sub-analysis of the TNT study, which involved subjects with CAD complicated
with diabetes, treatment using a high statin dose significantly suppressed cardiovascular
and cerebrovascular events by 25% and 31%, respectively, compared to treatment using
the usual statin dose
753).
A meta-analysis of clinical studies using IVUS, which has been implemented overseas,
reported that diabetes was an independent risk factor in cases where the coronary
plaques were found to be progressing, regardless of whether their LDL-C levels had
been decreased to ≥ 70 mg/dL with treatment
754). It has been demonstrated that coronary plaque volume progression, the incidence
rate of cardiovascular events, and the post-treatment LDL-C level show a significant
positive correlation with one another. This suggests the importance of a stricter
LDL-C-lowering therapy if CAD is complicated with diabetes. The sub-analysis of JAPAN-ACS
755), a study conducted in Japan involving patients with ACS, showed that the presence
of diabetes posed a strong negative risk on plaque regression. Even if the LDL-C level
is controlled to the same extent as that of nondiabetic patients, the rate of plaque
regression in diabetic patients is markedly low. However, this study also reported
that significant plaque-regressing effects can be achieved if the LDL-C level is controlled
at < 75 mg/dL
756). Furthermore, the ZEUS study, despite being small-scale, reported that strict
LDL-C-lowering therapy using statins and ezetimibe in combination is useful for regressing
plaques in CAD complicated with diabetes
644).
iv)
Noncardiogenic Cerebral Infarction
ASCVD that occurs with atherosclerosis as an underlying basis, such as CAD, cerebrovascular
diseases, and PAD, are mutually high-risk conditions for vascular complications. It
was demonstrated in the REACH registry, a registry study on patients with ASCVD or
overlapping risks factors for ASCVD, that approximately 16% registered cases are complicated
with two or more ASCVD
757). A comparison between the database of the Texas Heart Association in the United
States and CREDO-Kyoto study, a registry study that involved subjects who had undergone
coronary revascularization in Japan, showed a significantly higher rate of complication
with cerebrovascular diseases in Japan (16.4% vs. 5.0%). However, it was confirmed
that the complication of cerebrovascular disease is a high-risk condition for cardiovascular
event in both Japan and the United States
752).
Results of secondary prevention studies on CAD conducted in western countries, such
as 4S, LIPID, and CARE, have revealed a high risk for the recurrence of cerebrovascular
and cardiovascular events in patients with CAD who have a cerebrovascular disease
history. However, it has been reported that LDL-C-lowering therapy using statins suppresses
the risk for recurrence of both cerebrovascular and cardiovascular events
758–760).
v)
Peripheral Arterial Disease (PAD)
In the comparison between the aforementioned database of the Texas Heart Association
in the US and CREDO-Kyoto study in Japan, it was confirmed that PAD is a high-risk
condition for cardiovascular event in both Japan and the US
752), though the complication rate of PAD was significantly higher in the US.
Patients with PAD who have a CAD history are at extremely high risk for total mortality
and fatal cardiovascular events
761–767). There are no reports of lipid intervention studies involving subjects with
PAD complicated by CAD. However, in the sub-analysis of IDEAL, a study that involved
subjects with myocardial infarction complicated with PAD, it was reported that an
LDL-C-lowering therapy using a high statin dose significantly suppressed cardiovascular
events compared to a moderate statin dose
767). It was also confirmed that the therapy prevented the new incidence of PAD by
30% in cases that were not already complicated with PAD.
A meta-analysis of clinical studies in which coronary plaque progression was analyzed
by IVUS showed that the inhibition of the progression and plaque regression is observed
when the LDL-C level is controlled at < 70 mg/dL, regardless of the presence or absence
of PAD. Thus, strict LDL-C lowering therapy in patients with PAD expect to suppress
CAD events because plaque regression has been shown to be associated with fewer cardiovascular
events
768).
vi)
Chronic Kidney Disease (CKD)
Stratified analyses of the eGFR have been performed in long-term observational studies
involving subjects with ACS and on post-PCI patients. The results of these studies
have found that, compared to patients with normal renal function, the risk for cardiovascular
events, including cerebrovascular disease, cardiac death, and total mortality increases
by 2–3-fold in those with CKD even when the CKD is mild. It has been reported that
the risk increases in association with the severity of the disease
740, 769, 770). In addition, according to the observational CREDO-Kyoto study, the
risk for cardiovascular death is 2.9-fold higher for post-PCI patients with CKD, and
the risk for total mortality increases by 2.1-fold
183). In particular, patients aged ≥ 55 years have a 3.7-fold increased risk for cardiovascular
events, including cerebrovascular diseases
174). Furthermore, patients with CKD and a serum creatinine level ≥ 2.0 mg/dL were
found to have a 7.0-fold increased risk for total mortality. This suggests that the
risk for cardiovascular events increases markedly with the presence of CKD in patients
who have undergone PCI
752).
For patients with CKD complicated with CAD, the preventive effects of lipid-lowering
therapy on cardiovascular events have been investigated in post hoc analyses of early-stage
secondary prevention studies using statins. These analyses have reported that statin
use suppresses cardiovascular events in patients with mild CKD and an eGFR < 75 mL/min/1.73
m2 771, 772). However, suppressive effects on cerebrovascular diseases were not demonstrated.
Furthermore, post hoc analyses of secondary prevention studies have shown that high-dose
statin treatment decreases cardiovascular event significantly, by approximately 30%,
in patients with moderate CKD compared to the usual dose
773, 774). In CREDO-Kyoto PCI/CABG Registry Cohort-2, a secondary-prevention cohort
study on CAD in Japan, patients with mild CKD and an eGFR of 30–60 mL/min/1.73 m2
who took oral statins had a significantly lower incidence rate of major cardiovascular
events. The incidence rate of cerebrovascular disease was also significantly lower
in patients who were taking oral statins
775). However, similar effects were not seen in patients with severe CKD whose eGFRs
were < 30 mL/min/1.73 m2 or in patients undergoing hemodialysis.
vii)
Metabolic Syndrome and an Overlap of Major Risk Factors
The results of a meta-analysis of 87 clinical studies have shown that the presence
of metabolic syndrome results in an added risk for total mortality, coronary events,
and cerebrovascular events for patients with CAD
327).
A sub-analysis was performed with just those complicated by metabolic syndrome among
all the subjects with CAD in the TNT study, and it was shown that an overlap of the
major risk factors poses a risk for cardiovascular events. The incidence rate of cardiovascular
events is particularly high in cases where three or more major risk factors are present.
However, it has been shown that cardiovascular event is significantly suppressed by
29% with high-dose statin therapy compared to a usual-dose statin therapy
776).
JCAD observational study in Japan also revealed that if three or more major risk factors
are present, the risk for cardiovascular events is 1.3-fold higher compared to having
two or fewer risk factors
182). In a study where patients who underwent PCI were followed up with for a long
period, the relative risk for cardiovascular events in those with metabolic syndrome
was 2.1-fold higher
777). However, statin administration resulted in a significant decrease in total mortality
by 44% and in coronary death by 47%
778).
viii)
Smoking
In patients with CAD who continue to smoke, the risk of recurrence of cardiovascular
events is higher than that observed in nonsmokers. The total mortality, cardiac death,
and sudden cardiac death risks are also significantly higher
779–783). In the REACH Registry, a registry study on patients with ASCVD, CAD, cerebrovascular
diseases, and PAD or overlapping risks factors for ASCVD, the incidence rate of cardiovascular
events in patients who continued to smoke was approximately 1.3-fold higher than that
observed in lifelong nonsmokers
784). In the OACIS study, even after adjusting for age, gender, DM, hypertension,
dyslipidemia, and therapeutic agents, the risk for total mortality in post-myocardial
infarction patients who continued smoking was 2.3-fold higher than in lifelong nonsmokers.
In contrast, the total mortality risk in patients who quitted smoking after myocardial
infarction incidence decreased to the same level as the nonsmokers. Compared to those
who continued smoking, the total mortality risk of patients who quitted smoking decreased
significantly by 61%
785). Many epidemiological studies have reported that regardless of age and gender,
the risk of recurrence of cardiovascular events decreases by approximately half after
the first year of smoking cessation and continue to decrease thereafter. Such studies
have also reported that the risk further decreases to almost the same level as that
of the lifelong nonsmokers approximately 10 years after smoking cessation
779–786).
On the basis of a composite analysis of secondary prevention studies, TNT and IDEA
787), and the post hoc analysis of the GREACE study
788), even with a strict LDL-C-lowering therapy using statins, the risk for cardiovascular
events is higher in patients who continue smoking than in lifelong nonsmokers or the
ex-smokers. Therefore, providing guidance on smoking cessation to patients who continue
to smoke is extremely important.
2)
Diabetes Mellitus (DM)
[Statement]
Not only hyperglycemia but also dyslipidemia and hypertension should be comprehensively
controlled soon after the onset of diabetes. (Evidence level: 1, recommendation level:
A)
More strict control of LDL-C should be considered among diabetic subjects with FH,
noncardiogenic cerebral infarction, PAD, microvascular complications (retinopathy
and nephropathy), metabolic syndrome, continuation of poor glycemic control, an overlap
of major risk factors of ASCVD, or smoking. (Consensus, recommendation level: A)
i)
Prevention and Treatment of ASCVD in Patients with DM
a)
Risk Factors for ASCVD
It has been reported that LDL-C, HDL-C, and HbA1c levels, as well as and systolic
blood pressure are risk factors for CAD, whereas hypertension, male gender, and atrial
fibrillation are risk factors for cerebral infarction
789). However, a study conducted in Japan (JDCS) has suggested that LDL-C and TG levels
are risk factors for CAD, and that systolic blood pressure is a risk factor for stroke
790). Other Japanese studies have reported that smoking, male gender, and high Lp(a)
791) are risk factors for CAD. It is important to manage these risk factors comprehensively
in patients with DM to prevent ASCVD. Lifestyle intervention is especially important
in diabetic subjects with metabolic syndrome. The presence of microvascular complications
such as diabetic nephropathy
792, 793) or retinopathy
794) is a predictive factor for CAD.
b)
Blood Glucose
Meta-analyses have clearly shown that tight blood glucose control leads to the suppression
of ASCVD incidence
795, 796). However, a longer duration of 8–15 years after strict glycemic control
is necessary for the suppression of ASCVD risk
797, 798). There is little evidence showing that tight blood glucose control with
specific drug can suppress the occurrence of ASCVD events. However, recent investigations
reported that the suppression of composite cardiovascular events and cardiovascular
death by SGT2 inhibitors
799), and that the suppressive effects of glucagonlike peptide-1 (GLP-1) receptor
agonists on ASCVD incidence
800, 801). On the other hand, strict blood glucose control increases the risk for
hypoglycemia, and hypoglycemia has been reported to be related to cardiovascular death
in the Japanese
802). Strict blood glucose control must be carefully carried out.
According to the J-EDIT study, a Japanese study that involved elderly subjects, stroke
risk was 2.63-fold higher in the group with HbA1c levels ≥ 8.5% than in the group
with HbA1c levels of 7.0–8.4%. On the other hand, subjects with HbA1c levels < 7.0%
also had a 2.35-fold higher risk. Thus, elderly patients with DM require both hyperglycemia
prevention while avoiding excess strict glucose control
803).
c)
Lipids
Patients with DM are often complicated with hyper-LDL cholesterolemia, hypertriglyceridemia,
and low HDL-C levels. In a meta-analysis including CARDS
804), LDL-C-lowering therapy using statins greatly decreases CAD-related mortality,
CVD, and cerebral infarction in diabetic patients. These effects were similar to those
in nondiabetic subjects
751).
In contrast, it was reported in the FIELD study that fibrates decrease CAD events
in primary prevention
805). In the ACCORD study involving high-risk subjects with DM, the sub-analysis suggested
that the risk for cardiovascular events might be significantly suppressed by adding
fibrate in patients who have hypertriglyceridemia and low HDL-C after statin administration
806). The additional administration of EPA was also reported to significantly decrease
coronary events in Japanese patients who were taking statins for treating hypercholesterolemia
complicated with impaired glucose metabolism
807). Furthermore, CVD risk decreases significantly because of a decrease of LDL-C
level from 94 mg/dL to 54 mg/dL when statins and ezetimibe are used for treatment
in patients with ACS. The effects were evident especially in patients with DM
808).
d)
Blood Pressure
Elevated blood pressure leads to an increased risk of ASCVD in DM subjects
809). In meta-analyses, blood pressure-lowering therapy was found to decrease risk
of cerebrovascular diseases
810). However, risk reduction of CAD has only been observed in subjects with hypertension
before treatment initiation
811), which indicates that the effects are limited for CAD prevention. Angiotensin-converting
enzyme inhibitors
812), angiotensin Ⅱ receptor blockers
813), and calcium channel antagonists
814) have been reported to be effective for preventing cardiovascular events in patients
with DM.
e)
Comprehensive Risk Management
Early comprehensive management of risk factors, such as hyperglycemia, hypertension,
dyslipidemia, smoking habit, and visceral fat obesity, is important in prevention
of ASCVD among diabetic subjects
815, 816). Lifestyle modification such as diet therapy
817), increasing physical activity
818), and smoking cessation
819) are important, but there is no evidence that lifestyle modifications alone decrease
the risk of ASCVD in patients with DM
820, 821). Several studies have suggested that a comprehensive and intensive therapy
for the risk factors, combined with lifestyle modification and drug therapy, has a
protective effect on ASCVD. These findings have also been reported in Japan
822, 823).
The ADA has recommended that aspirin use for the primary ASCVD prevention should be
considered
824) for high-risk men and women aged ≥ 50 years. However, the JPAD studies conducted
in Japan did not show any protective effects of aspirin on cardiovascular events in
patients with DM
825, 826).
ii)
LDL-C control for ASCVD prevention
a)
Lipid Management for Primary Prevention
Recently published US guidelines did not refer definitive achievement goals of plasma
lipids, but recommended statin administration without monitoring of lipid levels during
the course of therapy
827). However, in the ESC/EAS guidelines, LDL-C level < 100 mg/dL is recommended as
the primary target for patients with type 2 DM
828). In Japan, the use of JAS guidelines for control of plasma lipids in diabetic
subjects has been recommended
829).
There are only a few studies involving Japanese patients with DM; however, a TG level
< 150 mg/dL and a HDL-C level ≥ 40 mg/dL are recommended as targets regardless of
the presence or absence of DM. The target for the primary prevention of CAD is < 120
mg/dL for LDL-C and < 150 mg/dL for non-HDL-C. Some clinical conditions in patients
with DM have been shown to have CAD risk. These conditions include the following:
(1) FH; (2) noncardiogenic cerebral infarction
830), (3) PAD
830); (4) microvascular complications (retinopathy, nephropathy, etc.)
792, 794, 831–833); (5) persistently poor glycemic control
143, 795, 834); (6) metabolic syndrome-related complications (visceral obesity)
835); (7) overlap of major risk factors
836, 837); and (8) smoking
836).
Table 12.
Diabetic Patients at Higher Risk for Developing CAD
Familial hypercholesterolemia (FH)
Noncardiogenic cerebral infarction
Peripheral arterial disease (PAD)
Microvascular complications (retinopathy, nephropathy, etc.)
Persistent poor glycemic control
Metabolic syndrome
Overlap of major risk factors
Smoking
Although all primary prevention patients with DM should predict LDL-C level < 120
mg/dL, patients who have any of the above listed characteristics should implement
stricter management (i.e., compulsory achievement of the target value). Furthermore,
diabetic patients with FH or more than one of above eight characteristics are at extremely
high ASCVD risk, the targets of secondary prevention should be considered.
In the CTT study, it was reported that decreasing LDL-C level by 38.7 mg/dL using
statins, cerebrovascular disease risk in DM patients is decreased by 21%. Thus, it
is likely that control of LDL-C is effective for the prevention of cerebrovascular
disease same as CAD prevention
838).
b)
Lipid Management for Secondary Prevention
Regardless of the presence or absence of DM, LDL-C level < 100 mg/dL and non-HDL-C
level < 130 mg/dL are recommended. Secondary-prevention of CAD in diabetic patients
shows a high rate of recurrence
137–139, 839), and it is difficult to achieve plaque regression in patients with DM
even with the recommended control of LDL-C-lowering therapy
840). In addition, DM has been reported to be the most important risk factor for CAD
recurrence in the Japanese
841). Thus, it is reasonable to set an LDL-C level of < 100mg/dL as the compulsory
target in secondary prevention for patients with DM
842). As mentioned in CQ20, among secondary prevention cases with diabetes complicated
with risk factors such as noncardiogenic cerebral infarction, PAD, CKD, metabolic
syndrome, overlap of major risk factors or smoking habit have a more higher risk of
recurrence. Thus, it is reasonable to control of LDL-C as the same target level of
FH or ACS, by achieving LDL-C level of < 70 mg/dL
754, 756).
3)
Cerebrovascular Disease
[Statement]
Statin therapy may prevent the development of cerebral infarction. (Evidence level:
2, recommendation level: A)
i)
Frequency
Cerebrovascular disease is classified into three types (cerebral hemorrhage, cerebral
infarction, and subarachnoid hemorrhage). According to the 2015 Stroke Data Bank,
the cerebrovascular disease incidence in Japan is reported to be approximately 18.5%
for cerebral hemorrhage, approximately 5.6% for subarachnoid hemorrhage, and 75.9%
for cerebral infarction
842). Compared to the cerebrovascular disease incidence in western countries, the
cerebral hemorrhage incidence in Japan is higher whereas the cerebral infarction incidence
is relatively low
843).
Cerebral infarction is further classified into three clinical types (lacunar infarction,
atherothrombotic cerebral infarction, and cardiogenic cerebral embolism). In the Hisayama
study, lacunar infarction accounted for approximately 50% cases of cerebral infarction,
whereas the incidence rates of atherothrombotic cerebral infarction and cardiogenic
cerebral embolism were just under 30% and just over 20%, respectively
844). The J-MUSIC study published in 2,000 saw a change in the incidence rates, with
a 38.8% rate for lacunar infarction, a 33.3% rate for atherothrombotic cerebral infarction,
and a 21.8% rate for cardiogenic cerebral embolism
845). The numbers were also different in the 2015 Stroke Data Bank, with an incidence
rate of 31.2% for lacunar infarction, 33.2% for atherothrombotic cerebral infarction,
and 27.7% for cardiogenic cerebral embolism
842). Cerebral infarction incidence in the western Caucasian population has been reported
to be approximately 30% for both lacunar infarction and atherothrombotic cerebral
infarction, and approximately 40% for cardiogenic cerebral embolism
846). It has been reported that in Japan, the number of cases of lacunar infarction
is decreasing whereas the number of cases of cardiogenic cerebral embolism is increasing.
ii)
Risk Factors for the Development of Cerebrovascular Disease
The results of NIPPON DATA80 indicate that the factors affecting mortality rate of
cerebrovascular disease in the Japanese are age, systolic blood pressure, smoking,
and hyperglycemia. Lipid levels, such as the TC level, are not recognized as risk
factors
50). Similarly, the consolidated results of 61 observational studies conducted in
western countries (approximately 0.9 million subjects) found no relationship between
the TC level and the mortality rate of cerebrovascular disease
847). The results of a meta-analysis of 18 cohort studies in Japan and China showed
that blood pressure is the most important risk factor for cerebrovascular disease,
and that the TC level has much less involvement than blood pressure
848).
In terms of the individual cerebrovascular diseases, studies have clearly revealed
that hypertension is a risk factor for cerebral hemorrhage, and that hypertension,
smoking, alcohol, and the presence of cerebral aneurysm are the major risk factors
for subarachnoid hemorrhage. With respect to cerebral infarction, the major risk factors
for cardiogenic cerebral embolism are hypertension and cardiac thrombi
849, 850).
A study of the risk factors for noncardiogenic cerebral infarction only revealed that
in the 2015 Stroke Data Bank, the dyslipidemia incidence in patients with noncardiogenic
cerebral infarction is 40–50%, a number that has been increasing in recent years
842). However, the results of epidemiological studies conducted in Japan have indicated
that there is no significant relationship between the serum cholesterol levels (TC,
LDL-C, and non-HDL-C) and the incidence rate of noncardiogenic cerebral infarction
36, 38, 40, 57, 64, 78, 337). In western countries, epidemiological studies such as
MRFIT have reported that an increased TC level is associated with an increased risk
for cerebral infarction
851–853). Furthermore, the consolidated results of nine cohort studies indicated that
cerebral infarction incidence is significantly decreased by 15% in patients with a
decrease of 1 mmol/L (38.6 mg/dL) in the LDL-C level
854). Similarly reported in the result from a meta-analysis of 21 large clinical trials
by CTT Collaboration, stroke incidence is decreased by 15% and cerebral infarction
incidence is decreased by 20% in patients with a decrease of 1 mmol/L (38.6 mg/dL)
in the LDL-C level
177). On the contrary, some reports have stated that the TC level is either not a
risk factor for cerebral infarction or has very little involvement
855, 856).
The results of the Hisayama study, which investigated cerebral infarction risk by
type, demonstrated that the LDL-C level is a risk factor for atherothrombotic cerebral
infarction. However, the LDL-C level is not related to the incidence of other types
of cerebral infarction
36). Furthermore, the Hisayama study reported that blood pressure has a strong effect
on lacunar infarction, atherothrombotic cerebral infarction, and, in women, cardiogenic
cerebral embolism
857). Reports published in various other countries have also indicated that the major
risk factor for cerebral infarction, including cardiogenic cerebral embolism, is hypertension
855). Thus, cholesterol level is recognized to be a risk factor only for atherothrombotic
cerebral infarction, whereas hypertension is considered to be the major risk factor
for all types of cerebral infarction, including atherothrombotic cerebral infarction
849).
Many reports, including those from Japan, have stated that hypocholesterolemia is
a risk factor for cerebral hemorrhage
40, 858). According to a meta-analysis of cohort studies, a decrease of 1 mmol/L (38.6
mg/dL) in the cholesterol level increases the cerebral hemorrhage incidence by 19%
854). In Japan, an LDL-C level of 80 mg/dL or less has also been reported to increase
the cerebral hemorrhage incidence
40). However, as described later, the results of a meta-analysis of prevention studies
on CAD did not indicate that cholesterol-lowering therapy leads to an increased cerebral
hemorrhage incidence
348).
There have been many reports, including those from Japan, stating that the lower the
HDL-C level, the higher the incidence rate of cerebral infarction
46, 859–861).
Many reports have also indicated that there is no clear relationship between the TG
level and cerebrovascular disease
856, 862, 863). However, the results of a meta-analysis of epidemiological surveys
conducted in the Asia-Pacific region, in which the fasting TG level was divided into
four groups, reported that the group of patients with the highest TG levels had a
50% higher risk of ischemic stroke compared to the group with the lowest TG levels
87). Furthermore, the results of cohort studies involving approximately 14,000 subjects
reported that ischemic stroke incidence increases in both men and women when postprandial
hypertriglyceridemia is present
864). These results indicate that a 1-mmol/L (88.5 mg/dL) increase in the postprandial
TG level increases ischemic stroke risk by 15%.
iii)
Lipid-Lowering Therapy and Cerebrovascular Disease
Although it has been established that statins are important in preventing stroke incidence,
there are still relatively few studies that have investigated their use for stroke
recurrence prevention. Stroke is investigated as a secondary endpoint in most studies.
The results of a meta-analysis of prevention studies conducted in the western counties
showed that cholesterol-lowering therapy using statins significantly decreased cerebral
infarction incidence by 19%. On the other hand, cerebral hemorrhage incidence did
not change significantly
348). It remains unclear as to why the statin administration decreases cerebrovascular
disease in observational studies given the fact that the cholesterol level is not
recognized as a risk factor for cerebrovascular disease.
There are two studies in which the recurrence of stroke was the primary endpoint:
the SPARCL
865) study and the J-STARS
619) study. In SPARCL, high doses of statins were administered to subjects who had
no CAD with a stroke or transient ischemic attack (TIA) history within 6 months following
the incidence. The recurrence rate of stroke in these subjects was compared with that
of subjects who received a placebo, and the results revealed that apart from a significant
decrease in the recurrence of stroke (−16%, p = 0.03), the incidence rate of CAD was
also significantly lower (− 35%, p = 0.003). A post hoc analysis found that cerebral
infarction incidence was significantly decreased (hazard ratio 0.78), but that of
cerebral hemorrhage was significantly increased (hazard ratio 1.66). However, it must
be noted that statin dose in this study was much higher than the upper limit approved
in Japan. The J-STARS study involved Japanese subjects with ischemic stroke, excluding
those with cardiogenic cerebral embolism. The results of a comparison between the
pravastatin group and the non-pravastatin group revealed that the former had a significantly
decreased incidence rate of atherothrombotic cerebral infarction (hazard ratio 0.33).
Meanwhile, the incidence rate of intracranial hemorrhage was the same as the non-statin
group (hazard ratio 1.00)
619). In terms of secondary prevention of noncardiogenic cerebral infarction, these
results suggest that statin therapy has suppressive effects on atherothrombotic cerebral
infarction incidence. Moreover, in regard to the results of SPARCL, which are contrary
to those of a meta-analysis
348) in which increased incidence of cerebral hemorrhage because of statin administration
was not observed, it has been shown that hemorrhage incidence does not increase in
the Japanese. However, regarding cerebral hemorrhage risk following cholesterol-lowering
therapy, further preventive studies need to be conducted.
Among the other studies conducted in Japan, the MEGA study, which involved subjects
with no history of CAD or stroke, showed that statin administration tends to decrease
stroke incidence, with hazard ratios of 0.66 (men) and 0.63 (women)
620). In particular, ischemic stroke incidence in men and stroke in women who were
≥ 55 years were significantly decreased
620, 621). The results of a sub-analysis of JELIS showed that treatment with statins
and EPA in patients with a stroke history significantly suppressed the recurrence
of stroke by approximately 20% compared with statin monotherapy
622).
There are also other reports suggesting that the outcome of cerebral infarction that
occurs during the course of treatment with statins is satisfactory
866), and that cerebral infarction risk increases as a result of discontinuing statin
treatment
867).
iv)
Measures to Prevent Cerebrovascular Disease
It is vital to control blood pressure because the greatest risk for cerebrovascular
disease is hypertension. Atrial fibrillation is a major risk factor for cardiogenic
cerebral embolism, and cerebral aneurysm is a significant risk factor for subarachnoid
hemorrhage. Therefore, it is necessary to appropriately manage these risk factors.
The relevant guidelines should be referenced when managing these risk factors
868).
In western countries, based on the results of a meta-analysis, lipid-lowering therapy
is recommended for the prevention of noncardiogenic cerebral infarction
847, 869). In Japan, because the proportion of atherothrombotic cerebral infarction
has been increasing, and that the MEGA study showed that statins are effective in
preventing cerebral infarction, appropriate lipid management should be carried out
in addition to adequate antihypertensive therapy to prevent cerebral infarction. For
the prevention of noncardiogenic cerebral infarction with underlying atherosclerosis,
it is advisable to implement a set of management criteria based on the criteria for
the ischemic heart disease prevention.
5.
Implementation of Comprehensive Risk Assessment and Management
[Statement]
For the prevention of cerebrovascular and cardiovascular diseases, comprehensive management
of the major risk factors, such as dyslipidemia, smoking, hypertension, and DM, should
be carried out as early as possible. (Recommendation level: A)
Lifestyle modification, including diet therapy, exercise therapy, and smoking cessation,
forms the basis of cerebrovascular and cardiovascular disease prevention. It is important
to continue to provide guidance on lifestyle modification even after initiating drug
therapy. (Recommendation level: A)
Cerebrovascular and cardiovascular diseases require multiple types of risk assessment
and management
870). In view of this, 11 academic societies led by The Japanese Society of Internal
Medicine, together with the Japan Medical Association and The Japanese Society of
Medical Sciences, jointly published an integrated management guideline titled “Comprehensive
Risk Management Chart for the Prevention of Cerebrovascular and Cardiovascular Diseases”
in April 2015 (hereafter abbreviated as “comprehensive chart”)
156). As shown in
Fig. 6
, its basic concept was to decrease the risk factors (obesity, hypertension, hyperglycemia,
serum lipid abnormalities, renal dysfunction, etc.) by comprehensively managing the
patient's lifestyle habits. However, in cases where various risk factors overlap,
other than comprehensive management including drug intervention, the comprehensive
chart also emphasized that specialized drug therapy for treating the underlying causes
is essential if the disease is hereditary or secondary.
Fig. 6.
Comprehensive Risks and Risk Factors for Lifestyle Habits
Joint Committee for Comprehensive Risk Management Chart for the Prevention of Cerebro-
and Cardiovascular Diseases, The Journal of The Japanese Society of Internal Medicine
2015, Vol. 104, No. 4, 824–860
In this section, we will describe the comprehensive risk assessment and their management
in six steps, based on the concept of the comprehensive chart (
Fig. 7
). The main target population is primarily first-visit patients assessed as “requiring
further investigation” because of the presence of risk factors for ASCVD. However,
for patients who have an ASCVD history, such as CAD, and for those already receiving
treatment or are being followed up for dyslipidemia, DM, or hypertension, reassessment
of the risk factors and determination of the effectiveness of their case management
should be carried out periodically.
Fig. 7.
Comprehensive risk assessment and their management in six steps
[Screening]
Step 1: Screening for Cerebro- and Cardiovascular Disease Risk Assessment
Exhaustive screening of the major risk factors is important for the comprehensive
risk management of cerebro- and cardiovascular diseases. In addition to blood biochemistry
tests, careful medical history-taking and examination should be carried out.
The screening consists of Step 1a (basic items), Step 1b (additional items), and Step
1c, (criteria for determining if the patient should be referred to a specialist).
If possible, it is advisable to collect fasting blood for laboratory testing in Step
1a. Blood for Step 1b should generally be collected in a fasting state.
Step 1 consists of the basic items for screening and the additional items presented
in Steps 1a and 1b, as well as the criteria for determining the necessity of patient
referral to a specialist in Step 1c.
i)
Step 1a
Step 1a consists of the basic screening items. The items for the medical history-taking,
physical findings, and tests necessary when assessing each patient's risk for ASCVD
are shown in
Fig. 8a
. In addition to subjective symptoms, complications, medical history, lifestyle habits
(smoking, passive smoking, and alcohol consumption), exercise habits, and sleep habits,
which are standard items specific to a physical examination, it is recommended to
check the patient's home blood pressure and family history during the medical history-taking.
Age, gender, height, body weight, and BMI (kg/m2) are the recommended items to include
in the physical findings, and the recommended examinations are in-clinic blood pressure,
pulse rate (regular or irregular), and chest auscultation. It is preferable to collect
fasting blood for the blood tests as much as possible. Other than TC, HDL-C, non-HDL-C
(TC − HDL-C), eGFR (serum creatinine), ALT, γ-GT, HbA1c, and blood glucose, it is
recommended to perform urinalysis (qualitative) and electrocardiography. If atrial
fibrillation is detected, the patient should be referred to a specialist depending
on the degree of abnormality.
Fig. 8a.
Step 1a Screening (Basic Items)
ii)
Step 1b
Step 1b consists of the additional items for screening, which are to be carried out
concurrently with 1a or if abnormalities are observed in 1a (
Fig. 8b
). For the physical findings, measurement of the abdominal circumference (waist circumference),
standing blood pressure (after 1–3 minutes of standing), ankle–brachial index (ABI),
arterial palpation in the extremities, and auscultation of vascular murmurs in the
neck and abdomen should be performed. In principle, the blood count, blood glucose,
TG, and LDL-C measurements should be tested using fasting blood, and in addition to
a chest X-ray and uric acid test, the urinary protein/creatinine ratio should be measured
if abnormalities are found in the urinalysis (qualitative). Whenever necessary, the
plasma aldosterone concentration/renin activity ratio should also be measured.
Fig. 8b.
Step 1b Screening (Additional Items)
iii)
Step 1c
Step 1c lists the circumstances in which referral to a specialist is likely to be
necessary based on the outcome of the above-mentioned screening (
Fig. 8c
).
Fig. 8c.
Step 1c Determination of Necessity for Referral to a Specialist
If the patient is suspected of having a history of or being complicated with stroke/
TIA, CAD, arrhythmia such as atrial fibrillation, aortic disease, or PAD
For patients with hypertension, if secondary hypertension (early incidence, acute
incidence, etc.), pregnancy-induced hypertension, hypertensive emergency or urgency
(untreated diastolic blood pressure ≥ 120 mmHg) is suspected, or if refractory hypertension
(blood pressure ≥ 180/110 mmHg despite undergoing treatment, or not achieving the
antihypertension goal with the combined use of three agents) is present
For patients with DM, if type 1 DM, HbA1c ≥ 8.0%, fasting blood glucose ≥ 200 mg/dL
(or random blood glucose ≥ 300 mg/dL), acute complications (hyperglycemic emergency),
or gestational diabetes is present
For patients with dyslipidemia, if LDL-C ≥ 180 mg/dL, HDL-C < 30 mg/dL, TG ≥ 500 mg/dL,
non-HDL-C ≥ 210 mg/dL, or if primary or secondary dyslipidemia is suspected (
Table 13
)
For patients with CKD, if advanced proteinuria (urinary protein/creatinine ratio ≥
0.50 g/gCr or ≥ 2+ by the litmus paper method), positivity for both urinary protein
and urinary blood (≥ 1 + by the litmus paper method), or eGFR < 50 mL/min/1.73 m2
(< 60 for those aged < 40 years and < 40 for those aged ≥ 70 years with stable renal
function) is observed. (The Japanese Society of Nephrology has eliminated the segmentation
by age and revised to eGFR < 45 mL/min./1.73 m2 in 2017
154).)
For patients with obesity, if severe obesity (BMI ≥ 35) or if secondary obesity (symptomatic
obesity) is suspected
Table 13.
Major Secondary Dyslipidemias
• Hypothyroidism
• Nephrotic syndrome
• Renal failure/uremia
• Primary biliary cirrhosis
• Obstructive jaundice
• Diabetes mellitus
• Cushing's syndrome
• Obesity
• Alcohol consumption
• Autoimmune diseases [systemic lupus erythematosus (SLE), etc.]
• Drug-induced dyslipidemia (diuretics, β-blockers, steroids, estrogen, retinoic acid,
cyclosporin, etc.)
• Pregnancy
Step 2:
Step 2 consists of the diagnosis of each risk factor as well as additional assessments.
It should be carried out using the five items in Table 4–15 as guidelines. Moreover,
for any of the conditions, carotid ultrasonography, echocardiography, coronary computed
tomography (CT), chest, and abdominal CT, magnetic resonance imaging (MRI), magnetic
resonance (MR) angiography, brachial–ankle pulse wave velocity (baPVW), or cardiac-ankle
vascular index (CAVI) should be performed as necessary.
For patients with hypertension (in-clinic blood pressure ≥ 140/90 mmHg or home blood
pressure ≥ 135/85 mmHg), 24-hour blood pressure should be measured as necessary (differentiation
of nocturnal hypertension and workplace hypertension).
If DM is suspected and cannot be ruled out (HbA1c 5.6–6.4%, fasting blood glucose
100–125 mg/dL or random blood glucose 140–199 mg/dL, or a strong family history of
DM or obesity), a 75-g OGTT should be performed (except when symptoms of DM are clearly
present).
If the patient is clearly diagnosed with DM, i.e., if both the HbA1c and blood glucose
level are indicative of diabetes in the same blood test, the blood glucose level is
indicative of diabetes and classic symptoms (thirst, polydipsia, polyuria, and weight
loss) are present, diabetic retinopathy is present, or a test done on a different
day was able to reconfirm findings indicative of diabetes (the blood glucose level
must at least be indicative of diabetes in either the first test or re-test
871)), funduscopy should be performed and the urine albumin/creatinine ratio (random
spot urine quantification) should be assessed.
For patients with dyslipidemia (LDL-C ≥ 140 mg/dL, HDL-C < 40 mg/dL, fasting TG ≥
150 mg/dL, or non-HDL-C ≥ 170 mg/dL
872)), in addition to checking for the presence of arcus corneae, Achilles tendon
thickening, cutaneous/tendon xanthomas and eruptive xanthomas, lipoprotein agarose
gel electrophoresis or polyacrylamide gel electrophoresis should be performed to measure
the apoproteins (AⅠ, AⅡ, B, CⅡ, CⅢ, E), small dense LDL particles, Lp (a), remnant
lipoprotein cholesterol particles, lipoprotein lipases, hepatic lipases, and lecithin–cholesterol
acyltransferases (LCAT).
CKD is diagnosed if the patient's eGFR persistently remains at < 60 mL/min/1.73 m2
or proteinuria is present for ≥ 3 months
153).
The diagnosis of metabolic syndrome should be based on the diagnostic criteria by
the eight academic societies for internal medicine.
Fig. 8d.
Step 2 Diagnosis of Each Risk Factor and Additional Items for Assessment*
Step 3:
Step 3 lists the risk factors that should be specifically taken note of for the prevention
of cerebrovascular and cardiovascular diseases and before initiating treatment. These
risk factors include: (1) smoking; (2) hypertension; (3) DM, including impaired glucose
intolerance; (4) dyslipidemia; (5) CKD; (6) obesity, particularly visceral fat obesity;
(7) aging and gender, i.e., men or postmenopausal women; and (8) family history, i.e.,
history or complication of cerebrovascular or cardiovascular diseases and lifestyle
diseases (hypertension, DM, or dyslipidemia) in biological grandparents, biological
parents, or blood siblings (especially cases of early incidence. It should always
be kept in mind that strict management is necessary in cases where multiple risk factors
are present (Fig. 8e).
Fig. 8e.
Step 3 Risk Factors to be Reviewed before Initiating Treatment
Step 4:
• The risk factors for dyslipidemia are stratified as described in Chapter 4-1.
1) Patients with a history of CAD are considered for secondary prevention
2) Among primary prevention patients, those with any of the following are considered
at high risk: (1) diabetes mellitus (excluding impaired glucose tolerance); (2) chronic
kidney disease (CKD); (3) noncardiogenic cerebral infarction; or (4) peripheral arterial
disease.
3) For primary prevention patients, if additional risks are absent, they should be
stratified into low-, moderate- and high-risk based on the absolute risk derived from
the Suita score or the total number of additional risk factors other than LDL-C, including:
(1) smoking; (2) hypertension; (3) low-HDL-C; (4) impaired glucose tolerance; or (5)
family history of early onset CAD (first-degree relatives aged < 55 years (men) or
< 65 years (women) at the time of onset).
4) In primary prevention, the patient is considered to be at high risk if the LDL-C
level is ≥ 180 mg/dL, regardless of the number of additional risk factors present.
• The management targets for hypertension are < 140/90 mmHg for patients aged < 75
years (home blood pressure < 135/85 mmHg), < 150/90 mmHg for those aged ≥ 75 years
(home blood pressure < 145/85 mmHg), < 140/90 mmHg if drug tolerance is noted (home
blood pressure < 135/85 mmHg), and < 130/80 mmHg for those complicated with diabetes
or proteinuria-positive CKD (home blood pressure < 125/75 mmHg).
• An HbA1c reading < 6.0% is recommended if the aim of diabetes management is normalization
of the blood glucose level. The recommended reading for preventing complications is
HbA1c < 7.0%. If it is difficult to intensify the treatment, the recommended HbA1c
reading is < 8.0%.
• For obesity management, the aim is to reduce body weight by 3–5%.
• The basis of metabolic syndrome is the excessive accumulation of visceral fat. Multiple
risk factors of ASCVD are present in this condition. The correction of obesity, especially
visceral fat, should be considered to be a management target. Likewise, for other
diseases such as hyperuricemia, keep in mind the prevention of ASCVD by deciding on
the appropriate therapy and management targets that are suited to each patient.
Fig. 8f
shows the management targets suitable for each risk factor and pathological condition.
As shown in the table, the management targets for hypertension and DM are in accordance
the guidelines of The Japanese Society of Hypertension
122) and The Japan Diabetes Society
871), respectively. However, particularly for the elderly, the management targets
should be established with the circumstances of individuals taken into consideration,
such as the activities of daily living (ADL), cognitive function, and QOL.
Fig. 8f.
Step 4 Setting Management Targets Suited to the Risk Factors for Each Pathological
Condition*
As mentioned in Chapter 3-1, regarding the management of dyslipidemia for the young
elderly aged ≥ 65 years but aged < 75 years, the risk for each patient is stratified
into secondary prevention, high-risk, moderate risk, or low risk
162). For all risk categories, the management target is ≥ 40 mg/dL for HDL-C and <
150 mg/dL for TG. With respect to LDL-C and non-HDL-C, the LDL-C management target
for the low-risk category is < 160 mg/dL (non-HDL-C < 190 mg/dL). The LDL-C management
target is < 140 mg/dL (non-HDL-C < 170 mg/dL) for the moderate-risk category and <
120 mg/dL (non-HDL-C < 150 mg/dL) for the high-risk category. A patient is at high
risk if he/she has a history of or is complicated with DM, CKD, cerebral infarction,
or PAD, regardless of age and gender. Similarly, a patient who has an LDL-C level
≥ 180 mg/dL is also considered to be at high risk regardless of the number of additional
risk factors present. This section can be applied to the risk stratification for patients
with secondary hyperlipidemia. Refer to “Chapter 7. The Elderly” for old old patients
(≥ 75 years).
As mentioned in Chapter 3-2, the management targets for hypertension are < 140/90
mmHg (home blood pressure < 135/85 mmHg) for patients aged < 75 years, < 150/90 mmHg
for those aged ≥ 75 years (home blood pressure < 145/85 mmHg), < 140/90 mmHg if drug
tolerance is noted (home blood pressure of < 135/85 mmHg), and < 130/80 mmHg for those
complicated with DM or proteinuria-positive CKD (home blood pressure < 125/75 mmHg).
For DM, an HbA1c reading < 6.0% is the recommended management target when the aim
of diabetes management is to normalize the blood glucose level. For preventing complications,
the recommended goal is HbA1c < 7.0%, and if it is difficult to intensify the treatment,
the recommended goal is HbA1c < 8.0%. In lipid management, patients with DM are stratified
into the high-risk category, and the management targets are LDL-C < 120 mg/dL and
non-HDL-C < 150 mg/dL. However, for patients predicted to be at a particularly high
risk for CAD, which include those who: (1) are complicated with FH; (2) are complicated
with noncardiogenic cerebral infarction; (3) are complicated with PAD; (4) are complicated
with microvascular complications (retinopathy, nephropathy, etc.); (5) have persistent
poor glycemic control; (6) are complicated with metabolic syndrome (visceral fat obesity);
(7) have multiple overlapping major risk factors, or (8) smoking, stricter management
with compulsory achievement of the management targets is necessary. Overlapping conditions
are considered to be particularly high-risk, and the same management targets as those
for secondary prevention should therefore also be considered.
The aim of obesity management should be an improvement of hypertension, DM, and dyslipidemia
by a 3–5% reduction in body weight
369, 873). Visceral fat accumulation is considered an independent risk factor for
CVD. It has been demonstrated in epidemiological studies in western countries as well
as in Japan that the presence of multiple risk factors, such as metabolic syndrome,
increases the risk for ASCVD (refer to Chapter 3-2, “Metabolic Syndrome”). Besides
the management of each risk factor, emphasis should be placed on the reduction of
visceral fat–the basis of metabolic syndrome–or in other words, the correction of
obesity.
The serum uric acid level is a predictive factor for the future incidence of hypertension
and is related to CKD incidence and progression
874). An elevated serum uric acid level is believed to be associated with an increase
in metabolic syndrome incidence. Therefore, therapeutic intervention should be considered
for patients with a history of hypertension, DM, or CAD if the serum uric acid level
is ≥ 8.0 mg/dL, even if they are asymptomatic with no gout attacks or gout stones.
However, lifestyle modification should still be the basis for therapy
875).
Step 5: Lifestyle Modification
Lifestyle modification is the core of ASCVD prevention, and physicians must refrain
from initiating drug therapy without further consideration of lifestyle. Nondrug therapies
should be continued during the course of treatment with drugs. In other words, guidance
on lifestyle modification should not be neglected. The main improvements are shown
in Fig. 8g.
Fig. 8g.
Step 5 Lifestyle modifications
With reference to and as mentioned in Chapter 3–4, among all the causes of ASCVD,
smoking cessation is the easiest intervention. Regardless of gender, smoking cessation
should be recommended for patients of all age groups to prevent ASCVD (Standard Procedure
for Smoking Cessation Therapy Version 6, 2014 by The Japanese Circulation Society,
The Japan Lung Cancer Society, Japanese Cancer Society, and The Japanese Respiratory
Society). The increased risk of CAD in nonsmokers because of passive smoking is also
a serious issue. Smoking cessation therapy is covered by health insurance if certain
conditions are met
876).
For obese patients (BMI ≥ 25), especially those with an accumulation of visceral fat
resulting from metabolic syndrome, a weight loss ≥ 3% in 3–6 months should be the
goal (refer to “4. Step 4” of this section). The optimization of energy and nutritional
intake, and the correction of improper dietary habits and behaviors form the basis
of treatment for patients with risk factors such as dyslipidemia, hypertension, DM,
or obesity. High-fat meats, animal fats, and excessive alcohol consumption should
be avoided while adopting a salt-reduced Japanese dietary pattern combined with an
intake of fish, soy, vegetables, seaweed, mushrooms, fruits, and unrefined grains.
Exercise has been shown to result in improvements in dyslipidemia (increase in HDL-C
level, etc.), decrease blood pressure, improve insulin resistance, and decrease blood
glucose levels. Patients should aim to perform aerobic exercise of moderate intensity
for ≥ 30 minutes a day, three times or more per week (daily if possible). Metabolic
Equivalent of Task (MET) is a unit that expresses the intensity of exercise in terms
of the equivalent number of times the metabolism is at rest, and moderate intensity
is defined as an intensity of ≥ 3 METs. Normal walking is equivalent to 3 METs, while
brisk walking is 4 METs and jogging is 7 METs; however, these values differ according
to each individual's physical fitness. Patients who do not regularly exercise should
be instructed to start with light and short exercises. However, patients complicated
with hypertension are subjected to exercise therapy only if they have a moderate or
lower blood pressure level (< 180/110 mmHg) and no CVD. Exercise therapy needs to
be prohibited or restricted for diabetic patients suffering from DM with extremely
poor metabolic control (fasting blood glucose ≥ 250 mg/dL or positivity for urine
ketone bodies of moderate severity or higher), new occurrence of fundal hemorrhage
because of proliferative retinopathy, CAD, or renal failure. If the patient is at
high risk, a medical checkup should be performed beforehand and the opinion of a specialist
should be sought on whether exercise therapy is possible or if there is a need for
exercise restriction.
Step 6: Drug Therapy
Drug therapy (Fig. 8h) should be carefully initiated or continued depending on the
individual risk and condition while continuously implementing lifestyle modification.
Meanwhile, rigid drug therapy is necessary for high-risk cases. For the details on
drug therapy for hypertension and DM, physicians should follow the guidelines for
each disease
122, 871).
Fig. 8h.
Step 6 Drug Therapy*
Special attention should be paid to adverse drug reactions if the patient is ≥ 75
years old or has renal dysfunction
877).
Chapter 5.
Familial Hypercholesterolemia
[Statement]
Familial hypercholesterolemia (FH) is a frequent autosomal hereditary disease associated
with a high risk of CAD. Its early diagnosis and intensive treatment are recommended.
(Evidence level: 3, Recommendation level: A)
For the treatment of heterozygous FH, strict lipid management, primarily with statin
therapy, is recommended. (Evidence level: 3, Recommendation level: A)
For the treatment of homozygotes FH and drug therapy-resistant severe heterozygous
FH, strict LDL cholesterol control by LDL apheresis is recommended. (Evidence level:
3, Recommendation level: A)
1.
Pathophysiology and Clinical Features of FH
FH is an autosomal dominant disease with 3 major features: (1) hyper-LDL-cholesterolemia,
(2) premature CAD and (3) tendon and skin xanthomas. FH is dominantly inherited except
for autosomal recessive hypercholesterolemia (ARH), a very rare form. FH patients
have hyper-LDL-cholesterolemia from their birth, resulting in having a considerably
high risk of CAD. Untreated heterozygous FH (HeFH) men 30 to 50 years of age and women
50 to 70 years of age are likely to develop CAD such as myocardial infarction and
angina pectoris
878). Early diagnosis and intensive treatment as well as family screening (cascade
screening) will contribute to the prevention of premature death in FH patients. HeFH
patients in Japan are observed in one in 200–500 of the general population, similar
to those in other countries, suggesting that there are over 300,000 patients. Accordingly,
FH is the most frequently encountered genetic disease in daily practice. Its diagnosis
and treatment in childhood are important when progression of atherosclerosis begins.
2.
Causative Genes of FH
Genetic analysis is not necessarily required for a diagnosis of FH. However, in addition
to hyper-LDL-cholesterolemia, the presence of mutation in the LDL receptor or other
genes involved in LDL receptor pathway gives a definitive diagnosis of FH. FH is caused
by pathogenic mutations in genes of LDL receptor, apolipoprotein B-100 (Apo B-100)
and PCSK9 which play an important role in LDL receptor pathway. In 60–80% of clinically
diagnosed HeFH have a mutation in these causative genes. Homozygous FH (HoFH) are
defined as having 2 pathogenic mutations in 2 alleles of the causative genes. ARH
is an extremely rare disease, caused by mutations in LDLRAP1 which protein is involved
in LDL receptor uptake.
3.
Diagnosis of FH
1)
Diagnostic Criteria
Diagnostic criteria are shown in
Table 14
. When diagnosing FH, it is necessary to pay great attention to family history in
the patient interview. This is especially noted for young patients because they have
a less chance to have Achilles tendon thickening. When serious illness develops concomitantly,
including acute myocardial infarction, there may be a temporary drop in LDL-C. Therefore,
palpation should be performed to examine the Achilles tendon and survey of the family
history must be conducted for all the patients with acute myocardial infarction.
Table 14.
Diagnostic criteria for heterozygous FH in adults (15 years of age or older)
• Hyper-LDL-cholesterolemia (an untreated LDL-C level ≥ 180 mg/dL)
• Tendon xanthomas (thickening of tendons on dorsal side of the hands, elbows, knees
or Achilles tendon hypertrophy) or xanthoma tuberosum
• Family history of FH or premature CAD (within the patient's second-degree relatives)
The diagnosis should be made after excluding secondary dyslipidemia.
If a patient meets two or more of the above-mentioned criteria, the condition should
be diagnosed as FH. In case of suspected heterozygous FH, making a diagnosis using
genetic testing is desirable.
Xanthelasma is not included in xanthoma tuberosum.
Achilles tendon hypertrophy is diagnosed if the Achilles tendon thickness is ≥ 9 mm
on X-ray imaging. (See Appendix)
An LDL-C level of ≥ 250 mg/dL strongly suggests FH.
If a patient is already receiving drug therapy, the lipid level that led to treatment
should be used as the reference for diagnosis.
Premature CAD is defined as the occurrence of CAD in men < 55 years of age or women
< 65 years of age, respectively.
If FH is diagnosed, it is preferable to also examine the patient's family members.
These diagnostic criteria also apply to HoFH.
HoFH can be diagnosed based on clinical features: serum total cholesterol of 600 mg/dL
or more, cutaneous xanthomas and ASCVD from childhood and parents' family history
of heFH. Cutaneous and tendon xanthomas frequently occur in parts subjected to mechanical
stimulation, such as the finger joints, elbow joints, knee joints and so on. If it
is difficult to distinguish between HoFH and severe HeFH, genetic analysis is useful.
Diagnostic criteria for pediatric FH are shown in
Table 15
. As there are few physical symptoms such as xanthomas in pediatric HeFH, diagnosis
has to be made on the basis of LDL-C and family history.
Table 15.
Pediatric FH diagnostic criteria
• Hyper-LDL cholesterolemia: LDL-C level of ≥ 140 mg/dL when untreated
(If total cholesterol level is ≥ 220 mg/dL, measure the LDL-C level)
• Family history of FH or premature CAD (blood relative closer than the two parents)
Excluding secondary hyperlipidemia, if two items are satisfied, FH is diagnosed.
During the growth phase, there are fluctuations in LDL-C; therefore, careful observation
is required.
In pediatric cases, there are few clinical symptoms such as xanthomatosis; therefore,
it is important to investigate the family history for FH. Use the family survey results
of those beyond the parents as a reference if necessary.
Early CAD is defined as CAD with an onset at < 55 years of age for males and < 65
years of age in females, respectively
If xanthoma is present, LDL-C is suspected to be extremely high (homozygote).
2)
X-ray Examination of Achilles Tendon
Achilles tendon thickening is diagnosed when the greatest dimension is ≥ 9 mm. While
it is also possible to use ultrasonography for evaluation, criteria have still to
be standardized. (Refer to Achilles tendon radiography procedure in appendix).
3)
Differential Diagnosis
Diseases that must be distinguished from FH include conditions that cause secondary
dyslipidemia (e.g. diabetes mellitus, hypothyroidism, nephrotic syndrome, cholestatic
liver disease, drug-induced diseases (due to steroids) and a similar disease, familial
combined hyperlipidemia (FCHL). FCHL can be distinguished from FH by the absence of
tendon xanthomas, the presence of small dense LDL, the presence of other types of
dyslipidemia (type IIa, type IIb, type IV) in patient's family and elevation of LDL-C
to a lesser extent than for FH patients.
4.
Treatment of Heterozygous FH
1)
Management Target Levels
Because FH is a disease associated with a very high risk of CAD, FH should be considered
to correspond to secondary prevention, and it is desirable to set a management target
for the LDL-C level at < 100 mg/dL. However, in many cases, it is difficult to achieve
the target level in clinical practice. Therefore, it is also acceptable to aim for
< 50% of the pretreatment level if the management target for LDL-C is not achieved.
In HeFH patients for secondary prevention, the LDL-C management target level is set
at < 70 mg/dL because they can be considered to be at even higher risk.
However, there is no clear evidence for the validity of these numerical targets because
clinical studies on FH without lipid-lowering therapy are ethically not permissible.
The achievement of the management target does not always assure the absence of future
cardiovascular events. In the treatment of FH, risk assessment cannot be applied using
the risk charts provided in these guidelines.
2)
Lifestyle Modification
Lifestyle modification should also be performed in FH patients as described in Chapter
4-2 Lifestyle Modification. However, due to the high risk of CAD, screening for CAD
before administering exercise therapy is essential. CAD should be evaluated using
patient interviews to determine the presence or absence of effort angina, and exercise
electrocardiography and echocardiography should be performed. If the existence of
CAD is suspected, administering treatment for CAD before initiating exercise therapy
is thus preferred. Smoking cessation and obesity management are also important.
3)
Drug Therapy
In many HeFH patients, adequate lipid management is not achieved through lifestyle
habit interventions alone, so drug therapy is usually combined with them. Statins
are the first-line drugs for FH treatment. A retrospective analysis of 329 HeFH patients
conducted in Japan revealed that statin use delayed the incidence of CAD
734). When sufficient efficacy is not obtained with the initial statin dose, increase
the dosage to the maximum tolerated dose and co-administer with ezetimibe. If efficacy
is still not adequate, PCSK9 inhibitors, resins and probucol are used (
Fig. 9
). When the attending physician determines that the risk is particularly high, such
as in secondary prevention patients and those with underlying diabetes, LDL-C should
be lowered as early as possible.
Fig. 9.
Treatment flow chart for adult (15 years or over) heterozygous FH
A retrospective study suggested that probucol delayed recurrence of CAD in HeFH. In
addition, it has been reported that the addition of the PCSK9 inhibitor evolocumab
(Rutherford-Ⅱ study
879)) or alirocumab (Odyssey FHI and FHII studies
880)) in HeFH patients already being treated with statin (and ezetimibe) the further
lowering of LDL-C (approx 60%) and Lp(a) was achieved relatively safely. However,
it remains unclear whether such combination therapies are more effective in suppressing
cardiovascular events in FH patients as compared to statin alone.
4)
Application of LDL Apheresis Therapy
In HeFH patients, LDL apheresis therapy should be considered if the total cholesterol
(TC) level does not decrease to 250 mg/dL or below following lifestyle habit improvement
and intensive drug therapy in the presence of CAD, LDL apheresis is indicated, and
it is desirable to consult a specialist.
5.
Treatment of Homozygous FH
1)
Target Levels for Management
In HoFH, it is essential to start intensive therapy including lowering LDL-C as early
as possible. LDL-C target levels for management in HoFH are < 100 mg/dL in primary
prevention patients and < 70 mg/dL in secondary prevention patients but in many cases
they are difficult to achieve.
2)
Lifestyle Modification
Similar to that recommended for patients with HeFH, lifestyle modification, including
diet therapy, exercise therapy, smoking cessation and obesity management, provides
the basis for treatment in patients with HoFH, although intensive LDL-C-lowering treatment
is necessary at an earlier age because patients with HoFH have an extremely high risk
for the development and progression of CAD. It is necessary to assess CAD, valvular
disease (aortic valve stenosis and supravalvular aortic stenosis in particular) and
aortic aneurysm, and make a careful judgment based on the findings before giving any
guidance on exercise therapy because progression of atherosclerosis is remarkable
in HoFH patients.
3)
Drug Therapy
In HoFH, in order to prevent the incidence and progression of CAD, intensive lipid-lowering
therapy should be initiated as early as possible at an early age (
Fig. 10
). The major mechanisms of action of statins, bile acid adsorbing resins and PCSK9
inhibitors are to enhance expression (activation) of LDL receptors. For the defective
type, in which only a small amount of LDL receptor activity remains, slight efficacy
is observed but in the negative type in which LDL receptor activity is completely
absent, no LDL-C lowering effect is observed
881, 882). A retrospective study found that the administration of statin and other
drugs was effective in reducing mortality rates in HoFH
883). It has been reported that MTP inhibitors, which were developed for HoFH patients,
lowered LDL-C by approximately 50%
693, 884). However, as the frequencies of the adverse events of fatty liver and diarrhea
are high, it is essential to control the fat and alcohol intake strictly. Probucol
reportedly exerts a certain LDL-C lowering effect on HoFH and may cause the regression
or disappearance of xanthoma in the skin or Achilles tendon
885). Nevertheless, for LDL-C control, LDL apheresis therapy once every 1–2 weeks
is still required in many cases. When patients are resistant to all of the above treatments
or show intolerance, liver transplantation may be considered.
Fig. 10.
Treatment flow chart for adult (15 years or over) homozygous FH
4)
LDL Apheresis in HoFH
In patients with HoFH, it is difficult to decrease the LDL-C level sufficiently using
existing drug therapies, and many patients require continued LDL apheresis with extracorporeal
circulation starting in childhood. Considering the inhibition of the progression of
CAD, the earlier LDL apheresis is initiated, the better; however, it is difficult
to perform LDL apheresis until the affected child can be kept in bed during apheresis.
Realistically, the timing of treatment initiation is 4 to 6 years of age, when children
can lie on bed and extracorporeal circulation can be performed; however, it is recommended
that the treatment be initiated as early as possible.
5)
Pregnancy and Delivery of Patients with HoFH
It is important to permit patients with HoFH to become pregnant as planned. Before
pregnancy, screening for atherosclerosis should be performed using carotid ultrasonography,
echocardiography and exercise tolerance tests to assess the status of atherosclerosis.
By three months before the planned pregnancy, treatment with lipid-lowering drugs
other than bile acid-binding resins should be discontinued. Because the cardiovascular
system is greatly stressed during late pregnancy, particularly at delivery, performing
LDL apheresis during pregnancy is desirable. LDL apheresis can also be safely administered
during pregnancy.
6)
HoFH Designated as an Intractable Disease
HoFH has been designated as an intractable disease in the Specified Disease Treatment
Research Program since 2009. The criteria for designation are as follows: patients
with HoFH definitively diagnosed using a genetic analysis of genes involved in the
LDL metabolic pathway or measurement of the LDL receptor activity are definitively
designated, and patients with remarkable hypercholesterolemia and those with cutaneous
xanthoma starting in childhood who are refractory to drug treatment should be designated.
6.
Treatment of Pediatric HeFH
When HeFH is diagnosed, patients should be provided with guidance regarding lifestyle
modification such as diet and exercise as quickly as possible in order to reduce the
risk for atherosclerosis by means of LDL-C lowering.
Fig. 11
shows a treatment flow chart for pediatric HeFH
886). For both boy and girl patients from the age of ≥ 10 years, pharmacotherapy needs
to be considered if the LDL-C level is persistently above 180 mg/dL. Statins are the
first line drugs starting from the minimal dose. In Japan, pitavastatin has been indicated
for pediatric FH patients of ≥ 10 years since June 2015. The target LDL-C level should
ideally be < 140 mg/dL. When there is a family history of premature CAD or diabetes
is also present, ensure that the LDL-C level is kept below 140 mg/dL. While it will
be difficult to achieve targets in serious cases, efforts should be made to achieve
a level as close to the target as possible through combination drug therapy. Guidance
on lifestyle modification including diet should be continued even after commencing
drug therapy.
Fig. 11.
Algorithm for treatment of pediatric FH heterozygote
Chapter 6.
Other Types of Primary Dyslipidemias
1.
Primary Hyperlipidemias other than Familial Hypercholesterolemia
Besides FH, there are various types of primary hyperlipidemias which are caused by
a mutation of single-gene and highly heritable. Classification of these diseases have
been proposed based on their pathogenesis and/or and genetic abnormalities (
Table 16
). Familial lipoprotein lipase (LPL) deficiency manifests as severe hyperchylomicronemia
and may present with eruptive cutaneous xanthomas or acute pancreatitis, although
it does not necessarily accompany ASCVD. On the other hand, familial type Ⅲ hyperlipoproteinemia
and FCHL are frequently associated with CVD; therefore, early diagnosis and initiation
of treatment is important. It is recommended to refer the patients with these disorders
to specialists. The clinically important diseases are described in depth below.
Table 16.
Categories of primary dyslipidemias
Primary hyperlipidemia
Primary hyperchylomicronemia
Familial lipoprotein lipase deficiency GPIHBP1 deficiency LMF1 deficiency Apoprotein
A-V deficiency Apoprotein C-Ⅱ deficiency Primary type V hyperlipidemia Others
Primary hypercholesterolemia
Familial hypercholesterolemia [LDL receptor deficiency or abnormality, PCSK9 abnormality,
familial apoB100 abnormality, LDLRAP1 abnormality (autosomal recessive hypercholesterolemia),
and others] Homozygous FH Heterozygous FH Polygenic hypercholesterolemia Familial
combined hyperlipidemia
Familial type Ⅲ hyperlipidemia
Apoprotein E abnormality Apoprotein E deficiency
Primary hypertriglyceridemia
Familial type Ⅲ hyperlipidemia
Primary high HDL cholesterolemia
CETP deficiency HL deficiency Others
Primary hypolipidemia
Abetalipoproteinemia (MTP abnormality)
Familial low betalipoproteinemia (ApoB or PCSK9 abnormality)
Familial low HDL lipoproteinemia
Tangier disease Familial LCAT deficiency and fish eye disease Apoprotein A-Ⅰ deficiency
Apoprotein A-Ⅰ abnormality Others
Other dyslipidemias
Sitosterolemia and cerebrotendinous xanthomatosis
2.
FCHL
1)
Causes
FCHL was initially proposed as hyperlipidemia with mixed phenotypes associated with
high prevalence of myocardial infarction
887). The patients with FCHL typically manifest type Ⅱb (or combined) hyperlipidemia
reflecting the variously combined effects of genetic and acquired factors (e.g., lifestyle
habits). The phenotype may change to type Ⅱa or Ⅳ hyperlipidemia in response to changes
in diet or age. The first degree relatives of affected patients are commonly associated
with type Ⅱa, Ⅱb or Ⅳ hyperlipidemia. FCHL, which was previously believed to be an
autosomal dominant monogenic disorder, is now considered to be an oligogenic disease
complicated with other multiple environmental factors
888). Genetic analyses have linked various genes to FCHL: LPL, USF-1, apoproteins
B, C-Ⅱ, A-Ⅰ/C-Ⅲ/A-Ⅳ gene cluster, LDLR, and PCSK9. Besides the genetic factors, environmental
factors such as over-nutrition, obesity, and lack of physical activity are believed
to contribute to the manifestation of FCHL. Moreover, the prevalence of this disease
is as high as 1% of the general population, and was reported to be 0.4% of the general
population of children in Japan
889).
2)
Clinical Symptoms
In patients with FCHL, the increase in the serum LDL-C levels is relatively mild compared
with that observed in patients with FH. In contrast to FH, Achilles tendon thickening
is not observed in patients with FCHL. The incidence of CAD in patients with FCHL
is high, although not as high as that in patients with FH
890, 891). In Japanese patients with FCHL, myocardial infarctions are commonly observed
in men ≥ 35 years of age and women ≥ 55 years of age. FCHL was reported to be found
in 32% of patients ≤ 65 years of age with myocardial infarctions in Japan
892).
3)
Laboratory Findings and Diagnosis
In patients with FCHL, the severity of hypercholesterolemia and hypertriglyceridemia
is mild to moderate. FCHL is associated with an increase in the amount of apolipoprotein
B and shift of the size of LDL to small (appearance of small dense LDL). The diagnosis
should be made according to the diagnostic criteria of the Research Committee for
Primary Hyperlipidemia, Research on Measures against Intractable Diseases established
by the Japanese Ministry of Health, Labour and Welfare (
Table 17
). FCHL is diagnosed if apolipoprotein B100/LDL-C ratio is > 1.0 or presence of small
dense LDL is confirmed using lipoprotein polyacrylamide gel disc electrophoresis (PAG).
A survey of familial history is optional for this diagnosis.
Table 17.
Diagnostic criteria of FCHL
Criteria
(1) Familial combined hyperlipidemia is associated primarily with phenotype Ⅱb and
possibly with phenotypes Ⅱa or Ⅳ
(2) An apoprotein B/LDL-C ratio of > 1.0 or the presence of small dense LDL (particle
size < 25.5 nm) should be established.
(3) Secondary hyperlipidemia, such as familial hypercholesterolemia or diabetes mellitus,
should be excluded.
(4) One or more of the first-degree relatives have phenotype Ⅱb, Ⅱa or Ⅳ hyperlipidemia
and at least one of such relatives, including the patient himself/herself, has phenotype
Ⅱb or Ⅱa.
Diagnosis
The diagnosis is confirmed if all of the above criteria ((1) to (4)) are met. However,
in daily practice, a diagnosis may simply be made if criteria (1) to (3) are met.
(Cited from the 2000 report of the Research Committee for Primary Hyperlipidemia,
Research on Measures Against Intractable Diseases established by the Japanese Ministry
of Health, Labour and Welfare)
4)
Treatment
Patients with FCHL should be treated according to a treatment guideline for FH. Lifestyle
modification and obesity management achieved via dietary and exercise therapy are
most important. Patients with FCHL respond well to dietary therapy, and the effects
of drugs are greater than those observed in patients with FH. With respect to drug
therapy, statins, fibrates and nicotinic acid derivatives are effective. The presence
or absence of ASCVD, such as CAD, is a prognostic factor.
3.
Familial Type Ⅲ Hyperlipidemia
1)
Causes
Familial type Ⅲ hyperlipidemia, a hereditary type of hyperlipidemia also called broad
β disease, is characterized by increased plasma levels of remnant lipoproteins, such
as intermediate-density lipoprotein (IDL), chylomicron remnants and β-VLDL
893, 894). Three isoforms are present for apoE, which is necessary for the hepatic
uptake of remnant lipoproteins: wild-type E3 and isoforms E2 and E4. Familial type
Ⅲ hyperlipidemia is caused by genetic abnormalities in apoE. Patients with familial
type Ⅲ hyperlipidemia typically have APOE2/E2 genotype. Other mutations of APOE gene,
such as APOE1, abnormal APOE3 and APOE deficiency are also known as the predisposing
factor. In Western countries, the incidence of familial type Ⅲ hyperlipidemia is estimated
to be approximately 0.4% and 0.2% for adult men and women, respectively
895). The incidence of E2/E2 is estimated to be approximately 0.2% in Japan; however,
only a small portion of the patients with E2/E2 develop familial type Ⅲ hyperlipidemia,
with an incidence of 0.01–0.02% in a general population.
Abnormalities in apoE impairs the hepatic uptake of chylomicron remnants and IDL,
leading to the accumulation of these lipoproteins in the blood. However, in many cases,
remarkable hyperlipidemia does not develop despite the presence of apo E2/E2, other
environmental conditions such as DM, obesity or hypothyroidism are necessary to develop
hyperlipidemia.
2)
Clinical Symptoms
Patients with familial type Ⅲ hyperlipidemia are characterized by the high incidence
of typical xanthoma such as xanthoma striatum palmare and/or xanthoma tuberosum, and
premature ASCVD [e.g., CAD, carotid atherosclerosis, renal arteriosclerosis or PAD]
and may develop renovascular hypertension or intermittent claudication due to PAD.
In Western countries, the risk of CAD is increased by five- to eight-fold
896). The incidence of complications of CAD is also high in Japan
897).
3)
Laboratory Findings and Diagnosis
Both the serum TC and TG levels are raised in this patient population. However, the
ranges of these parameters vary from slightly increased in patients with normal TC
or TG levels to up to 500 mg/dL or 2,000 mg/dL, respectively. The diagnosis is made
based on the diagnostic criteria of the Specific Disease Primary Hyperlipidemia Research
Group of the Ministry of Health and Welfare (
Table 18
). This disease can be screened by a positive broad β pattern on lipoprotein polyacrylamide
gel disc electrophoresis in patients with increases in both TC and TG and apoE/TC
ratios of > 0.05. Other indicators, such as apoE/B > 0.20 and apoE/CⅢ > 1.0
898), TC/apoB > 6.2 and TG/apoB < 10
899), RLP-C/TG > 0.1
895), non-HDL-C/apoB > 3
900), and apoB48/TG > 0.11
901), have also been proposed. LDL-C levels are low on lipoprotein analysis using
ultracentrifugation or HPLC. Ultracentrifugation can be used to confirm a significant
increase of cholesterol in IDL fraction (1.006 < d < 1.019) and high cholesterol/TG
ratio (≥ 0.42) in the VLDL fractions (d < 1.006). Finally, isoelectric focusing, Western
Blotting, or genetic analysis can be used to demonstrate an apoE isoform abnormality.
Table 18.
Diagnostic criteria of familial type Ⅲ hyperlipidemia
Major criteria
1) Both the serum cholesterol and serum TG levels are high.
2) Electrophoresis of plasma lipoproteins shows a continuous broad β pattern from
VLDL to LDL.
3) Abnormalities in apolipoprotein E (E2/E2, E deficiency, etc.) are established by
electrophoresis of apolipoproteins.
Minor criteria
1) Xanthoma (particularly xanthoma striatum palmare)
2) An increased serum apolipoprotein E concentration (apolipoprotein E/TC ratio ≥
0.05)
3) A VLDL-C/serum TG ratio of ≥ 0.25
4) A decreased level of LDL-C
5) The presence of cardiovascular disease, such as arteriosclerosis obliterans or
ischemic heart disease
Diagnosis
The diagnosis is confirmed if all three major criteria are met.
Familial type Ⅲ hyperlipidemia is suspected if two of the three major criteria and
at least one of the minor criteria are met.
(Cited from the 1987 report of the Research Committee for Primary Hyperlipidemia,
Research on Measures Against Intractable Diseases established by the Japanese Ministry
of Health, Labour and Welfare)
4)
Treatment
Dietary fat restriction is essential. Patients with familial type Ⅲ hyperlipidemia
respond relatively well to lifestyle modification including dietary and exercise therapy;
thus, early diagnosis and treatment are extremely important. Treatment of associating
comorbidities, such as DM, obesity or hypothyroidism is also effective for treating
dyslipidemia. With respect to drug therapy, fibrates are the first-line drugs; however,
nicotinic acid derivatives and statins are also effective. The prognosis is favorable
as long as diagnosis is appropriately made and treatment is initiated early. Periodic
examinations is essential to prevent the development of CAD, carotid atherosclerosis
and PAD. Consultations with specialists are also recommended.
4.
Other primary dyslipidemias
Primary hyperchylomicronemia (e.g., familial LPL deficiency and apoC-Ⅱ deficiency)
exhibits severe hypertriglyceridemia due to marked hyperchylomicronemia. In a typical
case, primary hyperchylomicronemia manifests as type I hyperlipidemia; however, some
patients may also exhibit type V hyperlipidemia. Primary hyperchylomicronemia often
causes acute pancreatitis; therefore, a strict fat restriction is required (≤ 15–20
g/day). In hypertriglyceridemia accompanying ApoA-V gene abnormalities, it is necessary
to prevent ASCVD. The following rare primary lipoprotein disorders have been listed
as intractable diseases in 2015: sitosterolemia that are frequently associated with
early-onset CAD, cerebrotendinous xanthomatosis, and Tangier disease were recently
listed as Detailed diagnostic and treatment guidelines can be found at the Japan Intractable
Diseases Information Center website under “Metabolic diseases” (www.nanbyou.or.jp/entry/504#04).
PROLIPID (PROspective registry study of primary hyperLIPIDemia) study, which aims
to investigate the prognostic outcome of three diseases of primary hyperlipidemia
(Homozygous and heterozygous FH, hyperchylomicronemia and familial type Ⅲ hyperlipidemia),
is currently underway since 2015.
Chapter 7.
Elderly
[Statement]
As is the case for nonelderly adults, hyper-LDL cholesterolemia is an important risk
factor of CAD among the elderly persons 65–74 years of age. (Evidence level: E-1a)
Statin therapy for hyper-LDL cholesterolemia in the elderly persons may be effective
for the secondary prevention of CAD as is the case for nonelderly adults. (Evidence
level: 1+, recommendation level: A)
Statin therapy for hyper-LDL cholesterolemia in the elderly persons 65–74 years of
age may be effective for the primary prevention of CAD and non-cardiogenic cerebral
infarction. (Evidence level: 1+, recommendation level: A)
The effects of lipid lowering therapy for hyper-LDL cholesterolemia in the primary
prevention of CAD are not clear in the elderly patients ≥ 75 years of age, and should
be handled for individual patients at the discretion of the attending physician. (Evidence
level: 1)
1.
Relationship between Dyslipidemia and ASCVD in the Elderly
As aging is a significant risk factor of ASCVD, the risk for ASCVD is higher in elderly
people than in nonelderly ones. The prognosis after the incidence of cerebrovascular
disease and CAD is also poor, which increases the risk for disability. Therefore,
primary and secondary preventions are extremely important. However, because aging
is a stronger risk factor than other risk factors associated with ASCVD, the weighting
of other risk factors such as dyslipidemia become relatively less. Nevertheless, these
risk factors should also be managed accordingly.
Epidemiological studies in Western countries have revealed that hyper-LDL cholesterolemia
is also a risk factor for CAD among the elderly (primarily in the young elderly: 65–74
years of age) as well as in nonelderly adults
902–907). Although, many of the studies in the elderly aged ≥ 75 years reported that
there was no relationship between the LDL-C level and the risk of CAD
908–910), a meta-analysis of 10 cohort studies in Japan (65,594 subjects, aged 70–89
years, EPOCH-JAPAN) reported that in men, total cholesterol ≥ 240mg/dL correlated
with significantly increased death from CAD. No significant relationship was found
in women. There was no significant relationship for stroke mortality in either sex
55). Furthermore, according to the NIPPON DATA 90 cohort data relating to the relationship
between non-HDL-C and ASCVD, a significant relationship was found between non-HDL-C
and CAD in elderly subjects aged ≥ 65 years, but no significant relationship was found
between non-HDL-C and cerebral infarction or stroke
911). A meta-analysis of 61 prospective studies including approximately 900 thousand
adult men and women in Europe and North America, confirmed the deaths of 55,000 subjects
from cardiovascular events during the reported observation periods, such as CAD and
cerebrovascular disease. Of these, a significant correlation was found between total
serum cholesterol at the beginning of the observation period and death from CAD in
the elderly (aged 70–89 years), although a relationship with stroke was not identified
912). In a further meta-analysis of 29 cohort studies in the Asia-Pacific region,
a significant positive correlation was found between total cholesterol and death from
CAD in not only individuals < 60 years but also in the 60–74 year group and ≥ 75 year
group; however, no relationship was identified between stroke and lipid levels
913). As such, some independent cohort studies did not find a positive correlation
between serum lipid levels and ASCVD in the elderly aged ≥ 65 years, but meta-analyses
have reported positive correlations between CAD and total cholesterol, non-HDL-C and
LDL-C. However, even meta-analyses have revealed no correlation between stroke and
these lipid levels.
In the Japan Cholesterol and Diabetes Mellitus Study, an observational study including
elderly Japanese people with diabetes, a significant relationship was found between
CAD and HDL-C as well as the LDL-C/HDL-C ratio, and between cerebrovascular disease
and HDL-C in the elderly aged ≥ 75 years; however, no relationship was found between
LDL-C and non-HDL-C and either of these diseases
914).
There is almost no clinical evidence related to the elderly aged ≥ 85 years, a cohort
which is expected to become larger in the future. This is because such subjects are
unlikely to participate in longitudinal studies. However, the Cardiovascular Health
Study has shown that in the elderly aged ≥ 85 years, LDL-C was not a risk factor for
cardiovascular events
915). It appears that aging itself has a greater impact on the prognosis of this elderly
age group.
2.
The Efficacy of LDL-C Lowering Therapy for Preventing ASCVD in the Elderly
1)
Preventive Effects of Statins on ASCVD
PROSPER, a large clinical study involving only elderly subjects, revealed that statin
therapy was able to prevent CAD
916). In this study, 3.2 years of statin administration on patients aged 70–82 years,
including secondary prevention patients, lowered the primary endpoint (CAD death +
nonfatal myocardial infarction + fatal and nonfatal stroke) by 15%, clearly demonstrating
that intervention with statins could also be applied to the elderly. The reduction
of CAD risk was more pronounced in men than in women as well as in secondary prevention
patients than primary prevention, although no significant difference was observed
in the interaction analysis.
Several meta-analyses by Cholesterol Treatment Trialists have been published, and
showed the following: in the > 65 years group, the relative risk of statin therapy
on major coronary artery events was 0.81 (95% confidence interval [CI]: 0.76–0.88]
(2005)
917), the relative risk on a major vascular event of statin and high-dose statin groups
in subjects aged 66–75 years was 0.78 (95% CI: 0.74–0.83) relative to the control
group or a low-dose statin group, and 0.84 (95% CI: 0.73–0.97) in the group > 75 years
(2010). Both meta-analyses demonstrated that statin therapy showed increased effects
than the control group, and that high-dose statins had greater effects than a low-dose
statin group in preventing an event
918).
A meta-analysis of 51,351 elderly subjects aged ≥ 60 years, including primary and
secondary prevention patients, who received intervention with statins showed that
statin therapy decreased total mortality by 15% (95% CI: 7–22%), death from CAD by
23% (95% CI: 15–29%), fatal and nonfatal myocardial infarction by 26% (95% CI: 22–30%),
and fatal and nonfatal stroke by 24% (95% CI: 10–35%) compared to the placebo. However,
the relative risk of cancer onset with statin therapy was 1.06 (95% CI: 0.95–1.18)
relative to the placebo, and the difference was not statistically significant. There
was no significant difference between statins and the placebo in terms of adverse
events, such as a ≥ 3-fold increase of AST and ALT, ≥ 10-fold increase of CK or termination
of the trial. However, muscle pain and gastrointestinal symptoms occurred significantly
more often in the statin group. Moreover, new-onset diabetes was significantly higher
in the statin group among those ≥ 65 years
919). A meta-analysis of CAD mortality risk in a secondary prevention intervention
trial, including elderly subjects aged ≥ 65 years, showed that the effects of secondary
prevention on the elderly are far greater than that would be predicted from the outcomes
in younger individuals
920). As such, the secondary prevention effects of statin in the elderly with CAD
history are evident and are recommended. The recently published J-STARS is a research
study investigating the efficacy of 10 mg pravastatin on patients with ischemic stroke
aged 45–80 years. Although no significant difference was found in terms of the primary
endpoint, statins decreased the incidence of atherothrombotic cerebral infarction
by 67%
921). Considering the mean patient age of 66 years in this study, approximately half
of the subjects were presumed to be elderly, and considering that the effects of statin
therapy were observed regardless of age group, these results suggest that statins
are capable of preventing the recurrence of atherothrombotic cerebral infarction in
the elderly.
Meanwhile, the MEGA Study on primary prevention in the elderly showed that the concurrent
risk of CAD and cerebral infarction decreased significantly in individuals aged ≥
65 years [hazard ratio: 0.60 (0.39–0.93)], which was related to the efficacy of statin
treatment in the elderly with high LDL-C
922). Another meta-analysis, involving only primary prevention studies, also indicated
that statin administration lowered the risk of all-cause mortality, major cardiovascular
events and major cerebrovascular events
923). Another meta-analysis of primary prevention including 24,674 elderly patients
(mean age: 73 years, 43% women) confirmed that statins decreased myocardial infarction
and stroke by approximately 40% and 25%, respectively
924). The efficacy of statin treatment has thus been established, at least for primary
prevention in younger elderly patients. Consequently, pharmaceutical therapy can be
recommended on the basis of the risk factors present. However, there is still a lack
of strong evidence for primary prevention in the elderly aged ≥ 75 years. As there
is no method of risk assessment for elderly patients aged ≥ 75 years, as indicated
in Chapter 2, treatment should be given, or dismissed, at the discretion of the attending
physician. In addition, as geriatric syndrome complications, such as frailty and sarcopenia,
are common in elderly aged ≥ 75 years, it is important to confirm whether patients
in this particular group have adequate protein intake when dietary counseling is provided.
2)
The Effects of Statins in Dementia Prevention
A selection of observational and interventional studies has attempted to investigate
the effects of statin treatment on dementia prevention. However, many of these reports
relate to subanalysis and secondary endpoints, and studies that set cognitive function
as the primary endpoint involved sample sizes that were too small. An observational
study suggested that statin treatment improves cognitive function
925), many research results do not support these effects
926, 927). A meta-analysis of interventional trials of four statins on patients with
Alzheimer's disease patients in a recent Cochrane review, however, failed to demonstrate
that statins could improve cognitive function
928). Therefore, we can conclude that the effects of statins in the prevention and
treatment of Alzheimer's disease are not positive. Although there is no research data
relating to the assessment of statin effects on vascular dementia, we do know that
stroke increases dementia risk by approximately 2-fold and that statins decrease the
incidence of stroke; consequently, the preventive effects of statins on vascular dementia
incidence can be expected. However, there are some case reports in which statins decreased
cognitive function, and must, therefore, be approached with caution.
3)
Frailty, a New Risk Factor that should be Considered in the Elderly
In the elderly, frailty is another factor which can require long-term care, much like
dementia. In fact, there have been recent studies reporting that the incidence of
cardiovascular events increases in elderly patients with frailty, or those who show
vulnerability to acute stressors, a condition that appears with age. For example,
White et al. conducted a prospective follow-up study dividing non-ST-elevating ACS
patients aged ≥ 65 years into three groups: frail, pre-frail, and nonfrail groups
using Fried criteria and found that the frail group had significantly higher primary
endpoints of cardiovascular, myocardial infarction and stroke mortality than the nonfrail
group (HR: 1.76; 95% CI: 1.36–2.28), and that all-cause mortality also increased significantly
(HR: 1.98; 95% CI: 1.47–2.68)
929). In another study, Sergi et al. divided 1,567 nonfrail elderly patients aged
65–96 years into three groups: a group meeting 1 Fried criterion, a group meeting
2 Fried criteria and a third group that did not meet any of the criteria; these groups
were followed-up for 4.4 years in relation to CAD, heart failure, stroke, PAD and
cardiovascular death as the primary endpoints. Even after adjustment for the confounding
factors, event incidence occurred significantly more frequently in the groups meeting
1 or 2 Fried criteria; in other words, those in the pre-frail groups, compared to
the robust group
930). This suggested that frailty, characterized by low grip strength and slower walking
speed, may represent a new risk factor for cardiovascular events in the elderly, and
that there may be a need to make more comprehensive assessments that include geriatric
syndromes such as frailty.
Sarcopenia is a pathological condition related to frailty. Sarcopenia is characterized
by decreased muscle mass associated with age, which decreases muscular strength and
walking speed, and has been suggested to not only cause falls and fractures but also
exert impact on cardiovascular events
931). Because statins cause muscle disorder as a side effect, it is concerned that
long-term continuous use may be related to sarcopenia incidence. For example, Scott
et al. showed that the use of statins in the community-dwelling elderly was linked
to decreased leg muscle strength
932); however, a subsequent meta-analysis by Krishnan et al. concluded that the earlier
study by Scott et al. was lacking in convincing evidence
933). Lynch et al. further reported that the use of statins in 3,422 elderly patients
in rehabilitation (mean age = 81.4 years) was associated with an improvement in the
activities of daily living
934). As such, at present, there is simply not enough evidence to support the fact
that statin treatment increases the risk of sarcopenia.
4)
The Advantages and Disadvantages of Statin Treatment during End-of-Life Care
Sometimes doctors cannot decide whether or not a patient's medication should be continued
or terminated, even during end-of-life care. Most clinical research tests the effects
of pharmaceutical drugs by initiating them; however, Kutner et al. randomly assigned
381 patients estimated to have ≤ 1 year of life expectancy into two groups: one group
for which treatment would be terminated and a second group that would continue taking
the prescribed statin. These authors set death as the primary endpoint, and also studied
quality of life (QOL) and financial effects. Results showed that there was no increase
in deaths or cardiovascular events when statin treatment was terminated, and instead
showed that QOL improved and that patients were able to save on their medical costs
935). At the end of life, it is sometimes difficult to continue taking medication
due to decreased appetite or dysphagia; hence, it is logical that being able to decrease
oral medication in a safe manner will lead to an improvement in patient QOL.
Because statins in primary prevention are thought to take 3–4 years to have an effect
upon the suppression of vascular events, the use of statins should only be considered
in cases with at least ≥ 3 years of life expectancy.
3.
Care of the Elderly
For preventing ASCVD in the elderly and maintaining QOL, it is important to manage
dyslipidemia, particularly hyper-LDL cholesterolemia, which is an important risk factor.
At the same time, it is important to consider the increase in secondary dyslipidemia,
which occurs with complications such as hypothyroidism. There are many aspects to
carefully consider in providing treatment to the elderly, such as the comorbidities
other than ASCVD that may impact upon vital prognosis, latent organ disorder, atypical
symptoms, decreased organ spare ability, decreased drug metabolism ability, malnutrition,
frailty, polypharmacy, and due to variability in physical functions, careful considerations
should be paid to treatment.
The basic treatment for dyslipidemia is dietary and exercise therapy for the elderly.
Drug therapy should not be given at ease without implementing nonpharmaceutical therapies
first. However, because adherence to strict diet therapies can worsen the nutritional
state of the elderly, particularly in the latterstage elderly population, and because
it is difficult for many to take on the same-level of physical activity as nonelderly
adults for exercise therapy, it is best to make an intervention which is adapted to
each individual's capacity. Pharmaceutical therapy should be prescribed with extreme
care with the understanding that elderly patients are more prone to side effects.
Chapter 8.
Women
[Statement]
It is important to manage risk factors, such as hypertension, diabetes, and smoking
regardless of menopause status. In particular, diabetes and smoking are related to
an increased the coronary artery disease (CAD) risk in women than in men. (Evidence
level: E-1a)
The intensity of treatment for hypertension and diabetes should be personalized for
each patient; however, smoking cessation is important for women across all age groups.
(Evidence level: 2, recommendation level: A)
In premenopausal women, lifestyle modification is the most important aspect of dyslipidemia
treatment. (Evidence level: 2, recommendation level: A)
Even before menopause, pharmacotherapy should be considered for high-risk women, such
as those with familial hypercholesterolemia or CAD, and primary prevention subjects
with high CAD risk. (Evidence level: 3, recommendation level: A)
Lifestyle modification is the fundamental aspect of treatment for dyslipidemia in
postmenopausal women; however, pharmacotherapy should be considered in patients with
high CAD risk. (Evidence level: 2, recommendation level: A)
1.
Current Status of ASCVD in Japanese Women
According to the gender-specific causes of death in the 2014 Population Census of
Japan, mortality rates for cardiovascular disease, including heart failure, and cerebrovascular
disease in women is 26.8%, which is higher than the rate of 22.3% in men and the rate
of 24.4% for malignant neoplasms
936). However, myocardial infarction incidence is lower in women than in men
937, 938) The epidemiological survey conducted in Japan between 1990 and the beginning
of 2000 revealed that the age-adjusted incidence (100,000 persons/year) of myocardial
infarction in women is 20–50% of that in men
98, 163, 939, 940). Although the incidence rate of myocardial infarction increases
after menopause, the rate is still lower than that in men
163). According to the 2013 demographic statistics, mortality rate (per 100,000 persons)
due to myocardial infarction in women is lower than that in men in the corresponding
age groups: approximately 20% of the men's rate in the 50s, 20–30% in the 60s, and
37–48% even in their 70s
936). In contrast, it has been reported that the mortality rate after a coronary event
is higher in women than in men among both Western
941–944) and Japanese subjects
945, 946). Aging among Japanese women is progressing and is accompanied by an increased
morbidity and mortality due to myocardial infarction
163, 936). Thus, it is important to take future measures for prevention and care even
in Japanese women.
Among the Japanese, the age-adjusted incidence of cerebral infarction is higher than
that of myocardial infarction. However, the incidence in women is approximately 50–70%
of that in men
98, 939, 940, 947–949). The incidence rate of cerebral infarction in women increases
with age, and it reaches 60–90% of that of the men for women aged ≥ 75 years. Compared
to myocardial infarction incidence, the gender difference in the rate of cerebral
infarction is small
163, 948, 949). Mortality rate due to cerebral infarction in women in 2013 (per 100,000
persons) is also lower than that in men
936). On the other hand, cross-sectional study of acute cerebral infarction reported
that the duration of hospitalization is longer for women than for men and that patient
status at the onset and after discharge is poorer for women than for men
950).
Among the Japanese, cerebral infarction incidence is higher than that of myocardial
infarction, and the gender differences in cerebral infarction incidence are smaller
than that of myocardial infarction. Furthermore, proportion of older women continues
to increase in Japan. Thus, the prevention and management of cerebral infarction among
women is an important issue for the future.
2.
Relationship between Risk Factors for Atherosclerosis and ASCVD in Women
1)
Serum Lipids
Age-related changes in serum lipid levels are significantly different between men
and women. Total cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C)
levels are higher in men than in women until the fourth decade of their lives; however,
because of menopause, the levels become higher in women than in men after the age
≥ 50 years
85). High-densitylipoprotein cholesterol (HDL-C) levels are higher in women than in
men among all age groups. Triglyceride (TG) levels are also higher in men than in
women, but this increases with age in women, and the difference between genders diminishes
after age 50 years
85). It is likely that the changes in serum lipid levels, especially changes in LDL-C
after menopause, may influence the ASCVD risk in women.
JALS-ECC
337), a longitudinal epidemiological study reported that CAD risk was significantly
higher in the high-TC group than in the low-TC group after adjustment for multiple
confounding factors in women. CIRCS also showed that myocardial infarction risk after
adjustment of multiple factors increase 1.42 times with each increase LDL-C by 30
mg/dl
37).
EPOCH-JAPAN studied the relationship between TC levels and CAD mortality risk, and
found that the risk was significantly higher in the high-TC group than in the low-TC
group for women aged between 40 and 69 years
951). The NIPPON DATA 80 also showed a significantly higher cardiovascular mortality
risk among women with hypercholesterolemia group
54). However, in the Ibaraki Prefectural Health Study, no significant correlation
was found between LDL-C and CAD mortality
38). Thus, cholesterol level is a significant risk factor for the CAD incidence among
Japanese women, and also might be a risk factor related to CAD mortality.
The JPHC Study
59) and EPOCH-JAPAN
951) examined the relationship between TC and cerebral infarction risk, and concluded
that no significant correlation existed among women.
Iso et al. reported that elevated TG level was also a significant risk factor for
the incidence of myocardial infarction and ischemic cardiovascular diseases in women
88, 93). In addition, JALS-ECC
337) and CIRCS
63) reported that non-HDL-C is a significant risk factor for CAD incidence but not
CAD mortality
66).
Thus, abnormalities in TC, LDL-C, TG, and non-HDL-C levels might be an important risk
factors of CAD for Japanese women.
2)
Smoking
The JPHC Study Cohort1
786) and Suita Study
108) found that the incidence rate of myocardial infarction was three to eight times
higher among smokers than among nonsmokers even among women. In addition, CAD-related
mortality risk was significantly higher in women smokers
952, 953). Meta-analyses involving studies conducted in Japan have reported that the
influence of smoking on CAD risk in women is greater than that in men
954). JACSS, a multicenter collaborative research of acute coronary syndrome (ACS)
in Japan, found that women who smoke had extremely higher ACS risk than men with smoking,
with an odds ratio of 8.2 in women compared to that of 4.0 in men
955).
Smoking is also a significant risk factor for cerebral infarction in women
108). Moreover, passive smoking increases cerebral hemorrhage risk but not cerebral
infarction risk among Japanese women
956).
Thus, smoking should be considered as an important risk factor for CAD and cerebral
infarction among Japanese women.
3)
Hypertension
Epidemiological studies in Japan did not demonstrate that hypertension was a significant
CAD risk factor in women
957, 958), although there was a trend for increase the CAD risk
958). However, it has been reported that hypertension was a significant risk factor
for cerebral infarction incidence among women
857, 957, 958). NIPPON DATA 80, which studied the relationship between hypertension
and cardiovascular mortality risk, reported that the association between the two was
significantly stronger for in younger women aged 30–59 years than in women aged ≥
60 years
959).
Thus, hypertension is an important risk factor for cerebral infarction among women,
and it is necessary to treat hypertension from a younger age.
4)
Diabetes
The JPHC
136, 146, 960), Hisayama
961), and Suita studies
962) reported that CAD and cerebral infarction risk as well as the related mortality
risk were significantly higher among patients with diabetes than among those without.
The NIPPON DATA 80 showed that CAD mortality risk was high among older women whose
random blood glucose ≥ 200 mg/dL
161). JACCS reported that the odds ratio for myocardial infarction incidence for female
diabetics was 6.12 compared to 2.90 for male diabetics, indicating a significant increased
myocardial infarction risk among women
954). In the meta-analyses, including the research in Japan, it was reported that
CAD risk and all-stroke risk were 44%
149) and 27%
150) higher, respectively for diabetic women than for diabetic men.
3.
Primary and Secondary ASCVD Prevention in Women
The fundamental strategy for ASCVD prevention is lifestyle modification. The Nurses'
Health Study (NHS) in US revealed that the increasing of favorable lifestyle factors
(e.g., smoking cessation, increase in physical activity, maintenance of ideal body
weight, restriction of alcohol consumption, and healthy eating habits) were associated
with lower risk of CAD
963) and sudden cardiac deaths
964). In addition, a collaborative analysis of NHS and Health Professionals Follow-up
Study reported that the relative cerebral infarction risk among women who had all
five factors described above was extremely low at 0.19, compared to women without
any of favorable lifestyle factors
965). Moreover, NHS, which included young women aged 27–44 years, showed that CAD
incidence was decreased by 98% who had six factors (the above described five factors
plus restricted TV-watching time) compared with women without any of these factors
966). Thus, maintaining a healthy lifestyle from a younger age is quite important
for preventing ASCVD in women.
Although effect of smoking on CAD risk is greater for women than for men
953), this effect is diminished after smoking cessation
108). Because smoking has a negative effect on pregnancy
967) and smoking cessation decreases ASCVD risk regardless of age
107), it is extremely important for women to stop smoking from a younger age.
Few large scale trials have investigated the primary prevention of CAD using statins
in women. In the MEGA Study conducted in Japan, 68% subjects were postmenopausal women
aged ≤ 70 years. In this study, statins did not decrease the risk of CAD and cerebral
infarction significantly in women
41). However, in the sub-analysis among women, risk of CAD combined with cerebral
infarction was significantly decreased among the women aged ≥ 55 years
620). In JUPITER, statins were administered to 3,426 female subjects, and the risks
of unstable angina and reperfusion therapy were significantly decreased compared to
the placebo group. However, significant risk reduction of myocardial infarction and
cerebrovascular events was not observed in women with statin therapy
968). In addition, the risk for the primary endpoints that include these events was
significantly lower among the women aged ≥ 65 years but not in women aged < 65 years
620). CTT reported that the significant risk reduction of CVD for 0.72 with each decrease
in LDL-C by 38.7 mg/dL for men without history of vascular diseases. On the other
hand, risk reduction was 0.85 for women, and this was not statistically significant
179).
Because effect of statins on the primary prevention of ASCVD is not evident in women,
the primary treatment strategy for women is lifestyle modification. However, drug
therapy should be considered for women with FH and CAD as well as for primary prevention
subjects who are at high CAD risk. There is little evidence that dyslipidemia increased
CAD risk in premenopausal women. Thus, lifestyle modification is fundamental for treating
dyslipidemia in premenopausal women after ruling out dyslipidemia due to secondary
causes. A consensus has not been reached about the teratogenic risks on a fetus by
statins during pregnancy
662, 969, 970), and there is insufficient knowledge on the secretion of statins into
breast milk. Thus, statin administration during pregnancy or lactation must be prohibited.
In secondary prevention, a meta-analysis of 11 studies, including 4S and CARE, reported
that statins significantly decreased cardiovascular event risk to 0.82 in men and
0.81 in women
971). The results of a CTT also showed a significant risk reduction of 0.84 for CVD
with each decrease in LDL-C by 38.7 mg/dL in women with a history of vascular diseases,
similar to that in men
179). J-STARS investigated the effect of statins on the prevention of recurrent stroke
in patients with cerebral infarction history. During 5-year study revealed that atherothrombotic
cerebral infarction risk decreased significantly to 67%; however, risk reduction in
women was not significant compared to that in men
619).
Thus, it is necessary to treat women for the secondary prevention of CAD; however,
the effect of statins on preventing the recurrence of cerebral infarction is not evident
in women.
Although strict glycemic control contributes to the CAD prevention in diabetics
972), it requires a longer duration to reveal a protective effect
973, 974). In addition, its effect is small compared to the risk reduction seen for
microvascular complications
834). Because of increase in risk of hypoglycemia, strict glycemic control should
be carefully considered by patients' conditions
972, 975). The effect of diabetes on ASCVD incidence is greater for women than for
men
149, 150). Thus, it is important to initiate early comprehensive management, including
risk factors other than hyperglycemia for ASCVD prevention.
Hypertension is an important risk factor for cerebral infarction in women and has
been suggested to be a CAD risk factor. The number of hypertensive subjects increases
with age both men and women, and the number of female patients surpasses that of males
from age 60 years
976). After menopause, LDL-C increases in women
950) and ASCVD risk increases. Thus, hypertension management becomes important in
postmenopausal women. Meta-analysis reported that there was no clear difference in
the risk reduction of CVD by hypertension treatment between men and women
977).
Intervention trial of hypertension among premenopausal women has not performed yet.
Thus, lifestyle modification is quite important among premenopausal women after ruling
out hypertension due to secondary causes. For the control of pregnancy-related and
postmenopausal hypertension, the guidelines of the Japanese Society of Hypertension
should be applied
122).
Hormone-replacement therapy (HRT) is effective treating postmenopausal disorders and
osteoporosis prevention. Multiple clinical trials on the relationship between HRT
and CVD risk have been reported. In HERS, women who had CAD were given HRT, did not
reveal any risk reduction of CAD or cerebrovascular disease
978, 979). In a study including 16,608 postmenopausal women, Women's Health Initiative
(WHI) examined the effect of HRT (conjugated estrogen + medroxyprogesterone acetate)
on middle-aged and older US women who suffered from disorders that disturbed their
quality of life. The results of this study showed a significant increase in cerebral
infarction risk (1.44)
980) and CAD (1.24) among women with HRT than among control women
981). In this study, only women with conjugated estrogen replacement therapy showed
a significant increase in cerebral infarction risk of 1.55
982). Although, the increase in the risk of HRT-related CAD and cerebrovascular diseases
are associated with age; there was no increased risk for either diseases among women
aged < 60 years and the risk for CAD was relatively low
982, 983).
The Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and
Women's Health developed a 2012 version of HRT guidelines
984). The guidelines prohibit the use of HRT for patients who have a history of myocardial
infarction, other CAD, and stroke. They also recommend the careful consideration of
HRT when patients are obese, aged ≥ 60 years, have been postmenopausal for ≥ 10 years
or have a history of coronary spasms and microvascular angina, severe hypertriglyceridemia,
or uncontrollable diabetes or hypertension. To date, several studies have reported
the negative effect of HRT on CVD risk; however, favorable effects of estrogen on
lipid metabolism and vascular function have been established, and transdermal estrogen
has been reported to significantly decrease myocardial infarction risk
985). Thus, the benefits and safety of different types and dosages of estrogen and
progestin not used in WHI, and the route of administration cannot be overlooked and
further research is needed
986).
Currently, CAD incidence among women is considerably lower in Japan than in Western
countries
938). A decrease in cerebrovascular disease incidence has also been observed because
hypertension control
938). On the other hand, new concerns related ASCVD risk such as westernized eating
habits and decreasing of physical activity become apparent. Moreover, in a 2014 survey,
10–15% women in their 20s and 30s reported smoking
987). Because women live longer than men, it is particularly important to introduce
healthy lifestyle and control of risk factors of ASCVD from a younger age in woman.
Chapter 9.
Children
[Statement]
Early detection and correct diagnosis of dyslipidemia are important. (Consensus, recommendation
level: A)
In cases of familial hypercholesterolemia, attempt to identify new patients (children)
in the family (cascade screening). (Consensus, recommendation level: A)
Provide patients with familial hypercholesterolemia with guidance on lifestyle habits,
including diet, while considering the indication of drug therapy. (Consensus, recommendation
level: A)
Nonpharmacological therapy is the main treatment for primary dyslipidemia other than
familial hypercholesterolemia. (Consensus, recommendation level: A)
In cases of secondary dyslipidemia, adequately treat the primary disease. (Consensus,
recommendation level: A)
It is recommended that children establish appropriate dietary and exercise habits
and maintain proper body weight. (Consensus, recommendation level: A)
1.
Early Detection of Dyslipidemia
Children do not have many opportunities to have their blood tested. If there is an
opportunity to collect and test their blood, TC and TG should be tested at least once.
Any abnormalities should be investigated in detail. For blood samples collected in
a fasting state, LDL-C is calculated based on TC, TG, and HDL-C. For blood samples
collected in a nonfasting state, LDL-C measured using the direct method and non-HDL-C
should be used as a reference.
2.
Criteria for Dyslipidemia in Children
Diagnostic criteria for dyslipidemia in children (i.e., elementary and junior high
school students) are presented in
Table 19
. These values are derived from a report by Okada et al.
988) based on a nationwide survey conducted in the 1990s. TC, LDL-C, and TG are based
on the 95th percentile values, and HDL-C is based on the 5th percentile value. Although
some age-related differences are seen, the entire group of children is represented
by a single value. Recent studies have also reported that lipid levels do not substantially
differ from the previously determined levels
989). Regarding the reference value for non-HDL-C, the 95th percentile value is reported
to be approximately 140 mg/dL in junior high school boys, whereas it is approximately
150 mg/dL in elementary school boys, as well as elementary and junior high school
girls
989).
Table 19.
Diagnostic Criteria for Dyslipidemia in children (elementary and junior high school
students) (fasting blood samples)
Total cholesterol (TC)
≥ 220 mg/dL
LDL cholesterol (LDL-C)
≥ 140 mg/dL
Triglycerides (TG)
≥ 140 mg/dL
HDL cholesterol (HDL-C)
< 40 mg/dL
TC, LDL-C, and TG are derived from the 95th percentile values and HDL-C is derived
from the 5th percentile value
988).
Postprandial TG levels in children were studied by Kobayashi et al.
990) during screening for lifestylerelated diseases and were found to increase within
1 h after eating and remained nearly constant until 3 h later, after which they decreased.
The 95th percentile value for postprandial TG is approximately 200 mg/dL.
3.
Primary Dyslipidemia
Primary hypercholesterolemia and primary hyperchylomicronemia are primary concerns
for children. Type Ⅲ hyperlipidemia is considered to be rare in children.
1)
Primary Hypercholesterolemia (Hyper-LDL-Cholesterolemia)
FH requires appropriate medical attention beginning from childhood. This is because
LDL-C values become extremely high because of abnormalities in gene encoding for the
LDL receptor system. Genetic testing results suggest that the incidence of FH is higher
than that previously described. When a child is suspected of having FH, interviews
to obtain a detailed family history and blood tests of family members (i.e., lipid
tests) should be conducted to identify any newly affected children and adults in the
family (e.g., cascade screening). It is recommended that proactive treatment be initiated
in childhood because CAD often occur at a young age. When LDL-C is ≥ 180 mg/dL even
with continuing guidance regarding lifestyle habits, it is recommended to consider
drug therapy from approximately 10 years of age (See Chapter 5 “Familial Hypercholesterolemia”).
For FCHL, there is no evidence indicating the necessity of proactive drug therapy
during childhood.
2)
Primary Hypertriglyceridemia
It is important to detect primary hyperchylomicronemia, which can cause pancreatitis,
particularly LPL deficiency, in children. Many reports have documented LPL gene mutations.
Other possible causes include a deficiency of apolipoprotein C-II, which activates
LPL, and mutations in apolipoprotein A-V genes.
Homozygotes have very severe hypertriglyceridemia (≥ 1,000 mg/dL). Diet therapy (fat
intake restriction and the use of medium-chain fatty-acid milk for infants) is the
primary form of treatment.
4.
Secondary Dyslipidemia
Various causes are involved in the development of secondary dyslipidemia. Among these,
obesity is frequently involved. In addition, thyroid hormones should always be tested
when the cause is unclear because some patients with hypothyroidism (e.g., Hashimoto's
thyroiditis) have severe hyper-LDL-cholesterolemia. Attention should also be paid
to druginduced dyslipidemia.
Obese patients require treatment to reduce the degree of obesity. Hyper-LDL-cholesterolemia
accompanying diabetes is also particularly problematic in children. Diabetes itself
is a major risk factor for arteriosclerosis, and blood glucose control alone seems
to be insufficient for preventing ASCVD (see Chapter 4 “Comprehensive Risk Management,
4-2) Diabetes”). The International Society for Pediatric and Adolescent Diabetes guidelines
991) state lipid management targets of < 100 mg/dL for LDL-C, > 35 mg/dL for HDL-C,
and < 150 mg/dL for TG. When LDL-C is above the target level, blood glucose control
is intensified and diet and exercise therapies for hyperlipidemia are added. For hypo-HDL-cholesterolemia
and hypertriglyceridemia, the basic approach is to improve lifestyle habits
991). In Japan, the general consensus is that LDL-C should be maintained at least
within the normal range (< 140 mg/dL); however, no explicit criteria are currently
available for drug therapy for children
992). Therefore, it is important to take care of children's diets and continue with
strict blood glucose control.
5.
Maintaining Proper Body Weight with Appropriate Diet and Exercise Habits
Pathological blood vessel changes associated with arteriosclerosis have been reported
to gradually occur in childhood
993, 994). It is important to prevent such changes from occurring and progressing
as much as possible. To achieve this, it is important to develop correct lifestyle
habits (e.g., diet) and maintain a proper body weight from childhood. Even in children,
obesity causes problems such as abnormal blood test values (e.g., adipocytokine secretion)
and blood pressure
995, 996). Thus, obesity in children is also considered to promote ASCVD similar to
that in adults, and attention paid to obesity during childhood helps reduce the risk
of future lifestyle-related diseases.
The 2015 Dietary Reference Intakes for Japanese
997) lists the desirable daily energy intake according to age and body size. Regarding
nutritional balance, the target ratios of energy intake from fat and carbohydrates
are 20–30% and 50–65%, respectively, which are same for all age groups (from 1 year
to ≥ 70 years). Fat intake should be moderate because in recent years, due to the
westernization of dietary habits, fat intake has increased. Therefore, it is recommended
that individuals consume a well-balanced amount of fish, soybeans (products), vegetables,
fruits, and seaweed, by utilizing Japanese food patterns as a main method, with no
preference to a particular type of food. Care should also be taken to avoid excess
salt intake.
Because BMI percentile (or standard deviation) method is inappropriate to evaluate
overweight and obesity in children, because of the large variability in body height,
it is better to assess the percentage of overweight (POW) based on comparison with
standard body weight
998). The POW is calculated as [(measured body weight–standard body weight)/standard
body weight] × 100 (%). In general, elementary and junior high school students are
classified as obese if the calculated POW is + 20% or higher (≥ 120% of the standard
body weight)
998). Like in obese adults, LDL-C and TG tend to be high in obese children, whereas
HDL-C tends to be low. Even if the calculated POW is not indicative of severe obesity
(≥ 50%), the child is considered to be “obesity disease”, a target of treatment for
reducing the severity of obesity, when he or she exhibits any obesity-related complications
996).
In obesity, the energy intake is increased and exceeds the necessary level; it should
be reversed to normal levels. Obese children should increase their vegetable intake
and avoid certain drinks and seasonings. The degree of obesity improves more easily
during childhood because body height continues to increase. Moreover, an exercise
habit should be established at the same time as dietary restrictions. In particular,
adequate guidance should be given to children who are obese or not accustomed to exercise.
In cases of severe obesity, energy intake may also need to be restricted.
Smoking is also an independent major risk factor for ASCVD, and smoking cessation
is known to reduce the risk of developing such diseases. Because passive smoking has
also been reported to increase the risk for CAD and diabetes, attention should be
paid to smoking not only by the patient themselves but also by other family members.