CONTENTS
CLASSIFICATION AND DIAGNOSIS OF DIABETES, p. S12
Classification of diabetes
Diagnosis of diabetes
Categories of increased risk for diabetes (prediabetes)
TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS, p. S13
Testing for type 2 diabetes and risk of future diabetes in adults
Testing for type 2 diabetes in children
Screening for type 1 diabetes
DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS, p. S15
PREVENTION/DELAY OF TYPE 2 DIABETES, p. S16
DIABETES CARE, p. S16
Initial evaluation
Management
Glycemic control
Assessment of glycemic control
Glucose monitoring
A1C
Glycemic goals in adults
Pharmacologic and overall approaches to treatment
Therapy for type 1 diabetes
Therapy for type 2 diabetes
Diabetes self-management education
Medical nutrition therapy
Physical activity
Psychosocial assessment and care
When treatment goals are not met
Hypoglycemia
Intercurrent illness
Bariatric surgery
Immunization
PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS, p. S27
Cardiovascular disease
Hypertension/blood pressure control
Dyslipidemia/lipid management
Antiplatelet agents
Smoking cessation
Coronary heart disease screening and treatment
Nephropathy screening and treatment
Retinopathy screening and treatment
Neuropathy screening and treatment
Foot care
DIABETES CARE IN SPECIFIC POPULATIONS, p. S38
Children and adolescents
Type 1 diabetes Glycemic control
Screening and management of chronic complications in children and adolescents with
type 1 diabetes
Nephropathy
Hypertension
Dyslipidemia
Retinopathy
Celiac disease
Hypothyroidism
Self-management
School and day care
Transition from pediatric to adult care
Type 2 diabetes
Monogenic diabetes syndromes
Preconception care
Older adults
Cystic fibrosis–related diabetes
DIABETES CARE IN SPECIFIC SETTINGS, p. S43
Diabetes care in the hospital
Glycemic targets in hospitalized patients
Anti-hyperglycemic agents in hospitalized patients
Preventing hypoglycemia
Diabetes care providers in the hospital
Self-management in the hospital
Diabetes self-management education in the hospital
Medical nutrition therapy in the hospital
Bedside blood glucose monitoring
Discharge planning
STRATEGIES FOR IMPROVING DIABETES CARE, p. S46
Diabetes is a chronic illness that requires continuing medical care and ongoing patient
self-management education and support to prevent acute complications and to reduce
the risk of long-term complications. Diabetes care is complex and requires that many
issues, beyond glycemic control, be addressed. A large body of evidence exists that
supports a range of interventions to improve diabetes outcomes.
These standards of care are intended to provide clinicians, patients, researchers,
payors, and other interested individuals with the components of diabetes care, general
treatment goals, and tools to evaluate the quality of care. While individual preferences,
comorbidities, and other patient factors may require modification of goals, targets
that are desirable for most patients with diabetes are provided. These standards are
not intended to preclude clinical judgment or more extensive evaluation and management
of the patient by other specialists as needed. For more detailed information about
management of diabetes, refer to references 1
–3.
The recommendations included are screening, diagnostic, and therapeutic actions that
are known or believed to favorably affect health outcomes of patients with diabetes.
A grading system (Table 1), developed by the American Diabetes Association (ADA) and
modeled after existing methods, was utilized to clarify and codify the evidence that
forms the basis for the recommendations. The level of evidence that supports each
recommendation is listed after each recommendation using the letters A, B, C, or E.
Table 1
ADA evidence grading system for clinical practice recommendations
Level of evidence
Description
A
Clear evidence from well-conducted, generalizable, randomized controlled trials that
are adequately powered, including:
Evidence from a well-conducted multicenter trial
Evidence from a meta-analysis that incorporated quality ratings in the analysis
Compelling nonexperimental evidence, i.e., “all or none” rule developed by Center
for Evidence Based Medicine at Oxford
Supportive evidence from well-conducted randomized controlled trials that are adequately
powered, including:
Evidence from a well-conducted trial at one or more institutions
Evidence from a meta-analysis that incorporated quality ratings in the analysis
B
Supportive evidence from well-conducted cohort studies
Evidence from a well-conducted prospective cohort study or registry
Evidence from a well-conducted meta-analysis of cohort studies
Supportive evidence from a well-conducted case-control study
C
Supportive evidence from poorly controlled or uncontrolled studies
Evidence from randomized clinical trials with one or more major or three or more minor
methodological flaws that could invalidate the results
Evidence from observational studies with high potential for bias (such as case series
with comparison to historical controls)
Evidence from case series or case reports
Conflicting evidence with the weight of evidence supporting the recommendation
E
Expert consensus or clinical experience
These standards of care are revised annually by the ADA's multidisciplinary Professional
Practice Committee, incorporating new evidence. Members of the Professional Practice
Committee and their disclosed conflicts of interest are listed on page S97. Subsequently,
as with all Position Statements, the standards of care are reviewed and approved by
the Executive Committee of ADA's Board of Directors.
I. CLASSIFICATION AND DIAGNOSIS OF DIABETES
A. Classification of diabetes
The classification of diabetes includes four clinical classes:
Type 1 diabetes (results from β-cell destruction, usually leading to absolute insulin
deficiency)
Type 2 diabetes (results from a progressive insulin secretory defect on the background
of insulin resistance)
Other specific types of diabetes due to other causes, e.g., genetic defects in β-cell
function, genetic defects in insulin action, diseases of the exocrine pancreas (such
as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of HIV/AIDS
or after organ transplantation)
Gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy that is not
clearly overt diabetes)
Some patients cannot be clearly classified as having type 1 or type 2 diabetes. Clinical
presentation and disease progression vary considerably in both types of diabetes.
Occasionally, patients who otherwise have type 2 diabetes may present with ketoacidosis.
Similarly, patients with type 1 diabetes may have a late onset and slow (but relentless)
progression of disease despite having features of autoimmune disease. Such difficulties
in diagnosis may occur in children, adolescents, and adults. The true diagnosis may
become more obvious over time.
B. Diagnosis of diabetes
For decades, the diagnosis of diabetes was based on plasma glucose criteria, either
the fasting plasma glucose (FPG) or the 2-h value in the 75-g oral glucose tolerance
test (OGTT) (4).
In 2009, an International Expert Committee that included representatives of the ADA,
the International Diabetes Federation (IDF), and the European Association for the
Study of Diabetes (EASD) recommended the use of the A1C test to diagnose diabetes,
with a threshold of ≥6.5% (5), and ADA adopted this criterion in 2010 (4). The diagnostic
test should be performed using a method that is certified by the National Glycohemoglobin
Standardization Program (NGSP) and standardized or traceable to the Diabetes Control
and Complications Trial (DCCT) reference assay. Point-of-care A1C assays are not sufficiently
accurate at this time to use for diagnostic purposes.
Epidemiologic datasets show a similar relationship between A1C and risk of retinopathy
as has been shown for the corresponding FPG and 2-h plasma glucose thresholds. The
A1C has several advantages to the FPG and OGTT, including greater convenience, since
fasting is not required; evidence to suggest greater preanalytical stability; and
less day-to-day perturbations during periods of stress and illness. These advantages
must be balanced by greater cost, the limited availability of A1C testing in certain
regions of the developing world, and the incomplete correlation between A1C and average
glucose in certain individuals. In addition, A1C levels can vary with patients' ethnicity
(6) as well as with certain anemias and hemoglobinopathies. For patients with an abnormal
hemoglobin but normal red cell turnover, such as sickle cell trait, an A1C assay without
interference from abnormal hemoglobins should be used (an updated list is available
at www.ngsp.org/interf.asp). For conditions with abnormal red cell turnover, such
as pregnancy, recent blood loss or transfusion, or some anemias, the diagnosis of
diabetes must employ glucose criteria exclusively.
The established glucose criteria for the diagnosis of diabetes (FPG and 2-h PG) remain
valid as well (Table 2). Just as there is less than 100% concordance between the FPG
and 2-h PG tests, there is not perfect concordance between A1C and either glucose-based
test. Analyses of National Health and Nutrition Examination Survey (NHANES) data indicate
that, assuming universal screening of the undiagnosed, the A1C cut point of ≥6.5%
identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut
point of ≥126 mg/dl (7.0 mmol/l) (7). However, in practice, a large portion of the
diabetic population remains unaware of their condition. Thus, the lower sensitivity
of A1C at the designated cut point may well be offset by the test's greater practicality,
and wider application of a more convenient test (A1C) may actually increase the number
of diagnoses made.
Table 2
Criteria for the diagnosis of diabetes
A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP
certified and standardized to the DCCT assay.*
or
FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least
8 h.*
or
2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed
as described by the World Health Organization, using a glucose load containing the
equivalent of 75 g anhydrous glucose dissolved in water.*
or
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random
plasma glucose ≥200 mg/dl (11.1 mmol/l)
*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat
testing.
As with most diagnostic tests, a test result diagnostic of diabetes should be repeated
to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such
as a patient with a hyperglycemic crisis or classic symptoms of hyperglycemia and
a random plasma glucose ≥200 mg/dl. It is preferable that the same test be repeated
for confirmation, since there will be a greater likelihood of concurrence in this
case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of
diabetes is confirmed. However, if two different tests (such as A1C and FPG) are both
above the diagnostic thresholds, the diagnosis of diabetes is also confirmed.
On the other hand, if two different tests are available in an individual and the results
are discordant, the test whose result is above the diagnostic cut point should be
repeated, and the diagnosis is made on the basis of the confirmed test. That is, if
a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the
FPG (<126 mg/dl or 7.0 mmol/l), or vice versa, that person should be considered to
have diabetes.
Since there is preanalytic and analytic variability of all the tests, it is also possible
that when a test whose result was above the diagnostic threshold is repeated, the
second value will be below the diagnostic cut point. This is least likely for A1C,
somewhat more likely for FPG, and most likely for the 2-h PG. Barring a laboratory
error, such patients are likely to have test results near the margins of the threshold
for a diagnosis. The healthcare professional might opt to follow the patient closely
and repeat the testing in 3–6 months.
The current diagnostic criteria for diabetes are summarized in Table 2.
C. Categories of increased risk for diabetes (prediabetes)
In 1997 and 2003, The Expert Committee on Diagnosis and Classification of Diabetes
Mellitus (8,9) recognized an intermediate group of individuals whose glucose levels,
although not meeting criteria for diabetes, are nevertheless too high to be considered
normal. These persons were defined as having impaired fasting glucose (IFG) (FPG levels
100–125 mg/dl [5.6–6.9 mmol/l]) or impaired glucose tolerance (IGT) (2-h PG values
in the OGTT of 140–199 mg/dl [7.8–11.0 mmol/l]). It should be noted that the World
Health Organization (WHO) and a number of other diabetes organizations define the
cutoff for IFG at 110 mg/dl (6.1 mmol/l).
Individuals with IFG and/or IGT have been referred to as having prediabetes, indicating
the relatively high risk for the future development of diabetes. IFG and IGT should
not be viewed as clinical entities in their own right but rather risk factors for
diabetes as well as cardiovascular disease (CVD). IFG and IGT are associated with
obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides
and/or low HDL cholesterol, and hypertension.
As is the case with the glucose measures, several prospective studies that used A1C
to predict the progression to diabetes demonstrated a strong, continuous association
between A1C and subsequent diabetes. In a systematic review of 44,203 individuals
from 16 cohort studies with a follow-up interval averaging 5.6 years (range 2.8–12
years), those with an A1C between 5.5 and 6.0% had a substantially increased risk
of diabetes with 5-year incidences ranging from 9–25%. An A1C range of 6.0–6.5% had
a 5-year risk of developing diabetes between 25–50% and relative risk 20 times higher
compared with an A1C of 5.0% (10). In a community-based study of black and white adults
without diabetes, baseline A1C was a stronger predictor of subsequent diabetes and
cardiovascular events than fasting glucose (11). Other analyses suggest that an A1C
of 5.7% is associated with diabetes risk similar to that of the high-risk participants
in the Diabetes Prevention Program (DPP).
Hence, it is reasonable to consider an A1C range of 5.7–6.4% as identifying individuals
with high risk for future diabetes, a state that may be referred to as prediabetes
(4). As is the case for individuals found to have IFG and IGT, individuals with an
A1C of 5.7–6.4% should be informed of their increased risk for diabetes as well as
CVD and counseled about effective strategies to lower their risks (see iv. prevention/delay
of type 2 diabetes). As with glucose measurements, the continuum of risk is curvilinear—as
A1C rises, the risk of diabetes rises disproportionately (10). Accordingly, interventions
should be most intensive and follow-up particularly vigilant for those with A1Cs above
6.0%, who should be considered to be at very high risk.
Table 3 summarizes the categories of increased risk for diabetes.
Table 3
Categories of increased risk for diabetes (prediabetes)*
FPG 100–125 mg/dl (5.6–6.9 mmol/l): IFG
or
2-h plasma glucose in the 75-g OGTT 140–199 mg/dl (7.8–11.0 mmol/l): IGT
or
A1C 5.7–6.4%
*For all three tests, risk is continuous, extending below the lower limit of the range
and becoming disproportionately greater at higher ends of the range.
II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS
Recommendations
Testing to detect type 2 diabetes and assess risk for future diabetes in asymptomatic
people should be considered in adults of any age who are overweight or obese (BMI
≥25 kg/m2) and who have one or more additional risk factors for diabetes (Table 4).
In those without these risk factors, testing should begin at age 45 years. (B)
If tests are normal, repeat testing carried out at least at 3-year intervals is reasonable.
(E)
To test for diabetes or to assess risk of future diabetes, A1C, FPG, or 2-h 75-g OGTT
is appropriate. (B)
In those identified with increased risk for future diabetes, identify and, if appropriate,
treat other CVD risk factors. (B)
For many illnesses, there is a major distinction between screening and diagnostic
testing. However, for diabetes, the same tests would be used for “screening” as for
diagnosis. Diabetes may be identified anywhere along a spectrum of clinical scenarios
ranging from a seemingly low-risk individual who happens to have glucose testing,
to a higher-risk individual whom the provider tests because of high suspicion of diabetes,
to the symptomatic patient. The discussion herein is primarily framed as testing for
diabetes in those without symptoms. Testing for diabetes will also detect individuals
at increased future risk for diabetes, herein referred to as having prediabetes.
Table 4
Criteria for testing for diabetes in asymptomatic adult individuals
Testing should be considered in all adults who are overweight (BMI ≥25 kg/m2
*) and have additional risk factors:
physical inactivity
first-degree relative with diabetes
high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American,
Pacific Islander)
women who delivered a baby weighing >9 lb or were diagnosed with GDM
hypertension (≥140/90 mmHg or on therapy for hypertension)
HDL cholesterol level <35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl
(2.82 mmol/l)
women with polycystic ovarian syndrome (PCOS)
A1C ≥5.7%, IGT, or IFG on previous testing
other clinical conditions associated with insulin resistance (e.g., severe obesity,
acanthosis nigricans)
history of CVD
In the absence of the above criteria, testing for diabetes should begin at age 45
years.
If results are normal, testing should be repeated at least at 3-year intervals, with
consideration of more frequent testing depending on initial results and risk status.
*At-risk BMI may be lower in some ethnic groups.
A. Testing for type 2 diabetes and risk of future diabetes in adults
Type 2 diabetes is frequently not diagnosed until complications appear, and approximately
one-fourth of all people with diabetes in the U.S. may be undiagnosed. The effectiveness
of early identification of prediabetes and diabetes through mass testing of asymptomatic
individuals has not been proven definitively, and rigorous trials to provide such
proof are unlikely to occur. However, mathematical modeling studies suggest that screening
independent of risk factors beginning at age 30 or 45 years is highly cost-effective
(<$11,000 per quality-adjusted life-year gained) (12). Prediabetes and diabetes meet
established criteria for conditions in which early detection is appropriate. Both
conditions are common and increasing in prevalence and impose significant public health
burdens. There is a long presymptomatic phase before the diagnosis of type 2 diabetes
is usually made. Relatively simple tests are available to detect preclinical disease.
Additionally, the duration of glycemic burden is a strong predictor of adverse outcomes,
and effective interventions exist to prevent progression of prediabetes to diabetes
(see iv. prevention/delay of type 2 diabetes) and to reduce risk of complications
of diabetes (see vi. prevention and management of diabetes complications).
Recommendations for testing for diabetes in asymptomatic, undiagnosed adults are listed
in Table 4. Testing should be considered in adults of any age with BMI ≥25 kg/m2 and
one or more of the known risk factors for diabetes. Because age is a major risk factor
for diabetes, testing of those without other risk factors should begin no later than
age 45 years.
Either A1C, FPG, or the 2-h OGTT is appropriate for testing. The 2-h OGTT identifies
people with either IFG or IGT and thus more people at increased risk for the development
of diabetes and CVD. It should be noted that the two tests do not necessarily detect
the same individuals. The efficacy of interventions for primary prevention of type
2 diabetes (13
–19) have primarily been demonstrated among individuals with IGT, not for individuals
with IFG (who do not also have IGT) or for individuals with specific A1C levels.
The appropriate interval between tests is not known (20). The rationale for the 3-year
interval is that false negatives will be repeated before substantial time elapses,
and there is little likelihood that an individual will develop significant complications
of diabetes within 3 years of a negative test result. In the modeling study, repeat
screening every 3 or 5 years was cost-effective (12).
Because of the need for follow-up and discussion of abnormal results, testing should
be carried out within the health care setting. Community screening outside a health
care setting is not recommended because people with positive tests may not seek, or
have access to, appropriate follow-up testing and care. Conversely, there may be failure
to ensure appropriate repeat testing for individuals who test negative. Community
screening may also be poorly targeted, i.e., it may fail to reach the groups most
at risk and inappropriately test those at low risk (the worried well) or even those
already diagnosed.
B. Testing for type 2 diabetes in children
The incidence of type 2 diabetes in adolescents has increased dramatically in the
last decade, especially in minority populations (21), although the disease remains
rare in the general pediatric population (22). Consistent with recommendations for
adults, children and youth at increased risk for the presence or the development of
type 2 diabetes should be tested within the health care setting. The recommendations
of the ADA Consensus Statement on Type 2 Diabetes in Children and Youth (23), with
some modifications, are summarized in Table 5.
Table 5
Testing for type 2 diabetes in asymptomatic children
Criteria
Overweight (BMI >85th percentile for age and sex, weight for height >85th percentile,
or weight >120% of ideal for height)
Plus any two of the following risk factors:
Family history of type 2 diabetes in first- or second-degree relative
Race/ethnicity (Native American, African American, Latino, Asian American, Pacific
Islander)
Signs of insulin resistance or conditions associated with insulin resistance (acanthosis
nigricans, hypertension, dyslipidemia, PCOS, or small-for-gestational-age birth weight)
Maternal history of diabetes or GDM during the child's gestation
Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger
age
Frequency: every 3 years
C. Screening for type 1 diabetes
Generally, people with type 1 diabetes present with acute symptoms of diabetes and
markedly elevated blood glucose levels, and most cases are diagnosed soon after the
onset of hyperglycemia. However, evidence from type 1 prevention studies suggests
that measurement of islet autoantibodies identifies individuals who are at risk for
developing type 1 diabetes. Such testing may be appropriate in high-risk individuals,
such as those with prior transient hyperglycemia or those who have relatives with
type 1 diabetes, in the context of clinical research studies (see, for example, http://www2.diabetestrialnet.org).
Widespread clinical testing of asymptomatic low-risk individuals cannot currently
be recommended, as it would identify very few individuals in the general population
who are at risk. Individuals who screen positive should be counseled about their risk
of developing diabetes. Clinical studies are being conducted to test various methods
of preventing type 1 diabetes, or reversing early type 1 diabetes, in those with evidence
of autoimmunity.
III. DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS
Recommendations
Screen for undiagnosed type 2 diabetes at the first prenatal visit in those with risk
factors, using standard diagnostic criteria. (B)
In pregnant women not known to have diabetes, screen for GDM at 24–28 weeks of gestation,
using a 75-g 2-h OGTT and the diagnostic cut points in Table 6. (B)
Screen women with GDM for persistent diabetes 6–12 weeks postpartum. (E)
Women with a history of GDM should have lifelong screening for the development of
diabetes or prediabetes at least every 3 years. (E)
For many years, GDM was defined as any degree of glucose intolerance with onset or
first recognition during pregnancy (8), whether or not the condition persisted after
pregnancy, and not excluding the possibility that unrecognized glucose intolerance
may have antedated or begun concomitantly with the pregnancy. This definition facilitated
a uniform strategy for detection and classification of GDM, but its limitations were
recognized for many years. As the ongoing epidemic of obesity and diabetes has led
to more type 2 diabetes in women of childbearing age, the number of pregnant women
with undiagnosed type 2 diabetes has increased (24). Because of this, it is reasonable
to screen women with risk factors for type 2 diabetes (Table 4) for diabetes at their
initial prenatal visit, using standard diagnostic criteria (Table 2). Women with diabetes
found at this visit should receive a diagnosis of overt, not gestational, diabetes.
Table 6
Screening for and diagnosis of GDM
Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at
24–28 weeks of gestation in women not previously diagnosed with overt diabetes.
The OGTT should be performed in the morning after an overnight fast of at least 8
h.
The diagnosis of GDM is made when any of the following plasma glucose values are exceeded:
Fasting ≥92 mg/dl (5.1 mmol/l)
1 h ≥180 mg/dl (10.0 mmol/l)
2 h ≥153 mg/dl (8.5 mmol/l)
GDM carries risks for the mother and neonate. The Hyperglycemia and Adverse Pregnancy
Outcomes (HAPO) study (25), a large-scale (∼25,000 pregnant women) multinational epidemiologic
study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously
increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously
considered normal for pregnancy. For most complications, there was no threshold for
risk. These results have led to careful reconsideration of the diagnostic criteria
for GDM. After deliberations in 2008–2009, the International Association of Diabetes
and Pregnancy Study Groups (IADPSG), an international consensus group with representatives
from multiple obstetrical and diabetes organizations, including ADA, developed revised
recommendations for diagnosing GDM. The group recommended that all women not known
to have diabetes undergo a 75-g OGTT at 24–28 weeks of gestation. Additionally, the
group developed diagnostic cut points for the fasting, 1-h, and 2-h plasma glucose
measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared
with the mean glucose levels in the HAPO study. Current screening and diagnostic strategies,
based on the IADPSG statement (26), are outlined in Table 6.
These new criteria will significantly increase the prevalence of GDM, primarily because
only one abnormal value, not two, is sufficient to make the diagnosis. The ADA recognizes
the anticipated significant increase in the incidence of GDM to be diagnosed by these
criteria and is sensitive to concerns about the “medicalization” of pregnancies previously
categorized as normal. These diagnostic criteria changes are being made in the context
of worrisome worldwide increases in obesity and diabetes rates, with the intent of
optimizing gestational outcomes for women and their babies.
Admittedly, there are few data from randomized clinical trials regarding therapeutic
interventions in women who will now be diagnosed with GDM based on only one blood
glucose value above the specified cut points (in contrast to the older criteria that
stipulated at least two abnormal values.) Expected benefits to their pregnancies and
offspring is inferred from intervention trials that focused on women with more mild
hyperglycemia than identified using older GDM diagnostic criteria and that found modest
benefits (27,28). The frequency of their follow-up and blood glucose monitoring is
not yet clear, but likely to be less intensive than women diagnosed by the older criteria.
Additional well-designed clinical studies are needed to determine the optimal intensity
of monitoring and treatment of women with GDM diagnosed by the new criteria (that
would not have met the prior definition of GDM). It is important to note that 80–90%
of women in both of the mild GDM studies (whose glucose values overlapped with the
thresholds recommended herein) could be managed with lifestyle therapy alone.
Because some cases of GDM may represent preexisting undiagnosed type 2 diabetes, women
with a history of GDM should be screened for diabetes 6–12 weeks postpartum, using
nonpregnant OGTT criteria. Women with a history of GDM have a greatly increased subsequent
risk for diabetes (29) and should be followed up with subsequent screening for the
development of diabetes or prediabetes, as outlined in ii. testing for diabetes in
asymptomatic patients.
IV. PREVENTION/DELAY OF TYPE 2 DIABETES
Recommendations
Patients with IGT (A), IFG (E), or an A1C of 5.7–6.4% (E) should be referred to an
effective ongoing support program targeting weight loss of 7% of body weight and increasing
physical activity to at least 150 min/week of moderate activity such as walking.
Follow-up counseling appears to be important for success. (B)
Based on potential cost savings of diabetes prevention, such programs should be covered
by third-party payors. (E)
Metformin therapy for prevention of type 2 diabetes may be considered in those at
the highest risk for developing diabetes, such as those with multiple risk factors,
especially if they demonstrate progression of hyperglycemia (e.g., A1C ≥6%) despite
lifestyle interventions. (B)
Monitoring for the development of diabetes in those with prediabetes should be performed
every year. (E)
Randomized controlled trials have shown that individuals at high risk for developing
diabetes (those with IFG, IGT, or both) can be given interventions that significantly
decrease the rate of onset of diabetes (13
–19). These interventions include intensive lifestyle modification programs that have
been shown to be very effective (58% reduction after 3 years) and use of the pharmacologic
agents metformin, α-glucosidase inhibitors, orlistat, and thiazolidinediones (TZDs),
each of which has been shown to decrease incident diabetes to various degrees. A summary
of major diabetes prevention trials is shown in Table 7.
Table 7
Therapies proven effective in diabetes prevention trials
Study (ref.)
n
Population
Mean age (years)
Duration (years)
Intervention (daily dose)
Incidence in control subjects (%/year)
Relative risk reduction (%) (95% CI)
3-Year number needed to treatδ
Lifestyle
Finnish DPS (14)
522
IGT, BMI ≥25 kg/m2
55
3.2
I-D&E
6
58 (30–70)
8.5
DPP (13)
2,161*
IGT, BMI ≥24 kg/m2, FPG >5.3 mmol/l
51
3
I-D&E
10.4
58 (48–66)
6.9
Da Qing (15)
259*
IGT (randomized groups)
45
6
G-D&E
14.5
38 (14–56)
7.9
Toranomon Study (35)
458
IGT (men), BMI = 24 kg/m2
∼55
4
I-D&E
2.4
67 (P < 0.043)†
20.6
Indian DPP (19)
269*
IGT
46
2.5
I-D&E
23
29 (21–37)
6.4
Medications
DPP (13)
2,155*
IGT, BMI >24 kg/m2, FPG >5.3 mmol/l
51
2.8
Metformin (1,700 mg)
10.4
31 (17–43)
13.9
Indian DPP (19)
269*
IGT
46
2.5
Metformin (500 mg)
23
26 (19–35)
6.9
STOP-NIDDM (17)
1,419
IGT, FPG >5.6 mmol/l
54
3.2
Acarbose (300 mg)
12.4
25 (10–37)
9.6
XENDOS (36)
3,277
BMI >30 kg/m2
43
4
Orlistat (360 mg)
2.4
37 (14–54)
45.5
DREAM (18)
5,269
IGT or IFG
55
3.0
Rosiglitazone (8 mg)
9.1
60 (54–65)
6.9
Voglibose Ph-3 (37)
1,780
IGT
56
3.0 (1-year Rx)
Vogliobose (0.2 mg)
12.0
40 (18–57)
21 (1-year Rx)
Modified and reprinted with permission (38).
Percentage points: δNumber needed to treat to prevent 1 case of diabetes, standardized
for a 3-year period to improve comparisons across studies.
*Number of participants in the indicated comparisons, not necessarily in entire study.
†Calculated from information in the article. DPP, Diabetes Prevention Program; DPS,
Diabetes Prevention Study; DREAM, Diabetes Reduction Assessment with Ramipril and
Rosiglitazone Medication; STOP-NIDDM, Study to Prevent Non-Insulin Dependent Diabetes;
XENDOS, Xenical in the prevention of Diabetes in Obese Subjects. I, individual; G,
group; D&E, diet and exercise.
Follow-up of all three large studies of lifestyle intervention has shown sustained
reduction in the rate of conversion to type 2 diabetes, with 43% reduction at 20 years
in the Da Qing study (30), 43% reduction at 7 years in the Finnish Diabetes Prevention
Study (DPS) (31) and 34% reduction at 10 years in the U.S. Diabetes Prevention Program
Outcomes Study (DPPOS) (32). A cost-effectiveness analysis suggested that lifestyle
interventions as delivered in the DPP are cost-effective (33). Group delivery of the
DPP intervention in community settings has the potential to be significantly less
expensive while still achieving similar weight loss (34).
Based on the results of clinical trials and the known risks of progression of prediabetes
to diabetes, persons with an A1C of 5.7–6.4%, IGT, or IFG should be counseled on lifestyle
changes with goals similar to those of the DPP (7% weight loss and moderate physical
activity of at least 150 min/week). Regarding the more difficult issue of drug therapy
for diabetes prevention, a consensus panel felt that metformin should be the only
drug considered (39). For other drugs, the issues of cost, side effects, and lack
of persistence of effect in some studies led the panel to not recommend their use
for diabetes prevention. Metformin, which was significantly less effective than lifestyle
in the DPP and DPPOS, reasonably may be recommended for very-high-risk individuals
(those with risk factors for diabetes and/or those with more severe or progressive
hyperglycemia). Of note, in the DPP metformin was most effective compared to lifestyle
in those with BMI of at least 35 kg/m2 and was not significantly better than placebo
in those over age 60 years.
V. DIABETES CARE
A. Initial evaluation
A complete medical evaluation should be performed to classify the diabetes, detect
the presence of diabetes complications, review previous treatment and glycemic control
in patients with established diabetes, assist in formulating a management plan, and
provide a basis for continuing care. Laboratory tests appropriate to the evaluation
of each patient's medical condition should be performed. A focus on the components
of comprehensive care (Table 8) will assist the health care team to ensure optimal
management of the patient with diabetes.
Table 8
Components of the comprehensive diabetes evaluation
Medical history
Age and characteristics of onset of diabetes (e.g., DKA, asymptomatic laboratory finding)
Eating patterns, physical activity habits, nutritional status, and weight history;
growth and development in children and adolescents
Diabetes education history
Review of previous treatment regimens and response to therapy (A1C records)
Current treatment of diabetes, including medications, meal plan, physical activity
patterns, and results of glucose monitoring and patient's use of data
DKA frequency, severity, and cause
Hypoglycemic episodes
Hypoglycemia awareness
Any severe hypoglycemia: frequency and cause
History of diabetes-related complications
Microvascular: retinopathy, nephropathy, neuropathy (sensory, including history of
foot lesions; autonomic, including sexual dysfunction and gastroparesis)
Macrovascular: CHD, cerebrovascular disease, PAD
Other: psychosocial problems*, dental disease*
Physical examination
Height, weight, BMI
Blood pressure determination, including orthostatic measurements when indicated
Fundoscopic examination*
Thyroid palpation
Skin examination (for acanthosis nigricans and insulin injection sites)
Comprehensive foot examination:
Inspection
Palpation of dorsalis pedis and posterior tibial pulses
Presence/absence of patellar and Achilles reflexes
Determination of proprioception, vibration, and monofilament sensation
Laboratory evaluation
A1C, if results not available within past 2–3 months
If not performed/available within past year:
Fasting lipid profile, including total, LDL and HDL cholesterol and triglycerides
Liver function tests
Test for urine albumin excretion with spot urine albumin-to-creatinine ratio
Serum creatinine and calculated GFR
Thyroid-stimulating hormone in type 1 diabetes, dyslipidemia, or women over age 50
years
Referrals
Annual dilated eye exam
Family planning for women of reproductive age
Registered dietitian for MNT
DSME
Dental examination
Mental health professional, if needed
*See appropriate referrals for these categories.
B. Management
People with diabetes should receive medical care from a physician-coordinated team.
Such teams may include, but are not limited to, physicians, nurse practitioners, physician's
assistants, nurses, dietitians, pharmacists, and mental health professionals with
expertise and a special interest in diabetes. It is essential in this collaborative
and integrated team approach that individuals with diabetes assume an active role
in their care.
The management plan should be formulated as a collaborative therapeutic alliance among
the patient and family, the physician, and other members of the health care team.
A variety of strategies and techniques should be used to provide adequate education
and development of problem-solving skills in the various aspects of diabetes management.
Implementation of the management plan requires that each aspect is understood and
agreed to by the patient and the care providers and that the goals and treatment plan
are reasonable. Any plan should recognize diabetes self-management education (DSME)
and ongoing diabetes support as an integral component of care. In developing the plan,
consideration should be given to the patient's age, school or work schedule and conditions,
physical activity, eating patterns, social situation and cultural factors, and presence
of complications of diabetes or other medical conditions.
C. Glycemic control
1. Assessment of glycemic control
Two primary techniques are available for health providers and patients to assess the
effectiveness of the management plan on glycemic control: patient self-monitoring
of blood glucose (SMBG) or interstitial glucose, and A1C.
a. Glucose monitoring
Recommendations
SMBG should be carried out three or more times daily for patients using multiple insulin
injections or insulin pump therapy. (A)
For patients using less-frequent insulin injections, noninsulin therapies, or medical
nutrition therapy (MNT) alone, SMBG may be useful as a guide to the success of therapy.
(E)
To achieve postprandial glucose targets, postprandial SMBG may be appropriate. (E)
When prescribing SMBG, ensure that patients receive initial instruction in, and routine
follow-up evaluation of, SMBG technique and their ability to use data to adjust therapy.
(E)
Continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens
can be a useful tool to lower A1C in selected adults (age ≥25 years) with type 1 diabetes.
(A)
Although the evidence for A1C-lowering is less strong in children, teens, and younger
adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing
use of the device. (C)
CGM may be a supplemental tool to SMBG in those with hypoglycemia unawareness and/or
frequent hypoglycemic episodes. (E)
Major clinical trials of insulin-treated patients that demonstrated the benefits of
intensive glycemic control on diabetes complications have included SMBG as part of
multifactorial interventions, suggesting that SMBG is a component of effective therapy.
SMBG allows patients to evaluate their individual response to therapy and assess whether
glycemic targets are being achieved. Results of SMBG can be useful in preventing hypoglycemia
and adjusting medications (particularly prandial insulin doses), MNT, and physical
activity.
The frequency and timing of SMBG should be dictated by the particular needs and goals
of the patient. SMBG is especially important for patients treated with insulin to
monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. For most patients
with type 1 diabetes and pregnant women taking insulin, SMBG is recommended three
or more times daily. For these populations, significantly more frequent testing may
be required to reach A1C targets safely without hypoglycemia. The optimal frequency
and timing of SMBG for patients with type 2 diabetes on noninsulin therapy is unclear.
A meta-analysis of SMBG in non–insulin-treated patients with type 2 diabetes concluded
that some regimen of SMBG was associated with a reduction in A1C of 0.4%. However,
many of the studies in this analysis also included patient education with diet and
exercise counseling and, in some cases, pharmacologic intervention, making it difficult
to assess the contribution of SMBG alone to improved control (40). Several recent
trials have called into question the clinical utility and cost-effectiveness of routine
SMBG in non–insulin-treated patients (41
–43).
Because the accuracy of SMBG is instrument and user dependent (44), it is important
to evaluate each patient's monitoring technique, both initially and at regular intervals
thereafter. In addition, optimal use of SMBG requires proper interpretation of the
data. Patients should be taught how to use the data to adjust food intake, exercise,
or pharmacological therapy to achieve specific glycemic goals, and these skills should
be reevaluated periodically.
CGM through the measurement of interstitial glucose (which correlates well with plasma
glucose) is available. These sensors require calibration with SMBG, and the latter
are still recommended for making acute treatment decisions. CGM devices also have
alarms for hypo- and hyperglycemic excursions. Small studies in selected patients
with type 1 diabetes have suggested that CGM use reduces the time spent in hypo- and
hyperglycemic ranges and may modestly improve glycemic control. A larger 26-week randomized
trial of 322 type 1 patients showed that adults age 25 years and older using intensive
insulin therapy and CGM experienced a 0.5% reduction in A1C (from ∼7.6% to 7.1%) compared
to usual intensive insulin therapy with SMBG (45). Sensor use in children, teens,
and adults up to age 24 years did not result in significant A1C lowering, and there
was no significant difference in hypoglycemia in any group. Importantly, the greatest
predictor of A1C-lowering in this study for all age-groups was frequency of sensor
use, which was lower in younger age-groups. In a smaller randomized controlled trial
of 129 adults and children with baseline A1C <7.0%, outcomes combining A1C and hypoglycemia
favored the group utilizing CGM, suggesting that CGM is also beneficial for individuals
with type 1 diabetes who have already achieved excellent control with A1C <7.0 (46).
Although CGM is an evolving technology, emerging data suggest that, in appropriately
selected patients who are motivated to wear it most of the time, it may offer benefit.
CGM may be particularly useful in those with hypoglycemia unawareness and/or frequent
episodes of hypoglycemia, and studies in this area are ongoing.
b. A1C
Recommendations
Perform the A1C test at least two times a year in patients who are meeting treatment
goals (and who have stable glycemic control). (E)
Perform the A1C test quarterly in patients whose therapy has changed or who are not
meeting glycemic goals. (E)
Use of point-of-care testing for A1C allows for timely decisions on therapy changes,
when needed. (E)
Because A1C is thought to reflect average glycemia over several months (44), and has
strong predictive value for diabetes complications (47,48), A1C testing should be
performed routinely in all patients with diabetes, at initial assessment and then
as part of continuing care. Measurement approximately every 3 months determines whether
a patient's glycemic targets have been reached and maintained. For any individual
patient, the frequency of A1C testing should be dependent on the clinical situation,
the treatment regimen used, and the judgment of the clinician. Some patients with
stable glycemia well within target may do well with testing only twice per year, while
unstable or highly intensively managed patients (e.g., pregnant type 1 women) may
be tested more frequently than every 3 months. The availability of the A1C result
at the time that the patient is seen (point-of-care testing) has been reported to
result in increased intensification of therapy and improvement in glycemic control
(49,50).
The A1C test is subject to certain limitations. Conditions that affect erythrocyte
turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly
when the A1C result does not correlate with the patient's clinical situation (44).
In addition, A1C does not provide a measure of glycemic variability or hypoglycemia.
For patients prone to glycemic variability (especially type 1 patients, or type 2
patients with severe insulin deficiency), glycemic control is best judged by the combination
of results of SMBG testing and the A1C. The A1C may also serve as a check on the accuracy
of the patient's meter (or the patient's reported SMBG results) and the adequacy of
the SMBG testing schedule.
Table 9 contains the correlation between A1C levels and mean plasma glucose levels
based on data from the international A1C-Derived Average Glucose (ADAG) trial utilizing
frequent SMBG and CGM in 507 adults (83% Caucasian) with type 1, type 2, and no diabetes
(51). The American Diabetes Association and American Association of Clinical Chemists
have determined that the correlation (r = 0.92) is strong enough to justify reporting
both an A1C result and an estimated average glucose (eAG) result when a clinician
orders the A1C test. The table in previous versions of the Standards of Medical Care
in Diabetes describing the correlation between A1C and mean glucose was derived from
relatively sparse data (one 7-point profile over 1 day per A1C reading) in the primarily
Caucasian type 1 diabetic participants in the DCCT (52). Clinicians should note that
the numbers in the table are now different, as they are based on ∼2,800 readings per
A1C in the ADAG trial.
Table 9
Correlation of A1C with average glucose
A1C (%)
Mean plasma glucose
mg/dl
mmol/l
6
126
7.0
7
154
8.6
8
183
10.2
9
212
11.8
10
240
13.4
11
269
14.9
12
298
16.5
These estimates are based on ADAG data of ∼2,700 glucose measurements over 3 months
per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation
between A1C and average glucose was 0.92 (51). A calculator for converting A1C results
into estimated average glucose (eAG), in either mg/dl or mmol/l, is available at http://professional.diabetes.org/eAG.
In the ADAG trial, there were no significant differences among racial and ethnic groups
in the regression lines between A1C and mean glucose, although there was a trend toward
a difference between African/African American participants and Caucasian ones that
might have been significant had more African/African American participants been studied.
A recent study comparing A1C with CGM data in 48 type 1 diabetic children found a
highly statistically significant correlation between A1C and mean blood glucose, although
the correlation (r = 0.7) was significantly lower than in the ADAG trial (53). Whether
there are significant differences in how A1C relates to average glucose in children
or in African American patients is an area for further study. For the time being,
the question has not led to different recommendations about testing A1C or to different
interpretations of the clinical meaning of given levels of A1C in those populations.
For patients in whom A1C/eAG and measured blood glucose appear discrepant, clinicians
should consider the possibilities of hemoglobinopathy or altered red cell turnover,
and the options of more frequent and/or different timing of SMBG or use of CGM. Other
measures of chronic glycemia such as fructosamine are available, but their linkage
to average glucose and their prognostic significance are not as clear as is the case
for A1C.
2. Glycemic goals in adults
Recommendations
Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic
complications of diabetes and, if implemented soon after the diagnosis of diabetes,
is associated with long-term reduction in macrovascular disease. Therefore, a reasonable
A1C goal for many nonpregnant adults is <7%. (B)
Because additional analyses from several randomized trials suggest a small but incremental
benefit in microvascular outcomes with A1C values closer to normal, providers might
reasonably suggest more stringent A1C goals for selected individual patients, if this
can be achieved without significant hypoglycemia or other adverse effects of treatment.
Such patients might include those with short duration of diabetes, long life expectancy,
and no significant CVD. (B)
Conversely, less stringent A1C goals may be appropriate for patients with a history
of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular
complications, extensive comorbid conditions, and those with longstanding diabetes
in whom the general goal is difficult to attain despite DSME, appropriate glucose
monitoring, and effective doses of multiple glucose-lowering agents including insulin.
(C)
Glycemic control is fundamental to the management of diabetes. The DCCT (47) (in patients
with type 1 diabetes), the Kumamoto study (54), and the UK Prospective Diabetes Study
(UKPDS) (55,56) (both in patients with type 2 diabetes) were prospective, randomized,
controlled trials of intensive versus standard glycemic control in patients with relatively
recently diagnosed diabetes. These trials showed definitively that improved glycemic
control is associated with significantly decreased rates of microvascular (retinopathy
and nephropathy) and neuropathic complications. Follow up of the DCCT cohorts in the
Epidemiology of Diabetes Interventions and Complications (EDIC) study (57,58) and
of the UKPDS cohort (59) has shown persistence of these microvascular benefits in
previously intensively treated subjects, even though their glycemic control has been
equivalent to that of previous standard arm subjects during follow-up.
Subsequent trials in patients with more long-standing type 2 diabetes, designed primarily
to look at the role of intensive glycemic control on cardiovascular outcomes also
confirmed a benefit, although more modest, on onset or progression of microvascular
complications. The Veterans Affairs Diabetes Trial (VADT) showed significant reductions
in albuminuria with intensive (achieved median A1C 6.9%) compared to standard glycemic
control, but no difference in retinopathy and neuropathy (60,61). The Action in Diabetes
and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation
(ADVANCE) study of intensive versus standard glycemic control in type 2 diabetes found
a statistically significant reduction in albuminuria with an A1C target of <6.5% (achieved
median A1C 6.3%) compared to standard therapy achieving a median A1C of 7.0% (62).
Recent analyses from the Action to Control Cardiovascular Risk in Diabetes (ACCORD)
trial have shown lower rates of measures of microvascular complications in the intensive
glycemic control arm compared with the standard arm (63,64).
Epidemiological analyses of the DCCT and UKPDS (47,48) demonstrate a curvilinear relationship
between A1C and microvascular complications. Such analyses suggest that, on a population
level, the greatest number of complications will be averted by taking patients from
very poor control to fair or good control. These analyses also suggest that further
lowering of A1C from 7 to 6% is associated with further reduction in the risk of microvascular
complications, albeit the absolute risk reductions become much smaller. Given the
substantially increased risk of hypoglycemia (particularly in those with type 1 diabetes,
but also in the recent type 2 trials), the concerning mortality findings in the ACCORD
trial (65), and the relatively much greater effort required to achieve near-normoglycemia,
the risks of lower targets may outweigh the potential benefits on microvascular complications
on a population level. However, selected individual patients, especially those with
little comorbidity and long life expectancy (who may reap the benefits of further
lowering of glycemia below 7%) may, at patient and provider judgment, adopt glycemic
targets as close to normal as possible as long as significant hypoglycemia does not
become a barrier.
Whereas many epidemiologic studies and meta-analyses (66,67) have clearly shown a
direct relationship between A1C and CVD, the potential of intensive glycemic control
to reduce CVD has been less clearly defined. In the DCCT, there was a trend toward
lower risk of CVD events with intensive control. However, 9-year post-DCCT follow-up
of the cohort has shown that participants previously randomized to the intensive arm
had a 42% reduction (P = 0.02) in CVD outcomes and a 57% reduction (P = 0.02) in the
risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those
previously in the standard arm (68). The benefit of intensive glycemic control in
this type 1 cohort has recently been shown to persist for several decades (69).
The UKPDS trial of type 2 diabetes observed a 16% reduction in cardiovascular complications
(combined fatal or nonfatal MI and sudden death) in the intensive glycemic control
arm, although this difference was not statistically significant (P = 0.052), and there
was no suggestion of benefit on other CVD outcomes such as stroke. However, 10 years
of follow-up of the UKPDS cohort demonstrated, for participants originally randomized
to intensive glycemic control compared with those randomized to conventional glycemic
control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy,
33% with metformin as initial pharmacotherapy, both statistically significant) and
in all-cause mortality (13 and 27%, respectively, both statistically significant)
(59).
Results of three large trials (ACCORD, ADVANCE, and VADT) suggested no significant
reduction in CVD outcomes with intensive glycemic control in these populations, who
had more advanced diabetes than UKPDS participants. Details of these three studies
are reviewed extensively in a recent ADA position statement (70).
The glycemic control arm of ACCORD was halted early due to the finding of an increased
rate of mortality in the intensive arm compared with the standard arm (1.41% vs. 1.14%
per year; HR 1.22 [95% CI 1.01 to 1.46]); with a similar increase in cardiovascular
deaths. The primary outcome of ACCORD (MI, stroke, or cardiovascular death) was lower
in the intensive glycemic control group, due to a reduction in nonfatal MI, but this
reduction was not statistically significant when the study was terminated (65).
The potential cause of excess deaths in the intensive group of the ACCORD has been
difficult to pinpoint. Exploratory analyses of the mortality findings of ACCORD (evaluating
variables including weight gain, use of any specific drug or drug combination, and
hypoglycemia) were reportedly unable to identify a clear explanation for the excess
mortality in the intensive arm. The ACCORD investigators subsequently published additional
analyses showing no increase in mortality in the intensive arm participants who achieved
A1C levels <7% or in those who lowered their A1C quickly after trial enrollment. In
fact, the converse was observed—those at highest risk for mortality were participants
in the intensive arm with the highest A1C levels (71).
The primary outcome of ADVANCE was a combination of microvascular events (nephropathy
and retinopathy) and major adverse cardiovascular events (MI, stroke, and cardiovascular
death). Intensive glycemic control significantly reduced the primary end point, although
this was due to a significant reduction in the microvascular outcome, primarily development
of macroalbuminuria, with no significant reduction in the macrovascular outcome. There
was no difference in overall or cardiovascular mortality between the intensive compared
with the standard glycemic control arms (62).
The VADT randomized participants with type 2 diabetes uncontrolled on insulin or maximal
dose oral agents (median entry A1C 9.4%) to a strategy of intensive glycemic control
(goal A1C <6.0%) or standard glycemic control, with a planned A1C separation of at
least 1.5%. The primary outcome of the VADT was a composite of CVD events. The cumulative
primary outcome was nonsignificantly lower in the intensive arm (60).
Unlike the UKPDS, which was carried out in patients with newly diagnosed diabetes,
all three of the recent type 2 cardiovascular trials were conducted in participants
with established diabetes (mean duration 8–11 years) and either known CVD or multiple
risk factors, suggesting the presence of established atherosclerosis. Subset analyses
of the three trials suggested a significant benefit of intensive glycemic control
on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or
or absence of known CVD. The DCCT-EDIC study and the long-term follow-up of the UKPDS
cohort both suggest that intensive glycemic control initiated soon after diagnosis
of diabetes in patients with a lower level of CVD risk may impart long-term protection
from CVD events. As is the case with microvascular complications, it may be that glycemic
control plays a greater role before macrovascular disease is well developed and minimal
or no role when it is advanced. Consistent with this concept, data from an ancillary
study of the VADT demonstrated that intensive glycemic control was quite effective
in reducing CVD events in individuals with less atherosclerosis at baseline (assessed
by coronary calcium) but not in persons with more extensive baseline atherosclerosis
(72).
The evidence for a cardiovascular benefit of intensive glycemic control primarily
rests on long-term follow-up of study cohorts treated early in the course of type
1 and type 2 diabetes and subset analyses of ACCORD, ADVANCE, and VADT. A recent group-level
meta-analysis of the latter three trials suggests that glucose lowering has a modest
(9%) but statistically significant reduction in major CVD outcomes, primarily nonfatal
MI, with no significant effect on mortality. A prespecified subgroup analysis suggested
that major CVD outcome reduction occurred in patients without known CVD at baseline
(HR 0.84 [95% CI 0.74–0.94]) (73). Conversely, the mortality findings in ACCORD and
subgroup analyses of VADT suggest that the potential risks of very intensive glycemic
control may outweigh its benefits in some patients, such as those with very long duration
of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced
age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia
in patients with advanced disease and should not aggressively attempt to achieve near-normal
A1C levels in patients in whom such a target cannot be reasonably easily and safely
achieved.
Recommended glycemic goals for many nonpregnant adults are shown in Table 10. The
recommendations are based on those for A1C values, with listed blood glucose levels
that appear to correlate with achievement of an A1C of <7%. Less-stringent treatment
goals may be appropriate for adults with limited life expectancies or advanced vascular
disease. Glycemic goals for children are provided in VII.A.1.a. Glycemic control.
Severe or frequent hypoglycemia is an absolute indication for the modification of
treatment regimens, including setting higher glycemic goals.
Table 10
Summary of glycemic recommendations for many nonpregnant adults with diabetes
A1C
<7.0%*
Preprandial capillary plasma glucose
70–130 mg/dl* (3.9–7.2 mmol/l)
Peak postprandial capillary plasma glucose†
Goals should be individualized based on*:
duration of diabetes
age/life expectancy
comorbid conditions
known CVD or advanced microvascular complications
hypoglycemia unawareness
individual patient considerations
More or less stringent glycemic goals may be appropriate for individual patients.
Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial
glucose goals.
<180 mg/dl* (<10.0 mmol/l)
Postprandial glucose measurements should be made 1–2 h after the beginning of the
meal, generally peak levels in patients with diabetes.
The issue of pre- versus postprandial SMBG targets is complex (74). Elevated postchallenge
(2-h OGTT) glucose values have been associated with increased cardiovascular risk
independent of FPG in some epidemiological studies. In diabetic subjects, some surrogate
measures of vascular pathology, such as endothelial dysfunction, are negatively affected
by postprandial hyperglycemia (75). It is clear that postprandial hyperglycemia, like
preprandial hyperglycemia, contributes to elevated A1C levels, with its relative contribution
being higher at A1C levels that are closer to 7%. However, outcome studies have clearly
shown A1C to be the primary predictor of complications, and landmark glycemic control
trials such as the DCCT and UKPDS relied overwhelmingly on preprandial SMBG. Additionally,
a randomized controlled trial in patients with known CVD found no CVD benefit of insulin
regimens targeting postprandial glucose compared with targeting preprandial glucose
(76). A reasonable recommendation for postprandial testing and targets is that for
individuals who have premeal glucose values within target but have A1C values above
target, monitoring postprandial plasma glucose (PPG) 1–2 h after the start of the
meal and treatment aimed at reducing PPG values to <180 mg/dl may help lower A1C.
As regards goals for glycemic control for women with GDM, recommendations from the
Fifth International Workshop-Conference on Gestational Diabetes (77) were to target
maternal capillary glucose concentrations of:
Preprandial ≤95 mg/dl (5.3 mmol/l) and either
1-h postmeal ≤140 mg/dl (7.8 mmol/l)
or
2-h postmeal ≤120 mg/dl (6.7 mmol/l)
For women with preexisting type 1 or type 2 diabetes who become pregnant, a recent
consensus statement (78) recommended the following as optimal glycemic goals, if they
can be achieved without excessive hypoglycemia:
premeal, bedtime, and overnight glucose 60–99 mg/dl (3.3–5.4 mmol/l)
peak postprandial glucose 100–129 mg/dl (5.4–7.1mmol/l)
A1C <6.0%
D. Pharmacologic and overall approaches to treatment
1. Therapy for type 1 diabetes
The DCCT clearly showed that intensive insulin therapy (three or more injections per
day of insulin, or continuous subcutaneous insulin infusion (CSII) (insulin pump therapy)
was a key part of improved glycemia and better outcomes (47,68). At the time of the
study, therapy was carried out with short- and intermediate-acting human insulins.
Despite better microvascular outcomes, intensive insulin therapy was associated with
a high rate in severe hypoglycemia (62 episodes per 100 patient-years of therapy).
Since the time of the DCCT, a number of rapid-acting and long-acting insulin analogs
have been developed. These analogs are associated with less hypoglycemia with equal
A1C-lowering in type 1 diabetes (79,80).
Therefore, recommended therapy for type 1 diabetes consists of the following components:
1) use of multiple dose insulin injections (three to four injections per day of basal
and prandial insulin) or CSII therapy; 2) matching of prandial insulin to carbohydrate
intake, premeal blood glucose, and anticipated activity; and 3) for many patients
(especially if hypoglycemia is a problem), use of insulin analogs. There are excellent
reviews available that guide the initiation and management of insulin therapy to achieve
desired glycemic goals (3,79,81).
Because of the increased frequency of other autoimmune diseases in type 1 diabetes,
screening for thyroid dysfunction, vitamin B12 deficiency, or celiac disease should
be considered based on signs and symptoms. Periodic screening in absence of symptoms
has been recommended, but the effectiveness and optimal frequency are unclear.
2. Therapy for type 2 diabetes
The ADA and the EASD published an expert consensus statement on the approach to management
of hyperglycemia in individuals with type 2 diabetes (82). Highlights of this approach
are: intervention at the time of diagnosis with metformin in combination with lifestyle
changes (MNT and exercise) and continuing timely augmentation of therapy with additional
agents (including early initiation of insulin therapy) as a means of achieving and
maintaining recommended levels of glycemic control (i.e., A1C <7% for most patients).
As A1C targets are not achieved, treatment intensification is based on the addition
of another agent from a different class. The overall objective is to achieve and maintain
glycemic control and to change interventions when therapeutic goals are not being
met.
The algorithm took into account the evidence for A1C-lowering of the individual interventions,
their additive effects, and their expense. The precise drugs used and their exact
sequence may not be as important as achieving and maintaining glycemic targets safely.
Medications not included in the consensus algorithm, owing to less glucose-lowering
effectiveness, limited clinical data, and/or relative expense, still may be appropriate
choices in individual patients to achieve glycemic goals. Initiation of insulin at
time of diagnosis is recommended for individuals presenting with weight loss or other
severe hyperglycemic symptoms or signs.
E. Diabetes self-management education
Recommendations
People with diabetes should receive diabetes self-management education (DSME) according
to national standards when their diabetes is diagnosed and as needed thereafter. (B)
Effective self-management and quality of life are the key outcomes of DSME and should
be measured and monitored as part of care. (C)
DSME should address psychosocial issues, since emotional well-being is associated
with positive diabetes outcomes. (C)
Because DSME can result in cost-savings and improved outcomes (B), DSME should be
adequately reimbursed by third-party payors. (E)
DSME is an essential element of diabetes care (83
–88), and national standards for DSME (89) are based on evidence for its benefits.
Education helps people with diabetes initiate effective self-management and cope with
diabetes when they are first diagnosed. Ongoing DSME and support also help people
with diabetes maintain effective self-management throughout a lifetime of diabetes
as they face new challenges and treatment advances become available. DSME helps patients
optimize metabolic control, prevent and manage complications, and maximize quality
of life in a cost-effective manner (90).
DSME is the ongoing process of facilitating the knowledge, skill, and ability necessary
for diabetes self-care. This process incorporates the needs, goals, and life experiences
of the person with diabetes. The overall objectives of DSME are to support informed
decision-making, self-care behaviors, problem-solving, and active collaboration with
the health care team to improve clinical outcomes, health status, and quality of life
in a cost-effective manner (89).
Current best practice of DSME is a skills-based approach that focuses on helping those
with diabetes to make informed self-management choices. DSME has changed from a didactic
approach focusing on providing information to more theoretically based empowerment
models that focus on helping those with diabetes make informed self-management decisions.
Care of diabetes has shifted to an approach that is more patient centered and places
the person with diabetes and his or her family at the center of the care model working
in collaboration with health care professionals. Patient-centered care is respectful
of and responsive to individual patient preferences, needs, and values and ensures
that patient values guide all decision making (91).
Evidence for the benefits of DSME
Multiple studies have found that DSME is associated with improved diabetes knowledge
and improved self-care behavior (83), improved clinical outcomes such as lower A1C
(84,85,87,88,92), lower self-reported weight (83), improved quality of life (86,93),
healthy coping (94), and lower costs (95). Better outcomes were reported for DSME
interventions that were longer and included follow-up support (83,96
–99), that were culturally (100,101) and age appropriate (102,103) and tailored to
individual needs and preferences, and that addressed psychosocial issues and incorporated
behavioral strategies (83,87,104
–106). Both individual and group approaches have been found effective (107
–110). There is growing evidence for the role of community health workers and peer
(111,112) and lay leaders (113) in delivering DSME and support in addition to the
core team (114).
Diabetes education is associated with increased use of primary and preventive services
and lower use of acute, inpatient hospital services (95). Patients who participate
in diabetes education are more likely to follow best practice treatment recommendations,
particularly among the Medicare population, and have lower Medicare and commercial
claim costs (115).
National standards for DSME
National standards for DSME are designed to define quality DSME and to assist diabetes
educators in a variety of settings to provide evidence-based education (89). The standards,
most recently revised in 2007, are reviewed and updated every 5 years by a task force
representing key organizations involved in the field of diabetes education and care.
Reimbursement for DSME
DSME, when provided by a program that meets the national standards for DSME and is
recognized by the ADA or other approval bodies, is reimbursed as partof the Medicare
program as overseen by the Centers for Medicare and Medicaid Services (CMS) (www.cms.hhs.gov/DiabetesSelfManagement).
DSME is also covered by a growing number of other health insurance plans.
F. Medical nutrition therapy
General recommendations
Individuals who have prediabetes or diabetes should receive individualized medical
nutrition therapy (MNT) as needed to achieve treatment goals, preferably provided
by a registered dietitian familiar with the components of diabetes MNT. (A)
Because MNT can result in cost-savings and improved outcomes (B), MNT should be adequately
covered by insurance and other payors. (E)
Energy balance, overweight, and obesity
In overweight and obese insulin-resistant individuals, modest weight loss has been
shown to reduce insulin resistance. Thus, weight loss is recommended for all overweight
or obese individuals who have or are at risk for diabetes. (A)
For weight loss, either low-carbohydrate, low-fat calorie-restricted, or Mediterranean
diets may be effective in the short-term (up to 2 years). (A)
For patients on low-carbohydrate diets, monitor lipid profiles, renal function, and
protein intake (in those with nephropathy), and adjust hypoglycemic therapy as needed.
(E)
Physical activity and behavior modification are important components of weight loss
programs and are most helpful in maintenance of weight loss. (B)
Recommendations for primary prevention of diabetes
Among individuals at high risk for developing type 2 diabetes, structured programs
that emphasize lifestyle changes that include moderate weight loss (7% body weight)
and regular physical activity (150 min/week), with dietary strategies including reduced
calories and reduced intake of dietary fat, can reduce the risk for developing diabetes
and are therefore recommended. (A)
Individuals at high risk for type 2 diabetes should be encouraged to achieve the U.S.
Department of Agriculture (USDA) recommendation for dietary fiber (14 g fiber/1,000
kcal) and foods containing whole grains (one-half of grain intake). (B)
Recommendations for management of diabetes
Macronutrients in diabetes management
The best mix of carbohydrate, protein, and fat may be adjusted to meet the metabolic
goals and individual preferences of the person with diabetes. (E)
Monitoring carbohydrate, whether by carbohydrate counting, choices, or experience-based
estimation, remains a key strategy in achieving glycemic control. (A)
For individuals with diabetes, the use of the glycemic index and glycemic load may
provide a modest additional benefit for glycemic control over that observed when total
carbohydrate is considered alone. (B)
Saturated fat intake should be <7% of total calories. (A)
Reducing intake of trans fat lowers LDL cholesterol and increases HDL cholesterol
(A), therefore intake of trans fat should be minimized. (E)
Other nutrition recommendations
If adults with diabetes choose to use alcohol, daily intake should be limited to a
moderate amount (one drink per day or less for adult women and two drinks per day
or less for adult men). (E)
Routine supplementation with antioxidants, such as vitamins E and C and carotene,
is not advised because of lack of evidence of efficacy and concern related to long-term
safety. (A)
Individualized meal planning should include optimization of food choices to meet recommended
dietary allowance (RDA)/dietary reference intake (DRI) for all micronutrients. (E)
MNT is an integral component of diabetes prevention, management, and self-management
education. In addition to its role in preventing and controlling diabetes, ADA recognizes
the importance of nutrition as an essential component of an overall healthy lifestyle.
A full review of the evidence regarding nutrition in preventing and controlling diabetes
and its complications and additional nutrition-related recommendations can be found
in the ADA position statement, “Nutrition Recommendations and Interventions for Diabetes,”
published in 2007 and updated for 2008 (116). Achieving nutrition-related goals requires
a coordinated team effort that includes the active involvement of the person with
prediabetes or diabetes. Because of the complexity of nutrition issues, it is recommended
that a registered dietitian who is knowledgeable and skilled in implementing nutrition
therapy into diabetes management and education be the team member who provides MNT.
Clinical trials/outcome studies of MNT have reported decreases in A1C at 3–6 months
ranging from 0.25% to 2.9% with higher reductions seen in type 2 diabetes of shorter
duration. Multiple studies have demonstrated sustained improvements in A1C at 12 months
and longer when an Registered Dietitian provided follow-up visits ranging from monthly
to three sessions per year (117
–124). Studies in nondiabetic people suggest that MNT reduces LDL cholesterol by 15–25
mg/dl up to 16% (125) and support a role for lifestyle modification in treating hypertension
(125,126).
Because of the effects of obesity on insulin resistance, weight loss is an important
therapeutic objective for overweight or obese individuals with prediabetes or diabetes
(127). Short-term studies have demonstrated that moderate weight loss (5% of body
weight) in subjects with type 2 diabetes is associated with decreased insulin resistance,
improved measures of glycemia and lipemia, and reduced blood pressure (128); longer-term
studies (52 weeks) showed mixed effects on A1C in adults with type 2 diabetes (129
–131), and in some studies results were confounded by pharmacologic weight loss therapy.
A systematic review of 80 weight loss studies of ≥1 year in duration demonstrated
that moderate weight loss achieved through diet alone, diet and exercise, and meal
replacements can be achieved and maintained (4.8–8% weight loss at 12 months) (132).
The multifactorial intensive lifestyle intervention employed in the DPP, which included
reduced intake of fat and calories, led to weight loss averaging 7% at 6 months and
maintenance of 5% weight loss at 3 years, associated with a 58% reduction in incidence
of type 2 diabetes (13). A recent randomized controlled trial looking at high-risk
individuals in Spain showed the Mediterranean dietary pattern reduced the incidence
of diabetes in the absence of weight loss by 52% compared to the low-fat control group
(133). Look AHEAD (Action for Health in Diabetes) is a large clinical trial designed
to determine whether long-term weight loss will improve glycemia and prevent cardiovascular
events in subjects with type 2 diabetes. One-year results of the intensive lifestyle
intervention in this trial show an average 8.6% weight loss, significant reduction
of A1C, and reduction in several CVD risk factors (134), with benefits sustained at
4 years (135). When completed, the Look AHEAD study should provide insight into the
effects of long-term weight loss on important clinical outcomes.
The optimal macronutrient distribution of weight loss diets has not been established.
Although low-fat diets have traditionally been promoted for weight loss, several randomized
controlled trials found that subjects on low-carbohydrate diets (<130 g/day of carbohydrate)
lost more weight at 6 months than subjects on low-fat diets (136,137); however, at
1 year, the difference in weight loss between the low-carbohydrate and low-fat diets
was not significant, and weight loss was modest with both diets. A study comparing
low-fat to low-carbohydrate diets, both combined with a comprehensive lifestyle program,
showed the same amount of weight loss (7%) at 2 years in both groups (138). Another
study of overweight women randomized to one of four diets showed significantly more
weight loss at 12 months with the Atkins low-carbohydrate diet than with higher-carbohydrate
diets (139). Changes in serum triglyceride and HDL cholesterol were more favorable
with the low-carbohydrate diets. In one study, those subjects with type 2 diabetes
demonstrated a greater decrease in A1C with a low-carbohydrate diet than with a low-fat
diet (137). A recent meta-analysis showed that at 6 months, low-carbohydrate diets
were associated with greater improvements in triglyceride and HDL cholesterol concentrations
than low-fat diets; however, LDL cholesterol was significantly higher on the low-carbohydrate
diets (140). In a 2-year dietary intervention study, Mediterranean and low-carbohydrate
diets were found to be effective and safe alternatives to a low-fat diet for weight
reduction in moderately obese participants (141).
The RDA for digestible carbohydrate is 130 g/day and is based on providing adequate
glucose as the required fuel for the central nervous system without reliance on glucose
production from ingested protein or fat. Although brain fuel needs can be met on lower-carbohydrate
diets, long term metabolic effects of very-low-carbohydrate diets are unclear, and
such diets eliminate many foods that are important sources of energy, fiber, vitamins,
and minerals and are important in dietary palatability (142).
Although numerous studies have attempted to identify the optimal mix of macronutrients
for meal plans of people with diabetes, it is unlikely that one such combination of
macronutrients exists. The best mix of carbohydrate, protein, and fat appears to vary
depending on individual circumstances. It must be clearly recognized that regardless
of the macronutrient mix, total caloric intake must be appropriate to weight management
goal. Further, individualization of the macronutrient composition will depend on the
metabolic status of the patient (e.g., lipid profile, renal function) and/or food
preferences. Plant-based diets (vegan or vegetarian) that are well planned and nutritionally
adequate have also been shown to improve metabolic control (143,144).
The primary goal with respect to dietary fat in individuals with diabetes is to limit
saturated fatty acids, trans fatty acids, and cholesterol intake so as to reduce risk
for CVD. Saturated and trans fatty acids are the principal dietary determinants of
plasma LDL cholesterol. There is a lack of evidence on the effects of specific fatty
acids on people with diabetes, so the recommended goals are consistent with those
for individuals with CVD (125,145).
Reimbursement for MNT
MNT, when delivered by a registered dietitian according to nutrition practice guidelines,
is reimbursed as part of the Medicare program as overseen by the Centers for Medicare
and Medicaid Services (CMS) (www.cms.hhs.gov/medicalnutritiontherapy).
G. Physical activity
Recommendations
People with diabetes should be advised to perform at least 150 min/week of moderate-intensity
aerobic physical activity (50–70% of maximum heart rate). (A)
In the absence of contraindications, people with type 2 diabetes should be encouraged
to perform resistance training three times per week. (A)
Exercise is an important part of the diabetes management plan. Regular exercise has
been shown to improve blood glucose control, reduce cardiovascular risk factors, contribute
to weight loss, and improve well-being. Furthermore, regular exercise may prevent
type 2 diabetes in high-risk individuals (13
–15). Structured exercise interventions of at least 8 weeks' duration have been shown
to lower A1C by an average of 0.66% in people with type 2 diabetes, even with no significant
change in BMI (146). Higher levels of exercise intensity are associated with greater
improvements in A1C and in fitness (147). A new joint position statement of the American
Diabetes Association and the American College of Sports Medicine summarizes the evidence
for the benefits of exercise in people with type 2 diabetes (148).
Frequency and type of exercise
The U.S. Department of Health and Human Services' Physical Activity Guidelines for
Americans (149) suggest that adults over age 18 years do 150 min/week of moderate-intensity,
or 75 min/week of vigorous aerobic physical activity, or an equivalent combination
of the two. In addition, the guidelines suggest that adults also do muscle-strengthening
activities that involve all major muscle groups two or more days per week. The guidelines
suggest that adults over age 65 years, or those with disabilities, follow the adult
guidelines if possible or (if this is not possible) be as physically active as they
are able. Studies included in the meta-analysis of effects of exercise interventions
on glycemic control (146) had a mean number of sessions per week of 3.4, with a mean
of 49 min/session. The DPP lifestyle intervention, which included 150 min/week of
moderate intensity exercise, had a beneficial effect on glycemia in those with prediabetes.
Therefore, it seems reasonable to recommend that people with diabetes try to follow
the physical activity guidelines for the general population.
Progressive resistance exercise improves insulin sensitivity in older men with type
2 diabetes to the same or even a greater extent as aerobic exercise (150). Clinical
trials have provided strong evidence for the A1C-lowering value of resistance training
in older adults with type 2 diabetes (151,152) and for an additive benefit of combined
aerobic and resistance exercise in adults with type 2 diabetes (153).
Evaluation of the diabetic patient before recommending an exercise program
Prior guidelines suggested that before recommending a program of physical activity,
the provider should assess patients with multiple cardiovascular risk factors for
coronary artery disease (CAD). As discussed more fully in VI.A.5. Coronary heart disease
screening and treatment, the area of screening asymptomatic diabetic patients for
CAD remains unclear, and a recent ADA consensus statement on this issue concluded
that routine screening is not recommended (154). Providers should use clinical judgment
in this area. Certainly, high risk patients should be encouraged to start with short
periods of low intensity exercise and increase the intensity and duration slowly.
Providers should assess patients for conditions that might contraindicate certain
types of exercise or predispose to injury, such as uncontrolled hypertension, severe
autonomic neuropathy, severe peripheral neuropathy or history of foot lesions, and
unstable proliferative retinopathy. The patient's age and previous physical activity
level should be considered.
Exercise in the presence of nonoptimal glycemic control
Hyperglycemia.
When people with type 1 diabetes are deprived of insulin for 12–48 h and are ketotic,
exercise can worsen hyperglycemia and ketosis (155); therefore, vigorous activity
should be avoided in the presence of ketosis. However, it is not necessary to postpone
exercise based simply on hyperglycemia, provided the patient feels well and urine
and/or blood ketones are negative.
Hypoglycemia.
In individuals taking insulin and/or insulin secretagogues, physical activity can
cause hypoglycemia if medication dose or carbohydrate consumption is not altered.
For individuals on these therapies, added carbohydrate should be ingested if pre-exercise
glucose levels are <100 mg/dl (5.6 mmol/l). Hypoglycemia is rare in diabetic individuals
who are not treated with insulin or insulin secretagogues, and no preventive measures
for hypoglycemia are usually advised in these cases.
Exercise in the presence of specific long-term complications of diabetes
Retinopathy.
In the presence of proliferative diabetic retinopathy (PDR) or severe nonproliferative
diabetic retinopathy (NPDR), vigorous aerobic or resistance exercise may be contraindicated
because of the risk of triggering vitreous hemorrhage or retinal detachment (156).
Peripheral neuropathy.
Decreased pain sensation in the extremities results in increased risk of skin breakdown
and infection and of Charcot joint destruction. Prior recommendations have advised
non–weight-bearing exercise for patients with severe peripheral neuropathy. However,
studies have shown that moderate-intensity walking may not lead to increased risk
of foot ulcers or re-ulceration in those with peripheral neuropathy (157). All individuals
with peripheral neuropathy should wear proper footwear and examine their feet daily
to detect lesions early. Anyone with a foot injury or open sore should be restricted
to non–weight-bearing activities.
Autonomic neuropathy.
Autonomic neuropathy can increase the risk of exercise-induced injury or adverse event
through decreased cardiac responsiveness to exercise, postural hypotension, impaired
thermoregulation, impaired night vision due to impaired papillary reaction, and unpredictable
carbohydrate delivery from gastroparesis predisposing to hypoglycemia (158). Autonomic
neuropathy is also strongly associated with CVD in people with diabetes (159,160).
People with diabetic autonomic neuropathy should undergo cardiac investigation before
beginning physical activity more intense than that to which they are accustomed.
Albuminuria and nephropathy.
Physical activity can acutely increase urinary protein excretion. However, there is
no evidence that vigorous exercise increases the rate of progression of diabetic kidney
disease, and there is likely no need for any specific exercise restrictions for people
with diabetic kidney disease (161).
H. Psychosocial assessment and care
Recommendations
Assessment of psychological and social situation should be included as an ongoing
part of the medical management of diabetes. (E)
Psychosocial screening and follow-up should include, but is not limited to, attitudes
about the illness, expectations for medical management and outcomes, affect/mood,
general and diabetes-related quality of life, resources (financial, social, and emotional),
and psychiatric history. (E)
Screen for psychosocial problems such as depression and diabetes-related distress,
anxiety, eating disorders, and cognitive impairment when self-management is poor.
(C)
Psychological and social problems can impair the individual's (162
–165) or family's ability to carry out diabetes care tasks and therefore compromise
health status. There are opportunities for the clinician to assess psychosocial status
in a timely and efficient manner so that referral for appropriate services can be
accomplished.
Key opportunities for screening of psychosocial status occur at diagnosis, during
regularly scheduled management visits, during hospitalizations, at discovery of complications,
or when problems with glucose control, quality of life, or adherence are identified.
Patients are likely to exhibit psychological vulnerability at diagnosis and when their
medical status changes, e.g., the end of the honeymoon period, when the need for intensified
treatment is evident, and when complications are discovered (164).
Issues known to impact self-management and health outcomes include but are not limited
to: attitudes about the illness, expectations for medical management and outcomes,
affect/mood, general and diabetes-related quality of life, diabetes-related distress
(166), resources (financial, social, and emotional) (167), and psychiatric history
(168
–170). Screening tools are available for a number of these areas (105). Indications
for referral to a mental health specialist familiar with diabetes management may include:
gross noncompliance with medical regimen (by self or others) (170), depression with
the possibility of self-harm, debilitating anxiety (alone or with depression), indications
of an eating disorder (171), or cognitive functioning that significantly impairs judgment.
It is preferable to incorporate psychological assessment and treatment into routine
care rather than waiting for identification of a specific problem or deterioration
in psychological status (105). Although the clinician may not feel qualified to treat
psychological problems, utilizing the patient-provider relationship as a foundation
for further treatment can increase the likelihood that the patient will accept referral
for other services. It is important to establish that emotional well-being is part
of diabetes management.
I. When treatment goals are not met
For a variety of reasons, some people with diabetes and their health care providers
do not achieve the desired goals of treatment (Table 10). Re-thinking the treatment
regimen may require assessment of barriers including income, health literacy, diabetes
distress, depression, and competing demands, including those related to family responsibilities
and dynamics. Other strategies may include culturally appropriate and enhanced DSME,
co-management with a diabetes team, referral to a medical social worker for assistance
with insurance coverage, or change in pharmacological therapy. Initiation of or increase
in SMBG, utilization of CGM, frequent contact with the patient, or referral to a mental
health professional or physician with special expertise in diabetes may be useful.
Providing patients with an algorithm for self-titration of insulin doses based on
SMBG results may be helpful for type 2 patients who take insulin (172).
J. Hypoglycemia
Recommendations
Glucose (15–20 g) is the preferred treatment for the conscious individual with hypoglycemia,
although any form of carbohydrate that contains glucose may be used. If SMBG 15 min
after treatment shows continued hypoglycemia, the treatment should be repeated. Once
SMBG glucose returns to normal, the individual should consume a meal or snack to prevent
recurrence of hypoglycemia. (E)
Glucagon should be prescribed for all individuals at significant risk of severe hypoglycemia,
and caregivers or family members of these individuals should be instructed in its
administration. Glucagon administration is not limited to health care professionals.
(E)
Individuals with hypoglycemia unawareness or one or more episodes of severe hypoglycemia
should be advised to raise their glycemic targets to strictly avoid further hypoglycemia
for at least several weeks, to partially reverse hypoglycemia unawareness and reduce
risk of future episodes. (B)
Hypoglycemia is the leading limiting factor in the glycemic management of type 1 and
insulin-treated type 2 diabetes (173). Mild hypoglycemia may be inconvenient or frightening
to patients with diabetes, and more severe hypoglycemia can cause acute harm to the
person with diabetes or others, if it causes falls, motor vehicle accidents, or other
injury. A large cohort study suggested that among older adults with type 2 diabetes,
a history of severe hypoglycemia was associated with greater risk of dementia (174).
Conversely, evidence from the DCCT/EDIC trial, which involved younger type 1 patients,
suggested no association of frequency of severe hypoglycemia with cognitive decline
(175). Treatment of hypoglycemia (plasma glucose <70 mg/dl) requires ingestion of
glucose- or carbohydrate-containing foods. The acute glycemic response correlates
better with the glucose content than with the carbohydrate content of the food. Although
pure glucose is the preferred treatment, any form of carbohydrate that contains glucose
will raise blood glucose. Added fat may retard and then prolong the acute glycemic
response. Ongoing activity of insulin or insulin secretagogues may lead to recurrence
of hypoglycemia unless further food is ingested after recovery.
Severe hypoglycemia (where the individual requires the assistance of another person
and cannot be treated with oral carbohydrate due to confusion or unconsciousness)
should be treated using emergency glucagon kits, which require a prescription. Those
in close contact with, or having custodial care of, people with hypoglycemia-prone
diabetes (family members, roommates, school personnel, child care providers, correctional
institution staff, or coworkers), should be instructed in use of such kits. An individual
does not need to be a health care professional to safely administer glucagon. Care
should be taken to ensure that unexpired glucagon kits are available.
Prevention of hypoglycemia is a critical component of diabetes management. Teaching
people with diabetes to balance insulin use, carbohydrate intake, and exercise is
a necessary but not always sufficient strategy. In type 1 diabetes and severely insulin-deficient
type 2 diabetes, the syndrome of hypoglycemia unawareness, or hypoglycemia-associated
autonomic failure, can severely compromise stringent diabetes control and quality
of life. The deficient counterregulatory hormone release and autonomic responses in
this syndrome are both risk factors for, and caused by, hypoglycemia. A corollary
to this “vicious cycle” is that several weeks of avoidance of hypoglycemia has been
demonstrated to improve counterregulation and awareness to some extent in many patients
(176). Hence, patients with one or more episodes of severe hypoglycemia may benefit
from at least short-term relaxation of glycemic targets.
K. Intercurrent illness
The stress of illness, trauma, and/or surgery frequently aggravates glycemic control
and may precipitate diabetic ketoacidosis (DKA) or nonketotic hyperosmolar state,
life-threatening conditions that require immediate medical care to prevent complications
and death. Any condition leading to deterioration in glycemic control necessitates
more frequent monitoring of blood glucose and (in ketosis-prone patients) urine or
blood ketones. Marked hyperglycemia requires temporary adjustment of the treatment
program and, if accompanied by ketosis, vomiting, or alteration in level of consciousness,
immediate interaction with the diabetes care team. The patient treated with noninsulin
therapies or MNT alone may temporarily require insulin. Adequate fluid and caloric
intake must be assured. Infection or dehydration are more likely to necessitate hospitalization
of the person with diabetes than the person without diabetes.
The hospitalized patient should be treated by a physician with expertise in the management
of diabetes. For further information on management of patients with hyperglycemia
in the hospital, see VIII.A. Diabetes care in the hospital. For further information
on management of DKA or nonketotic hyperosmolar state, refer to the ADA consensus
statement on hyperglycemic crises (172).
L. Bariatric surgery
Recommendations
Bariatric surgery may be considered for adults with BMI >35 kg/m2 and type 2 diabetes,
especially if the diabetes or associated comorbidities are difficult to control with
lifestyle and pharmacologic therapy. (B)
Patients with type 2 diabetes who have undergone bariatric surgery need life-long
lifestyle support and medical monitoring. (E)
Although small trials have shown glycemic benefit of bariatric surgery in patients
with type 2 diabetes and BMI of 30–35 kg/m2, there is currently insufficient evidence
to generally recommend surgery in patients with BMI <35 kg/m2 outside of a research
protocol. (E)
The long-term benefits, cost-effectiveness, and risks of bariatric surgery in individuals
with type 2 diabetes should be studied in well-designed controlled trials with optimal
medical and lifestyle therapy as the comparator. (E)
Gastric reduction surgery, either gastric banding or procedures that involve bypassing,
transposing, or resecting sections of the small intestine, when part of a comprehensive
team approach, can be an effective weight loss treatment for severe obesity, and national
guidelines support its consideration for people with type 2 diabetes who have BMI
exceeding 35 kg/m2. Bariatric surgery has been shown to lead to near- or complete
normalization of glycemia in ∼55–95% of patients with type 2 diabetes, depending on
the surgical procedure. A meta-analysis of studies of bariatric surgery involving
3,188 patients with diabetes reported that 78% had remission of diabetes (normalization
of blood glucose levels in the absence of medications), and that the remission rates
were sustained in studies that had follow-up exceeding 2 years (177). Remission rates
tend to be lower with procedures that only constrict the stomach, and higher with
those that bypass portions of the small intestine. Additionally, there is a suggestion
that intestinal bypass procedures may have glycemic effects that are independent of
their effects on weight, perhaps involving the incretin axis.
One randomized controlled trial compared adjustable gastric banding to “best available”
medical and lifestyle therapy in subjects with type 2 diabetes diagnosed less than
2 years before randomization and BMI 30–40 kg/m2 (178). In this trial, 73% of surgically
treated patients achieved “remission” of their diabetes, compared with 13% of those
treated medically. The latter group lost only 1.7% of body weight, suggesting that
their therapy was not optimal. Overall the trial had 60 subjects, and only 13 had
a BMI under 35 kg/m2, making it difficult to generalize these results widely to diabetic
patients who are less severely obese or with longer duration of diabetes. In a more
recent study involving 110 patients with type 2 diabetes and a mean BMI of 47 kg/m2,
Roux-en-Y gastric bypass resulted in a mean loss of excess weight of 63% at 1 year
and 84% at 2 years (179).
Bariatric surgery is costly in the short term and has some risks. Rates of morbidity
and mortality directly related to the surgery have been reduced considerably in recent
years, with 30-day mortality rates now 0.28%, similar to those of laparoscopic cholecystectomy
(180). Longer-term concerns include vitamin and mineral deficiencies, osteoporosis,
and rare but often severe hypoglycemia from insulin hypersecretion. Cohort studies
attempting to match subjects suggest that the procedure may reduce longer-term mortality
rates (181), and it is reasonable to postulate that there may be recouping of costs
over the long run. Recent retrospective analyses and modeling studies suggest that
these procedures may be cost effective, when one considers reduction in subsequent
health care costs (182
–184). However, studies of the mechanisms of glycemic improvement and long-term benefits
and risks of bariatric surgery in individuals with type 2 diabetes, especially those
who are not severely obese, will require well-designed clinical trials, with optimal
medical and lifestyle therapy of diabetes and cardiovascular risk factors as the comparator.
M. Immunization
Recommendations
Annually provide an influenza vaccine to all diabetic patients at least 6 months of
age. (C)
Administer pneumococcal polysaccharide vaccine to all diabetic patients ≥2 years of
age. A one-time revaccination is recommended for individuals >64 years of age previously
immunized when they were <65 years of age if the vaccine was administered >5 years
ago. Other indications for repeat vaccination include nephrotic syndrome, chronic
renal disease, and other immunocompromised states, such as after transplantation.
(C)
Influenza and pneumonia are common, preventable infectious diseases associated with
high mortality and morbidity in the elderly and in people with chronic diseases. Though
there are limited studies reporting the morbidity and mortality of influenza and pneumococcal
pneumonia specifically in people with diabetes, observational studies of patients
with a variety of chronic illnesses, including diabetes, show that these conditions
are associated with an increase in hospitalizations for influenza and its complications.
People with diabetes may be at increased risk of the bacteremic form of pneumococcal
infection and have been reported to have a high risk of nosocomial bacteremia, which
has a mortality rate as high as 50% (185).
Safe and effective vaccines are available that can greatly reduce the risk of serious
complications from these diseases (186,187). In a case-control series, influenza vaccine
was shown to reduce diabetes-related hospital admission by as much as 79% during flu
epidemics (186). There is sufficient evidence to support that people with diabetes
have appropriate serologic and clinical responses to these vaccinations. The Centers
for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices
recommends influenza and pneumococcal vaccines for all individuals with diabetes (http://www.cdc.gov/vaccines/recs/).
VI. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS
A. CVD
CVD is the major cause of morbidity and mortality for individuals with diabetes, and
the largest contributor to the direct and indirect costs of diabetes. The common conditions
coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk
factors for CVD, and diabetes itself confers independent risk. Numerous studies have
shown the efficacy of controlling individual cardiovascular risk factors in preventing
or slowing CVD in people with diabetes. Large benefits are seen when multiple risk
factors are addressed globally (188,189). Risk for coronary heart disease (CHD) and
for CVD in general can be estimated using multivariable risk factor approaches, and
such a strategy may be desirable to undertake in adult patients prior to instituting
preventive therapy.
1. Hypertension/blood pressure control
Recommendations
Screening and diagnosis
Blood pressure should be measured at every routine diabetes visit. Patients found
to have systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg should
have blood pressure confirmed on a separate day. Repeat systolic blood pressure ≥130
mmHg or diastolic blood pressure ≥80 mmHg confirms a diagnosis of hypertension. (C)
Goals
A goal systolic blood pressure <130 mmHg is appropriate for most patients with diabetes.
(C)
Based on patient characteristics and response to therapy, higher or lower systolic
blood pressure targets may be appropriate. (B)
Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg. (B)
Treatment
Patients with a systolic blood pressure of 130–139 mmHg or a diastolic blood pressure
of 80–89 mmHg may be given lifestyle therapy alone for a maximum of 3 months and then,
if targets are not achieved, be treated with addition of pharmacological agents. (E)
Patients with more severe hypertension (systolic blood pressure ≥140 or diastolic
blood pressure ≥90 mmHg) at diagnosis or follow-up should receive pharmacologic therapy
in addition to lifestyle therapy. (A)
Lifestyle therapy for hypertension consists of: weight loss, if overweight; Dietary
Approaches to Stop Hypertension (DASH)-style dietary pattern including reducing sodium
and increasing potassium intake; moderation of alcohol intake; and increased physical
activity. (B)
Pharmacologic therapy for patients with diabetes and hypertension should be with a
regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated,
the other should be substituted. If needed to achieve blood pressure targets, a thiazide
diuretic should be added to those with an estimated GFR (eGFR) (see below) ≥30 ml/min/1.73
m2 and a loop diuretic for those with an eGFR <30 ml/min/1.73 m2. (C)
Multiple drug therapy (two or more agents at maximal doses) is generally required
to achieve blood pressure targets. (B)
If ACE inhibitors, ARBs, or diuretics are used, kidney function and serum potassium
levels should be monitored. (E)
In pregnant patients with diabetes and chronic hypertension, blood pressure target
goals of 110–129/65–79 mmHg are suggested in the interest of long-term maternal health
and minimizing impaired fetal growth. ACE inhibitors and ARBs are contraindicated
during pregnancy. (E)
Hypertension is a common comorbidity of diabetes, affecting the majority of patients,
with prevalence depending on type of diabetes, age, obesity, and ethnicity. Hypertension
is a major risk factor for both CVD and microvascular complications. In type 1 diabetes,
hypertension is often the result of underlying nephropathy, while in type 2 diabetes
it usually coexists with other cardiometabolic risk factors.
Screening and diagnosis
Measurement of blood pressure in the office should be done by a trained individual
and should follow the guidelines established for nondiabetic individuals: measurement
in the seated position, with feet on the floor and arm supported at heart level, after
5 min of rest. Cuff size should be appropriate for the upper arm circumference. Elevated
values should be confirmed on a separate day. Because of the clear synergistic risks
of hypertension and diabetes, the diagnostic cut-off for a diagnosis of hypertension
is lower in people with diabetes (blood pressure ≥130/80) than those without diabetes
(blood pressure 140/90 mmHg) (190).
Home blood pressure self-monitoring and 24-h ambulatory blood pressure monitoring
may provide additional evidence of “white coat” and masked hypertension and other
discrepancies between office and “true” blood pressure, and in studies in nondiabetic
populations, home measurements may better correlate with CVD risk than office measurements
(191,192). However, the preponderance of the clear evidence of benefits of treatment
of hypertension in people with diabetes is based on office measurements.
Treatment goals
Epidemiologic analyses show that blood pressure values >115/75 mmHg are associated
with increased cardiovascular event rates and mortality in individuals with diabetes
(190,193,194). Randomized clinical trials have demonstrated the benefit (reduction
in CHD events, stroke, and nephropathy) of lowering blood pressure to <140 mmHg systolic
and <80 mmHg diastolic in individuals with diabetes (190,195
–197). The ACCORD trial examined whether lowering blood pressure to a systolic <120
mmHg provides greater cardiovascular protection than a systolic blood pressure level
of 130–140 mmHg in patients with type 2 diabetes at high risk for CVD (198). The blood
pressure achieved was 119/64 mmHg in the intensive group and 133/70 mmHg in the standard
group; the difference achieved was attained with an average of 3.4 medications per
participant in the intensive group and 2.1 in the standard therapy group. The primary
outcome was a composite of nonfatal MI, nonfatal stroke, and CVD death; the hazard
ratio for the primary end point in the intensive group was 0.88 (95% CI 0.73–1.06;
P = 0.20). Of the prespecified secondary end points, only stroke and nonfatal stroke
were statistically significantly reduced by intensive blood pressure treatment, with
a hazard ratio of 0.59 (95% CI 0.39–0.89, P = 0.01) and 0.63 (95% CI 0.41–0.96, P
= 0.03), respectively. If this finding is real, the number needed to treat to prevent
one stroke over the course of 5 years with intensive blood pressure management is
89.
In predefined subgroup analyses, there was a suggestion of heterogeneity (P = 0.08)
based on whether participants were randomized to standard or intensive glycemia intervention.
In those randomized to standard glycemic control, the event rate for the primary end
point was 1.89 per year in the intensive blood pressure arm and 2.47 in the standard
blood pressure arm, while the respective rates in the intensive glycemia arm were
1.85 and 1.73. If this observation is true, it suggests that intensive management
to a systolic blood pressure target of <120 mmHg may be of benefit in those who are
not targeting an A1C of <6% and/or that the benefit of intensive blood pressure management
is diminished by more intensive glycemia management targeting an A1C of <6%.
Other recent randomized trial data include those from ADVANCE, in which treatment
with an angiotensin-converting enzyme inhibitor and a thiazide-type diuretic reduced
the rate of death but not the composite macrovascular outcome. However, the ADVANCE
trial had no specified targets for the randomized comparison, and the mean systolic
blood pressure in the intensive group (135 mmHg) was not as low as the mean systolic
blood pressure in the ACCORD standard therapy group (199). A post hoc analysis of
blood pressure control in 6,400 patients with diabetes and CAD enrolled in the International
Verapamil-Trandolapril (INVEST) trial demonstrated that “tight control” (<130 mmHg)
was not associated with improved CV outcomes compared with “usual care” (130–140 mmHg)
(200).
Only the ACCORD blood pressure trial formally has examined treatment targets <130
mmHg in diabetes. It is possible that lowering systolic blood pressure from the low-130s
to less than 120 mmHg does not further reduce coronary events or death, and that most
of the benefit from lowering blood pressure is achieved by targeting a goal of <140
mmHg. However, this has not been formally assessed.
The absence of significant harm, the trends toward benefit in stroke, and the potential
heterogeneity with respect to intensive glycemia management suggests that previously
recommended targets are reasonable pending further analyses and results. Systolic
blood pressure targets more or less stringent than <130 mmHg may be appropriate for
individual patients, based on response to therapy, medication tolerance, and individual
characteristics, keeping in mind that most analyses have suggested that outcomes are
worse if the systolic blood pressure is >140 mmHg.
Treatment strategies
Although there are no well-controlled studies of diet and exercise in the treatment
of hypertension in individuals with diabetes, the Dietary Approaches to Stop Hypertension
(DASH) study in nondiabetic individuals has shown anti-hypertensive effects similar
to pharmacologic monotherapy. Lifestyle therapy consists of reducing sodium intake
(to <1,500 mg/day) and excess body weight; increasing consumption of fruits, vegetables
(8–10 servings/day), and low-fat dairy products (2–3 servings/day); avoiding excessive
alcohol consumption (no more than 2 servings/day in men and no more than 1 serving/day
in women) (201); and increasing activity levels (190). These nonpharmacological strategies
may also positively affect glycemia and lipid control. Their effects on cardiovascular
events have not been established. An initial trial of nonpharmacologic therapy may
be reasonable in diabetic individuals with mild hypertension (systolic blood pressure
130–139 mmHg or diastolic blood pressure 80–89 mmHg). If systolic blood pressure is
≥140 mmHg and/or diastolic is ≥90 mmHg at the time of diagnosis, pharmacologic therapy
should be initiated along with nonpharmacologic therapy (190).
Lowering of blood pressure with regimens based on a variety of antihypertensive drugs,
including ACE inhibitors, ARBs, β-blockers, diuretics, and calcium channel blockers,
has been shown to be effective in reducing cardiovascular events. Several studies
suggested that ACE inhibitors may be superior to dihydropyridine calcium channel blockers
in reducing cardiovascular events (202
–204). However, a variety of other studies have shown no specific advantage to ACE
inhibitors as initial treatment of hypertension in the general hypertensive population,
but rather an advantage on cardiovascular outcomes of initial therapy with low-dose
thiazide diuretics (190,205,206).
In people with diabetes, inhibitors of the renin-angiotensin system (RAS) may have
unique advantages for initial or early therapy of hypertension. In a nonhypertension
trial of high-risk individuals, including a large subset with diabetes, an ACE inhibitor
reduced CVD outcomes (207). In patients with congestive heart failure (CHF), including
diabetic subgroups, ARBs have been shown to reduce major CVD outcomes (208
–211), and in type 2 patients with significant nephropathy, ARBs were superior to
calcium channel blockers for reducing heart failure (212). Though evidence for distinct
advantages of RAS inhibitors on CVD outcomes in diabetes remains conflicting (195,206),
the high CVD risks associated with diabetes, and the high prevalence of undiagnosed
CVD, may still favor recommendations for their use as first-line hypertension therapy
in people with diabetes (190). Recently, the blood pressure arm of the ADVANCE trial
demonstrated that routine administration of a fixed combination of the ACE inhibitor
perindopril and the diuretic indapamide significantly reduced combined microvascular
and macrovascular outcomes, as well as CVD and total mortality. The improved outcomes
could also have been due to lower achieved blood pressure in the perindopril-indapamide
arm (199). In addition, the Avoiding Cardiovascular Events through Combination Therapy
in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed a decrease
in morbidity and mortality in those receiving benazapril and amlodipine versus benazapril
and hydrochlorothiazide. The compelling benefits of RAS inhibitors in diabetic patients
with albuminuria or renal insufficiency provide additional rationale for use of these
agents (see VI.B. Nephropathy screening and treatment).
An important caveat is that most patients with hypertension require multi-drug therapy
to reach treatment goals, especially diabetic patients whose targets are lower. Many
patients will require three or more drugs to reach target goals (190). If blood pressure
is refractory to optimal doses of at least three antihypertensive agents of different
classifications, one of which should be a diuretic, clinicians should consider an
evaluation for secondary forms of hypertension.
During pregnancy in diabetic women with chronic hypertension, target blood pressure
goals of systolic blood pressure 110–129 mmHg and diastolic blood pressure 65–79 mmHg
are reasonable, as they contribute to long-term maternal health. Lower blood pressure
levels may be associated with impaired fetal growth. During pregnancy, treatment with
ACE inhibitors and ARBs is contraindicated, since they can cause fetal damage. Antihypertensive
drugs known to be effective and safe in pregnancy include methyldopa, labetalol, diltiazem,
clonidine, and prazosin. Chronic diuretic use during pregnancy has been associated
with restricted maternal plasma volume, which might reduce uteroplacental perfusion
(213).
2. Dyslipidemia/lipid management
Recommendations
Screening
In most adult patients, measure fasting lipid profile at least annually. In adults
with low-risk lipid values (LDL cholesterol <100 mg/dl, HDL cholesterol >50 mg/dl,
and triglycerides <150 mg/dl), lipid assessments may be repeated every 2 years. (E)
Treatment recommendations and goals
Lifestyle modification focusing on the reduction of saturated fat, trans fat, and
cholesterol intake; increase of omega-3 fatty acids, viscous fiber, and plant stanols/sterols;
weight loss (if indicated); and increased physical activity should be recommended
to improve the lipid profile in patients with diabetes. (A)
Statin therapy should be added to lifestyle therapy, regardless of baseline lipid
levels, for diabetic patients:
with overt CVD. (A)
without CVD who are over age 40 years and have one or more other CVD risk factors.
(A)
For patients at lower risk than above (e.g., without overt CVD and under age 40 years),
statin therapy should be considered in addition to lifestyle therapy if LDL cholesterol
remains above 100 mg/dl or in those with multiple CVD risk factors. (E)
In individuals without overt CVD, the primary goal is an LDL cholesterol <100 mg/dl
(2.6 mmol/l). (A)
In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l),
using a high dose of a statin, is an option. (B)
If drug-treated patients do not reach the above targets on maximal tolerated statin
therapy, a reduction in LDL cholesterol of ∼30–40% from baseline is an alternative
therapeutic goal. (A)
Triglyceride levels <150 mg/dl (1.7 mmol/l) and HDL cholesterol >40 mg/dl (1.0 mmol/l)
in men and >50 mg/dl (1.3 mmol/l) in women, are desirable. However, LDL cholesterol–targeted
statin therapy remains the preferred strategy. (C)
If targets are not reached on maximally tolerated doses of statins, combination therapy
using statins and other lipid-lowering agents may be considered to achieve lipid targets
but has not been evaluated in outcome studies for either CVD outcomes or safety. (E)
Statin therapy is contraindicated in pregnancy. (E)
Evidence for benefits of lipid-lowering therapy
Patients with type 2 diabetes have an increased prevalence of lipid abnormalities,
contributing to their high risk of CVD. For the past decade or more, multiple clinical
trials demonstrated significant effects of pharmacologic (primarily statin) therapy
on CVD outcomes in subjects with CHD and for primary CVD prevention (214). Sub-analyses
of diabetic subgroups of larger trials (215
–219) and trials specifically in subjects with diabetes (220,221) showed significant
primary and secondary prevention of CVD events ± CHD deaths in diabetic populations.
As shown in Table 11, and similar to findings in nondiabetic subjects, reduction in
“hard” CVD outcomes (CHD death and nonfatal MI) can be more clearly seen in diabetic
subjects with high baseline CVD risk (known CVD and/or very high LDL cholesterol levels),
but overall the benefits of statin therapy in people with diabetes at moderate or
high risk for CVD are convincing.
Table 11
Reduction in 10-year risk of major CVD endpoints (CHD death/non-fatal MI) in major
statin trials, or substudies of major trials, in diabetic subjects (n = 16,032)
Study (ref.)
CVD
Statin dose and comparator
Risk reduction (%)
Relative risk reduction (%)
Absolute risk reduction (%)
LDL cholesterol reduction (mg/dl)
LDL cholesterol reduction (%)
4S-DM (215)
2°
Simvastatin 20–40 mg vs. placebo
85.7 to 43.2
50
42.5
186 to 119
36
ASPEN 2° (220)
2°
Atorvastatin 10 mg vs. placebo
39.5 to 24.5
34
15
112 to 79
29
HPS-DM (216)
2°
Simvastatin 40 mg vs. placebo
43.8 to 36.3
17
7.5
123 to 84
31
CARE-DM (217)
2°
Pravastatin 40 mg vs. placebo
40.8 to 35.4
13
5.4
136 to 99
27
TNT-DM (218)
2°
Atorvastatin 80 mg vs. 10 mg
26.3 to 21.6
18
4.7
99 to 77
22
HPS-DM (216)
1°
Simvastatin 40 mg vs. placebo
17.5 to 11.5
34
6.0
124 to 86
31
CARDS (221)
1°
Atorvastatin 10 mg vs. placebo
11.5 to 7.5
35
4
118 to 71
40
ASPEN 1° (220)
1°
Atorvastatin 10 mg vs. placebo
9.8 to 7.9
19
1.9
114 to 80
30
ASCOT-DM (219)
1°
Atorvastatin 10 mg vs. placebo
11.1 to 10.2
8
0.9
125 to 82
34
Studies were of differing lengths (3.3–5.4 years) and used somewhat different outcomes,
but all reported rates of CVD death and nonfatal MI. In this tabulation, results of
the statin on 10-year risk of major CVD endpoints (CHD death/nonfatal MI) are listed
for comparison between studies. Correlation between 10-year CVD risk of the control
group and the absolute risk reduction with statin therapy is highly significant (P
= 0.0007). Analyses provided by Craig Williams, PharmD, Oregon Health & Science University,
2007.
Low levels of HDL cholesterol, often associated with elevated triglyceride levels,
are the most prevalent pattern of dyslipidemia in persons with type 2 diabetes. However,
the evidence base for drugs that target these lipid fractions is significantly less
robust than that for statin therapy (222). Nicotinic acid has been shown to reduce
CVD outcomes (223), although the study was done in a nondiabetic cohort. Gemfibrozil
has been shown to decrease rates of CVD events in subjects without diabetes (224,225)
and in the diabetic subgroup in one of the larger trials (224). However, in a large
trial specific to diabetic patients, fenofibrate failed to reduce overall cardiovascular
outcomes (226).
Dyslipidemia treatment and target lipid levels
For most patients with diabetes, the first priority of dyslipidemia therapy (unless
severe hypertriglyceridemia is the immediate issue) is to lower LDL cholesterol to
a target goal of <100 mg/dl (2.60 mmol/l) (227). Lifestyle intervention, including
MNT, increased physical activity, weight loss, and smoking cessation, may allow some
patients to reach lipid goals. Nutrition intervention should be tailored according
to each patient's age, type of diabetes, pharmacological treatment, lipid levels,
and other medical conditions and should focus on the reduction of saturated fat, cholesterol,
and trans unsaturated fat intake and increases in omega-3 fatty acids, viscous fiber
(such as in oats, legumes, citrus), and plant stanols/sterols. Glycemic control can
also beneficially modify plasma lipid levels, particularly in patients with very high
triglycerides and poor glycemic control.
In those with clinical CVD or over age 40 years with other CVD risk factors, pharmacological
treatment should be added to lifestyle therapy regardless of baseline lipid levels.
Statins are the drugs of choice for LDL cholesterol lowering.
In patients other than those described above, statin treatment should be considered
if there is an inadequate LDL cholesterol response to lifestyle modifications and
improved glucose control, or if the patient has increased cardiovascular risk (e.g.,
multiple cardiovascular risk factors or long duration of diabetes). Very little clinical
trial evidence exists for type 2 diabetic patients under age 40 years or for type
1 patients of any age. In the Heart Protection Study (lower age limit 40 years), the
subgroup of 600 patients with type 1 diabetes had a proportionately similar reduction
in risk as patients with type 2 diabetes, although not statistically significant (216).
Although the data are not definitive, consideration should be given to similar lipid-lowering
goals in type 1 diabetic patients as in type 2 diabetic patients, particularly if
they have other cardiovascular risk factors.
Alternative LDL cholesterol goals
Virtually all trials of statins and CVD outcomes tested specific doses of statins
against placebo, other doses of statin, or other statins, rather than aiming for specific
LDL cholesterol goals (228). As can be seen in Table 11, placebo-controlled trials
generally achieved LDL cholesterol reductions of 30–40% from baseline. Hence, LDL
cholesterol lowering of this magnitude is an acceptable outcome for patients who cannot
reach LDL cholesterol goals due to severe baseline elevations in LDL cholesterol and/or
intolerance of maximal, or any, statin doses. Additionally for those with baseline
LDL cholesterol minimally above 100 mg/dl, prescribing statin therapy to lower LDL
cholesterol about 30–40% from baseline is probably more effective than prescribing
just enough to get LDL cholesterol slightly below 100 mg/dl.
Recent clinical trials in high-risk patients, such as those with acute coronary syndromes
or previous cardiovascular events (229
–231), have demonstrated that more aggressive therapy with high doses of statins to
achieve an LDL cholesterol of <70 mg/dl led to a significant reduction in further
events. Therefore, a reduction in LDL cholesterol to a goal of <70 mg/dl is an option
in very-high-risk diabetic patients with overt CVD (232).
In individual patients, LDL cholesterol lowering with statins is highly variable,
and this variable response is poorly understood (233). Reduction of CVD events with
statins correlates very closely with LDL cholesterol lowering (214). When maximally
tolerated doses of statins fail to significantly lower LDL cholesterol (<30% reduction
from patients baseline), the primary aim of combination therapy should be to achieve
additional LDL cholesterol lowering. Niacin, fenofibrate, ezetimibe, and bile acid
sequestrants all offer additional LDL cholesterol lowering. The evidence that combination
therapy provides a significant increment in CVD risk reduction over statin therapy
alone is still elusive.
In 2008, a consensus panel convened by the American Diabetes Association and the American
College of Cardiology recommended a greater focus on non-HDL cholesterol and apo lipoprotein
B (apo B) in patients who are likely to have small LDL particles, such as people with
diabetes (234). The consensus panel suggested that for statin-treated patients in
whom the LDL cholesterol goal would be <70 mg/dl (non-HDL cholesterol <100 mg/dl),
apo B should be measured and treated to <80 mg/dl. For patients on statins with an
LDL cholesterol goal of <100 mg/dl (non-HDL cholesterol <130 mg/dl), apo B should
be measured and treated to <90 mg/dl.
Treatment of other lipoprotein fractions or targets
Severe hypertriglyceridemia may warrant immediate therapy of this abnormality with
lifestyle and usually pharmacologic therapy (fibric acid derivative, niacin, or fish
oil) to reduce the risk of acute pancreatitis. In the absence of severe hypertriglyceridemia,
therapy targeting HDL cholesterol or triglycerides has intuitive appeal but lacks
the evidence base of statin therapy. If the HDL cholesterol is <40 mg/dl and the LDL
cholesterol between 100 and 129 mg/dl, gemfibrozil or niacin might be used, especially
if a patient is intolerant to statins. Niacin is the most effective drug for raising
HDL cholesterol. It can significantly increase blood glucose at high doses, but recent
studies demonstrate that at modest doses (750–2,000 mg/day), significant improvements
in LDL cholesterol, HDL cholesterol, and triglyceride levels are accompanied by only
modest changes in glucose that are generally amenable to adjustment of diabetes therapy
(235,236).
Combination therapy
Combination therapy, with a statin and a fibrate or statin and niacin, may be efficacious
for treatment for all three lipid fractions, but this combination is associated with
an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis. The
risk of rhabdomyolysis is higher with higher doses of statins and with renal insufficiency
and seems to be lower when statins are combined with fenofibrate than gemfibrozil
(237). In the recent ACCORD study, the combination of fenofibrate and simvastatin
did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction,
or nonfatal stroke, as compared with simvastatin alone, in patients with type 2 diabetes
who were at high risk for CVD. However, prespecified subgroup analyses suggested heterogeneity
in treatment effects according to sex, with a benefit for men and possible harm for
women, and a possible benefit of combination therapy for patients with both triglyceride
level ≥204 mg/dl and HDL cholesterol level ≤34 mg/dl (238). Other ongoing trials may
provide much-needed evidence for the effects of combination therapy on cardiovascular
outcomes.
Table 12 summarizes common treatment goals for A1C, blood pressure, and HDL cholesterol.
Table 12
Summary of recommendations for glycemic blood pressure and lipid control for most
adults with diabetes
A1C
<7.0%*
Blood pressure
<130/80 mmHg†
Lipids
LDL cholesterol
<100 mg/dl (<2.6 mmol/l)‡
*More or less stringent glycemic goals may be appropriate for individual patients.
Goals should be individualized based on: duration of diabetes, age/life expectancy,
comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia
unawareness, and individual patient considerations.
†Based on patient characteristics and response to therapy, higher or lower systolic
blood pressure targets may be appropriate.
‡In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l),
using a high dose of a statin, is an option.
3. Antiplatelet agents
Recommendations
Consider aspirin therapy (75–162 mg/day) as a primary prevention strategy in those
with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%).
This includes most men >50 years of age or women >60 years of age who have at least
one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia,
or albuminuria). (C)
Aspirin should not be recommended for CVD prevention for adults with diabetes at low
CVD risk (10-year CVD risk <5%, such as in men <50 and women <60 years of age with
no major additional CVD risk factors), since the potential adverse effects from bleeding
likely offset the potential benefits. (C)
In patients in these age-groups with multiple other risk factors (e.g., 10-year risk
5–10%), clinical judgment is required. (E)
Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with
diabetes with a history of CVD. (A)
For patients with CVD and documented aspirin allergy, clopidogrel (75 mg/day) should
be used. (B)
Combination therapy with ASA (75–162 mg/day) and clopidogrel (75 mg/day) is reasonable
for up to a year after an acute coronary syndrome. (B)
ADA and the American Heart Association (AHA) have, in the past, jointly recommended
that low-dose aspirin therapy be used as a primary prevention strategy in those with
diabetes at increased cardiovascular risk, including those who are over 40 years of
age or those with additional risk factors (family history of CVD, hypertension, smoking,
dyslipidemia, or albuminuria) (188). These recommendations were derived from several
older trials that included small numbers of patients with diabetes.
Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality
in high-risk patients with previous myocardial infarction or stroke (secondary prevention).
Its net benefit in primary prevention among patients with no previous cardiovascular
events is more controversial, both for patients with and without a history of diabetes
(239). Two recent randomized controlled trials of aspirin specifically in patients
with diabetes failed to show a significant reduction in CVD end points, raising further
questions about the efficacy of aspirin for primary prevention in people with diabetes
(240,241).
The Anti-thrombotic Trialists' (ATT) collaborators recently published an individual
patient-level meta-analysis of the six large trials of aspirin for primary prevention
in the general population. These trials collectively enrolled over 95,000 participants,
including almost 4,000 with diabetes. Overall, they found that aspirin reduced the
risk of vascular events by 12% (RR 0.88 [95% CI 0.82– 0.94]). The largest reduction
was for nonfatal myocardial infarction with little effect on CHD death (RR 0.95 [95%
CI 0.78–1.15]) or total stroke. There was some evidence of a difference in aspirin
effect by sex. Aspirin significantly reduced CHD events in men but not in women. Conversely,
aspirin had no effect on stroke in men but significantly reduced stroke in women.
Notably, sex differences in aspirin's effects have not been observed in studies of
secondary prevention (239). In the six trials examined by the ATT collaborators, the
effects of aspirin on major vascular events were similar for patients with or without
diabetes: RR 0.88 (95% CI 0.67–1.15) and 0.87 (0.79–0.96), respectively. The CI was
wider for those with diabetes because of their smaller number.
Based on the currently available evidence, aspirin appears to have a modest effect
on ischemic vascular events with the absolute decrease in events depending on the
underlying CVD risk. The main adverse effects appear to be an increased risk of gastrointestinal
bleeding. The excess risk may be as high as 1–5 per 1,000 per year in real-world settings.
In adults with CVD risk greater than 1% per year, the number of CVD events prevented
will be similar to or greater than the number of episodes of bleeding induced, although
these complications do not have equal effects on long-term health (242).
In 2010, a position statement of the ADA, AHA, and American College of Cardiology
Foundation (ACCF) updated prior joint recommendations for primary prevention (243).
Low dose (75–162 mg/day) aspirin use for primary prevention is reasonable for adults
with diabetes and no previous history of vascular disease who are at increased CVD
risk (10-year risk of CVD events over 10%) and who are not at increased risk for bleeding.
This generally includes most men over age 50 years and women over age 60 years who
also have one or more of the following major risk factors: smoking, hypertension,
dyslipidemia, family history of premature CVD, and albuminuria.
However, aspirin is no longer recommended for those at low CVD risk (women under age
60 years and men under age 50 years with no major CVD risk factors; 10-year CVD risk
under 5%) as the low benefit is likely to be outweighed by the risks of significant
bleeding. Clinical judgment should be used for those at intermediate risk (younger
patients with one or more risk factors, or older patients with no risk factors; those
with 10-year CVD risk of 5–10%) until further research is available. Use of aspirin
in patients under the age of 21 years is contraindicated due to the associated risk
of Reye's syndrome.
Average daily dosages used in most clinical trials involving patients with diabetes
ranged from 50 to 650 mg but were mostly in the range of 100 to 325 mg/day. There
is little evidence to support any specific dose, but using the lowest possible dosage
may help reduce side effects (244). Although platelets from patients with diabetes
have altered function, it is unclear what, if any, impact that finding has on the
required dose of aspirin for cardioprotective effects in the patient with diabetes.
Many alternate pathways for platelet activation exist that are independent of thromboxane
A2 and thus not sensitive to the effects of aspirin (245). Therefore, while “aspirin
resistance” appears higher in the diabetic patients when measured by a variety of
ex vivo and in vitro methods (platelet aggrenometry, measurement of thromboxane B2),
these observations alone are insufficient to empirically recommend higher doses of
aspirin be used in the diabetic patient at this time.
Clopidogrel has been demonstrated to reduce CVD events in diabetic individuals (246).
It is recommended as adjunctive therapy in the first year after an acute coronary
syndrome or as alternative therapy in aspirin-intolerant patients.
4. Smoking cessation
Recommendations
Advise all patients not to smoke. (A)
Include smoking cessation counseling and other forms of treatment as a routine component
of diabetes care. (B)
A large body of evidence from epidemiological, case-control, and cohort studies provides
convincing documentation of the causal link between cigarette smoking and health risks.
Much of the work documenting the impact of smoking on health did not separately discuss
results on subsets of individuals with diabetes, but suggests that the identified
risks are at least equivalent to those found in the general population. Other studies
of individuals with diabetes consistently demonstrate that smokers have a heightened
risk of CVD, premature death, and increased rate of microvascular complications of
diabetes. Smoking may have a role in the development of type 2 diabetes.
The routine and thorough assessment of tobacco use is important as a means of preventing
smoking or encouraging cessation. A number of large randomized clinical trials have
demonstrated the efficacy and cost-effectiveness of brief counseling in smoking cessation,
including the use of quit lines, in the reduction of tobacco use. For the patient
motivated to quit, the addition of pharmacological therapy to counseling is more effective
than either treatment alone. Special considerations should include assessment of level
of nicotine dependence, which is associated with difficulty in quitting and relapse
(247).
5. CHD screening and treatment
Recommendations
Screening
In asymptomatic patients, routine screening for CAD is not recommended, as it does
not improve outcomes as long as CVD risk factors are treated. (A)
Treatment
In patients with known CVD, ACE inhibitor (C) and aspirin and statin therapy (A) (if
not contraindicated) should be used to reduce the risk of cardiovascular events.
In patients with a prior myocardial infarction, β-blockers should be continued for
at least 2 years after the event (B).
Longer term use of β-blockers in the absence of hypertension is reasonable if well
tolerated, but data are lacking. (E)
Avoid TZD treatment in patients with symptomatic heart failure. (C)
Metformin may be used in patients with stable CHF if renal function is normal. It
should be avoided in unstable or hospitalized patients with CHF. (C)
Screening for CAD is reviewed in a recently updated consensus statement (154). To
identify the presence of CAD in diabetic patients without clear or suggestive symptoms,
a risk factor–based approach to the initial diagnostic evaluation and subsequent follow-up
has intuitive appeal. However, recent studies concluded that using this approach fails
to identify which patients with type 2 diabetes will have silent ischemia on screening
tests (159,248).
Candidates for cardiac testing include those with 1) typical or atypical cardiac symptoms
and 2) an abnormal resting ECG. The screening of asymptomatic patients remains controversial,
especially as intensive medical therapy, indicated in diabetic patients at high risk
for CVD, has an increasing evidence base for providing equal outcomes to invasive
revascularization, including in diabetic patients (249,250). There is also some evidence
that silent myocardial ischemia may reverse over time, adding to the controversy concerning
aggressive screening strategies (251). Finally, a recent randomized observational
trial demonstrated no clinical benefit to routine screening of asymptomatic patients
with type 2 diabetes and normal ECGs (252). Despite abnormal myocardial perfusion
imaging in more than one in five patients, cardiac outcomes were essentially equal
(and very low) in screened versus unscreened patients. Accordingly, the overall effectiveness,
especially the cost-effectiveness, of such an indiscriminate screening strategy is
now questioned.
Newer noninvasive CAD screening methods, such as computed tomography (CT) and CT angiography
have gained in popularity. These tests infer the presence of coronary atherosclerosis
by measuring the amount of calcium in coronary arteries and, in some circumstances,
by direct visualization of luminal stenoses. Although asymptomatic diabetic patients
found to have a higher coronary disease burden have more future cardiac events (253
–255), the role of these tests beyond risk stratification is not clear. Their routine
use leads to radiation exposure and may result in unnecessary invasive testing such
as coronary angiography and revascularization procedures. The ultimate balance of
benefit, cost, and risks of such an approach in asymptomatic patients remains controversial,
particularly in the modern setting of aggressive CVD risk factor control.
In all patients with diabetes, cardiovascular risk factors should be assessed at least
annually. These risk factors include dyslipidemia, hypertension, smoking, a positive
family history of premature coronary disease, and the presence of micro- or macroalbuminuria.
Abnormal risk factors should be treated as described elsewhere in these guidelines.
Patients at increased CHD risk should receive aspirin and a statin and ACE inhibitor
or ARB therapy if hypertensive, unless there are contraindications to a particular
drug class. While clear benefit exists for ACE inhibitor and ARB therapy in patients
with nephropathy or hypertension, the benefits in patients with CVD in the absence
of these conditions is less clear, especially when LDL cholesterol is concomitantly
controlled (256,257).
B. Nephropathy screening and treatment
Recommendations
General recommendations
To reduce the risk or slow the progression of nephropathy, optimize glucose control.
(A)
To reduce the risk or slow the progression of nephropathy, optimize blood pressure
control. (A)
Screening
Perform an annual test to assess urine albumin excretion in type 1 diabetic patients
with diabetes duration of 5 years and in all type 2 diabetic patients starting at
diagnosis. (E)
Measure serum creatinine at least annually in all adults with diabetes regardless
of the degree of urine albumin excretion. The serum creatinine should be used to estimate
GFR and stage the level of chronic kidney disease (CKD), if present. (E)
Treatment
In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either
ACE inhibitors or ARBs should be used. (A)
While there are no adequate head-to-head comparisons of ACE inhibitors and ARBs, there
is clinical trial support for each of the following statements:
In patients with type 1 diabetes, with hypertension and any degree of albuminuria,
ACE inhibitors have been shown to delay the progression of nephropathy. (A)
In patients with type 2 diabetes, hypertension, and microalbuminuria, both ACE inhibitors
and ARBs have been shown to delay the progression to macroalbuminuria. (A)
In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency
(serum creatinine >1.5 mg/dl), ARBs have been shown to delay the progression of nephropathy.
(A)
If one class is not tolerated, the other should be substituted. (E)
Reduction of protein intake to 0.8–1.0 g · kg body wt−1 · day−1 in individuals with
diabetes and the earlier stages of CKD and to 0.8 g · kg body wt−1 · day−1 in the
later stages of CKD may improve measures of renal function (urine albumin excretion
rate, GFR) and is recommended. (B)
When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine and potassium
levels for the development of acute kidney disease and hyperkalemia. (E)
Continued monitoring of urine albumin excretion to assess both response to therapy
and progression of disease is recommended. (E)
When eGFR <60 ml/min/1.73 m2, evaluate and manage potential complications of CKD.
(E)
Consider referral to a physician experienced in the care of kidney disease when there
is uncertainty about the etiology of kidney disease (heavy proteinuria, active urine
sediment, absence of retinopathy, rapid decline in GFR), difficult management issues,
or advanced kidney disease. (B)
Diabetic nephropathy occurs in 20–40% of patients with diabetes and is the single
leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range
of 30–299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic
nephropathy in type 1 diabetes and a marker for development of nephropathy in type
2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk
(258,259). Patients with microalbuminuria who progress to macroalbuminuria (300 mg/24
h) are likely to progress to ESRD (260,261). However, a number of interventions have
been demonstrated to reduce the risk and slow the progression of renal disease.
Intensive diabetes management with the goal of achieving near-normoglycemia has been
shown in large prospective randomized studies to delay the onset of microalbuminuria
and the progression of micro- to macroalbuminuria in patients with type 1 (262,263)
and type 2 (55,56) diabetes. The UKPDS provided strong evidence that control of blood
pressure can reduce the development of nephropathy (195). In addition, large prospective
randomized studies in patients with type 1 diabetes have demonstrated that achievement
of lower levels of systolic blood pressure (<140 mmHg) resulting from treatment using
ACE inhibitors provides a selective benefit over other antihypertensive drug classes
in delaying the progression from micro- to macroalbuminuria and can slow the decline
in GFR in patients with macroalbuminuria (264
–266). In type 2 diabetes with hypertension and normoalbuminuria, RAS inhibition has
been demonstrated to delay onset of microalbuminuria (267).
In addition, ACE inhibitors have been shown to reduce major CVD outcomes (i.e., myocardial
infarction, stroke, death) in patients with diabetes (207), thus further supporting
the use of these agents in patients with microalbuminuria, a CVD risk factor. ARBs
do not prevent microalbuminuria in normotensive patients with type 1 or type 2 diabetes
(268,269); however, ARBs have been shown to reduce the rate of progression from micro-
to macroalbuminuria as well as ESRD in patients with type 2 diabetes (270
–272). Some evidence suggests that ARBs have a smaller magnitude of rise in potassium
compared with ACE inhibitors in people with nephropathy (273,274). Combinations of
drugs that block the renin-angiotensin-aldosterone system (e.g., an ACE inhibitor
plus an ARB, a mineralocorticoid antagonist, or a direct renin inhibitor) have been
shown to provide additional lowering of albuminuria (275
–278). However, the long-term effects of such combinations on renal or cardiovascular
outcomes have not yet been evaluated in clinical trials, and they are associated with
increased risk for hyperkalemia.
Other drugs, such as diuretics, calcium channel blockers, and β-blockers should be
used as additional therapy to further lower blood pressure in patients already treated
with ACE inhibitors or ARBs (212), or as alternate therapy in the rare individual
unable to tolerate ACE inhibitors or ARBs.
Studies in patients with varying stages of nephropathy have shown that protein restriction
of dietary protein helps slow the progression of albuminuria, GFR decline, and occurrence
of ESRD (279
–282). Dietary protein restriction should be considered particularly in patients whose
nephropathy seems to be progressing despite optimal glucose and blood pressure control
and use of ACE inhibitor and/or ARBs (282).
Assessment of albuminuria status and renal function
Screening for microalbuminuria can be performed by measurement of the albumin-to-creatinine
ratio in a random spot collection; 24-h or timed collections are more burdensome and
add little to prediction or accuracy (283,284). Measurement of a spot urine for albumin
only, whether by immunoassay or by using a dipstick test specific for microalbumin,
without simultaneously measuring urine creatinine, is somewhat less expensive but
susceptible to false-negative and -positive determinations as a result of variation
in urine concentration due to hydration and other factors.
Abnormalities of albumin excretion are defined in Table 13. Because of variability
in urinary albumin excretion, two of three specimens collected within a 3- to 6-month
period should be abnormal before considering a patient to have crossed one of these
diagnostic thresholds. Exercise within 24 h, infection, fever, CHF, marked hyperglycemia,
and marked hypertension may elevate urinary albumin excretion over baseline values.
Table 13
Definitions of abnormalities in albumin excretion
Category
Spot collection (μg/mg creatinine)
Normal
<30
Microalbuminuria
30–299
Macro (clinical)-albuminuria
≥300
Information on presence of abnormal urine albumin excretion in addition to level of
GFR may be used to stage CKD. The National Kidney Foundation classification (Table
14) is primarily based on GFR levels and therefore differs from other systems, in
which staging is based primarily on urinary albumin excretion (285). Studies have
found decreased GFR in the absence of increased urine albumin excretion in a substantial
percentage of adults with diabetes (286). Serum creatinine should therefore be measured
at least annually in all adults with diabetes, regardless of the degree of urine albumin
excretion.
Table 14
Stages of CKD
Stage
Description
GFR (ml/min per 1.73 m2 body surface area)
1
Kidney damage* with normal or increased GFR
≥90
2
Kidney damage* with mildly decreased GFR
60–89
3
Moderately decreased GFR
30–59
4
Severely decreased GFR
15–29
5
Kidney failure
<15 or dialysis
*Kidney damage defined as abnormalities on pathologic, urine, blood, or imaging tests.
Adapted from ref. 284.
Serum creatinine should be used to estimate GFR and to stage the level of CKD, if
present. eGFR is commonly co-reported by laboratories or can be estimated using formulae
such as the Modification of Diet in Renal Disease (MDRD) study equation (287). Recent
reports have indicated that the MDRD is more accurate for the diagnosis and stratification
of CKD in patients with diabetes than the Cockcroft-Gault formula (288). GFR calculators
are available at http://www.nkdep.nih.gov.
The role of continued annual quantitative assessment of albumin excretion after diagnosis
of microalbuminuria and institution of ACE inhibitor or ARB therapy and blood pressure
control is unclear. Continued surveillance can assess both response to therapy and
progression of disease. Some suggest that reducing abnormal albuminuria (>30 mg/g)
to the normal or near-normal range may improve renal and cardiovascular prognosis,
but this approach has not been formally evaluated in prospective trials.
Complications of kidney disease correlate with level of kidney function. When the
eGFR is less than 60 ml/min/1.73 m2, screening for complications of CKD is indicated
(Table 15). Early vaccination against hepatitis B is indicated in patients likely
to progress to end-stage kidney disease.
Table 15
Management of CKD in diabetes
GFR (ml/min/1.73 m2)
Recommended
All patients
Yearly measurement of creatinine, urinary albumin excretion, potassium
45–60
Referral to nephrology if possibility for nondiabetic kidney disease exists (duration
type 1 diabetes <10 years, heavy proteinuria, abnormal findings on renal ultrasound,
resistant hypertension, rapid fall in GFR, or active urinary sediment)
Consider need for dose adjustment of medications
Monitor eGFR every 6 months
Monitor electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, parathyroid hormone
at least yearly
Assure vitamin D sufficiency
Consider bone density testing
Referral for dietary counselling
30–44
Monitor eGFR every 3 months
Monitor electrolytes, bicarbonate, calcium, phosphorus, parathyroid hormone, hemoglobin,
albumin, weight every 3–6 months
Consider need for dose adjustment of medications
<30
Referral to nephrologist
Adapted from http://www.kidney.org/professionals/KDOQI/guideline_diabetes/.
Consider referral to a physician experienced in the care of kidney disease when there
is uncertainty about the etiology of kidney disease (heavy proteinuria, active urine
sediment, absence of retinopathy, rapid decline in GFR, resistant hypertension), difficult
management issues, or advanced kidney disease. The threshold for referral may vary
depending on the frequency with which a provider encounters diabetic patients with
significant kidney disease. Consultation with a nephrologist when stage 4 CKD develops
has been found to reduce cost, improve quality of care, and keep people off dialysis
longer (289). However, nonrenal specialists should not delay educating their patients
about the progressive nature of diabetic kidney disease; the renal preservation benefits
of aggressive treatment of blood pressure, blood glucose, and hyperlipidemia; and
the potential need for renal replacement therapy.
C. Retinopathy screening and treatment
Recommendations
General recommendations
To reduce the risk or slow the progression of retinopathy, optimize glycemic control.
(A)
To reduce the risk or slow the progression of retinopathy, optimize blood pressure
control. (A)
Screening
Adults and children aged 10 years or older with type 1 diabetes should have an initial
dilated and comprehensive eye examination by an ophthalmologist or optometrist within
5 years after the onset of diabetes. (B)
Patients with type 2 diabetes should have an initial dilated and comprehensive eye
examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes.
(B)
Subsequent examinations for type 1 and type 2 diabetic patients should be repeated
annually by an ophthalmologist or optometrist. Less frequent exams (every 2–3 years)
may be considered following one or more normal eye exams. Examinations will be required
more frequently if retinopathy is progressing. (B)
High-quality fundus photographs can detect most clinically significant diabetic retinopathy.
Interpretation of the images should be performed by a trained eye care provider. While
retinal photography may serve as a screening tool for retinopathy, it is not a substitute
for a comprehensive eye exam, which should be performed at least initially and at
intervals thereafter as recommended by an eye care professional. (E)
Women with preexisting diabetes who are planning a pregnancy or who have become pregnant
should have a comprehensive eye examination and should be counseled on the risk of
development and/or progression of diabetic retinopathy. Eye examination should occur
in the first trimester with close follow-up throughout pregnancy and for 1 year postpartum.
(B)
Treatment
Promptly refer patients with any level of macular edema, severe NPDR, or any PDR to
an ophthalmologist who is knowledgeable and experienced in the management and treatment
of diabetic retinopathy. (A)
Laser photocoagulation therapy is indicated to reduce the risk of vision loss in patients
with high-risk PDR, clinically significant macular edema, and in some cases of severe
NPDR. (A)
The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection,
as this therapy does not increase the risk of retinal hemorrhage. (A)
Diabetic retinopathy is a highly specific vascular complication of both type 1 and
type 2 diabetes, with prevalence strongly related to the duration of diabetes. Diabetic
retinopathy is the most frequent cause of new cases of blindness among adults aged
20–74 years. Glaucoma, cataracts, and other disorders of the eye occur earlier and
more frequently in people with diabetes.
In addition to duration of diabetes, other factors that increase the risk of, or are
associated with, retinopathy include chronic hyperglycemia (290), the presence of
nephropathy (291), and hypertension (292). Intensive diabetes management with the
goal of achieving near normoglycemia has been shown in large prospective randomized
studies to prevent and/or delay the onset and progression of diabetic retinopathy
(47,55, 56,64). Lowering blood pressure has been shown to decrease the progression
of retinopathy (195). Several case series and a controlled prospective study suggest
that pregnancy in type 1 diabetic patients may aggravate retinopathy (293,294); laser
photocoagulation surgery can minimize this risk (294).
One of the main motivations for screening for diabetic retinopathy is the established
efficacy of laser photocoagulation surgery in preventing vision loss. Two large trials,
the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy
Study (ETDRS), provide the strongest support for the therapeutic benefits of photocoagulation
surgery.
The DRS (295) showed that panretinal photocoagulation surgery reduced the risk of
severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes,
with greatest risk-to-benefit ratio in those with baseline disease (disc neovascularization
or vitreous hemorrhage).
The ETDRS (296) established the benefit of focal laser photocoagulation surgery in
eyes with macular edema, particularly those with clinically significant macular edema,
with reduction of doubling of the visual angle (e.g., 20/50 to 20/100) from 20% in
untreated eyes to 8% in treated eyes. The ETDRS also verified the benefits of panretinal
photocoagulation for high-risk PDR and in older-onset patients with severe NPDR or
less-than-high-risk PDR.
Laser photocoagulation surgery in both trials was beneficial in reducing the risk
of further vision loss, but generally not beneficial in reversing already diminished
acuity. This preventive effect and the fact that patients with PDR or macular edema
may be asymptomatic provide strong support for a screening program to detect diabetic
retinopathy.
As retinopathy is estimated to take at least 5 years to develop after the onset of
hyperglycemia, patients with type 1 diabetes should have an initial dilated and comprehensive
eye examination within 5 years after the onset of diabetes. Patients with type 2 diabetes,
who generally have had years of undiagnosed diabetes and who have a significant risk
of prevalent DR at time of diabetes diagnosis, should have an initial dilated and
comprehensive eye examination soon after diagnosis. Examinations should be performed
by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing
the presence of diabetic retinopathy and is aware of its management. Subsequent examinations
for type 1 and type 2 diabetic patients are generally repeated annually. Less-frequent
exams (every 2–3 years) may be cost effective after one or more normal eye exams,
while examinations will be required more frequently if retinopathy is progressing
(297).
The use of retinal photography with remote reading by experts has great potential
in areas where qualified eye care professionals are not available, and may also enhance
efficiency and reduce costs when the expertise of ophthalmologists can be utilized
for more complex examinations and for therapy (298). In-person exams are still necessary
when the photos are unacceptable and for follow-up of abnormalities detected. Photos
are not a substitute for a comprehensive eye exam, which should be performed at least
initially and at intervals thereafter as recommended by an eye care professional.
Results of eye examinations should be documented and transmitted to the referring
health care professional. For a detailed review of the evidence and further discussion
of diabetic retinopathy, see the ADA's technical review and position statement on
this subject (297,300).
D. Neuropathy screening and treatment (301)
Recommendations
All patients should be screened for distal symmetric polyneuropathy (DPN) at diagnosis
and at least annually thereafter, using simple clinical tests. (B)
Electrophysiological testing is rarely needed, except in situations where the clinical
features are atypical. (E)
Screening for signs and symptoms of autonomic neuropathy should be instituted at diagnosis
of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes. Special testing
is rarely needed and may not affect management or outcomes. (E)
Medications for the relief of specific symptoms related to DPN and autonomic neuropathy
are recommended, as they improve the quality of life of the patient. (E)
The diabetic neuropathies are heterogeneous with diverse clinical manifestations.
They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor
DPN and autonomic neuropathy. Although DPN is a diagnosis of exclusion, complex investigations
to exclude other conditions are rarely needed.
The early recognition and appropriate management of neuropathy in the patient with
diabetes is important for a number of reasons: 1) nondiabetic neuropathies may be
present in patients with diabetes and may be treatable, 2) a number of treatment options
exist for symptomatic diabetic neuropathy, 3) up to 50% of DPN may be asymptomatic
and patients are at risk of insensate injury to their feet, and 4) autonomic neuropathy
and particularly cardiovascular autonomic neuropathy is associated with substantial
morbidity and even mortality. Specific treatment for the underlying nerve damage is
currently not available, other than improved glycemic control, which may modestly
slow progression (63) but not reverse neuronal loss. Effective symptomatic treatments
are available for some manifestations of DPN and autonomic neuropathy.
Diagnosis of neuropathy
Distal symmetric polyneuropathy.
Patients with diabetes should be screened annually for DPN using tests such as pinprick
sensation, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure
sensation at the distal plantar aspect of both great toes and metatarsal joints, and
assessment of ankle reflexes. Combinations of more than one test have >87% sensitivity
in detecting DPN. Loss of 10-g monofilament perception and reduced vibration perception
predict foot ulcers (301). Importantly, in patients with neuropathy, particularly
when severe, causes other than diabetes should always be considered, such as neurotoxic
mediations, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency (especially
in those taking metformin for prolonged periods (302), renal disease, chronic inflammatory
demyelinating neuropathy, inherited neuropathies, and vasculitis (303).
Diabetic autonomic neuropathy (304).
The symptoms and signs of autonomic dysfunction should be elicited carefully during
the history and physical examination. Major clinical manifestations of diabetic autonomic
neuropathy include resting tachycardia, exercise intolerance, orthostatic hypotension,
constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired
neurovascular function, and, potentially, autonomic failure in response to hypoglycemia.
Cardiovascular autonomic neuropathy, a CVD risk factor (93), is the most studied and
clinically important form of diabetic autonomic neuropathy. Cardiovascular autonomic
neuropathy may be indicated by resting tachycardia (>100 bpm) or orthostasis (a fall
in systolic blood pressure >20 mmHg upon standing without an appropriate heart rate
response); it is also associated with increased cardiac event rates.
Gastrointestinal neuropathies (e.g., esophageal enteropathy, gastroparesis, constipation,
diarrhea, fecal incontinence) are common, and any section of the gastrointestinal
tract may be affected. Gastroparesis should be suspected in individuals with erratic
glucose control or with upper gastrointestinal symptoms without other identified cause.
Evaluation of solid-phase gastric emptying using double-isotope scintigraphy may be
done if symptoms are suggestive, but test results often correlate poorly with symptoms.
Constipation is the most common lower-gastrointestinal symptom but can alternate with
episodes of diarrhea.
Diabetic autonomic neuropathy is also associated with genitourinary tract disturbances.
In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde
ejaculation. Evaluation of bladder dysfunction should be performed for individuals
with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence,
or a palpable bladder.
Symptomatic treatments
DPN.
The first step in management of patients with DPN should be to aim for stable and
optimal glycemic control. Although controlled trial evidence is lacking, several observational
studies suggest that neuropathic symptoms improve not only with optimization of control,
but also with the avoidance of extreme blood glucose fluctuations. Patients with painful
DPN may benefit from pharmacological treatment of their symptoms: many agents have
efficacy confirmed in published randomized controlled trials, several of which are
Food and Drug Administration (FDA)-approved for the management of painful DPN.
Treatment of autonomic neuropathy
Gastroparesis symptoms may improve with dietary changes and prokinetic agents such
as metoclopramide or erythromycin. Treatments for erectile dysfunction may include
phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins,
vacuum devices, or penile prostheses. Interventions for other manifestations of autonomic
neuropathy are described in the ADA statement on neuropathy (301). As with DPN treatments,
these interventions do not change the underlying pathology and natural history of
the disease process, but may have a positive impact on the quality of life of the
patient.
E. Foot care
Recommendations
For all patients with diabetes, perform an annual comprehensive foot examination to
identify risk factors predictive of ulcers and amputations. The foot examination should
include inspection, assessment of foot pulses, and testing for loss of protective
sensation (10-g monofilament plus testing any one of: vibration using 128-Hz tuning
fork, pinprick sensation, ankle reflexes, or vibration perception threshold). (B)
Provide general foot self-care education to all patients with diabetes. (B)
A multidisciplinary approach is recommended for individuals with foot ulcers and high-risk
feet, especially those with a history of prior ulcer or amputation. (B)
Refer patients who smoke, have loss of protective sensation and structural abnormalities,
or have history of prior lower-extremity complications to foot care specialists for
ongoing preventive care and life-long surveillance. (C)
Initial screening for peripheral arterial disease (PAD) should include a history for
claudication and an assessment of the pedal pulses. Consider obtaining an ankle-brachial
index (ABI), as many patients with PAD are asymptomatic. (C)
Refer patients with significant claudication or a positive ABI for further vascular
assessment and consider exercise, medications, and surgical options. (C)
Amputation and foot ulceration, consequences of diabetic neuropathy and/or PAD, are
common and major causes of morbidity and disability in people with diabetes. Early
recognition and management of risk factors can prevent or delay adverse outcomes.
The risk of ulcers or amputations is increased in people who have the following risk
factors:
Previous amputation
Past foot ulcer history
Peripheral neuropathy
Foot deformity
Peripheral vascular disease
Visual impairment
Diabetic nephropathy (especially patients on dialysis)
Poor glycemic control
Cigarette smoking
Many studies have been published proposing a range of tests that might usefully identify
patients at risk of foot ulceration, creating confusion among practitioners as to
which screening tests should be adopted in clinical practice. An ADA task force was
therefore assembled in 2008 to concisely summarize recent literature in this area
and then recommend what should be included in the comprehensive foot exam for adult
patients with diabetes. Their recommendations are summarized below, but clinicians
should refer to the task force report (305) for further details and practical descriptions
of how to perform components of the comprehensive foot examination.
At least annually, all adults with diabetes should undergo a comprehensive foot examination
to identify high risk conditions. Clinicians should ask about history of previous
foot ulceration or amputation, neuropathic or peripheral vascular symptoms, impaired
vision, tobacco use, and foot care practices. A general inspection of skin integrity
and musculoskeletal deformities should be done in a well lit room. Vascular assessment
would include inspection and assessment of pedal pulses.
The neurologic exam recommended is designed to identify loss of protective sensation
(LOPS) rather than early neuropathy. The clinical examination to identify LOPS is
simple and requires no expensive equipment. Five simple clinical tests (use of a 10-g
monofilament, vibration testing using a 128-Hz tuning fork, tests of pinprick sensation,
ankle reflex assessment, and testing vibration perception threshold with a biothesiometer),
each with evidence from well-conducted prospective clinical cohort studies, are considered
useful in the diagnosis of LOPS in the diabetic foot. The task force agrees that any
of the five tests listed could be used by clinicians to identify LOPS, although ideally
two of these should be regularly performed during the screening exam—normally the
10-g monofilament and one other test. One or more abnormal tests would suggest LOPS,
while at least two normal tests (and no abnormal test) would rule out LOPS. The last
test listed, vibration assessment using a biothesiometer or similar instrument, is
widely used in the U.S.; however, identification of the patient with LOPS can easily
be carried out without this or other expensive equipment.
Initial screening for PAD should include a history for claudication and an assessment
of the pedal pulses. A diagnostic ABI should be performed in any patient with symptoms
of PAD. Due to the high estimated prevalence of PAD in patients with diabetes and
the fact that many patients with PAD are asymptomatic, an ADA consensus statement
on PAD (306) suggested that a screening ABI be performed in patients over 50 years
of age and be considered in patients under 50 years of age who have other PAD risk
factors (e.g., smoking, hypertension, hyperlipidemia, or duration of diabetes >10
years). Refer patients with significant symptoms or a positive ABI for further vascular
assessment and consider exercise, medications, and surgical options (306).
Patients with diabetes and high-risk foot conditions should be educated regarding
their risk factors and appropriate management. Patients at risk should understand
the implications of the LOPS, the importance of foot monitoring on a daily basis,
the proper care of the foot, including nail and skin care, and the selection of appropriate
footwear. Patients with LOPS should be educated on ways to substitute other sensory
modalities (hand palpation, visual inspection) for surveillance of early foot problems.
Patients' understanding of these issues and their physical ability to conduct proper
foot surveillance and care should be assessed. Patients with visual difficulties,
physical constraints preventing movement, or cognitive problems that impair their
ability to assess the condition of the foot and to institute appropriate responses
will need other people, such as family members, to assist in their care.
People with neuropathy or evidence of increased plantar pressure (e.g., erythema,
warmth, callus, or measured pressure) may be adequately managed with well-fitted walking
shoes or athletic shoes that cushion the feet and redistribute pressure. Callus can
be debrided with a scalpel by a foot care specialist or other health professional
with experience and training in foot care. People with bony deformities (e.g., hammertoes,
prominent metatarsal heads, bunions) may need extra-wide or -depth shoes. People with
extreme bony deformities (e.g., Charcot foot) who cannot be accommodated with commercial
therapeutic footwear may need custom-molded shoes.
Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular
surgeon, or rehabilitation specialist experienced in the management of individuals
with diabetes.
VII. DIABETES CARE IN SPECIFIC POPULATIONS
A. Children and adolescents
1. Type 1 diabetes
Three-quarters of all cases of type 1 diabetes are diagnosed in individuals <18 years
of age. It is appropriate to consider the unique aspects of care and management of
children and adolescents with type 1 diabetes. Children with diabetes differ from
adults in many respects, including changes in insulin sensitivity related to sexual
maturity and physical growth, ability to provide self-care, supervision in child care
and school, and unique neurological vulnerability to hypoglycemia and DKA. Attention
to such issues as family dynamics, developmental stages, and physiological differences
related to sexual maturity are all essential in developing and implementing an optimal
diabetes regimen. Although recommendations for children and adolescents are less likely
to be based on clinical trial evidence, expert opinion and a review of available and
relevant experimental data are summarized in the ADA statement on care of children
and adolescents with type 1 diabetes (307).
Ideally, the care of a child or adolescent with type 1 diabetes should be provided
by a multidisciplinary team of specialists trained in the care of children with pediatric
diabetes. At the very least, education of the child and family should be provided
by health care providers trained and experienced in childhood diabetes and sensitive
to the challenges posed by diabetes in this age-group. At the time of initial diagnosis,
it is essential that diabetes education be provided in a timely fashion, with the
expectation that the balance between adult supervision and self-care should be defined
by, and will evolve according to, physical, psychological, and emotional maturity.
MNT and psychological support should be provided at diagnosis, and regularly thereafter,
by individuals experienced with the nutritional and behavioral needs of the growing
child and family.
a. Glycemic control
Recommendations
Consider age when setting glycemic goals in children and adolescents with type 1 diabetes.
(E)
While current standards for diabetes management reflect the need to maintain glucose
control as near to normal as safely possible, special consideration should be given
to the unique risks of hypoglycemia in young children. Glycemic goals may need to
be modified to take into account the fact that most children <6 or 7 years of age
have a form of “hypoglycemic unawareness,” including immaturity of and a relative
inability to recognize and respond to hypoglycemic symptoms, placing them at greater
risk for severe hypoglycemia and its sequelae. In addition, and unlike the case in
adults, young children under the age of 5 years may be at risk for permanent cognitive
impairment after episodes of severe hypoglycemia (308
–310). Furthermore, findings from the DCCT demonstrated that near-normalization of
blood glucose levels was more difficult to achieve in adolescents than adults. Nevertheless,
the increased frequency of use of basal-bolus regimens and insulin pumps in youth
from infancy through adolescence has been associated with more children reaching ADA
blood glucose targets (311,312) in those families in which both parents and the child
with diabetes participate jointly to perform the required diabetes-related tasks.
Furthermore, recent studies documenting neurocognitive sequelae of hyperglycemia in
children provide another compelling motivation for achieving glycemic targets (313,314).
In selecting glycemic goals, the benefits on long-term health outcomes of achieving
a lower A1C should be balanced against the risks of hypoglycemia and the developmental
burdens of intensive regimens in children and youth. Age-specific glycemic and A1C
goals are presented in Table 16.
Table 16
Plasma blood glucose and A1C goals for type 1 diabetes by age-group
Plasma blood glucose goal range (mg/dl)
A1C (%)
Rationale
Before meals
Bedtime/overnight
Toddlers and preschoolers (0–6 years)
100–180
110–200
<8.5
Vulnerability to hypoglycemia
Insulin sensitivity
Unpredictability in dietary intake and physical activity
A lower goal (<8.0%) is reasonable if it can be achieved without excessive hypoglycemia
School age (6–12 years)
90–180
100–180
<8
Vulnerability to hypoglycemia
A lower goal (<7.5%) is reasonable if it can be achieved without excessive hypoglycemia
Adolescents and young adults (13–19 years)
90–130
90–150
<7.5
A lower goal (<7.0%) is reasonable if it can be achieved without excessive hypoglycemia
Key concepts in setting glycemic goals
Goals should be individualized and lower goals may be reasonable based on benefit-risk
assessment.
Blood glucose goals should be modified in children with frequent hypoglycemia or hypoglycemia
unawareness.
Postprandial blood glucose values should be measured when there is a discrepancy between
pre-prandial blood glucose values and A1C levels and to help assess glycemia in those
on basal/bolus regimens.
b. Screening and management of chronic complications in children and adolescents with
type 1 diabetes
i. Nephropathy
Recommendations
Annual screening for microalbuminuria, with a random spot urine sample for albumin-to-creatinine
(ACR) ratio, should be considered once the child is 10 years of age and has had diabetes
for 5 years. (E)
Confirmed, persistently elevated ACR on two additional urine specimens from different
days should be treated with an ACE inhibitor, titrated to normalization of albumin
excretion if possible. (E)
ii. Hypertension
Recommendations
Treatment of high-normal blood pressure (systolic or diastolic blood pressure consistently
above the 90th percentile for age, sex, and height) should include dietary intervention
and exercise aimed at weight control and increased physical activity, if appropriate.
If target blood pressure is not reached with 3–6 months of lifestyle intervention,
pharmacologic treatment should be considered. (E)
Pharmacologic treatment of hypertension (systolic or diastolic blood pressure consistently
above the 95th percentile for age, sex, and height or consistently greater than 130/80
mmHg, if 95% exceeds that value) should be initiated as soon as the diagnosis is confirmed.
(E)
ACE inhibitors should be considered for the initial treatment of hypertension, following
appropriate reproductive counseling due to its potential teratogenic effects. (E)
The goal of treatment is a blood pressure consistently <130/80 or below the 90th percentile
for age, sex, and height, whichever is lower. (E)
It is important that blood pressure measurements are determined correctly, using the
appropriate size cuff, and with the child seated and relaxed. Hypertension should
be confirmed on at least three separate days. Normal blood pressure levels for age,
sex, and height and appropriate methods for determinations are available online at
www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_ped.pdf.
iii. Dyslipidemia
Recommendations
Screening
If there is a family history of hypercholesterolemia (total cholesterol >240 mg/dl)
or a cardiovascular event before age 55 years, or if family history is unknown, then
a fasting lipid profile should be performed on children >2 years of age soon after
diagnosis (after glucose control has been established). If family history is not of
concern, then the first lipid screening should be considered at puberty (≥10 years).
All children diagnosed with diabetes at or after puberty should have a fasting lipid
profile performed soon after diagnosis (after glucose control has been established).
(E)
For both age-groups, if lipids are abnormal, annual monitoring is recommended. If
LDL cholesterol values are within the accepted risk levels (<100 mg/dl [2.6 mmol/l]),
a lipid profile should be repeated every 5 years. (E)
Treatment
Initial therapy should consist of optimization of glucose control and MNT using a
Step 2 AHA diet aimed at a decrease in the amount of saturated fat in the diet. (E)
After the age of 10 years, the addition of a statin in patients who, after MNT and
lifestyle changes, have LDL cholesterol >160 mg/dl (4.1 mmol/l), or LDL cholesterol
>130 mg/dl (3.4 mmol/l) and one or more CVD risk factors, is reasonable. (E)
The goal of therapy is an LDL cholesterol value <100 mg/dl (2.6 mmol/l). (E)
People diagnosed with type 1 diabetes in childhood have a high risk of early subclinical
(315
–317) and clinical (318) CVD. Although intervention data are lacking, the AHA categorizes
children with type 1 diabetes in the highest tier for cardiovascular risk and recommends
both lifestyle and pharmacologic treatment for those with elevated LDL cholesterol
levels (319,320). Initial therapy should be with a Step 2 AHA diet, which restricts
saturated fat to 7% of total calories and restricts dietary cholesterol to 200 mg/day.
Data from randomized clinical trials in children as young as 7 months of age indicate
that this diet is safe and does not interfere with normal growth and development (321,322).
Neither long-term safety nor cardiovascular outcome efficacy of statin therapy has
been established for children. However, recent studies have shown short-term safety
equivalent to that seen in adults, and efficacy in lowering LDL cholesterol levels,
improving endothelial function, and causing regression of carotid intimal thickening
(323
–325). No statin is approved for use under the age of 10 years, and statin treatment
should generally not be used in children with type 1 diabetes prior to this age.
iv. Retinopathy
Recommendations
The first ophthalmologic examination should be obtained once the child is 10 years
of age and has had diabetes for 3–5 years. (E)
After the initial examination, annual routine follow-up is generally recommended.
Less frequent examinations may be acceptable on the advice of an eye care professional.
(E)
Although retinopathy most commonly occurs after the onset of puberty and after 5–10
years of diabetes duration, it has been reported in prepubertal children and with
diabetes duration of only 1–2 years. Referrals should be made to eye care professionals
with expertise in diabetic retinopathy, an understanding of the risk for retinopathy
in the pediatric population, and experience in counseling the pediatric patient and
family on the importance of early prevention/intervention.
v. Celiac disease
Recommendations
Children with type 1 diabetes should be screened for celiac disease by measuring tissue
transglutaminase or anti-endomysial antibodies, with documentation of normal total
serum IgA levels, soon after the diagnosis of diabetes. (E)
Testing should be repeated in children with growth failure, failure to gain weight,
weight loss, diarrhea, flatulence, abdominal pain, or signs of malabsorption, or in
children with frequent unexplained hypoglycemia or deterioration in glycemic control.
(E)
Children with positive antibodies should be referred to a gastroenterologist for evaluation
with endoscopy and biopsy. (E)
Children with biopsy-confirmed celiac disease should be placed on a gluten-free diet
and have consultation with a dietitian experienced in managing both diabetes and celiac
disease. (E)
Celiac disease is an immune-mediated disorder that occurs with increased frequency
in patients with type 1 diabetes (1–16% of individuals compared with 0.3–1% in the
general population) (326,327). Symptoms of celiac disease include diarrhea, weight
loss or poor weight gain, growth failure, abdominal pain, chronic fatigue, malnutrition
due to malabsorption, other gastrointestinal problems, and unexplained hypoglycemia
or erratic blood glucose concentrations.
The advent of routine periodic screening has led to the diagnosis of celiac disease
in asymptomatic children. While several studies have documented short-term benefits
of gluten restriction on growth and bone mineral density in asymptomatic children
diagnosed with celiac disease by routine screening, there is little literature available
regarding the long-term benefit of gluten-free diets in this population.
vi. Hypothyroidism
Recommendations
Children with type 1 diabetes should be screened for thyroid peroxidase and thyroglobulin
antibodies at diagnosis. (E)
TSH concentrations should be measured after metabolic control has been established.
If normal, they should be re-checked every 1–2 years, or if the patient develops symptoms
of thyroid dysfunction, thyromegaly, or an abnormal growth rate. (E)
Auto-immune thyroid disease is the most common autoimmune disorder associated with
diabetes, occurring in 17–30% of patients with type 1 diabetes (328). The presence
of thyroid auto-antibodies is predictive of thyroid dysfunction, generally hypothyroidism
but less commonly hyperthyroidism (329). Subclinical hypothyroidism may be associated
with increased risk of symptomatic hypoglycemia (330) and with reduced linear growth
(331). Hyperthyroidism alters glucose metabolism, potentially resulting in deterioration
of metabolic control.
c. Self-management
No matter how sound the medical regimen, it can only be as good as the ability of
the family and/or individual to implement it. Family involvement in diabetes remains
an important component of optimal diabetes management throughout childhood and into
adolescence. Health care providers who care for children and adolescents, therefore,
must be capable of evaluating the behavioral, emotional, and psychosocial factors
that interfere with implementation and then must work with the individual and family
to resolve problems that occur and/or to modify goals as appropriate.
d. School and day care
Because a sizable portion of a child's day is spent in school, close communication
with and cooperation of school or day care personnel is essential for optimal diabetes
management, safety, and maximal academic opportunities. See the ADA position statement
on Diabetes Care in the School and Day Care Setting (332) for further discussion.
e. Transition from pediatric to adult care
As they approach the young adult years, older adolescents are at increasing physical,
behavioral, and other risks (333,334). As they leave both their home and their pediatric
diabetes care providers, these older teens may become disengaged from the health care
system, leading to lapses in medical care and deterioration in glycemic control (335).
Though scientific evidence is limited to date, it is clear that early and ongoing
attention be given to comprehensive and coordinated planning for seamless transition
of all youth from pediatric to adult health care (336,337). The National Diabetes
Education Program (NDEP) has materials available to facilitate this transition process
(http://ndep.nih.gov/transitions/).
2. Type 2 diabetes
The incidence of type 2 diabetes in adolescents is increasing, especially in ethnic
minority populations (21). Distinction between type 1 and type 2 diabetes in children
can be difficult, since the prevalence of overweight in children continues to rise
and since autoantigens and ketosis may be present in a substantial number of patients
with features of type 2 diabetes (including obesity and acanthosis nigricans). Such
a distinction at the time of diagnosis is critical since treatment regimens, educational
approaches, and dietary counsel will differ markedly between the two diagnoses.
Type 2 diabetes has a significant prevalence of comorbidities already present at the
time of diagnosis (338). It is recommended that blood pressure measurement, a fasting
lipid profile, microalbuminuria assessment, and dilated eye examination be performed
at the time of diagnosis. Thereafter, screening guidelines and treatment recommendations
for hypertension, dyslipidemia, microalbuminuria, and retinopathy in youth with type
2 diabetes are similar to those for youth with type 1 diabetes. Additional problems
that may need to be addressed include polycystic ovary disease and the various comorbidities
associated with pediatric obesity such as sleep apnea, hepatic steatosis, orthopedic
complications, and psychosocial concerns. The ADA consensus statement on this subject
(23) provides guidance on the prevention, screening, and treatment of type 2 diabetes
and its comorbidities in young people.
3. Monogenic diabetes syndromes
Monogenic forms of diabetes (neonatal diabetes or maturity-onset diabetes of the young)
represent a small fraction of children with diabetes (<5%), but the ready availability
of commercial genetic testing is now enabling a true genetic diagnosis with increasing
frequency. It is important to correctly diagnose one of the monogenic forms of diabetes,
as these children may be incorrectly diagnosed with type 1 or type 2 diabetes, leading
to nonoptimal treatment regimens and delays in diagnosing other family members.
The diagnosis of monogenic diabetes should be considered in the following settings:
diabetes diagnosed within the first 6 months of life; in children with strong family
history of diabetes but without typical features of type 2 diabetes (nonobese, low-risk
ethnic group); in children with mild fasting hyperglycemia (100–150 mg/dl [5.5–8.5
mmol]), especially if young and nonobese; and in children with diabetes but with negative
auto-antibodies without signs of obesity or insulin resistance. A recent international
consensus document discusses in further detail the diagnosis and management of children
with monogenic forms of diabetes (339).
B. Preconception care
Recommendations
A1C levels should be as close to normal as possible (<7%) in an individual patient
before conception is attempted. (B)
Starting at puberty, preconception counseling should be incorporated in the routine
diabetes clinic visit for all women of child-bearing potential. (C)
Women with diabetes who are contemplating pregnancy should be evaluated and, if indicated,
treated for diabetic retinopathy, nephropathy, neuropathy, and CVD. (E)
Medications used by such women should be evaluated prior to conception, since drugs
commonly used to treat diabetes and its complications may be contraindicated or not
recommended in pregnancy, including statins, ACE inhibitors, ARBs, and most noninsulin
therapies. (E)
Since many pregnancies are unplanned, consider the potential risks and benefits of
medications that are contraindicated in pregnancy in all women of childbearing potential,
and counsel women using such medications accordingly. (E)
Major congenital malformations remain the leading cause of mortality and serious morbidity
in infants of mothers with type 1 and type 2 diabetes. Observational studies indicate
that the risk of malformations increases continuously with increasing maternal glycemia
during the first 6–8 weeks of gestation, as defined by first-trimester A1C concentrations.
There is no threshold for A1C values below which risk disappears entirely. However,
malformation rates above the 1–2% background rate of nondiabetic pregnancies appear
to be limited to pregnancies in which first-trimester A1C concentrations are >1% above
the normal range for a nondiabetic pregnant woman.
Preconception care of diabetes appears to reduce the risk of congenital malformations.
Five nonrandomized studies compared rates of major malformations in infants between
women who participated in preconception diabetes care programs and women who initiated
intensive diabetes management after they were already pregnant. The preconception
care programs were multidisciplinary and designed to train patients in diabetes self-management
with diet, intensified insulin therapy, and SMBG. Goals were set to achieve normal
blood glucose concentrations, and >80% of subjects achieved normal A1C concentrations
before they became pregnant. In all five studies, the incidence of major congenital
malformations in women who participated in preconception care (range 1.0–1.7% of infants)
was much lower than the incidence in women who did not participate (range 1.4–10.9%
of infants) (78). One limitation of these studies is that participation in preconception
care was self-selected rather than randomized. Thus, it is impossible to be certain
that the lower malformation rates resulted fully from improved diabetes care. Nonetheless,
the evidence supports the concept that malformations can be reduced or prevented by
careful management of diabetes before pregnancy.
Planned pregnancies greatly facilitate preconception diabetes care. Unfortunately,
nearly two-thirds of pregnancies in women with diabetes are unplanned, leading to
a persistent excess of malformations in infants of diabetic mothers. To minimize the
occurrence of these devastating malformations, standard care for all women with diabetes
who have child-bearing potential, beginning at the onset of puberty or at diagnosis,
should include 1) education about the risk of malformations associated with unplanned
pregnancies and poor metabolic control; and 2) use of effective contraception at all
times, unless the patient has good metabolic control and is actively trying to conceive.
Women contemplating pregnancy need to be seen frequently by a multidisciplinary team
experienced in the management of diabetes before and during pregnancy. The goals of
preconception care are to 1) involve and empower the patient in the management of
her diabetes, 2) achieve the lowest A1C test results possible without excessive hypoglycemia,
3) assure effective contraception until stable and acceptable glycemia is achieved,
and 4) identify, evaluate, and treat long-term diabetes complications such as retinopathy,
nephropathy, neuropathy, hypertension, and CHD (78).
Among the drugs commonly used in the treatment of patients with diabetes, a number
may be relatively or absolutely contraindicated during pregnancy. Statins are category
X (contraindicated for use in pregnancy) and should be discontinued before conception,
as should ACE inhibitors (340). ARBs are category C (risk cannot be ruled out) in
the first trimester but category D (positive evidence of risk) in later pregnancy
and should generally be discontinued before pregnancy. Since many pregnancies are
unplanned, health care professionals caring for any woman of childbearing potential
should consider the potential risks and benefits of medications that are contraindicated
in pregnancy. Women using medications such as statins or ACE inhibitors need ongoing
family planning counseling. Among the oral antidiabetic agents, metformin and acarbose
are classified as category B (no evidence of risk in humans) and all others as category
C. Potential risks and benefits of oral antidiabetic agents in the preconception period
must be carefully weighed, recognizing that data are insufficient to establish the
safety of these agents in pregnancy.
For further discussion of preconception care, see the ADA's consensus statement on
preexisting diabetes and pregnancy (78) and the position statement (341) on this subject.
C. Older adults
Recommendations
Older adults who are functional, cognitively intact, and have significant life expectancy
should receive diabetes care using goals developed for younger adults. (E)
Glycemic goals for older adults not meeting the above criteria may be relaxed using
individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic
complications should be avoided in all patients. (E)
Other cardiovascular risk factors should be treated in older adults with consideration
of the time frame of benefit and the individual patient. Treatment of hypertension
is indicated in virtually all older adults, and lipid and aspirin therapy may benefit
those with life expectancy at least equal to the time frame of primary or secondary
prevention trials. (E)
Screening for diabetes complications should be individualized in older adults, but
particular attention should be paid to complications that would lead to functional
impairment. (E)
Diabetes is an important health condition for the aging population; at least 20% of
patients over the age of 65 years have diabetes, and this number can be expected to
grow rapidly in the coming decades. Older individuals with diabetes have higher rates
of premature death, functional disability, and coexisting illnesses such as hypertension,
CHD, and stroke than those without diabetes. Older adults with diabetes are also at
greater risk than other older adults for several common geriatric syndromes, such
as polypharmacy, depression, cognitive impairment, urinary incontinence, injurious
falls, and persistent pain.
The American Geriatric Society's guidelines for improving the care of the older person
with diabetes (342) have influenced the following discussion and recommendations.
The care of older adults with diabetes is complicated by their clinical and functional
heterogeneity. Some older individuals developed diabetes years earlier and may have
significant complications; others who are newly diagnosed may have had years of undiagnosed
diabetes with resultant complications or may have few complications from the disease.
Some older adults with diabetes are frail and have other underlying chronic conditions,
substantial diabetes-related comorbidity, or limited physical or cognitive functioning.
Other older individuals with diabetes have little comorbidity and are active. Life
expectancies are highly variable for this population, but often longer than clinicians
realize. Providers caring for older adults with diabetes must take this heterogeneity
into consideration when setting and prioritizing treatment goals.
There are few long-term studies in older adults demonstrating the benefits of intensive
glycemic, blood pressure, and lipid control. Patients who can be expected to live
long enough to reap the benefits of long-term intensive diabetes management and who
are active, have good cognitive function, and are willing should be provided with
the needed education and skills to do so and be treated using the goals for younger
adults with diabetes.
For patients with advanced diabetes complications, life-limiting comorbid illness,
or substantial cognitive or functional impairment, it is reasonable to set less-intensive
glycemic target goals. These patients are less likely to benefit from reducing the
risk of microvascular complications and more likely to suffer serious adverse effects
from hypoglycemia. However, patients with poorly controlled diabetes may be subject
to acute complications of diabetes, including dehydration, poor wound healing, and
hyperglycemic hyperosmolar coma. Glycemic goals at a minimum should avoid these consequences.
Although control of hyperglycemia may be important in older individuals with diabetes,
greater reductions in morbidity and mortality may result from control of other cardiovascular
risk factors rather than from tight glycemic control alone. There is strong evidence
from clinical trials of the value of treating hypertension in the elderly (343,344).
There is less evidence for lipid-lowering and aspirin therapy, although the benefits
of these interventions for primary and secondary prevention are likely to apply to
older adults whose life expectancies equal or exceed the time frames seen in clinical
trials.
Special care is required in prescribing and monitoring pharmacologic therapy in older
adults. Metformin is often contraindicated because of renal insufficiency or significant
heart failure. TZDs can cause fluid retention, which may exacerbate or lead to heart
failure. They are contraindicated in patients with CHF (New York Heart Association
class III and class IV) and if used at all should be used very cautiously in those
with, or at risk for, milder degrees of CHF. Sulfonylureas, other insulin secretagogues,
and insulin can cause hypoglycemia. Insulin use requires that patients or caregivers
have good visual and motor skills and cognitive ability. Drugs should be started at
the lowest dose and titrated up gradually until targets are reached or side effects
develop.
Screening for diabetes complications in older adults also should be individualized.
Particular attention should be paid to complications that can develop over short periods
of time and/or that would significantly impair functional status, such as visual and
lower-extremity complications.
D. Cystic fibrosis–related diabetes
Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity in persons
with CF, occurring in about 20% of adolescents and 40–50% of adults. The additional
diagnosis of diabetes in this population is associated with worse nutritional status,
more-severe inflammatory lung disease, and greater mortality from respiratory failure.
For reasons that are not well understood, women with CFRD are particularly vulnerable
to excess morbidity and mortality. Insulin insufficiency related to partial fibrotic
destruction of the islet mass is the primary defect in CFRD. Genetically determined
function of the remaining β-cells and insulin resistance associated with infection
and inflammation may also play a role. Encouraging new data suggest that early detection
and aggressive insulin therapy have narrowed the gap in mortality between CF patients
with and without diabetes, and have eliminated the sex difference in mortality.
A consensus conference on CFRD was co-sponsored in 2009 by the American Diabetes Association,
the Cystic Fibrosis Foundation, and the Pediatric Endocrine Society. Recommendations
for the clinical management of CFRD can be found in an ADA position statement (344a).
VIII. DIABETES CARE IN SPECIFIC SETTINGS
A. Diabetes care in the hospital
Recommendations
All patients with diabetes admitted to the hospital should have their diabetes clearly
identified in the medical record. (E)
All patients with diabetes should have an order for blood glucose monitoring, with
results available to all members of the health care team. (E)
Goals for blood glucose levels:
Critically ill patients: Insulin therapy should be initiated for treatment of persistent
hyperglycemia starting at a threshold of no greater than 180 mg/dl (10 mmol/l). Once
insulin therapy is started, a glucose range of 140–180 mg/dl (7.8–10 mmol/l) is recommended
for the majority of critically ill patients. (A)
More stringent goals, such as 110–140 mg/dl (6.1–7.8 mmol/l) may be appropriate for
selected patients, as long as this can be achieved without significant hypoglycemia.
(C)
Critically ill patients require an intravenous insulin protocol that has demonstrated
efficacy and safety in achieving the desired glucose range without increasing risk
for severe hypoglycemia. (E)
Non–critically ill patients: There is no clear evidence for specific blood glucose
goals. If treated with insulin, the premeal blood glucose target should generally
be <140 mg/dl (7.8 mmol/l) with random blood glucose <180 mg/dl (10.0 mmol/l), provided
these targets can be safely achieved. More stringent targets may be appropriate in
stable patients with previous tight glycemic control. Less stringent targets may be
appropriate in those with severe comorbidites. (E)
Scheduled subcutaneous insulin with basal, nutritional, and correction components
is the preferred method for achieving and maintaining glucose control in noncritically
ill patients. (C) Using correction dose or “supplemental” insulin to correct premeal
hyperglycemia in addition to scheduled prandial and basal insulin is recommended.
(E)
Glucose monitoring should be initiated in any patient not known to be diabetic who
receives therapy associated with high risk for hyperglycemia, including high-dose
glucocorticoid therapy, initiation of enteral or parenteral nutrition, or other medications
such as octreotide or immunosuppressive medications. (B) If hyperglycemia is documented
and persistent, treatment is necessary. Such patients should be treated to the same
glycemic goals as patients with known diabetes. (E)
A hypoglycemia management protocol should be adopted and implemented by each hospital
or hospital system. A plan for treating hypoglycemia should be established for each
patient. Episodes of hypoglycemia in the hospital should be documented in the medial
record and tracked. (E)
All patients with diabetes admitted to the hospital should have an A1C obtained if
the result of testing in the previous 2–3 months is not available. (E)
Patients with hyperglycemia in the hospital who do not have a diagnosis of diabetes
should have appropriate plans for follow-up testing and care documented at discharge.
(E)
Hyperglycemia in the hospital is extensively reviewed in an ADA technical review (345).
A recent updated consensus statement by the American Association of Clinical Endocrinologists
(AACE) and the ADA (346) forms the basis for the discussion and guidelines in this
section.
The literature on hospitalized patients with hyperglycemia typically describes three
categories:
Medical history of diabetes: diabetes has been previously diagnosed and acknowledged
by the patient's treating physician.
Unrecognized diabetes: hyperglycemia (fasting blood glucose ≥126 mg/dl or random blood
glucose ≥200 mg/dl) occurring during hospitalization and confirmed as diabetes after
hospitalization by standard diagnostic criteria but unrecognized as diabetes by the
treating physician during hospitalization.
Hospital-related hyperglycemia: hyperglycemia (fasting blood glucose ≥126 mg/dl or
random blood glucose ≥200 mg/dl) occurring during the hospitalization that reverts
to normal after hospital discharge.
The management of hyperglycemia in the hospital has often been considered secondary
in importance to the condition that prompted admission (345). However, a body of literature
now supports targeted glucose control in the hospital setting for potential improved
clinical outcomes. Hyperglycemia in the hospital may result from stress, decompensation
of type 1 or type 2 or other forms of diabetes, and/or may be iatrogenic due to withholding
of anti-hyperglycemic medications or administration of hyperglycemia-provoking agents
such as glucocorticoids or vasopressors.
People with diabetes are more likely to be hospitalized and to have longer lengths
of stay than those without diabetes. A recent survey estimated that 22% of all hospital
inpatient days were incurred by people with diabetes and that hospital inpatient care
accounted for half of the $174 billion total U.S. medical expenditures for this disease
(347). This is due, in part, to the continued expansion of the worldwide epidemic
of type 2 diabetes. While the costs of illness-related stress hyperglycemia are not
known, they are likely to be significant given the poor prognosis of such patients
(348
–351).
There is substantial observational evidence linking hyperglycemia in hospitalized
patients (with or without diabetes) to poor outcomes. Cohort studies as well as a
few early randomized controlled trials (RCTs) suggested that intensive treatment of
hyperglycemia improved hospital outcomes (345,350,351). In general, these studies
were heterogeneous in terms of patient population, blood glucose targets and insulin
protocols, provision of nutritional support, and the proportion of patients receiving
insulin, which limits the ability to make meaningful comparisons among them. Recent
trials in critically ill patients have failed to show a significant improvement in
mortality with intensive glycemic control (352,353) or have even shown increased mortality
risk (354). Moreover, these recent RCTs have highlighted the risk of severe hypoglycemia
resulting from such efforts (352
–357).
The largest study to date, NICE-SUGAR, a multicenter, multinational RCT, compared
the effect of intensive glycemic control (target 81–108 mg/dl, mean blood glucose
attained 115 mg/dl) to standard glycemic control (target 144–180 mg/dl, mean blood
glucose attained 144 mg/dl) on outcomes among 6,104 critically ill participants, the
majority of whom (>95%) required mechanical ventilation (354). Ninety-day mortality
was significantly higher in the intensive versus the conventional group (78 more deaths;
27.5% vs. 24.9%, P = 0.02) in both surgical and medical patients. Mortality from cardiovascular
causes was more common in the intensive group (76 more deaths; 41.6% vs. 35.8%; P
= 0.02). Severe hypoglycemia was also more common in the intensively treated group
(6.8% vs. 0.5%; P < 0.001). The precise reason for the increased mortality in the
tightly controlled group is unknown. The results of this study lie in stark contrast
to a famous 2001 single-center study that reported a 42% relative reduction in intensive-care
unit (ICU) mortality in critically ill surgical patients treated to a target blood
glucose of 80–110 mg/dl (350). Importantly, the control group in NICE-SUGAR had reasonably
good blood glucose management maintained at a mean glucose of 144 mg/dl, only 29 mg/dl
above the intensively managed patients. Accordingly, this study's findings do not
disprove the notion that glycemic control in the ICU is important. However, they do
strongly suggest that it is not necessary to target blood glucose values <140 mg/dl,
and that a highly stringent target of <110 mg/dl may actually be dangerous.
In a recent meta-analysis of 26 trials (N = 13,567), which included the NICE-SUGAR
data, the pooled relative risk (RR) of death with intensive insulin therapy was 0.93
as compared with conventional therapy (95% CI 0.83–1.04) (357). Approximately half
of these trials reported hypoglycemia, with a pooled RR of intensive therapy of 6.0
(95% CI 4.5–8.0). The specific ICU setting influenced the findings, with patients
in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63 [95%
CI 0.44–0.91]), while those in other critical care settings did not (medical ICU,
RR 1.0 [95% CI 0.78–1.28]; “mixed” ICU, RR 0.99 [95% CI 0.86–1.12]). It was concluded
that overall, intensive insulin therapy increased the risk of hypoglycemia but provided
no overall benefit on mortality in the critically ill, although a possible mortality
benefit to patients admitted to the surgical ICU (RR 0.63 [95% CI 0.44–0.91]) was
suggested.
1. Glycemic targets in hospitalized patients
Definition of glucose abnormalities in the hospital setting
Hyperglycemia has been defined as any blood glucose level >140 mg/dl (7.8 mmol/l).
Levels that are significantly and persistently above this may require treatment in
hospitalized patients. In patients without a previous diagnosis of diabetes, elevated
blood glucose may be due to “stress hyperglycemia,” a condition that can be established
by a review of prior records or measurement of an A1C. A1C values >6.5% suggest that
diabetes preceded hospitalization (358). Hypoglycemia has been defined as any blood
glucose level <70 mg/dl (3.9 mmol/l). This is the standard definition in outpatients
and correlates with the initial threshold for the release of counterregulatory hormones.
Severe hypoglycemia in hospitalized patients has been defined by many as <40 mg/dl
(2.2 mmol/l), although this is lower than the ∼50 mg/dl (2.8 mmol/l) level at which
cognitive impairment begins in normal individuals (359). As with hyperglycemia, hypoglycemia
among inpatients is also associated with adverse short- and long-term outcomes. Early
recognition and treatment of mild to moderate hypoglycemia (40 and 69 mg/dl) (2.2
and 3.8 mmol/l) can prevent deterioration to a more severe episode with potential
adverse sequelae (346).
Critically ill patients
Based on the weight of the available evidence, for the majority of critically ill
patients in the ICU setting, insulin infusion should be used to control hyperglycemia,
with a starting threshold of no higher than 180 mg/dl (10.0 mmol/l). Once intravenous
insulin is started, the glucose level should be maintained between 140 and 180 mg/dl
(7.8 and 10.0 mmol/l). Greater benefit maybe realized at the lower end of this range.
Although strong evidence is lacking, somewhat lower glucose targets may be appropriate
in selected patients. However, targets less than 110 mg/dl (6.1 mmol/l) are not recommended.
Use of insulin infusion protocols with demonstrated safety and efficacy, resulting
in low rates of hypoglycemia, are highly recommended (346).
Noncritically ill patients
With no prospective RCT data to inform specific glycemic targets in noncritically
ill patients, recommendations are based on clinical experience and judgment. For the
majority of noncritically ill patients treated with insulin, premeal glucose targets
should generally be <140 mg/dl (7.8 mmol/l) with random blood glucose levels <180
mg/dl (10.0 mmol/l), as long as these targets can be safely achieved. To avoid hypoglycemia,
consideration should be given to reassessing the insulin regimen if blood glucose
levels fall below 100 mg/dl (5.6 mmol/l). Modification of the regimen is required
when blood glucose values are <70 mg/dl (3.9 mmol/l), unless the event is easily explained
by other factors (such as a missed meal, etc.)
Occasional patients with a prior history of successful tight glycemic control in the
outpatient setting who are clinically stable may be maintained with a glucose range
below the above cut points. Conversely, higher glucose ranges may be acceptable in
terminally ill patients or in patients with severe comorbidities, as well as in those
in patient-care settings where frequent glucose monitoring or close nursing supervision
is not feasible.
Clinical judgment, combined with ongoing assessment of the patient's clinical status,
including changes in the trajectory of glucose measures, the severity of illness,
nutritional status, or concurrent use of medications that might affect glucose levels
(e.g., steroids, octreotide) must be incorporated into the day-to-day decisions regarding
insulin dosing (346).
2. Anti-hyperglycemic agents in hospitalized patients
In the hospital setting, insulin therapy is the preferred method of glycemic control
in majority of clinical situations (346). In the ICU, intravenous infusion is the
preferred route of insulin administration. When the patient is transitioned off intravenous
insulin to subcutaneous therapy, precautions should be taken to prevent hyperglycemia
escape (360,361). Outside of critical care units, scheduled subcutaneous insulin which
delivers basal, nutritional, and correction (supplemental) components is preferred.
Prolonged therapy with sliding scale insulin (SSI) as the sole regimen is ineffective
in the majority of patients, increases risk of both hypoglycemia and hyperglycemia,
and has recently been shown to be associated with adverse outcomes in general surgery
patients with type 2 diabetes (362). SSI is potentially dangerous in type 1 diabetes
(346). The reader is referred to several recent publications and reviews that describe
currently available insulin preparations and protocols and provide guidance in use
of insulin therapy in specific clinical settings including parenteral nutrition (363),
enteral tube feedings, and with high-dose glucocorticoid therapy (346).
There are no data on the safety and efficacy of oral agents and injectable noninsulin
therapies such as GLP1 analogs and pramlintide in the hospital. They are generally
considered to have a limited role in the management of hyperglycemia in conjunction
with acute illness. Continuation of these agents may be appropriate in selected stable
patients who are expected to consume meals at regular intervals and they may be initiated
or resumed in anticipation of discharge once the patient is clinically stable. Specific
caution is required with metformin, due to the possibility that a contraindication
may develop during the hospitalization, such as renal insufficiency, unstable hemodynamic
status, or need for an imaging study that requires a radio-contrast dye.
3. Preventing hypoglycemia
Hypoglycemia, especially in insulin-treated patients, is the leading limiting factor
in the glycemic management of type 1 and type 2 diabetes (173). In the hospital, multiple
additional risk factors for hypoglycemia are present. Patients with or without diabetes
may experience hypoglycemia in the hospital in association with altered nutritional
state, heart failure, renal or liver disease, malignancy, infection, or sepsis. Additional
triggering events leading to iatrogenic hypoglycemia include sudden reduction of corticosteroid
dose, altered ability of the patient to report symptoms, reduction of oral intake,
emesis, new NPO status, inappropriate timing of short- or rapid-acting insulin in
relation to meals, reduction of rate of administration of intravenous dextrose, and
unexpected interruption of enteral feedings or parenteral nutrition.
Despite the preventable nature of many inpatient episodes of hypoglycemia, institutions
are more likely to have nursing protocols for the treatment of hypoglycemia than for
its prevention. Tracking such episodes and analyzing their causes are important quality
improvement activities (346).
4. Diabetes care providers in the hospital
Inpatient diabetes management may be effectively championed and/or provided by primary
care physicians, endocrinologists, intensivists, or hospitalists. Involvement of appropriately
trained specialists or specialty teams may reduce length of stay, improve glycemic
control, and improve outcomes (346). In the care of diabetes, implementation of standardized
order sets for scheduled and correction-dose insulin may reduce reliance on sliding-scale
management. As hospitals move to comply with “meaningful use” regulations for electronic
health records, as mandated by the Health Information Technology Act, efforts should
be made to assure that all components of structured insulin order sets are incorporated
into electronic insulin order sets (364,365).
A team approach is needed to establish hospital pathways. To achieve glycemic targets
associated with improved hospital outcomes, hospitals will need multidisciplinary
support to develop insulin management protocols that effectively and safely enable
achievement of glycemic targets (366).
5. Self-management in the hospital
Self-management of diabetes in the hospital may be appropriate for competent adult
patients who: have a stable level of consciousness, have reasonably stable daily insulin
requirements, successfully conduct self-management of diabetes at home, have physical
skills needed to successfully self-administer insulin and perform SMBG, have adequate
oral intake, and are proficient in carbohydrate counting, use of multiple daily insulin
injections or insulin pump therapy, and sick-day management. The patient and physician,
in consultation with nursing staff, must agree that patient self-management is appropriate
under the conditions of hospitalization.
Patients who use CSII pump therapy in the outpatient setting can be candidates for
diabetes self-management in the hospital, provided that they have the mental and physical
capacity to do so (346). A hospital policy and procedures delineating inpatient guidelines
for CSII pump therapy are advisable. The availability of hospital personnel with expertise
in CSII therapy is essential. It is important that nursing personnel document basal
rates and bolus doses taken on a regular basis (at least daily).
6. DSME in the hospital
Teaching diabetes self-management to patients in hospitals is a challenging task.
Patients are ill, under increased stress related to their hospitalization and diagnosis,
and in an environment not conducive to learning. Ideally, people with diabetes should
be taught at a time and place conducive to learning—as an outpatient in a recognized
program of diabetes education.
For the hospitalized patient, diabetes “survival skills” education is generally a
feasible approach. Patients and/or family members receive sufficient information and
training to enable safe care at home. Those newly diagnosed with diabetes or who are
new to insulin and/or blood glucose monitoring need to be instructed before discharge.
Those patients hospitalized because of a crisis related to diabetes management or
poor care at home need education to prevent subsequent episodes of hospitalization.
An assessment of the need for a home health referral or referral to an outpatient
diabetes education program should be part of discharge planning for all patients.
7. MNT in the hospital
The goals of MNT are to optimize glycemic control, to provide adequate calories to
meet metabolic demands, and to create a discharge plan for follow-up care (345,367).
ADA does not endorse any single meal plan or specified percentages of macronutrients,
and the term “ADA diet” should no longer be used. Current nutrition recommendations
advise individualization based on treatment goals, physiologic parameters, and medication
usage. Consistent carbohydrate meal plans are preferred by many hospitals since they
facilitate matching the prandial insulin dose to the amount of carbohydrate consumed
(368). Because of the complexity of nutrition issues in the hospital, a registered
dietitian, knowledgeable and skilled in MNT, should serve as an inpatient team member.
The dietitian is responsible for integrating information about the patient's clinical
condition, eating, and lifestyle habits and for establishing treatment goals in order
to determine a realistic plan for nutrition therapy (369,370).
8. Bedside blood glucose monitoring
Point-of-care (POC) blood glucose monitoring performed at the bedside is used to guide
insulin dosing. In the patient who is receiving nutrition, the timing of glucose monitoring
should match carbohydrate exposure. In the patient who is not receiving nutrition,
glucose monitoring is performed every 4 to 6 h (371,372). More frequent blood glucose
testing ranging from every 30 min to every 2 h is required for patients on intravenous
insulin infusions.
Safety standards should be established for blood glucose monitoring, prohibiting sharing
of fingerstick lancing devices, lancets, and needles to reduce the risk of transmission
of blood borne diseases. Shared lancing devices carry essentially the same risk as
shared syringes and needles (373).
Accuracy of blood glucose measurements using POC meters has limitations that must
be considered. Although the FDA allows a ±20% error for blood glucose meters, questions
about the appropriateness of these criteria have been raised (388). Glucose measures
differ significantly between plasma and whole blood, terms that are often used interchangeably
and can lead to misinterpretation. Most commercially available capillary blood glucose
meters introduce a correction factor of ∼1.12 to report a “plasma adjusted” value
(374).
Significant discrepancies between capillary, venous, and arterial plasma samples have
been observed in patients with low or high hemoglobin concentrations, hypoperfusion,
and the presence of interfering substances particularly maltose, as contained in immunoglobulins
(375). Analytical variability has been described with several POC meters (376). Increasingly,
newer generation POC blood glucose meters correct for variation in hematocrit and
for interfering substances. Any glucose result that does not correlate with the patient's
status should be confirmed through conventional laboratory sampling of plasma glucose.
The FDA has become increasingly concerned about the use of POC blood glucose meters
in the hospital and is presently reviewing matters related to their use.
9. Discharge planning
Transition from the acute care setting is a high-risk time for all patients, not just
those with diabetes or new hyperglycemia. Although there is an extensive literature
concerning safe transition within and from the hospital, little of it is specific
to diabetes (377). It is important to remember that diabetes discharge planning is
not a separate entity, but part of an overall discharge plan. As such, discharge planning
begins at admission to the hospital and is updated as projected patient needs change.
Inpatients may be discharged to varied settings, including home (with or without visiting
nurse services), assisted living, rehabilitation, or skilled nursing facilities. The
latter two sites are generally staffed by health professionals; therefore diabetes
discharge planning will be limited to communication of medication and diet orders.
For the patient who is discharged to assisted living or to home, the optimal program
will need to consider the type and severity of diabetes, the effects of the patient's
illness on blood glucose levels, and the capacities and desires of the patient. Smooth
transition to outpatient care should be ensured. The Agency for Healthcare Research
and Quality recommends that at a minimum, discharge plans include:
Medication reconciliation: The patient's medications must be cross-checked to ensure
that no chronic medications were stopped and to ensure the safety of new prescriptions.
Whenever possible, prescriptions for new or changed medication should be filled and
reviewed with the patient and family at or before discharge
Structured discharge communication: Information on medication changes, pending tests
and studies, and follow-up needs must be accurately and promptly communicated to outpatient
physicians, as soon as possible after discharge.
Ideally the inpatient care providers or case managers/discharge planners will schedule
follow-up visit(s) with the appropriate professionals, including primary care provider,
endocrinologist, and diabetes educator (378).
An outpatient follow-up visit with the primary care provider, endocrinologist, or
diabetes educator within 1 month of discharge is advised for all patients having hyperglycemia
in the hospital. Clear communication with outpatient providers either directly or
via hospital discharge summaries facilitates safe transitions to outpatient care.
Providing information regarding the cause or the plan for determining the cause of
hyperglycemia, related complications and comorbidities, and recommended treatments
can assist outpatient providers as they assume ongoing care.
It is important that patients be provided with appropriate durable medical equipment,
medication, supplies, and prescriptions at the time of discharge in order to avoid
a potentially dangerous hiatus in care. These supplies/prescriptions should include:
Insulin (vials or pens) (if needed)
Syringes or pen needles (if needed)
Oral medications (if needed)
Blood glucose meter and strips
Lancets and lancing device
Urine ketone strips (type 1)
Glucagon emergency kit (insulin-treated)
Medical alert application/charm
IX. STRATEGIES FOR IMPROVING DIABETES CARE
There has been steady improvement in the proportion of diabetic patients achieving
recommended levels of A1C, blood pressure, and LDL cholesterol in the last 10 years,
both in primary care settings and in endocrinology practices. Mean A1C nationally
has declined from 7.82% in 1999–2000 to 7.18% in 2004 based on National Health and
Nutrition Examination Survey (NHANES) data (379). This has been accompanied by improvements
in lipids and blood pressure control and led to substantial reductions in end-stage
microvascular complications in those with diabetes (380). Nevertheless, in some studies
only 57.1% of adults with diagnosed diabetes achieved an A1C of <7%, only 45.5% had
a blood pressure <130/80 mmHg, and just 46.5% had a total cholesterol <200 mg/dl,
with only 12.2% of people with diabetes achieving all three treatment goals (381).
Moreover, there is persistent variation in quality of diabetes care across providers
and across practice settings even after adjusting for patient factors that indicates
the potential for substantial further improvements in diabetes care.
While numerous interventions to improve adherence to the recommended standards have
been implemented, a major contributor to suboptimal care is a delivery system that
too often is fragmented, lacks clinical information capabilities, often duplicates
services, and is poorly designed for the delivery of chronic care. The Chronic Care
Model (CCM) includes six core elements for the provision of optimal care of patients
with chronic disease: 1) delivery system design (moving from a reactive to a proactive
care delivery system, where planned visits are coordinated through a team-based approach;
2) self-management support; 3) decision support (basing care on consistent, effective
care guidelines); 4) clinical information systems (using registries that can provide
patient-specific and population-based support to the care team); 5) community resources
and policies (identifying or developing resources to support healthy lifestyles);
and 6) health systems (to create a quality-oriented culture). Alterations in reimbursement
that reward the provision of quality care, as defined by the attainment of evidence-based
quality measures, will also be required to achieve desired outcome goals. Redefinition
of the roles of the clinic staff and promoting self-management on the part of the
patient are fundamental to the successful implementation of the CCM (382). Collaborative,
multidisciplinary teams are best suited to provide such care for people with chronic
conditions like diabetes and to facilitate patients' performance of appropriate self-management.
A rapidly evolving literature suggests that there are three major strategies to successfully
improve the quality of diabetes care delivered by a team of providers. NDEP maintains
an online resource (www.betterdiabetescare.nih.gov) to help health care professionals
design and implement more effective health care delivery systems for those with diabetes.
Three specific objectives, with references to literature that outlines practical strategies
to achieve each, are outlined below.
Objective 1
Provider and team behavior change: Facilitate timely and appropriate intensification
of lifestyle and/or pharmaceutical therapy of patients who have not achieved beneficial
levels of blood pressure, lipid, or glucose control.
Clinical information systems including registries that can prospectively identify
and track those requiring assessments and/or treatment modifications by the team.
Electronic medical record-based clinical decision support at the point of care, both
personalize and standardize care and can be used by multiple providers (383).
Use of checklists and/or flow sheets that mirror guidelines.
Detailed treatment algorithms enabling multiple team members to “treat to target”
and appropriately intensify therapy.
Availability of care or disease management services (384) by nurses, pharmacists,
and other providers using detailed algorithms often catalyzing reduction in A1C, blood
pressure, and LDL cholesterol (385,386).
Objective 2
Patient behavior change: Implement a systematic approach to support patients' behavior
change efforts as needed including 1) healthy lifestyle (physical activity, healthy
eating, nonuse of tobacco, weight management, effective coping, medication taking
and management); 2) prevention of diabetes complications (screening for eye, foot,
and renal complications; immunizations); and 3) achievement of appropriate blood pressure,
lipid, and glucose goals.
Delivery of high-quality DSME, which has been shown to improve patient self-management,
satisfaction, and glucose control (115,387).
Delivery of ongoing diabetes self-management support (DSMS) to ensure that gains achieved
during DSME are sustained (128–129). National DSME standards call for an integrated
approach that includes clinical content and skills, behavioral strategies (goal-setting,
problem solving), and addressing emotional concerns in each needed curriculum content
area. Provision of continuing education and support (DSMS) improves maintenance of
gains regardless of the educational methodology (89).
Provision of automated reminders via multiple communication channels to various subgroups
of diabetic patients (96).
Objective 3
Change the system of care: Research on the comprehensive CCM suggests additional strategies
to improve diabetes care, including the following:
Basing care on consistent, evidence-based care guidelines
Redefining and expanding the roles of the clinic staff (382)
Collaborative, multidisciplinary teams to provide high-quality care and support patients'
appropriate self-management
Audit and feedback of process and outcome data to providers to encourage population-based
care improvement strategies
Care management, one of the most effective diabetes quality improvement strategies
to improve glycemic control (384).
Identifying and/or developing community resources and public policy that support healthy
lifestyles
Alterations in reimbursement that reward the provision of appropriate and high-quality
care and accommodate the need to personalize care goals, providing additional incentives
to improve diabetes care (382,388
–392)
The most successful practices have an institutional priority for quality of care,
expanding the role of teams and staff, redesigning their delivery system, activating
and educating their patients, and using electronic health record tools (393,394).
Recent initiatives such as the Patient Centered Medical Home show promise in improving
outcomes through coordinated primary care and offer new opportunities for team-based
chronic disease care (395).
It is clear that optimal diabetes management requires an organized, systematic approach
and involvement of a coordinated team of dedicated health care professionals working
in an environment where patient-centered high-quality care is a priority.