Dietary Magnesium Intake Ameliorates the Association Between Household Pesticide Exposure and Type 2 Diabetes: Data From NHANES, 2007–2018

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

NHANES is the cornerstone for national nutrition monitoring to inform nutrition and health policy. Nutritional assessment in NHANES is described with a focus on dietary data collection, analysis, and uses in nutrition monitoring. NHANES has been collecting thorough data on diet, nutritional status, and chronic disease in cross-sectional surveys with nationally representative samples since the early 1970s. Continuous data collection began in 1999 with public data release in 2-y cycles on ∼10,000 participants. In 2002, the Continuing Survey of Food Intakes by Individuals and the NHANES dietary component were merged, forming a consolidated dietary data collection known as What We Eat in America; since then, 24-h recalls have been collected on 2 d using the USDA’s Automated Multiple-Pass Method. Detailed and targeted food-frequency questionnaires have been collected in some NHANES cycles. Dietary supplement use data have been collected (in detail since 2007) so that total nutrient intakes can be described for the population. The continuous NHANES can adapt its content to address emerging public health needs and reflect federal priorities. Changes in data collection methods are made after expert input and validation/crossover studies. NHANES dietary data are used to describe intake of foods, nutrients, food groups, and dietary patterns by the US population and large sociodemographic groups to plan and evaluate nutrition programs and policies. Usual dietary intake distributions can be estimated after adjusting for day-to-day variation. NHANES remains open and flexible to incorporate improvements while maintaining data quality and providing timely data to track the nation’s nutrition and health status. In summary, NHANES collects dietary data in the context of its broad, multipurpose goals; the strengths and limitations of these data are also discussed in this review.

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 used 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 multidisciplinary Professional Practice Committee, and new evidence is incorporated. Members of the Professional Practice Committee and their disclosed conflicts of interest are listed in the Introduction. 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 A. Classification 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 diabetes (such as in the treatment of AIDS or after organ transplantation) gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy) 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 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 Recommendations For decades, the diagnosis of diabetes has been based on plasma glucose (PG) criteria, either fasting PG (FPG) or 2-h 75-g oral glucose tolerance test (OGTT) values. In 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus revised the diagnostic criteria using the observed association between glucose levels and presence of retinopathy as the key factor with which to identify threshold FPG and 2-h PG levels. The committee examined data from three cross-sectional epidemiologic studies that assessed retinopathy with fundus photography or direct ophthalmoscopy and measured glycemia as FPG, 2-h PG, and HbA1c (A1C). The studies demonstrated glycemic levels below which there was little prevalent retinopathy and above which the prevalence of retinopathy increased in an apparently linear fashion. The deciles of FPG, 2-h PG, and A1C at which retinopathy began to increase were the same for each measure within each population. The analyses helped to inform a then-new diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) for FPG and confirmed the long-standing diagnostic 2-h PG value of ≥200 mg/dl (11.1 mmol/l) (4). ADA has not previously recommended the use of A1C for diagnosing diabetes, in part due to lack of standardization of the assay. However, A1C assays are now highly standardized, and their results can be uniformly applied both temporally and across populations. In a recent report (5), after an extensive review of both established and emerging epidemiological evidence, an international expert committee recommended the use of the A1C test to diagnose diabetes with a threshold of ≥6.5%, and ADA affirms this decision (6). The diagnostic test should be performed using a method 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 relationship between A1C and the risk of retinopathy similar to that which has been shown for corresponding FPG and 2-h PG thresholds. The A1C has several advantages to the FPG, 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, limited availability of A1C testing in certain regions of the developing world, and incomplete correlation between A1C and average glucose in certain individuals. In addition, the A1C can be misleading in patients with certain forms of anemia and hemoglobinopathies. For patients with a hemoglobinopathy but normal red cell turnover, such as sickle cell trait, an A1C assay without interference from abnormal hemoglobins should be used (an updated list of A1C assays and whether abnormal hemoglobins impact them is available at www.ngsp.org/prog/index3.html). For conditions with abnormal red cell turnover, such as pregnancy or anemias from hemolysis and iron deficiency, the diagnosis of diabetes must use glucose criteria exclusively. The established glucose criteria for the diagnosis of diabetes (FPG and 2-h PG) remain valid. Patients with severe hyperglycemia such as those who present with severe classic hyperglycemic symptoms or hyperglycemic crisis can continue to be diagnosed when a random (or casual) PG of ≥200 mg/dl (11.1 mmol/l) is found. It is likely that in such cases the health care professional would also conduct an A1C test as part of the initial assessment of the severity of the diabetes and that it would be above the diagnostic cut point. However, in rapidly evolving diabetes such as the development of type 1 in some children, the A1C may not be significantly elevated despite frank diabetes. Just as there is 6.0%, who should be considered to be at very high risk. However, just as an individual with a fasting glucose of 98 mg/dl (5.4 mmol/l) may not be at negligible risk for diabetes, individuals with an A1C 9 lb or were diagnosed with GDM hypertension (≥140/90 mmHg or on therapy for hypertension) HDL cholesterol level 250 mg/dl (2.82 mmol/l) women with polycystic ovary syndrome 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 2. In the absence of the above criteria, testing diabetes should begin at age 45 years 3. 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. 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. Type 2 diabetes has a long asymptomatic phase and significant clinical risk markers. 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 who the provider tests because of high suspicion of diabetes, to the symptomatic patient. The discussion herein is primarily framed as testing for diabetes in individuals without symptoms. Testing for diabetes will also detect individuals at increased future risk for diabetes, herein referred to as pre-diabetic. 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. Although the effectiveness of early identification of pre-diabetes and diabetes through mass testing of asymptomatic individuals has not been proven definitively (and rigorous trials to provide such proof are unlikely to occur), pre-diabetes and diabetes meet established criteria for conditions in which early detection is appropriate. Both conditions are common, are 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 (9). Additionally, the duration of glycemic burden is a strong predictor of adverse outcomes, and effective interventions exist to prevent progression of pre-diabetes 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 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 at age 45 years. Either A1C, FPG, or 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 (10). The efficacy of interventions for primary prevention of type 2 diabetes (11 –17) has primarily been demonstrated among individuals with IGT, but not for individuals with IFG (who do not also have IGT) or those with specific A1C levels. The appropriate interval between tests is not known (18). 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. 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 (19,20). 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 (23). The recommendations of the ADA consensus statement on type 2 diabetes in children and youth, 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, polycystic ovary syndrome, or small for gestational age birthweight) 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 diabetes 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 GDM Recommendations Screen for GDM using risk factor analysis and, if appropriate, an OGTT. (C) Women with GDM should be screened for diabetes 6–12 weeks postpartum and should be followed up with subsequent screening for the development of diabetes or pre-diabetes. (E) For many years, GDM has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy (4). Although most cases resolve with delivery, the definition applied whether the condition persisted after pregnancy and did not exclude 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). 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, recommended that high-risk women found to have diabetes at their initial prenatal visit using standard criteria (Table 2) receive a diagnosis of overt, not gestational, diabetes. Approximately 7% of all pregnancies (ranging from 1 to 14% depending on the population studied and the diagnostic tests used) are complicated by GDM, resulting in more than 200,000 cases annually. Because of the risks of GDM to the mother and neonate, screening and diagnosis are warranted. Current screening and diagnostic strategies, based on the 2004 ADA position statement on GDM (25), are outlined in Table 6. Table 6 Screening for and diagnosis of GDM Carry out diabetes risk assessment at the first prenatal visit. Women at very high risk should be screened for diabetes as soon as possible after the confirmation of pregnancy. Criteria for very high risk are: Severe obesity Prior history of GDM or delivery of large-for-gestational-age infant Presence of glycosuria Diagnosis of PCOS Strong family history of type 2 diabetes Screening/diagnosis at this stage of pregnancy should use standard diagnostic testing (Table 2). All women of greater than low risk of GDM, including those above not found to have diabetes early in pregnancy, should undergo GDM testing at 24–28 weeks of gestation. Low-risk status, which does not require GDM screening, is defined as women with ALL of the following characteristics: Age 6%, hypertension, low HDL cholesterol, elevated triglycerides, or family history of diabetes in a first-degree relative) and who are obese and under 60 years of age. (E) Monitoring for the development of diabetes in those with pre-diabetes 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 (11 –17). 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, 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 treat* Lifestyle     Finnish DPS (12) 522 IGT, BMI ≥25 kg/m2 55 3.2 I-D&E 6 58 (30–70) 8.5     DPP (11) 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 (13) 259† IGT (randomized groups) 45 6 G-D&E 14.5 38 (14–56) 7.9     Toranomon Study (31) 458 IGT (men), BMI = 24 kg/m2 ∼55 4 I-D&E 2.4 67 (P 24 kg/m2, FPG >5.3 mmol/l 51 2.8 Metformin (1,700 mg) 10.4 31 (17–43) 13.9     Indian DPP (17) 269† IGT 46 2.5 Metformin (500 mg) 23 26 (19–35) 6.9     STOP NIDDM (15) 1,419 IGT, FPG >5.6 mmol/l 54 3.2 Acarbose (300 mg) 12.4 25 (10–37) 9.6     XENDOS (32) 3,277 BMI >30 kg/m2 43 4 Orlistat (360 mg) 2.4 37 (14–54) 45.5     DREAM (16) 5,269 IGT or IFG 55 3.0 Rosiglitazone (8 mg) 9.1 60 (54–65) 6.9     Voglibose Ph-3 (33) 1,780 IGT 56 3.0 (1-year Rx) Vogliobose (0.2 mg) 12.0 40 (18–57) 21 (1-year Rx)     ACT-NOW (34) 602 IGT or IFG 52 2.6 Pioglitizone (45 mg) 6.8 81 (61–91) 6.3 Modified and reprinted with permission (35). Percentage points: *Number 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. ACT-NOW, ACTos Now Study for the Prevention of Diabetes; 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. Two studies of lifestyle intervention have shown persistent reduction in the role of conversion to type 2 diabetes with 3 years (29) to 14 years (30) of postintervention follow-up. Based on the results of clinical trials and the known risks of progression of pre-diabetes to diabetes, an ADA Consensus Development Panel (36) concluded that people with IGT and/or IFG should be counseled on lifestyle changes with goals similar to those of the DPP (5–10% weight loss and moderate physical activity of ∼30 min/day). Regarding the more difficult issue of drug therapy for diabetes prevention, the consensus panel felt that metformin should be the only drug considered for use in diabetes prevention. For other drugs, the issues of cost, side effects, and lack of persistence of effect in some studies led the panel to not recommend use for diabetes prevention. Metformin use was recommended only for very-high-risk individuals (those with combined IGT and IFG who are obese and have at least one other risk factor for diabetes) who are under 60 years of age. In addition, the panel highlighted the evidence that in the DPP, metformin was most effective compared with lifestyle in individuals with BMI ≥35 kg/m2 and those under 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/creatinine ratio Serum creatinine and calculated GFR TSH 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 on-going 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 using 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) The ADA consensus and position statements on SMBG provide a comprehensive review of the subject (37,38). 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 in order 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 (39). Several recent trials have called into question the clinical utility and cost-effectiveness of routine SMBG in non–insulin-treated patients (40 –42). Because the accuracy of SMBG is instrument and user dependent (43), 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 PG) 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 diabetic 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 with usual intensive insulin therapy with SMBG (44). Sensor use in children, teens, and adults 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 6.5) vs. planned separation of 1.5     Protocol for glycemic control (I vs. S)* Multiple drugs in both arms Multiple drugs added to gliclizide vs. multiple drugs with no gliclizide Multiple drugs in both arms     Management of other risk factors Embedded blood pressure and lipid trials Embedded blood pressure trial Protocol for intensive treatment in both arms On-study characteristics     Achieved median A1C (%) (I vs. S) 6.4 vs. 7.5 6.3 vs. 7.0 6.9 vs. 8.5     On insulin at study end (%) (I vs. S)* 77 vs. 55* 40 vs. 24 89 vs. 0.74 Weight changes (kg)     Intensive glycemic control arm +3.5 −0.1 +7.8     Standard glycemic control arm +0.4 −1.0 +3.4     Severe hypoglycemia (participants with one or more episodes during study) (%)     Intensive glycemic control arm 16.2 2.7 21.2     Standard glycemic control arm 5.1 1.5 9.9 Outcomes     Definition of primary outcome Nonfatal MI, nonfatal stroke, CVD death Microvascular plus macrovascular (nonfatal MI, nonfatal stroke, CVD death) outcomes Nonfatal MI, nonfatal stroke, CVD death, hospitalization for heart failure, revascularization     HR for primary outcome (95% CI) 0.90 (0.78–1.04) 0.9 (0.82–0.98); macrovascular 0.94 (0.84–1.06) 0.88 (0.74–1.05)     HR for mortality findings (95% CI) 1.22 (1.01–1.46) 0.93 (0.83–1.06) 1.07 (0.81–1.42) *Insulin rates for ACCORD are for any use during the study. I, intensive glycemic control; S, standard glycemic control. Abridged from ref. 52. The ACCORD study randomized 10,251 participants with either history of a CVD event or significant CVD risk to a strategy of intensive glycemic control (target A1C 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. 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 reported that 78% of individuals with type 2 diabetes had complete “resolution” of diabetes (normalization of blood glucose levels in the absence of medications) and that the resolution rates were sustained in studies that had follow-up exceeding 2 years (110). Resolution rates are 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. A recent randomized controlled trial compared adjustable gastric banding to the “best available” medical and lifestyle therapy in subjects with type 2 diabetes diagnosed 64 years of age previously immunized when they were 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% (178). Safe and effective vaccines are available that can greatly reduce the risk of serious complications from these diseases (179,180). In a case-control series, influenza vaccine was shown to reduce diabetes-related hospital admission by as much as 79% during flu epidemics (179). 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's Advisory Committee on Immunization Practices recommends influenza and pneumococcal vaccines for all individuals with diabetes (http://www.cdc.gov/vaccines/recs/). For a complete discussion on the prevention of influenza and pneumococcal disease in people with diabetes, consult the technical review and position statement on this subject (178,181). VI. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS A. Cardiovascular disease 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 (182,183). Risk for coronary heart disease and 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 Patients with diabetes should be treated to a systolic blood pressure 115/75 mmHg is associated with increased cardiovascular event rates and mortality in individuals with diabetes (184,190,191). Therefore, a target blood pressure goal of 50 mg/dl, and triglycerides 100 mg/dl or in those with multiple CVD risk factors. (E) In individuals without overt CVD, the primary goal is an LDL 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) a. 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. Over the past decade or more, multiple clinical trials have demonstrated significant effects of pharmacologic (primarily statin) therapy on CVD outcomes in subjects with CHD and for primary CVD prevention (210). Analyses of diabetic subgroups of larger trials (211 –215) and trials specifically in subjects with diabetes (216,217) showed significant primary and secondary prevention of CVD events with and without CHD deaths in diabetic populations. As shown in Table 12, 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 12 Reduction in 10-year risk of major CVD endpoints (CHD death/non-fatal MI) in major statin trials, or sub-studies of major trials, in diabetic subjects (N = 16,032) Study (ref.) CVD prevention Statin dose and comparator Risk reduction Relative risk reduction Absolute risk reduction LDL cholesterol reduction (%) 4S-DM (211) 2° Simvastatin 20–40 mg vs. placebo 85.7 to 43.2% 50% 42.5% 186 to 119 mg/dl (36%) ASPEN 2° (216) 2° Atorvastatin 10 mg vs. placebo 39.5 to 24.5% 34% 12.7% 112 to 79 mg/dl (29%) HPS-DM (212) 2° Simvastatin 40 mg vs. placebo 43.8 to 36.3% 17% 7.5% 123 to 84 mg/dl (31%) CARE-DM (213) 2° Pravastatin 40 mg vs. placebo 40.8 to 35.4% 13% 5.4% 136 to 99 mg/dl (27%) TNT-DM (214) 2° Atorvastatin 80 mg vs. 10 mg 26.3 to 21.6% 18% 4.7% 99 to 77 mg/dl (22%) HPS-DM (212) 1° Simvastatin 40 mg vs. placebo 17.5 to 11.5% 34% 6.0% 124 to 86 mg/dl (31%) CARDS (234) 1° Atorvastatin 10 mg vs. placebo 11.5 to 7.5% 35% 4.0% 118 to 71 mg/dl (40%) ASPEN 1° (216) 1° Atorvastatin 10 mg vs. placebo 9.8 to 7.9% 19% 1.9% 114 to 80 mg/dl (30%) ASCOT-DM (215) 1° Atorvastatin 10 mg vs. placebo 11.1 to 10.2% 8% 0.9% 125 to 82 mg/dl (34%) Studies were of differing lengths (3.3–5.4 years) and used somewhat different outcomes, but all reported rates of CVD death and non-fatal MI. In this tabulation, results of the statin on 10-year risk of major CVD endpoints (CHD death/non-fatal 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 people with type 2 diabetes. However, the evidence base for drugs that target these lipid fractions is significantly less robust than that for statin therapy (217). Nicotinic acid has been shown to reduce CVD outcomes (218), although the study was done in a nondiabetic cohort. Gemfibrozil has been shown to decrease rates of CVD events in subjects without diabetes (219,220) and in a diabetic subgroup of a larger trial (219). However, in a large trial specific to diabetic patients, fenofibrate failed to reduce overall cardiovascular outcomes (221). b. 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, prescribing statin therapy to lower LDL cholesterol to ∼30–40% from baseline is probably more effective than prescribing just enough to get LDL cholesterol slightly 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) There is not sufficient evidence to recommend aspirin for primary prevention in lower risk individuals, such as men 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. Aspirin should not be 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 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 and 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) Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease (active urine sediment, absence of retinopathy, or 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 (259,260). Patients with microalbuminuria who progress to macroalbuminuria (≥300 mg/24 h) are likely to progress to ESRD (261,262). 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 (263,264) and type 2 (57,58) diabetes. The UKPDS provided strong evidence that control of blood pressure can reduce the development of nephropathy (187). In addition, large prospective randomized studies in patients with type 1 diabetes have demonstrated that achievement of lower levels of systolic blood pressure ( 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 anemia, malnutrition, and metabolic bone disease is indicated. Early vaccination against Hepatitis B is indicated in patients likely to progress to end-stage kidney disease. Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease (active urine sediment, absence of retinopathy, or rapid decline in GFR), 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 (289,290). 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 pregnancy or who have become pregnant should have a comprehensive eye examination and 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 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 (291), the presence of nephropathy (292), and hypertension (293). 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 (53,57,58). Lowering blood pressure has been shown to decrease the progression of retinopathy (187). Several case series and a controlled prospective study suggest that pregnancy in type 1 diabetic patients may aggravate retinopathy (294,295); laser photocoagulation surgery can minimize this risk (295). 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 (296) 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. The benefit was greatest among patients whose baseline evaluation revealed high-risk characteristics (chiefly disc neovascularization or vitreous hemorrhage). Given the risks of modest loss of visual acuity and contraction of the visual field from panretinal laser surgery, such therapy is primarily recommended for eyes with PDR approaching or having high-risk characteristics. The ETDRS (297) 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., 20/50–20/100) from 20% in untreated eyes to 8% in treated eyes. The ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR, but not for mild or moderate NPDR. In older-onset patients with severe NPDR or less-than-high-risk PDR, the risk of severe vision loss or vitrectomy was reduced 50% by early laser photocoagulation surgery at these stages. 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 (298), 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 (299) and who have a significant risk of prevalent diabetic retinopathy at the 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 (300 –302), while examinations will be required more frequently if retinopathy is progressing. Examinations can also be done with retinal photographs (with or without dilation of the pupil) read by experienced experts. 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. This technology 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 used for more complex examinations and for therapy (303). 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 technical review and position statement on this subject (304,305). D. Neuropathy screening and treatment (306) 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 cardiovascular 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; 4) autonomic neuropathy may involve every system in the body; and 5) cardiovascular autonomic neuropathy causes substantial morbidity and mortality. Specific treatment for the underlying nerve damage is not currently available, other than improved glycemic control, which may slow progression but not reverse neuronal loss. Effective symptomatic treatments are available for some manifestations of DPN and autonomic neuropathy. 1. Diagnosis of neuropathy a. 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 (306). b. Diabetic autonomic neuropathy (307). 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, “brittle diabetes,” and hypoglycemic autonomic failure. 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), orthostasis (a fall in systolic blood pressure >20 mmHg upon standing without an appropriate heart rate response), or other disturbances in autonomic nervous system function involving the skin, pupils, or gastrointestinal and genitourinary systems. Gastrointestinal neuropathies (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and 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. 2. Symptomatic treatments a. Distal symmetric polyneuropathy. 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, with several FDA-approved for the management of painful DPN. See Table 16 for examples of agents to treat DPN pain. Table 16 Table of drugs to treat symptomatic DPN Class Examples Typical doses* Tricyclic drugs Amitriptyline 10–75 mg at bedtime Nortriptyline 25–75 mg at bedtime Imipramine 25–75 mg at bedtime Anticonvulsants Gabapentin 300–1,200 mg t.i.d. Carbamazepine 200–400 mg t.i.d. Pregabalin† 100 mg t.i.d. 5-Hydroxytryptamine and norepinephrine uptake inhibitor Duloxetine† 60–120 mg daily fs Substance P inhibitor Capsaicin cream 0.025–0.075% applied t.i.d.-q.i.d. *Dose response may vary; initial doses need to be low and titrated up. †Has FDA indication for treatment of painful diabetic neuropathy. b. Diabetic 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 (306). 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 (LOPS) (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 LOPS 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 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 (308) 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 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 (309) suggested that a screening of ABI be performed in patients over 50 years of age and 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 (309). 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, or 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. For a complete discussion, see the ADA consensus statement on diabetic foot wound care (310). 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 1% higher than that achieved by adult DCCT subjects and above current ADA recommendations for patients in general. However, the increased frequency of use of basal bolus regimens (including insulin pumps) in youth from infancy through adolescence has been associated with more children reaching ADA blood glucose targets (315,316) in those families in which both parents and the child with diabetes are motivated to perform the required diabetes-related tasks. In selecting glycemic goals, the benefits on long-term health outcomes of achieving a lower A1C must be weighed against the unique risks of hypoglycemia and the difficulties achieving near-normoglycemia in children and youth. Age-specific glycemic and A1C goals are presented in Table 17. Table 17 Plasma blood glucose and A1C goals for type 1 diabetes by age-group Values by age (years) Plasma blood glucose goal range (mg/dl) A1C Rationale Before meals Bedtime/overnight Toddlers and preschoolers (0–6) 100–180 110–200 7.5%) High risk and vulnerability to hypoglycemia School age (6–12) 90–180 100–180 130/80 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. (E) The goal of treatment is a blood pressure consistently 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 performed 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 ( 160 mg/dl (4.1 mmol/l) or LDL cholesterol >130 mg/dl (3.4 mmol/l) and one or more CVD risk factors. (E) The goal of therapy is an LDL cholesterol value 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 (335 –339). 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). 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 (76). 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. 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 related ADA consensus statement (76) and position statement (341) on preexisting diabetes and pregnancy. C. Older adults Recommendations Older adults who are functional, are 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 that demonstrate 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 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 vision and lower-extremity complications. D. Cystic fibrosis–related diabetes Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in people with cystic fibrosis, occurring in ∼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 cystic fibrosis patients with and without diabetes and have eliminated the sex difference in mortality. A consensus conference on CFRD was cosponsored in 2009 by ADA, the Cystic Fibrosis Foundation, and the Lawson Wilkins Pediatric Endocrine Society. Recommendations for the clinical management of CFRD will be found in the consensus report to be published in 2010. VIII. DIABETES CARE IN SPECIFIC SETTINGS 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 ≤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) These 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 95%) required mechanical ventilation (355). Ninety-day mortality was significantly higher in the intensive versus the conventional group (target 144–180 mg/dl) (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 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 (359). Hypoglycemia has been defined as any blood glucose <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 (177). 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 (177,360,361). 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 (361,362). i. 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 ≤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 may be 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 <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. ii. 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 <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, 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 (363). 2. Treatment options 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. Outside of critical care units, subcutaneous insulin is used much more frequently. Oral agents have a limited role in the inpatient setting. a. Intravenous insulin infusions. In the critical care setting, continuous intravenous insulin infusion has been shown to be the most effective method for achieving specific glycemic targets (346). Because of the very short half-life of circulating insulin, intravenous delivery allows rapid dosing adjustments to address alterations in patients' status. Intravenous insulin is ideally administered via validated written or computerized protocols that allow for predefined adjustments to the insulin infusion rate according to glycemic fluctuations and insulin dose. An extensive review of the merits and deficiencies of published protocols is beyond the intent of this statement, and the reader is referred to several available reports and reviews (364 –366). Continued education of staff with periodic ongoing review of patient data are critical for successful implementation of any insulin protocol (364 –366). Patients who receive intravenous insulin infusion will usually require transition to subcutaneous insulin when they begin eating regular meals or are transferred to lower intensity care. Typically, a percentage (usually 75–80%) of the total daily intravenous infusion dose is proportionately divided into basal and prandial components (see below). Importantly, subcutaneous insulin must be given 1–4 h prior to discontinuation of intravenous insulin to prevent hyperglycemia (367). b. Subcutaneous insulin. Scheduled subcutaneous insulin is the preferred method for achieving and maintaining glucose control in non-ICU patients with diabetes or stress hyperglycemia. The recommended components of inpatient subcutaneous insulin regimens include a basal, nutritional, and supplemental (correction) component (345,346,368). Each component can be met by one of several available insulin products, depending on the particular hospital situation. The reader is referred to several recent publications and reviews that describe currently available insulin preparations and protocols (366 –370). A topic that deserves particular attention is the persistent overuse of what has been branded as sliding scale insulin (SSI) for management of hyperglycemia. The term “correction insulin,” which refers to the use of additional short or rapid-acting insulin with scheduled insulin doses to treat blood glucose above desired targets, is preferred (345). Prolonged therapy with SSI as the sole regimen is ineffective in the majority of patients (and potentially dangerous in type 1 diabetes) (370 –375). c. Noninsulin agents. These agents are inappropriate in the majority of hospitalized patients because they are less titratable than insulin in the short tem and are meant to be used in patients eating on a regular meal schedule. Continuation of these agents may be appropriate in selected stable patients who are expected to consume meals at regular intervals. 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 (345,376). Injectable noninsulin therapies such as exenatide and pramlintide have limitations similar to those of oral agents in the hospital setting. d. Specific clinical situations i. Insulin pumps. 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 (346,368). It is important that nursing personnel document basal rates and bolus doses on a regular basis (at least daily). The availability of hospital personnel with expertise in CSII therapy is essential. ii. Enteral nutrition. Hyperglycemia is a common side effect of inpatient enteral nutrition therapy (377). A recent report using a combination of basal insulin with correction insulin achieved a mean glucose value of 160 mg/dl (8.9 mmol/l). Similar results were achieved in the group randomized to receive SSI alone; however, 48% of patients required the addition of intermediate-acting insulin to achieve glycemic targets (373). iii. Parenteral nutrition. The high glucose load in standard parenteral nutrition frequently results in hyperglycemia, which is associated with a higher incidence of complications and mortality in critically ill ICU patients (378). Insulin therapy is highly recommended, with glucose targets as defined previously by severity of illness. iv. Glucocorticoid therapy. Hyperglycemia is a common complication of corticosteroid therapy (363). Several approaches have been proposed for treatment of this condition, but there are no published protocols or studies that investigate the efficacy of these approaches. A reasonable approach is to institute glucose monitoring for at least 48 h in all patients receiving high dose glucocorticoid therapy and initiate insulin as appropriate. In patients who are already being treated for hyperglycemia, early adjustment of insulin doses is recommended. Importantly, during steroid tapers, insulin dosing should be proactively adjusted to avoid hypoglycemia. v. Hypoglycemia prevention. Hypoglycemia, especially in insulin-treated patients, is the leading limiting factor in the glycemic management of type 1 and type 2 diabetes (174). In the hospital, multiple additional risk factors for hypoglycemia are present, even among patients who are neither “brittle” nor tightly controlled. 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 (379,379,380). Additional triggering events leading to iatrogenic hypoglycemia include sudden reduction of corticosteroid dose, altered ability of the patient to self-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. 3. Diabetes care providers in the hospital Inpatient diabetes management may be effectively provided by primary care physicians, endocrinologists, or hospitalists. Involvement of appropriately trained specialists or specialty teams may reduce length of stay, improve glycemic control, and improve outcomes (381 –384). In the care of diabetes, implementation of standardized order sets for scheduled and correction-dose insulin may reduce reliance on sliding-scale management. 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 protocols for subcutaneous insulin therapy that effectively and safely achieve glycemic targets (385). 4. 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. For patients conducting self-management in the hospital, it is imperative that basal, prandial, and correction doses of insulin and results of bedside glucose monitoring be recorded as part of the patient's hospital medical record. While many institutions allow patients on insulin pumps to continue these devices in the hospital, others express concern regarding use of a device unfamiliar to staff, particularly in patients who are not able to manage their own pump therapy. If a patient is too ill to self-manage either multiple daily injections or CSII, then appropriate subcutaneous doses can be calculated on the basis of their basal and bolus insulin needs during hospitalization, with adjustments for changes in nutritional or metabolic status. 5. 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. 6. MNT in the hospital Hospital diets continue to be ordered by calorie levels based on the “ADA diet.” However, since 1994 the ADA has not endorsed 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. 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 (386,387). 7. Bedside blood glucose monitoring Bedside blood glucose monitoring using point-of-care glucose meters is performed before meals and bedtime in the majority of inpatients who are eating usual meals. In patients who are receiving continuous enteral or parenteral nutrition, glucose monitoring is optimally performed every 4–6 h. In patients who are receiving cycled enteral or parenteral nutrition, the schedule for glucose monitoring can be individualized but should be frequent enough to detect hyperglycemia during feedings and risk of hypoglycemia when feedings are interrupted (374,376). More frequent blood glucose testing ranging from every 30 min to every 2 h is required for patients on intravenous insulin infusions. Safe and rational glycemic management relies on the accuracy of blood glucose measurements using point-of-care blood glucose meters, which have several important limitations. Although the FDA allows a ±20% error for glucose meters, questions about the appropriateness of this criterion have been raised (388). Glucose measures differ significantly between plasma and whole blood, terms which are often used interchangeably and can lead to misinterpretation. Most commercially available capillary glucose meters introduce a correction factor of ∼1.12 to report a “plasma-adjusted” value (389). 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 (389,390). Analytical variability has been described with several point-of-care meters (391). Any glucose result that does not correlate with the patient's status should be confirmed through conventional laboratory sampling of PG. While laboratory measurement of PG has less variability and interference, multiple daily phlebotomies are not practical. The use of indwelling lines as the sampling source also poses risks for infection. Studies performed using continuous interstitial glucose monitoring systems in the critical care setting (392) currently are limited by the lack of reliability in the hypoglycemic range as well as by cost. 8. Discharge planning It is important to anticipate the postdischarge antihyperglycemic regimen in all patients with diabetes or newly discovered hyperglycemia. 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, especially in those new to insulin therapy or in whom the diabetes regimen has been substantially altered during the hospitalization. All patients in whom the diagnosis of diabetes is new should have, at minimum, “survival skills” training prior to discharge. It is recommended that the following areas be reviewed and addressed prior to hospital discharge: level of understanding related to the diagnosis of diabetes SMBG and explanation of home blood glucose goals definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia identification of health care provider who will provide diabetes care after discharge information on consistent eating patterns when and how to take blood glucose–lowering medications including insulin administration (if going home on insulin) sick-day management proper use and disposal of needles and syringes More expanded diabetes education can be arranged in the community. 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. IX. STRATEGIES FOR IMPROVING DIABETES CARE The implementation of the standards of care for diabetes has been suboptimal in most clinical settings. A recent report (393) indicated that 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. Most distressing was that only 12.2% of people with diabetes achieved all three treatment goals. While numerous interventions to improve adherence to the recommended standards have been implemented, the challenge of providing uniformly effective diabetes care has thus far defied a simple solution. 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 five core elements for the provision of optimal care of patients with chronic disease: delivery system design, self-management support, decision support, clinical information systems, and community resources and policies. 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 (394). Collaborative, multidisciplinary teams are best suited to provide such care for people with chronic conditions like diabetes and to empower patients' performance of appropriate self-management. Alterations in reimbursement that reward the provision of quality care, as defined by the attainment of quality measures developed by such programs as the ADA/National Committee for Quality Assurance Diabetes Provider Recognition Program, will also be required to achieve desired outcome goals. In recent years, numerous health care organizations, ranging from large health care systems such as the U.S. Veteran's Administration to small private practices, have implemented strategies to improve diabetes care. Successful programs have published results showing improvement in process measures such as measurement of A1C, lipids, and blood pressure. Effects on in important intermediate outcomes, such as mean A1C for populations, have been more difficult to demonstrate (395 –397), although examples do exist (398 –402), often taking more than 1 year to manifest (394). Features of successful programs reported in the literature include Delivery of DSME: increases adherence to standard of care and educating patients on glycemic targets and improves the percentage of patients who reach goal A1C (142,403) Adoption of practice guidelines, with participation of health care professionals in the process of development: Guidelines should be readily accessible at the point of service, preferably as computerized reminders at the point of care. Guidelines should begin with a summary of their major recommendations instructing health care professionals what to do and how to do it. Use of checklists that mirror guidelines: successful at improving adherence to standards of care Systems changes: such as provision of automated reminders to health care professionals and patients and audit and feedback of process and outcome data to providers Quality improvement programs combining continuous quality improvement or other cycles of analysis and intervention with provider performance data Practice changes: such as availability of point of care testing of A1C, scheduling planned diabetes visits, clustering of dedicated diabetes visits into specific times within a primary care practice schedule, or group visits and/or visits with multiple health care professionals on a single day Tracking systems with either an electronic medical record or patient registry: helpful at increasing adherence to standards of care by prospectively identifying those requiring assessments and/or treatment modifications. They likely could have greater efficacy if they suggested specific therapeutic interventions to be considered for a particular patient at a particular point in time (404). Availability of case or (preferably) care management services (405): Nurses, pharmacists, and other nonphysician health care professionals using detailed algorithms working under the supervision of physicians have demonstrated the greatest reduction in A1C and blood pressure (406,407). Evidence suggests that these individual initiatives work best when provided as components of a multifactorial intervention. When practices are compared, those that address more of the CCM elements demonstrate lower A1C levels and lower cardiovascular risk scores (408). The most successful practices have an institutional priority for quality of care, involve all of the staff in their initiatives, redesign their delivery system, activate and educate their patients, and use electronic health record tools (409,410). 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. 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 quality care is a priority.