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      Standards of Medical Care in Diabetes—2010

      American Diabetes Association

      Diabetes Care

      American Diabetes Association

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          Abstract

          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 <100% concordance between the FPG and 2-h PG tests, there is not perfect concordance between A1C and either glucose-based test. Analyses of National Health and Nutrition Examination Survey (NHANES) data indicate that, assuming universal screening of the undiagnosed, the A1C cut point of ≥6.5% identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of ≥126 mg/dl (7.0 mmol/l) (E. Gregg, personal communication). However, in practice, a large portion of the diabetic population remains unaware of their condition. Thus, the lower sensitivity of A1C at the designated cut point may well be offset by the test's greater practicality, and wider application of a more convenient test (A1C) may actually increase the number of diagnoses made. As with most diagnostic tests, a test result diagnostic of diabetes should be repeated to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such as a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. It is preferable that the same test be repeated for confirmation, since there will be a greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, there are scenarios in which results of two different tests (e.g., FPG and A1C) are available for the same patient. In this situation, if the two different tests are both above the diagnostic threshold, the diagnosis of diabetes is confirmed. On the other hand, if two different tests are available in an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the confirmed test. That is, if a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the FPG (<126 mg/dl or 7.0 mmol/l), or vice versa, that person should be considered to have diabetes. Admittedly, in most circumstance the “nondiabetic” test is likely to be in a range very close to the threshold that defines diabetes. Since there is preanalytic and analytic variability of all the tests, it is also possible that when a test whose result was above the diagnostic threshold is repeated, the second value will be below the diagnostic cut point. This is least likely for A1C, somewhat more likely for FPG, and most likely for the 2-h PG. Barring a laboratory error, such patients are likely to have test results near the margins of the threshold for a diagnosis. The healthcare professional might opt to follow the patient closely and repeat the testing in 3–6 months. The current diagnostic criteria for diabetes are summarized in Table 2. Table 2 Criteria for the diagnosis of diabetes 1. A1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* OR 2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* OR 3. Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l). *In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing. C. Categories of increased risk for diabetes In 1997 and 2003, The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (4,7) recognized an intermediate group of individuals whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered normal. This group was defined as having impaired fasting glucose (IFG) (FPG levels of 100 mg/dl [5.6 mmol/l] to 125 mg/dl [6.9 mmol/l]) or impaired glucose tolerance (IGT) (2-h OGTT values of 140 mg/dl [7.8 mmol/l] to 199 mg/dl [11.0 mmol/l]). Individuals with IFG and/or IGT have been referred to as having pre-diabetes, indicating the relatively high risk for the future development of diabetes. IFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease (CVD). IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. Structured lifestyle intervention, aimed at increasing physical activity and producing 5–10% loss of body weight, and certain pharmacological agents have been demonstrated to prevent or delay the development of diabetes in people with IGT (see Table 7). It should be noted that the 2003 ADA Expert Committee report reduced the lower FPG cut point to define IFG from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), in part to make the prevalence of IFG more similar to that of IGT. However, the World Health Organization (WHO) and many other diabetes organizations did not adopt this change. As the A1C becomes increasingly used to diagnose diabetes in individuals with risk factors, it will also identify those at high risk for developing diabetes in the future. As was the case with the glucose measures, defining a lower limit of an intermediate category of A1C is somewhat arbitrary, since risk of diabetes with any measure or surrogate of glycemia is a continuum extending well into the normal ranges. To maximize equity and efficiency of preventive interventions, such an A1C cut point, should balance the costs of false negatives (failing to identify those who are going to develop diabetes) against the costs of false positives (falsely identifying and then spending intervention resources on those who were not going to develop diabetes anyway). Linear regression analyses of nationally representative U.S. data (NHANES 2005–2006) indicate that among the nondiabetic adult population, an FPG of 110 mg/dl corresponds to an A1C of 5.6%, while an FPG of 100 mg/dl corresponds to an A1C of 5.4%. Receiver operating curve analyses of these data indicate that an A1C value of 5.7%, compared with other cut points, has the best combination of sensitivity (39%) and specificity (91%) to identify cases of IFG (FPG ≥100 mg/dl [5.6 mmol/l]) (R.T. Ackerman, Personal Communication). Other analyses suggest that an A1C of 5.7% is associated with diabetes risk similar to that of the high-risk participants in the Diabetes Prevention Program (DPP) (R.T. Ackerman, personal communication). Hence, it is reasonable to consider an A1C range of 5.7–6.4% as identifying individuals with high risk for future diabetes and to whom the term pre-diabetes may be applied (6). As is the case for individuals found to have IFG and IGT, individuals with an A1C of 5.7–6.4% should be informed of their increased risk for diabetes as well as CVD and counseled about effective strategies to lower their risks (see IV. PREVENTION/DELAY OF TYPE 2 DIABETES). As with glucose measurements, the continuum of risk is curvilinear, so that as A1C rises, the risk of diabetes rises disproportionately. Accordingly, interventions should be most intensive and follow-up should be particularly vigilant for those with an A1C >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 <5.7% may still be at risk, depending on the level of A1C and presence of other risk factors, such as obesity and family history. Table 3 summarizes the categories of increased risk for diabetes. Table 3 Categories of increased risk for diabetes* FPG 100–125 mg/dl (5.6–6.9 mmol/l) [IFG] 2-h PG on the 75-g OGTT 140–199 mg/dl (7.8–11.0 mmol/l) [IGT] A1C 5.7–6.4% *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range. II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS Recommendations Testing to detect type 2 diabetes and assess risk for future diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI ≥25 kg/m2) and who have one or more additional risk factors for diabetes (Table 4). In those without these risk factors, testing should begin at age 45 years. (B) If tests are normal, repeat testing should be carried out at least at 3-year intervals. (E) To test for diabetes or to assess risk of future diabetes, either A1C, FPG, or 2-h 75-g OGTT are appropriate. (B) In those identified with increased risk for future diabetes, identify and, if appropriate, treat other CVD risk factors. (B) Table 4 Criteria for testing for diabetes in asymptomatic adult individuals 1. Testing should be considered in all adults who are overweight (BMI ≥25 kg/m2 *) and have additional risk factors: physical inactivity first-degree relative with diabetes members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacific Islander) women who delivered a baby weighing >9 lb or were diagnosed with GDM hypertension (≥140/90 mmHg or on therapy for hypertension) HDL cholesterol level <35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl (2.82 mmol/l) women with polycystic 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 <25 years Weight normal before pregnancy Member of an ethnic group with a low prevalence of diabetes No known diabetes in first-degree relatives No history of abnormal glucose tolerance No history of poor obstetrical outcome Two approaches may be followed for GDM screening at 24–28 weeks: Two-step approach: Perform initial screening by measuring plasma or serum glucose 1 h after a 50-g load of ≥140 mg/dl identifies ∼80% of women with GDM, while the sensitivity is further increased to ∼90% by a threshold of ≥130 mg/dl. Perform a diagnostic 100-g OGTT on a separate day in women who exceed the chosen threshold on 50-g screening. One-step approach (may be preferred in clinics with high prevalence of GDM): Perform a diagnostic 100-g OGTT in all women to be tested at 24–28 weeks. The 100-g OGTT should be performed in the morning after an overnight fast of at least 8 h. To make a diagnosis of GDM, at least two of the following plasma glucose values must be found: Fasting ≥95 mg/dl 1-h ≥180 mg/dl 2-h ≥155 mg/dl 3-h ≥140 mg/dl Results of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study (26), a large-scale (∼25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. The IADPSG recommended that all women not known to have prior diabetes undergo a 75-g OGTT at 24–28 weeks of gestation. The group developed diagnostic cut points for the fasting, 1-h, and 2-h PG measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with women with the mean glucose levels in the HAPO study. At the time of this update to the Standards of Medical Care in Diabetes, ADA is planning to work with U.S. obstetrical organizations to consider adoption of the IADPSG diagnostic criteria and to discuss the implications of this change. While this change will significantly increase the prevalence of GDM, there is mounting evidence that treating even mild GDM reduces morbidity for both mother and baby (27). Because women with a history of GDM have a greatly increased subsequent risk for diabetes (28), they should be screened for diabetes 6–12 weeks postpartum, using nonpregnant OGTT criteria, and should be followed up with subsequent screening for the development of diabetes or pre-diabetes, as outlined in II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS. Information on the National Diabetes Education Program (NDEP) campaign to prevent type 2 diabetes in women with GDM can be found at http://ndep.nih.gov/media/NeverTooEarly_Tipsheet.pdf. IV. PREVENTION/DELAY OF TYPE 2 DIABETES Recommendations Patients with IGT (A), IFG (E), or an A1C of 5.7–6.4% (E) should be referred to an effective ongoing support program for weight loss of 5–10% of body weight and an increase in physical activity of at least 150 min/week of moderate activity such as walking. Follow-up counseling appears to be important for success. (B) Based on potential cost savings of diabetes prevention, such counseling should be covered by third-party payors. (E) In addition to lifestyle counseling, metformin may be considered in those who are at very high risk for developing diabetes (combined IFG and IGT plus other risk factors such as A1C >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 < 0.043)‡ 20.6     Indian DPP (17) 269† IGT 46 2.5 I-D&E 23 29 (21–37) 6.4 Medications     DPP (11) 2,155† IGT, BMI >24 kg/m2, FPG >5.3 mmol/l 51 2.8 Metformin (1,700 mg) 10.4 31 (17–43) 13.9     Indian DPP (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 <7.0%, outcomes combining A1C and hypoglycemia favored the group using CGM, suggesting that CGM is also beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0% (45). Although CGM is an evolving technology, emerging data suggest that it may offer benefit in appropriately selected patients who are motivated to wear it most of the time. CGM may be particularly useful in those with hypoglycemia unawareness and/or frequent episodes of hypoglycemia, and studies in this area are ongoing. b. A1C Recommendations Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). (E) Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. (E) Use of point-of-care testing for A1C allows for timely decisions on therapy changes, when needed. (E) Because A1C is thought to reflect average glycemia over several months (43) and has strong predictive value for diabetes complications (11,46), A1C testing should be performed routinely in all patients with diabetes, at initial assessment and then as part of continuing care. Measurement approximately every 3 months determines whether a patient's glycemic targets have been reached and maintained. For any individual patient, the frequency of A1C testing should be dependent on the clinical situation, the treatment regimen used, and the judgment of the clinician. Some patients with stable glycemia well within target may do well with testing only twice per year, while unstable or highly intensively managed patients (e.g., pregnant type 1 diabetic women) may be tested more frequently than every 3 months. The availability of the A1C result at the time that the patient is seen (point-of-care testing) has been reported to result in increased intensification of therapy and improvement in glycemic control (47,48). The A1C test is subject to certain limitations. Conditions that affect erythrocyte turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient's clinical situation (43). In addition, A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability (especially type 1 diabetic patients, or type 2 diabetic patients with severe insulin deficiency), glycemic control is best judged by the combination of results of SMBG testing and the A1C. The A1C may also serve as a check on the accuracy of the patient's meter (or the patient's reported SMBG results) and the adequacy of the SMBG testing schedule. Table 9 contains the correlation between A1C levels and mean PG levels based on data from the international A1C-Derived Average Glucose (ADAG) trial using frequent SMBG and CGM in 507 adults (83% Caucasian) with type 1, type 2, and no diabetes (49). ADA and the American Association of Clinical Chemists have determined that the correlation (r = 0.92) is strong enough to justify reporting both an A1C result and an estimated average glucose (eAG) result when a clinician orders the A1C test. In previous versions of the Standards of Medical Care in Diabetes, the table describing the correlation between A1C and mean glucose was derived from relatively sparse data (one seven-point profile over 1 day per A1C reading) in the primarily Caucasian type 1 participants in the DCCT (50). Clinicians should note that the numbers in the table are now different, as they are based on ∼2,800 readings per A1C in the ADAG trial. Table 9 Correlation of A1C with average glucose A1C (%) Mean plasma glucose mg/dl mmol/l 6 126 7.0 7 154 8.6 8 183 10.2 9 212 11.8 10 240 13.4 11 269 14.9 12 298 16.5 These estimates are based on ADAG data of ∼2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92 (49). A calculator for converting A1C results into estimated average glucose (eAG), in either mg/dl or mmol/l, is available at http://professional.diabetes.org/eAG. In the ADAG trial, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although there was a trend toward a difference between Africans/African Americans participants and Caucasians that might have been significant had more Africans/African Americans been studied. A recent study comparing A1C to CGM data in 48 type 1 diabetic children found a highly statistically significant correlation between A1C and mean blood glucose, although the correlation (r = 0.7) was significantly lower than in the ADAG trial (51). Whether there are significant differences in how A1C relates to average glucose in children or in African American patients is an area for further study. For the time being, the question has not led to different recommendations about testing A1C or different interpretations of the clinical meaning of given levels of A1C in those populations. For patients in whom A1C/eAG and measured blood glucose appear discrepant, clinicians should consider the possibilities of hemoglobinopathy or altered red cell turnover and the options of more frequent and/or different timing of SMBG or use of CGM. Other measures of chronic glycemia such as fructosamine are available, but their linkage to average glucose and their prognostic significance are not as clear as is the case for A1C. 2. Glycemic goals in adults Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, for microvascular disease prevention, the A1C goal for nonpregnant adults in general is <7%. (A) In type 1 and type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. Long-term follow-up of the DCCT and UK Prospective Diabetes Study (UKPDS) cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable for many adults for macrovascular risk reduction. (B) Subgroup analyses of clinical trials such as the DCCT and UKPDS, and evidence for reduced proteinuria in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD. (B) Conversely, less-stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive comorbid conditions and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. (C) Glycemic control is fundamental to the management of diabetes. The DCCT, a prospective, randomized, controlled trial of intensive versus standard glycemic control in patients with relatively recently diagnosed type 1 diabetes, showed definitively that improved glycemic control is associated with significantly decreased rates of microvascular (retinopathy and nephropathy) as well as neuropathic complications (53). Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study has shown persistence of this effect in previously intensively treated subjects, even though their glycemic control has been equivalent to that of previous standard arm subjects during follow-up (54,55). In type 2 diabetes, the Kumamoto study (56) and the UKPDS (57,58) demonstrated significant reductions in microvascular and neuropathic complications with intensive therapy. Similar to the DCCT-EDIC findings, long-term follow-up of the UKPDS cohort has recently demonstrated a “legacy effect” of early intensive glycemic control on long-term rates of microvascular complications, even with loss of glycemic separation between the intensive and standard cohorts after the end of the randomized controlled trial (59). The more recent Veterans Affairs Diabetes Trial (VADT) in type 2 diabetes also showed significant reductions in albuminuria with intensive (achieved median A1C 6.9%) compared with standard glycemic control but no difference in retinopathy and neuropathy (60,61). In each of these large randomized prospective clinical trials, treatment regimens that reduced average A1C to 7% (1% above the upper limits of normal) were associated with fewer markers of long-term microvascular complications; however, intensive control was found to increase the risk of severe hypoglycemia and led to weight gain (46,60,62). Epidemiological analyses of the DCCT and UKPDS (46,53) demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from very poor control to fair or good control. These analyses also suggest that further lowering of A1C from 7 to 6% is associated with further reduction in the risk of microvascular complications, albeit the absolute risk reductions become much smaller. The ADVANCE study of intensive versus standard glycemic control in type 2 diabetes found a statistically significant reduction in albuminuria with an A1C target of <6.5% (achieved median A1C 6.3%) compared with standard therapy achieving a median A1C of 7.0% (63). Given the substantially increased risk of hypoglycemia (particularly in those with type 1 diabetes, but also in the recent type 2 diabetes trials described below), the concerning mortality findings in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial described below and the relatively much greater effort required to achieve near-normoglycemia, the risks of lower targets may outweigh the potential benefits on microvascular complications on a population level. However, selected individual patients, especially those with little comorbidity and long life expectancy (who may reap the benefits of further lowering glycemia below 7%) may, at patient and provider judgment, adopt glycemic targets as close to normal as possible as long as significant hypoglycemia does not become a barrier. Whereas many epidemiologic studies and meta-analyses (64,65) have clearly shown a direct relationship between A1C and CVD, the potential of intensive glycemic control to reduce CVD has been less clearly defined. In the DCCT, there was a trend toward lower risk of CVD events with intensive control (risk reduction 41%, 95% CI 10–68%), but the number of events was small. However, 9-year post-DCCT follow-up of the cohort has shown that participants previously randomized to the intensive arm had a 42% reduction (P = 0.02) in CVD outcomes and a 57% reduction (P = 0.02) in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with participants previously in the standard arm (66). The benefit of intensive glycemic control in this type 1 diabetic cohort has recently been shown to persist for up to 30 years (67). The UKPDS trial of type 2 diabetes observed a 16% reduction in cardiovascular complications (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm, although this difference was not statistically significant (P = 0.052), and there was no suggestion of benefit on other CVD outcomes such as stroke. In an epidemiologic analysis of the study cohort, a continuous association was observed such that for every percentage point lower median on-study A1C (e.g., 8–7%), there was a statistically significant 18% reduction in CVD events, again with no glycemic threshold. A recent report of 10 years of follow-up of the UKPDS cohort described, for the participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant) (59). Because of ongoing uncertainty regarding whether intensive glycemic control can reduce the increased risk of CVD events in people with type 2 diabetes, several large long-term trials were launched in the past decade to compare the effects of intensive versus standard glycemic control on CVD outcomes in relatively high-risk participants with established type 2 diabetes. In 2008, results of three large trials (ACCORD, ADVANCE, and VADT) suggested no significant reduction in CVD outcomes with intensive glycemic control in these populations. Details of these three studies are shown in Table 10, and their results and implications are reviewed more extensively in a recent ADA position statement (52). Table 10