David M. Nathan

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement of the American Diabetes Association and the European Association for the Study of Diabetes

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes

Members of the International Expert Committee have recommended that diabetes should be diagnosed if A1C is ≤6.5%, without need to measure the plasma glucose concentration (1). We are concerned that practical limitations will lead to false positives and negatives with this approach. A given A1C instrument may identify some but not other abnormal hemoglobins (http://www.ngsp.org/prog/index2.html). How, therefore, can we be sure whether a hemoglobinopathy is causing (or preventing) diagnosis? Before diagnosis, should we not also exclude iron deficiency anemia, which may increase A1C by 1–1.5%, as well as hemolytic anemia and renal failure or chronic infections, which also lower …

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

BACKGROUND Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).

Retinopathy and nephropathy in patients with type I diabetes four years after a trial of intensive therapy

BACKGROUND Among patients with type 1 diabetes mellitus, intensive therapy (with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [hemoglobin A1c]) markedly reduces the risk of microvascular complications as compared with conventional therapy. To assess whether these benefits persist, we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial (DCCT). METHODS At the end of the DCCT, the patients in the conventional-therapy group were offered intensive therapy, and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended, and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year, approximately half of whom were from each treatment group. RESULTS The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT (average, 9.1 percent and 7.2 percent, respectively) narrowed during follow-up (median during 4 years, 8.2 percent and 7.9 percent, respectively, P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the intensive-therapy group than in the conventional-therapy group (odds reduction, 72 percent to 87 percent, P<0.001). The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group. CONCLUSIONS The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least four years, despite increasing hyperglycemia.

Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial.

OBJECTIVE—The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes 1-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events. RESEARCH DESIGN AND METHODS—This study consisted of a multicentered, randomized, controlled trial of 5,145 individuals with type 2 diabetes, aged 45–74 years, with BMI >25 kg/m2 (>27 kg/m2 if taking insulin). An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. RESULTS—Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% in DSE group (P < 0.001). Mean fitness increased in ILI by 20.9 vs. 5.8% in DSE (P < 0.001). A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI (P < 0.001) vs. from 7.3 to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to-creatinine ratio improved significantly more in ILI than DSE participants (all P < 0.01). CONCLUSIONS—At 1 year, ILI resulted in clinically significant weight loss in people with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk.

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement From the American Diabetes Association and the European Association for the Study of Diabetes

The epidemic of type 2 diabetes in the latter part of the 20th and in the early 21st century, and the recognition that achieving specific glycemic goals can substantially reduce morbidity, have made the effective treatment of hyperglycemia a top priority (1–3). While the management of hyperglycemia, the hallmark metabolic abnormality associated with type 2 diabetes, has historically had center stage in the treatment of diabetes, therapies directed at other coincident features, such as dyslipidemia, hypertension, hypercoagulability, obesity, and insulin resistance, have also been a major focus of research and therapy. Maintaining glycemic levels as close to the nondiabetic range as possible has been demonstrated to have a powerful beneficial impact on diabetes-specific complications, including retinopathy, nephropathy, and neuropathy in the setting of type 1 diabetes (4,5); in type 2 diabetes, more intensive treatment strategies have likewise been demonstrated to reduce complications (6–8). Intensive glycemic management resulting in lower HbA1c (A1C) levels has also been shown to have a beneficial effect on cardiovascular disease (CVD) complications in type 1 diabetes (9,10); however, the role of intensive diabetes therapy on CVD in type 2 diabetes remains under active investigation (11,12). Some therapies directed at lowering glucose levels have additional benefits with regard to CVD risk factors, while others lower glucose without additional benefits. The development of new classes of blood glucose–lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has increased the treatment options for type 2 diabetes. Whether used alone or in combination with other blood glucose–lowering interventions, the availability of the newer agents has provided an increased number of choices for practitioners and patients and heightened uncertainty regarding the most appropriate means of treating this widespread disease. Although numerous reviews on the …

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

BACKGROUND Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence Based Laboratory Medicine Committee of the AACC jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A(1c) (Hb A(1c)) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

Translating the A1C Assay Into Estimated Average Glucose Values

OBJECTIVE—The A1C assay, expressed as the percent of hemoglobin that is glycated, measures chronic glycemia and is widely used to judge the adequacy of diabetes treatment and adjust therapy. Day-to-day management is guided by self-monitoring of capillary glucose concentrations (milligrams per deciliter or millimoles per liter). We sought to define the mathematical relationship between A1C and average glucose (AG) levels and determine whether A1C could be expressed and reported as AG in the same units as used in self-monitoring. RESEARCH DESIGN AND METHODS—A total of 507 subjects, including 268 patients with type 1 diabetes, 159 with type 2 diabetes, and 80 nondiabetic subjects from 10 international centers, was included in the analyses. A1C levels obtained at the end of 3 months and measured in a central laboratory were compared with the AG levels during the previous 3 months. AG was calculated by combining weighted results from at least 2 days of continuous glucose monitoring performed four times, with seven-point daily self-monitoring of capillary (fingerstick) glucose performed at least 3 days per week. RESULTS—Approximately 2,700 glucose values were obtained by each subject during 3 months. Linear regression analysis between the A1C and AG values provided the tightest correlations (AGmg/dl = 28.7 × A1C − 46.7, R2 = 0.84, P < 0.0001), allowing calculation of an estimated average glucose (eAG) for A1C values. The linear regression equations did not differ significantly across subgroups based on age, sex, diabetes type, race/ethnicity, or smoking status. CONCLUSIONS—A1C levels can be expressed as eAG for most patients with type 1 and type 2 diabetes.

Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for care

Type 2 diabetes is now epidemic. In the U.S., there has been a 61% increase in incidence between 1990 and 2001 (1). There are currently 1.5 million new cases per year, and the prevalence in 2005 was almost 21 million (2). The epidemic has affected developed and developing countries alike, and the worldwide prevalence of diabetes is projected to increase dramatically by 2025 (3). The increase in type 2 diabetes is related to lifestyle changes that have resulted in overweight, obesity, and decreased physical activity levels. These environmental changes, superimposed on genetic predisposition, increase insulin resistance, which, in concert with progressive β-cell failure, results in rising glycemia in the nondiabetic range. In addition to the risk for diabetes, insulin resistance and impaired insulin secretion are accompanied by a host of major cardiovascular disease (CVD) risk factors including hypertension and dyslipidemia. Further reduction in insulin secretion over time results in increasing glycemia and the development of diabetes, which in turn is associated with the development of microvascular and cardiovascular complications. The transition from the early metabolic abnormalities that precede diabetes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), to diabetes may take many years; however, current estimates indicate that most individuals (perhaps up to 70%) with these pre-diabetic states eventually develop diabetes (4–10). During the pre-diabetic state, the risk of a CVD event is modestly increased (11–22). With the development of diabetes, however, there is a large increase in risk for CVD, as well as for long-term complications affecting the eyes, kidneys, and nervous system. The complications of diabetes, which are the cause of major morbidity and mortality, are related to its duration, chronic level of glycemia, and other risk factors. Although clinical trials have demonstrated the effectiveness of intensive glycemic and blood pressure control to …

Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the look AHEAD trial

BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease (CVD) risk factors in individuals with type 2 diabetes mellitus, but no long-term data are available. We examined the effects of lifestyle intervention on changes in weight, fitness, and CVD risk factors during a 4-year study. METHODS The Look AHEAD (Action for Health in Diabetes) trial is a multicenter randomized clinical trial comparing the effects of an intensive lifestyle intervention (ILI) and diabetes support and education (DSE; the control group) on the incidence of major CVD events in 5145 overweight or obese individuals (59.5% female; mean age, 58.7 years) with type 2 diabetes mellitus. More than 93% of participants provided outcomes data at each annual assessment. RESULTS Averaged across 4 years, ILI participants had a greater percentage of weight loss than DSE participants (-6.15% vs -0.88%; P < .001) and greater improvements in treadmill fitness (12.74% vs 1.96%; P < .001), hemoglobin A(1c) level (-0.36% vs -0.09%; P < .001), systolic (-5.33 vs -2.97 mm Hg; P < .001) and diastolic (-2.92 vs -2.48 mm Hg; P = .01) blood pressure, and levels of high-density lipoprotein cholesterol (3.67 vs 1.97 mg/dL; P < .001) and triglycerides (-25.56 vs -19.75 mg/dL; P < .001). Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants (-11.27 vs -12.84 mg/dL; P = .009) owing to greater use of medications to lower lipid levels in the DSE group. At 4 years, ILI participants maintained greater improvements than DSE participants in weight, fitness, hemoglobin A(1c) levels, systolic blood pressure, and high-density lipoprotein cholesterol levels. CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and CVD risk factors in individuals with type 2 diabetes. Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.