Bernard Zinman

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 …

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 …

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 …

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

OBJECTIVE To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m2. RESULTS Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy

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.

Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

BACKGROUND Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system. METHODS We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. RESULTS A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo. CONCLUSIONS Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)

Modern-Day Clinical Course of Type 1 Diabetes Mellitus After 30 Years’ Duration: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005)

BACKGROUND Clinical treatment goals of type 1 diabetes mellitus (T1DM) have changed since the Diabetes Control and Complications Trial (DCCT) demonstrated reduced long-term complications with intensive diabetes therapy. There have been few longitudinal studies to describe the clinical course of T1DM in the age of intensive therapy. Our objective was to describe the current-day clinical course of T1DM. METHODS An analysis of the cumulative incidence of long-term complications was performed. The DCCT (1983-1993) assigned patients to conventional or intensive therapy. Since 1993, the DCCT has been observational, and intensive therapy was recommended for all patients. The Pittsburgh Epidemiology of Diabetes Complications (EDC) study is an observational study of patients with T1DM from Allegheny County, Pennsylvania. The study population comprised the DCCT T1DM cohort (N = 1441) and a subset of the EDC cohort (n = 161) selected to match DCCT entry criteria. In the DCCT, intensive therapy aimed for a near-normal glycemic level with 3 or more daily insulin injections or an insulin pump. Conventional therapy, with 1 to 2 daily insulin injections, was not designed to achieve specific glycemic targets. Main outcome measures included the incidences of proliferative retinopathy, nephropathy (albumin excretion rate >300 mg/24 h, creatinine level >or=2 mg/dL [to convert to micromoles per liter, multiply by 88.4], or renal replacement), and cardiovascular disease. RESULTS After 30 years of diabetes, the cumulative incidences of proliferative retinopathy, nephropathy, and cardiovascular disease were 50%, 25%, and 14%, respectively, in the DCCT conventional treatment group, and 47%, 17%, and 14%, respectively, in the EDC cohort. The DCCT intensive therapy group had substantially lower cumulative incidences (21%, 9%, and 9%) and fewer than 1% became blind, required kidney replacement, or had an amputation because of diabetes during that time. CONCLUSION The frequencies of serious complications in patients with T1DM, especially when treated intensively, are lower than that reported historically.

Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT).

OBJECTIVE—The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS—Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS—In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS—Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

The prevention or delay of type 2 diabetes: American Diabetes Association and National Institute of Diabetes, Digestive and Kidney Diseases

D iabetes is one of the most costly and burdensome chronic diseases of our time and is a condition that is increasing in epidemic proportions in the U.S. and throughout the world (1). The complications resulting from the disease are a significant cause of morbidity and mortality and are associated with the damage or failure of various organs such as the eyes, kidneys, and nerves. Individuals with type 2 diabetes are also at a significantly higher risk for coronary heart disease, peripheral vascular disease, and stroke, and they have a greater likelihood of having hypertension, dyslipidemia, and obesity (2–6). There is also growing evidence that at glucose levels above normal but below the diabetes threshold diagnostic now referred to as pre-diabetes, there is a substantially increased risk of cardiovascular disease (CVD) and death (5,7–10). In these individuals, CVD risk factors are also more prevalent (5–7,9,11–14), which further increases the risk but is not sufficient to totally explain it. In contrast to the clear benefit of glucose lowering to prevent or retard the progression of microvascular complications associated with diabetes (15– 18,21), it is less clear whether the high rate of CVD in people with impaired glucose homeostasis, i.e., those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or diabetes, is caused by elevated blood glucose levels or will respond to treatments that lower blood glucose. Epidemiological studies have shown a clear relationship (19,20), whereas intervention trials in people with diabetes suggest, but have not demonstrated, a clear benefit of glycemic control (15,16,21,22). Additionally, there are no studies that have investigated a benefit of glucose lowering on macrovascular disease in subjects with only pre-diabetes (IFG or IGT) but not diabetes. Although the treatment of diabetes has become increasingly sophisticated, with over a dozen pharmacological agents available to lower blood glucose, a multitude of ancillary supplies and equipment available, and a clear recognition by health care professionals and patients that diabetes is a serious disease, the normalization of blood glucose for any appreciable period of time is seldom achieved (23). In addition, in well-controlled socalled “intensively” treated patients, serious complications still occur (15–18,21), and the economic and personal burden of diabetes remains. Furthermore, microvascular disease is already present in many individuals with undiagnosed or newly diagnosed type 2 diabetes (11,24– 28). Given these facts, it is not surprising that studies have been initiated in the last decade to determine the feasibility and benefit of various strategies to prevent or delay the onset of type 2 diabetes. Two early reports (29,30) suggested that changes in lifestyle can prevent diabetes, but weaknesses in study design limited their general relevance. Recently, however, four well-designed randomized controlled trials have been reported (31–35). In the Finnish study (31), 522 middleaged (mean age 55 years) obese (mean BMI 31 kg/m) subjects with IGT were randomized to receive either brief diet and exercise counseling (control group) or intensive individualized instruction on weight reduction, food intake, and guidance on increasing physical activity (intervention group). After an average follow-up of 3.2 years, there was a 58% relative reduction in the incidence of diabetes in the intervention group compared with the control subjects. A strong correlation was also seen between the ability to stop the progression to diabetes and the degree to which subjects were able to achieve one or more of the following: lose weight (goal of 5.0% weight reduction), reduce fat intake (goal of 30% of calories), reduce saturated fat intake (goal of 10% of calories), increase fiber intake (goal of 15 g/1,000 kcal), and exercise (goal of 150 min/week). No untoward effects of the lifestyle interventions were observed. In the Diabetes Prevention Program (DPP) (32–34), the 3,234 enrolled subjects were slightly younger (mean age 51 years) and more obese (mean BMI 34 kg/m) but had nearly identical glucose intolerance compared with subjects in the Finnish study. About 45% of the participants were from minority groups (e.g, AfricanAmerican, Hispanic), and 20% were 60 years of age. Subjects were randomized to one of three intervention groups, which included the intensive nutrition and exercise counseling (“lifestyle”) group or either of two masked medication treatment groups: the biguanide metformin group or the placebo group. The latter interventions were combined with standard diet and exercise recommendations. After an average follow-up of 2.8 years (range 1.8–4.6 years), a 58% relative reduction in the progression to diabetes was observed in the lifestyle group (absolute incidence 4.8%), and a 31% relative reduction in the progression of diabetes was observed in the metformin group (absolute incidence 7.8%) compared with control subjects (absolute incidence 11.0%). ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●