OBJECTIVETo compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of dulaglutide 1.5 mg versus placebo in HbA 1c change at 26 weeks. RESEARCH DESIGN AND METHODSThis 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 mg, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500-3,000 mg) and pioglitazone (30-45 mg). Mean baseline HbA 1c was 8.1% (65 mmol/mol). RESULTSLeast squares mean 6 SE HbA 1c change from baseline to the primary end point was 21.51 6 0.06% (216.5 6 0.7 mmol/mol) for dulaglutide 1.5 mg, 21.30 6 0.06% (214.2 6 0.7 mmol/mol) for dulaglutide 0.75 mg, 20.99 6 0.06% (210.8 6 0.7 mmol/mol) for exenatide, and 20.46 6 0.08% (25.0 6 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P < 0.001) and exenatide at 26 and 52 weeks (both adjusted one-sided P < 0.001). Greater percentages of patients reached HbA 1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P < 0.001). At 26 and 52 weeks, total hypoglycemia incidence was lower in patients receiving dulaglutide 1.5 mg than in those receiving exenatide; no dulaglutide-treated patients reported severe hypoglycemia. The most common gastrointestinal adverse events for dulaglutide were nausea, vomiting, and diarrhea. Events were mostly mild to moderate and transient. CONCLUSIONSBoth once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile.

Insulin resistance and ␤-cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n ‫؍‬ 1,082), metformin (850 mg twice a day) (n ‫؍‬ 1,073), or intensive lifestyle intervention (n ‫؍‬ 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio ‫؍‬ 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio ‫؍‬ 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio ‫؍‬ 0.46 -0.95 per SD increase and 0.29 -0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of ␤-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and ␤-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and ␤-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of ␤-cell function.

OBJECTIVETo evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL).RESEARCH DESIGN AND METHODSThis 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A1c [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning.RESULTSAt 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (−0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: −0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001).CONCLUSIONSIn patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

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The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance. The 27 clinical centers in the U.S. are recruiting at least 3,000 participants of both sexes, ~50% of whom are minority patients and 20% of whom are ≥65 years old, to be assigned at random to one of three intervention groups: an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groupsmetformin or placebo-combined with standard diet and exercise recommendations. Participants are being recruited during a 2 2/3-year period, and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002. The primary outcome is the development of diabetes, diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria. The 3,000 participants will provide 90% power to detect a 33% reduction in an expected diabetes incidence rate of at least 6.5% per year in the placebo group. Secondary outcomes include cardiovascular disease and its risk factors; changes in glycemia, β-cell function, insulin sensitivity, obesity, diet, physical activity, and health-related quality of life; and occurrence of adverse events. A fourth treatment group-troglilazone combined with standard diet and exercise recommendations-was included initially but discontinued because of the liver toxicity of the drug. This randomized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk. AbbreviationsADA, American Diabetes Association; DPP, Diabetes Prevention Program; FPG, fasting plasma glucose; IGT, impaired glucose tolerance; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; OGTT, oral glucose tolerance test; WHO, World Health Organization Type 2 diabetes is a common chronic disease affecting an estimated 12% of 40-to 74-yearold people in the U.S. (1). It is a major cause of premature mortality and morbidity due to cardiovascular, renal, ophthalmic, and neurologic diseases. Although treatment of type 2 diabetes can improve hyperglycemia, normalization of glycemia and glycohemoglobin is rarely achieved or maintained. Furthermore, macro-vascular disease and its risk factors are often already present in individuals at high risk of developing type 2 diabetes (2). Therefore, a policy RESEARCH GOALS PrimaryThe primary research goal is a comparison of the efficacy and safety of each of three interventions (an intensive lifestyle intervention or standard lifestyle recommendations combined with metformin or placebo) in preventing or delaying the development of diabetes. Diabetes is diagnosed by fasting plasma glucose (FPG) or glucose tolerance testing according to the 1997 American Diabetes Association (ADA) criteria (1). SecondarySecondary research goals i...