Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.

Aims/hypothesis The aim of this 52-week, open-label, noninferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart. Materials and methods Patients on metformin and a sulfonylurea were randomised to exenatide (n=253; 5 μg twice daily for 4 weeks, 10 μg thereafter) or biphasic insulin aspart (n=248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment.Results Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean±SEM, HbA 1c change: exenatide −1.04± 0.07%, biphasic insulin aspart −0.89±0.06%; difference −0.15 [95% CI −0.32 to 0.01]%). Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference −5.4 (95% CI −5.9 to −5.0) kg]. Both treatments reduced fasting serum glucose (exenatide −1.8±0.2 mmol/l, p<0.001; biphasic insulin aspart −1.7±0.2 mmol/l, p<0.001). Greater reductions in postprandial glucose excursions following morning (p < 0.001), midday (p = 0.002) and evening meals (p<0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide. Conclusions/interpretation Exenatide treatment resulted in HbA 1c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined.

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Pioglitazone, a thiazolidinedione, improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes, whereas metformin, a biguanide, exerts its effect primarily by decreasing hepatic glucose output. In the first head-to-head, double-blind clinical trial comparing these two oral antihyperglycemic medications (OAMs), we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy. Subjects were randomized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg (77% of pioglitazone patients) and 2550 mg (73% of metformin patients), as indicated, to achieve fasting plasma glucose levels of less than 7.0 mmol/liter (126 mg/dl). Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose. At endpoint, pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity, as determined by reduction of fasting serum insulin (P = 0.003) and by analysis of homeostasis model assessment for insulin sensitivity (HOMA-S; P = 0.002). Both OAM therapies were well tolerated. Therefore, pioglitazone and metformin are equally efficacious in regard to glycemic control, but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action. The more pronounced improvement in indicators of insulin sensitivity by pioglitazone, as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive, may be of interest for further clinical evaluation.

Background: Insulin resistance is often associated with increased triglyceride (TG) and decreased HDL-cholesterol (HDL-C) concentrations and increased small LDL particles. The Atherogenic Index of Plasma (AIP), defined as log(TG/HDL-C), has recently been proposed as a marker of plasma atherogenicity because it is increased in people at higher risk for coronary heart disease and is inversely correlated with LDL particle size. We studied the effect of pioglitazone, a thiazolidinedione that reduces insulin resistance, on the AIP of patients with type 2 diabetes. Methods: The data for the analysis of AIP in this report were obtained from four randomized, double-blind, multicenter, parallel-group, placebo-controlled clinical trials. Pioglitazone was used as monotherapy in one study and in combination therapy in three studies.

Objective: The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbAlc), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia. Methods:Patients with type 2 diabetes mellitus (HbAlc >6.5% and <9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, piogfitazone 30 mg QD, or pioglitazone 45 mg QD in double-blind fashion for 16 weeks at 41 centers in Canada and Spain. Results:A total of 297 patients were randomized (99 in each group). Overall, 286 (96.3%) were white. Mean (SD) age was 58.4 (10.9) years (range, 24-85 years), mean (SD) body mass index was 31.4 (4.8) kg/m 2, mean (SD) duration of type 2 diabetes mellitus was 20.0 (37.4) months, and 30.6% of patients were receiving medication for dyslipidemia. Treatment with pioglitazone 30 or 45 mg QD for 16 weeks reduced mean HbAlc by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbAlc of 0.2% was observed in the placebo group (P = 0.025). In patients with medium (>7% to <8%) or high (>8% to <9.8%) baseline HbAlc, both doses of pioglitazone significantly reduced HbAlc (both P < 0.001 vs placebo). Pioglitazone 30 and 45 mg significantly reduced fasting serum insulin versus placebo (P = 0.008 and P = 0.006, respectively) and increased insulin sensitivity by Homeostasis Model Assessment versus placebo (P = 0.039 and P = 0.001, respectively). Relative to placebo, pioglitazone 30 and 45 mg significantly increased high-density lipoprotein cholesterol (HDL-C [P = 0.028 and P < 0.001, respectively]) and lowered the atherogenic index of plasma (P = 0.018 and P < 0,001, respectively). Pioglitazone 45 mg also significantly reduced serum triglycerides, apolipoprotein B, and total cholesterol:HDL-C ratio versus placebo (P = 0,007, P = 0.015, and P = 0.005, respectively). Pioglitazone 30 and 45 mg were associated with a significant reduction in serum alanine aminotransferase relative to placebo (P = 0.036 and P = 0.005, respectively). Pioglitazone appeared to be safe and was well tolerated.Conclusions: In the present study, pioglitazone 30 and 45 mg produced significant improvements in HbAlc, insulin sensitivity, and lipid profile in OAMnaive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia. (Clin Ther.

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FOR THE GLAL STUDY GROUPOBJECTIVE -The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested.RESEARCH DESIGN AND METHODS -This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA 1c and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed.RESULTS -A greater proportion of patients treated with pioglitazone maintained HbA 1c Ͻ8% over the 2-year period than those treated with gliclazide. A difference between the KaplanMeier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA 1c Ͻ8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA 1c , a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment.CONCLUSIONS -Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment. Diabetes Care 28:544 -550, 2005T ype 2 diabetes, with its core defects of insulin resistance and relative insulin deficiency, is a progressive disease. Insulin resistance remains generally stable throughout the natural history of the disease, but there is a progressive loss of glycemic control due to the continuing loss of ␤-cell function. The U.K. Prospective Diabetes Study (1) showed that at diagnosis, patients have already lost ϳ50% of their ␤-cell function, which was further reduced to ϳ30% at 5 years.The standard approach at initial diagnosis for many patients with type 2 diabetes is a prescription of diet and physical activity to correct their hyperglycemia. When glycemic targets cannot be attained or maintained with this approach, an oral antihyperglycemic medication (OAM) is added to the lifestyle regimen. When monotherapy fails, treatment is changed to combination OAM therapy, OAMs plus insulin, or insulin therapy (2). Most patients initially respond to OAM monotherapy when they use it. However, with continued therapy, some patients can no longer achieve their glycemic target. The inability to maintain the glycemic target may indicate progression of disease rather than lack of response to a drug (3,4).Sulfonylureas, first introduced in the mid-1950s, are commonly used as monotherapy in patients with type 2 diabete...