Matthias Herz

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus.

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 (HbA(1c)), 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 (HbA(1c) >/=6.5% and </=9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, pioglitazone 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 HbA(1c) by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbA(1c) 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 HbA(1c), both doses of pioglitazone significantly reduced HbA(1c) (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 HbA(1c), insulin sensitivity, and lipid profile in OAM-naive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia.

Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial

BACKGROUND Pioglitazone and glimepiride improve glycemic control in patients with type 2 diabetes mellitus by different mechanisms. Pioglitazone is a thiazolidinedione that reduces insulin resistance, and glimepiride is a sulfonylurea insulin secretagogue. OBJECTIVE The goals of this study were to compare changes in measures of glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes who received pioglitazone or glimepiride for 1 year. METHODS This was a multicenter, 52-week, double-blind, parallel-group trial. Patients were randomized to receive monotherapy with either glimepiride (2 mg QD initially) or pioglitazone (15 mg QD initially). Doses were titrated (maximal doses: pioglitazone 45 mg, glimepiride 8 mg) to achieve glycemic targets (fasting blood glucose < or =7 mmol/L and 1-hour postprandial blood glucose < or =10 mmol/L). Insulin sensitivity (primary end point) was evaluated in terms of the Homeostasis Model Assessment for Insulin Sensitivity (HOMA-S), the Quantitative Insulin Sensitivity Check Index (QUICKI), and fasting serum insulin (FSI) concentrations. Glycemic control was evaluated in terms of glycosylated hemoglobin (HbA(1c)) values and fasting plasma glucose (FPG) concentrations. Patients were encouraged to maintain their individual diet and exercise regimens throughout the study. RESULTS Two hundred forty-four patients (125 women, 119 men; all but 1 Hispanic) were randomized to receive pioglitazone (n = 121) or glimepiride (n = 123). In the intent-to-treat sample, pioglitazone and glimepirede produced comparable reductions in HbA(1c) from baseline to the end of the study (-0.78% and -0.68%, respectively). The pioglitazone group had significantly higher HbA(1c) values compared with the glimepiride group after 12 weeks of therapy (8.66% vs 7.80%; P = 0.007) but had significantly lower values after 52 weeks (7.46% vs 7.77%; P = 0.027). Pioglitazone significantly reduced FPG compared with glimepiride (-0.6 vs 0.6 mmol/L; P = 0.01). Pioglitazone therapy was associated with significant increases in insulin sensitivity (reduced insulin resistance), whereas glimepiride had no effect. HOMA-S values changed 18.0% for pioglitazone and -7.9% for glimepiride (P < 0.001), QUICKI values changed a respective 0.013 and -0.007 (P < 0.001), and FSI values were -21.1 and 15.1 pmol/L (P< 0.001). Both drugs were well tolerated, with pioglitazone associated with more peripheral edema (number of treatment-emergent cases: 35/121[28.9%] vs 17/123 [13.8%]; P = 0.005) and fewer hypoglycemic episodes (19 [15.7%] vs 38 [30.9%]; P = 0.024). The incidence of weight gain was not significantly different between treatment groups. CONCLUSIONS These data suggest that long-term treatment with pioglitazone enhances insulin sensitivity relative to glimepiride in Mexican patients with type 2 diabetes and that pioglitazone may have a more sustained antihyperglycemic effect.

Comparative efficacy of preprandial or postprandial humalog® mix75/25™ versus glyburide in patients 60 to 80 years of age with type 2 diabetes mellitus☆

BACKGROUND Humalog Mix75/25 (Mix75/25) is a novel premixed insulin containing 75% neutral protamine lispro (an intermediate-acting insulin) and 25% insulin lispro. OBJECTIVE The purpose of this study was to compare glycemic control and hypoglycemia rates with Mix75/25 versus glyburide, and with preprandial versus postprandial Mix75/25, in patients aged 60 to 80 years with type 2 diabetes mellitus and persistent hyperglycemia on sulfonylurea therapy. METHODS In this open-label, 16-week, parallel-group study, patients were randomized to 1 of 2 treatments: glyburide 15 mg/d (or up to the maximum daily dose) or Mix75/25. The Mix75/25 group was randomly subdivided into preprandial (immediately before breakfast and dinner) and postprandial (within 15 minutes after the start of breakfast and dinner) injection subgroups. The primary outcomes were glycemic control and rate of hypoglycemia. RESULTS A total of 143 patients were randomized; 127 completed the study. The change in glycosylated hemoglobin (HbA(1c)) from baseline to end point was significantly greater with Mix75/25 than with glyburide (mean +/- SEM, -1.14% +/- 0.18% vs -0.36% +/- 0.15%, P = 0.001). HbA(1c) changes with preprandial and postprandial Mix75/25 were not significantly different (-1.20% +/- 0.26% vs -1.08% +/- 0.26%, P = 0.748). Fasting blood glucose (BG), 2-hour postprandial BG, and mean daily BG reductions were greater with Mix75/25 than with glyburide (P < 0.001); preprandial and postprandial Mix75/25 administration did not differ significantly with respect to any of these BG variables. The hypoglycemia rate increased with Mix75/25 by 0.17 +/- 0.02 episodes per patient per 30 days, but there was no change with glyburide (P = 0.077). Body weight increased by 1.02 +/- 0.35 kg with Mix75/25 and decreased by 0.85 +/- 0.18 kg with glyburide (P < 0.001). CONCLUSIONS Compared with glyburide, Mix75/25 significantly improved glycemic control in older patients with type 2 diabetes mellitus, could be administered after meals without compromising glycemic control, and was well tolerated.

Effects of a fixed mixture of 25% insulin lispro and 75% NPL on plasma glucose during and after moderate physical exercise in patients with type 2 diabetes.

Summary Objective: To compare the plasma glucose (PG) response with a fixed mixture of 25% insulin lispro and 75% NPL (Mix25), prior to a meal and 3 h before exercise, to human insulin 30/70 (30/70) in patients with type 2 diabetes. Research design and methods: Thirty-seven patients were treated in a randomized, open-label, 8-week, two-period crossover study. Mix25 was injected 5 min before breakfast and dinner throughout the study, as was 30/70 on inpatient test days and on outpatient dose titration days. Following the 4-week outpatient phase, patients were hospitalized, and exercised at a heart rate of 120 beats/min on a cycle ergometer two times for 30 min, separated by 30 min rest, starting 3 h after a 339 kcal breakfast. Results: The 2-h postprandial PG was significantly lower with Mix25 ((mean ± SEM) 10.5 ± 0.4 mmol/lvs 11.6 ± 0.4 mmol/l; p = 0.016). Maximum decrease in PG from onset of exercise to end of exercise was significantly less with Mix25 (-3.6 ± 0.29 mmol/l vs -4.7 ± 0.31 mmol/l; p = 0.001). The maximum decrease in PG over 6 h, after exercise onset, was significantly less with Mix25 (-4.3 ± 0.4 mmol/l vs -5.9 ± 0.4 mmol/l; p < 0.001). The frequency of hypoglycemia (blood glucose (BG) < 3 mmol/l or symptoms) during the inpatient test was not different between treatments. During the outpatient phase, the frequency of patient-recorded hypoglycemia was significantly lower with Mix25 (0.7 ± 0.2 episodes/30d vs 1.2 ± 0.3 episodes/30 d; p = 0.042). Conclusions: Mix25 resulted in better postprandial PG control without an increase in exercise-induced hypoglycemia. The smaller decrease in PG during the postprandial phase after exercise may suggest a lower risk of exercise-induced hypoglycemia with Mix25 than with human insulin 30/70, especially for patients in tight glycemic control.