Effect of tesaglitazar, a dual PPARα/γ agonist, on glucose and lipid abnormalities in patients with type 2 diabetes:: a 12-week dose-ranging trial

Objective: The Glucose and Lipid Assessment in Diabetes ( GLAD) trial examined the dose-response relationship of the dual peroxisome proliferator-activated receptor (PPAR) activated alpha/gamma agonist tesaglitazar in type 2 diabetic patients. Study design: GLAD was a 12-week, multicenter, international, randomized, parallel-group trial. Five-hundred men and women aged group 30 - 80 years with type 2 diabetes (fasting plasma glucose [FPG] >= 126 mg/dL [>= 7.0 = mmol/L]) received once-daily, double-blind placebo or tesaglitazar (0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg) or open-label pioglitazone (45 mg), included as a therapeutic benchmark. Main outcome measures: Placebo-corrected changes from baseline in FPG (primary end point), plasma lipids, and insulin-resistance measures. Results: At baseline, the mean patient age was 56.1 years, 57.5 years, and 58.9 years for placebo, across tesaglitazar groups, and for pioglitazone, respectively. For the corresponding groups, mean body mass index was 30.6 kg/m(2), 30.9kg/m(2), and 29.7, kg/m(2), and mean HbA(1c) was 7.0%, 7.2%, and 7.0%, respectively. At 12 weeks, tesaglitazar 0.5 mg, 1.0 mg, 2.0 mg, and 3.0 mg produced statistically significant reductions in FPG (-30.3 mg/dL, - 41.1 mg/dL, - 55.0 mg/dL, - 60.9 mg/dL; p < 0.0001), triglycerides (-17.2%, - 32.9%, - 41.0%, - 40.9%; p < 0.01), and apolipoprotein B (-15.0%, -15.7%, -21.0%, -22.3%, respectively; p < 0.0001). Tesaglitazar at doses = 1.0 mg significantly increased high-density lipoprotein-cholesterol (HDL-C) (15.0%, 13.0%, 12.9%; p < 0.001), and reduced non-HDL-C (-13.2%, -22.2%, -25.0%; p < 0.0001), very-low-density lipoprotein-cholesterol (VLDL-C) (-36.9%, -49.8%, -52.5%; p < 0.0001), and total cholesterol (-6.8%, -14.1%, -15.5%, respectively; p < 0.01). Tesaglitazar = 0.5 mg improved insulin-resistance measures. Although no formal statistical analyses were performed between active treatments, improvements in efficacy measures with tesaglitazar 1.0 mg were numerically similar to or greater than those with pioglitazone. Similar numbers of adverse events occurred in the tesaglitazar <= 1.0 mg, placebo, and pioglitazone arms, but there was an increasing frequency of discontinuations due to pre-specified hematologic and clinical-chemistry criteria with tesaglitazar doses >= 1.0 mg. Conclusions: In type 2 diabetic patients, tesaglitazar dose-dependently reduced FPG levels at doses >= 0.5 mg. Other markers of glycemic control, atherogenic dyslipidemia, and measures associated with insulin resistance were improved at doses >= 0.5 mg or >= 1.0 mg. Study limitations included that the majority of patients were white, patients had good glycemic control at baseline, and the increased number of early withdrawals in the tesaglitazar 2.0 mg and 3.0 mg doses limits conclusions about the efficacy of these doses. The 0.5 mg and 1.0 mg tesaglitazar doses were identified for further investigation.