aleglitazar and Metabolic-Syndrome

The present single-centre, randomized, double-blind, placebo-controlled phase II study investigated the effect of the balanced dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on whole-body and liver insulin sensitivity, β-cell function and other components of cardiometabolic syndrome after 16 weeks of treatment in patients with type 2 diabetes inadequately controlled with metformin monotherapy who received once-daily 150 µg aleglitazar or matching placebo as add-on therapy to metformin. Baseline and 16-week assessments included a two-step hyperinsulinaemic-euglycaemic clamp, followed by a hyperglycaemic clamp, as well as evaluation of glycated haemoglobin (HbA1c), lipids and safety variables. The primary endpoint was change in whole-body insulin sensitivity (M-value) from baseline compared with placebo, derived from the second clamp step. M-value improved significantly from baseline with aleglitazar (n = 16) compared with placebo (n = 24; p = 0.05 for difference between arms). We found statistically significant treatment differences with aleglitazar versus placebo in fasting hepatic insulin resistance index (p = 0.01), and in total glucose disposal (p = 0.03) at the second insulin infusion step. Aleglitazar treatment resulted in significant improvements in HbA1c and lipids and was well tolerated.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Metabolic Syndrome; Middle Aged; Oxazoles; PPAR alpha; PPAR gamma; Thiophenes; Treatment Outcome

Glycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ (PPARα/γ) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys.. A 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period.. Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043).. Aleglitazar, a dual PPARα/γ agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM.

Topics: Administration, Oral; Animals; Apolipoprotein A-I; Apolipoprotein A-II; Biomarkers; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Eating; Glycated Hemoglobin; Hypertriglyceridemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Macaca mulatta; Male; Metabolic Syndrome; Obesity; Oxazoles; PPAR alpha; PPAR gamma; Prediabetic State; Thiophenes; Time Factors; Triglycerides; Weight Loss