aleglitazar and Hypoglycemia

To evaluate the potential efficacy, safety and tolerability of aleglitazar as monotherapy or add-on therapy to metformin or to a sulphonylurea (either alone or in combination with metformin).. We conducted a pooled analysis of data from three randomized phase III clinical trials of aleglitazar in patients with type 2 diabetes (n = 591). The three studies focused on: (i) aleglitazar alone; (ii) aleglitazar and metformin; and (iii) aleglitazar and sulphonylurea with or without metformin. Patients were randomized to 26 weeks' treatment with aleglitazar 150 µg/day or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) concentration from baseline to week 26. Secondary endpoints included changes in lipids, fasting plasma glucose and homeostatic model assessment of insulin resistance (HOMA-IR) at week 26.. Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. Aleglitazar treatment was associated with more beneficial changes in lipid profiles and HOMA-IR values than was placebo. Aleglitazar was generally well tolerated, with no reports of congestive heart failure. The incidence of peripheral oedema was similar in both groups. Change in body weight was +1.37 kg with aleglitazar and -0.53 kg with placebo. Hypoglycaemia was more frequently reported with aleglitazar (7.8%) than with placebo (1.7%), a result probably driven by the type of background medication.. Development of aleglitazar was halted because of a lack of cardiovascular efficacy and peroxisome proliferator-activated receptor-related side effects in patients with type 2 diabetes post-acute coronary syndrome; however, in the present studies, aleglitazar was well tolerated and effective in improving HbA1c, insulin resistance and lipid variables.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Metformin; Middle Aged; Oxazoles; Sulfonylurea Compounds; Thiophenes

Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to <6.5%) with previous CV complications.. ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar.. At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012).. Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics.

Topics: Aged; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Early Termination of Clinical Trials; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Myalgia; Myocardial Infarction; Myositis; Oxazoles; Peripheral Arterial Disease; PPAR alpha; PPAR gamma; Prediabetic State; Stroke; Thiophenes; Treatment Outcome