• Cardiology Clinical Trials
• Lipid Disorders
• Diabetes Mellitus

• Cardiology Clinical Trials
• Cardiology & Cardiovascular Medicine
• Lipid Disorders
• Diabetes Mellitus

A dual agonist of peroxisome proliferator-activated receptors (PPARs) did not reduce adverse cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus (T2DM) Findings from the Phase 3, multinational, AleCardio study [Lincoff AM et al. JAMA 2014] were announced by A. Michael Lincoff, MD, Cleveland Clinic, Cleveland, Ohio, USA.

Aleglitazar is a PPAR agonist with balanced affinity for the PPAR-α and PPAR-γ subtypes. The primary effect of agonists of PPAR-α is to improve the plasma lipid profile, and the primary effect of agonists of PPAR-γ is to improve insulin sensitivity. A dual PPAR agonist, therefore, was hypothesized to combine favorable actions on lipoproteins with insulin-sensitizing and glucose-lowering affects that might translate into a reduction in adverse CV outcomes, explained Dr. Lincoff.

In a Phase 2 trial, aleglitazar was associated with greater reductions in HbA1C and blood levels of triglycerides, and a greater increase in high-density lipoprotein cholesterol (HDL-C) than either placebo or the PPAR-γ agonist pioglitazone [Henry RR et al. Lancet 2009].

In AleCardio, 7226 patients with T2DM who were hospitalized with a recent acute coronary syndrome were randomly assigned in a double-blind fashion to aleglitazar 150 μg/day, or placebo in addition to standard care. The trial was conducted at 720 sites in 26 countries. Patients could be randomized up to 12 weeks after discharge to allow clinical stabilization or completion of planned revascularization. The primary endpoint of the study was the composite of time to CV death, nonfatal myocardial infarction, and nonfatal stroke. The anticipated follow-up duration to achieve 950 primary endpoints was ∼2.5 years.

At baseline, patients were a mean age of 61 years. About two thirds were taking metformin, one third were on a sulfonylurea, and ∼30% were being treated with insulin. More than 90% were on aspirin and a statin.

The Data Safety Monitoring Board recommended early termination of the trial due to a higher incidence of heart failure in the aleglitazar arm. The trial was terminated after a median follow-up of 104 weeks.

The primary composite endpoint occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo arm (Table 1), for an HR of 0.96 that was not significant (p=0.57).

Heart failure occurred more frequently in the aleglitazar arm compared with the placebo arm (4.7% vs 3.8%; HR, 1.24; p=0.06). Peripheral edema also developed significantly more often in the aleglitazar arm (14.0% vs 6.6%; p<0.001). By Month 24, mean serum creatinine increased by 0.11 mg/dL in the aleglitazar arm and by 0.01 mg/dL in the placebo arm (p<0.001), a difference that was reversible by 4 weeks after discontinuation of aleglitazar. Gastrointestinal hemorrhage was also significantly more common in the aleglitazar group (HR, 1.44; p=0.03).

HbA1C was significantly lower among patients assigned to aleglitazar compared with placebo, with the mean change from baseline being −0.99% in the aleglitazar arm and −0.36% in the placebo arm. At 3 months, HDL-C levels increased from baseline by 26.9% in the aleglitazar arm and 8.4% in the placebo arm. Triglyceride levels increased in the placebo arm and decreased by 23.9% in the aleglitazar arm. The level of low-density lipoprotein cholesterol increased in both groups, but more so in the aleglitazar arm.

The adverse effects associated with aleglitazar highlight the difficulties in developing PPAR-activating drugs where gene modulation can result in complex metabolic effects and unpredictable therapeutic profiles, concluded Dr. Lincoff.

• © 2014 MD Conference Express®