Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial
What is the impact of the dual peroxisome proliferator-activated receptor agonist (aleglitazar) on the risk of cardiovascular morbidity and mortality among patients with diabetes mellitus and recent acute coronary syndrome (ACS)?
AleCardio was a randomized, double-blind, placebo-controlled, multicenter, superiority trial. Patients hospitalized for ACS with either established or newly diagnosed type 2 diabetes were eligible. Patients were randomized to aleglitazar 150 mg or placebo once daily. The primary efficacy endpoint was the time to first cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Hospitalization due to heart failure and changes in renal function were principal safety endpoints.
Because of increased rates of safety endpoints in the aleglitazar group and futility for efficacy, the trial was terminated prematurely after a median follow-up of 104 weeks. Rates of heart failure (3.4% vs. 2.8%, p = 0.14), gastrointestinal hemorrhage (2.4% vs. 1.7%, p = 0.03), and renal dysfunction (7.4% vs. 2.7%, p < 0.001) were increased in the aleglitazar group, compared to placebo.
The authors concluded that use of aleglitazar did not reduce the risk of cardiovascular outcomes and increased the risk of adverse effects in patients with type 2 diabetes and recent ACS.
While the metabolic effects of PPAR activators may be favorable, these may have been counterbalanced by adverse effects in this trial. Heart failure is an established risk of PPAR-gamma activators. Furthermore, the metabolic effects of aleglitazar may not have been of sufficient magnitude to translate into meaningful improvement in clinical outcomes; and, longer duration of exposure might be necessary to accrue and demonstrate benefit. On balance, the authors provide convincing evidence against the use of aleglitazar for cardiovascular risk reduction following ACS in patients with type 2 diabetes mellitus.
Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, PPAR gamma, Diabetes Mellitus, Type 2, Oxazoles, Heart Failure, Cardiovascular Diseases, Medical Futility, Peroxisome Proliferator-Activated Receptors, Gastrointestinal Hemorrhage, Hospitalization, ACC Annual Scientific Session
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