The phase III AleCardio trial of the drug aleglitazar was brought to an early end last year when data showed patients with type 2 diabetes and recent acute coronary syndrome treated with the medication began developing higher rates of heart failure, kidney events and gastrointestinal bleeding with no offsetting cardiovascular benefits. All other studies implementing the drug have also been put to a halt. The data was presented March 30 as part of ACC.14 in Washington, DC, and simultaneously published in the Journal of the American Medical Association.

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Before its adverse effects were discovered aleglitazar first garnered interest among researchers for its influence on PPAR gamma and alpha cellular receptors and the regulation of glucose and lipids, which in turn could help patients with type 2 diabetes battle sudden blockages of blood flow to the heart. Randomly assigning 7,226 patients averaging 61 years of age to a daily 150 μg dose of aleglitazar or placebo, the study was designed to continue until 7,000 patients had been followed for 2.5 years and 950 primary endpoint events had been evaluated. The trial was cut short however, after just 522 events. While heart failure, bone fractures and reversible renal issues are known to occur for this particular class of drug, researchers failed to find any hoped-for countervailing benefit in the main efficacy endpoint.

“The only unprecedented adverse effect was gastrointestinal hemorrhage, and none of the safety signals were overwhelming,” said Michael Lincoff, MD, director of C5Research, the Cleveland Clinic Coordinating Center for Clinical Research in Cleveland. “The issue was futility of cardiovascular superiority, with primary efficacy endpoints reached for 9.5 percent of aleglitazar group compared with 10 percent of the placebo group.”

Over the course of the study limited lifespan instances of heart failure did not reach a level of significant difference for the aleglitazar group, but exhibited a strong trend at 3.4 percent compared with 2.8 percent for the placebo group. The gastrointestinal hemorrhage rate for aleglitazar was also higher at 2.4 percent compared to 1.7 percent for the placebo. Finally the rate of reversible kidney events was significantly higher at 7.4 percent for aleglitazar compared to 2.7 percent for the placebo group.

“This study highlights the difficulty in predicting cardiovascular outcomes based upon beneficial effects on metabolic endpoints, particularly in agents that affect a complex spectrum of pathways and especially multiple-gene activators such as this one,” says Lincoff. “This study may well mark the end of this class of drug being tested clinically.”

Keywords: PPAR gamma, Diabetes Mellitus, Type 2, Oxazoles, Heart Failure, Fractures, Bone, Medical Futility, Kidney, Gastrointestinal Hemorrhage