The AleCardio trial was halted early due to safety concerns and lack of efficacy. Investigators reported patients with diabetes and acute coronary syndrome experienced elevated risk of heart failure, gastrointestinal hemorrhage, and renal dysfunction with no mitigating cardiovascular benefit.
For individuals with type 2 diabetes mellitus, cardiovascular complications continue as the leading cause of mortality, and no medical intervention has completely ameliorated this risk. However, despite promising data from earlier trials with aleglitazar, the AleCardio phase 3 clinical trial failed to show benefit for a drug whose mechanism of action gave researchers hope of benefit in patients with type 2 diabetes after acute coronary syndrome.
A. Michael Lincoff, MD, of the Cleveland Clinic’s Department of Cardiovascular Medicine and C5Research shared these findings at a Late-Breaking Clinical Trials session at the American College of Cardiology 2014 Scientific Session on March 30, 2014, in Washington, DC.
Researchers seeking medications to improve insulin sensitivity, reduce glucose levels, and improve lipid profile in patients with type 2 diabetes have turned to the peroxisome proliferator-activated receptor (PPAR) pathway. The investigational drug aleglitazar targets both PPARα and PPARγ receptors; other agonists of PPAR subtypes have benefit for lipid profiles (Fibrates, PPARα agonists) and in reducing insulin resistance (thiazolidinediones, PPARγ agonists). Phase 2 clinical trials of the dual PPARα/γ agent aleglitazar showed improvement in lipid profile and glycated hemoglobin, though elevations in serum creatinine and fluid retention were also noted by investigators.
For the AleCardio study, patients who had been hospitalized for acute coronary syndrome and who had either newly diagnosed or previously known type 2 diabetes were eligible for enrollment. Patients with significant heart failure, chronic kidney disease, severe peripheral edema, or very elevated triglycerides (>400 mg/dL) were excluded. Patients were randomized 1:1 to aleglitazar 150 mcg daily or to placebo.
A total of 7,226 patients from 720 sites in 26 countries were enrolled in the study, and divided essentially equally between the treatment arms; mean age was about 61 years old, and nearly two-thirds of participants were men. Most patients (76%) had a biomarker-positive myocardial infarction as the qualifying event, and nearly all (90%) had an established type 2 diabetes diagnosis at the time of enrollment, with a mean time from diagnosis of 8.6 years.
For AleCardio, researchers defined the primary efficacy endpoint as the time to first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular mortality. Secondary endpoints included hospitalization for unstable angina in composite with the primary endpoint, a composite including all-cause death along with nonfatal MI or nonfatal stroke, unplanned coronary revascularization, as well as all individual components of the composites.
Importantly, safety endpoints included doubling or greater than 50% increase in serum creatinine, development of end-stage renal disease, or hospitalization for heart failure. A blinded committee adjudicated suspected cardiovascular events and any deaths.
An unplanned interim analysis was conducted because the data and safety monitoring board had identified a higher incidence of specific adverse events in the intervention arm of the study. A futility analysis indicated that there was less than 1% chance of demonstrating aleglitazar’s superiority over placebo to P<.05 on study completion, and the study was terminated in July 2013. Subjects had been on the study drug for a median 89 weeks at the time of termination.
Though overall numbers were small, more instances of heart failure, gastrointestinal hemorrhage, and renal dysfunction occurred in the aleglitazar group. At the time of study termination, MI, cerebrovascular event, or death (the composite primary endpoint) had occurred in 344 patients receiving aleglitazar (9.5%), and 360 patients in the placebo group (10.0%, P = .57).
In a nuanced discussion after the presentation, Lincoff took care to note that the primary reason for terminating the trial was the lack of primary efficacy, rather than a “red-flag” safety profile. Against a background of a vigorous lipid-lowering regime including statins in this high-risk group, the effect of aleglitazar may not have been marked enough to make a difference in study outcomes, he remarked.
At the press conference following the morning’s Late-Breaking Clinical Trials session, Howard Bauchner, MD, Editor in Chief of JAMA, lauded cardiologists for achieving such a high standard of care that interventions such as these may show little added benefit. Still, he set the findings in the context of a large and growing population with type 2 diabetes facing grave risks: “Large segments of our population,” he said, “continue to struggle.”