WASHINGTON — Results from the phase 3 AleCardio trial, which was terminated early, showed higher rates of HF, renal dysfunction and gastrointestional hemorrhage and no CV benefit when patients with type 2 diabetes and recent ACS were treated with aleglitazar.
"There has been an explosion in the prevalence of diabetes, but no therapy specifically targeted to diabetes has been shown to reduce the risk of CV events, which are the most important source of mortality and morbidity among patients with diabetes," A. Michael Lincoff, MD, director of the Cleveland Clinic Coordinating Center for Clinical Research, said here.
In this superiority trial, the researchers hypothesized that aleglitazar (Roche) would reduce both CV morbidity and mortality among recipients compared with placebo.
A. Michael Lincoff
The trial was stopped in July after a median follow-up of 104 weeks on a recommendation from the data and safety monitoring board, which cited futility and increased frequency of safety endpoints, according to a presentation at the American College of Cardiology Scientific Sessions.
At the study’s termination, the primary efficacy endpoint of time to CV-related death, nonfatal MI or nonfatal stroke had occurred in 9.5% of patients randomly assigned aleglitazar compared with 10% of patients assigned placebo (HR=0.96; 95% CI, 0.83-1.11). The drug “had no detectable effect on the rates of any individual component of the primary endpoint,” despite significant reductions observed in hospitalization for unstable angina and unplanned revascularizations, the researchers wrote in JAMA.
Rates of serious adverse events were increased among aleglitazar recipients, including HF (3.4% vs. 2.8%; P=.14), renal dysfunction (7.4% vs. 2.7%; P<.001) and gastrointestinal hemorrhage (2.4% vs. 1.7%; P=.03) compared with placebo. Rates of bone fracture were numerically higher in the aleglitazar group (2.3% of patients compared with 1.8%; HR=1.3; 95% CI, 0.94-1.8).
In other results, aleglitazar showed significant reductions in glycated hemoglobin at 3 months (mean change from baseline, –0.99% vs. –0.3%; P<.001) and the need for permanent insulin therapy (18.4% vs. 20.6%; P=.02).
Both HDL and LDL increased significantly at 3 months in the aleglitazar group compared with placebo (HDL: 26.9% vs. 8.4%; LDL: 12.9% vs. 9.5%; P<.001 for both). Levels of triglycerides and apolipoprotein B decreased in the aleglitazar group (23.9% and 2.7% decrease, respectively), but increased in the placebo group (10.9% and 4.6% increases, respectively; P<.001 for both comparisons).
The researchers found no evidence that treatment effects differed by specific subgroup.
The double blind, placebo-controlled, superiority trial included 7,226 patients with type 2 diabetes hospitalized for ACS (MI or unstable angina) at 720 hospitals in 26 countries who were enrolled between February 2010 and May 2012. Participants were randomly assigned to receive daily aleglitazar 150 mcg or placebo along with standard ACS, diabetes and CHD-risk factor care. Participants underwent outpatient follow-up visits at 1, 3, 6, 9 and 12 months after randomization, with alternating visits and contact via telephone every 3 months after.
Planned follow-up was for at least 2.5 years and 950 primary endpoint events were positively adjudicated, according to the study.
“This is a difficult class of drugs with very complex mechanisms and targets and unique patterns of gene modulation that make it very difficult and unpredictable to determine the therapeutic profiles, but for this drug, these findings don't support the use to reduce CV risk,” Lincoff said. – by Adam Taliercio
For more information:
Lincoff AM. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Sessions; March 29-31, 2014; Washington, D.C.
Lincoff AM. JAMA. 2014;doi:10.1001/jama.2014.3321.
Disclosure: Lincoff reports receiving research grants from AstraZeneca, CSL Laboratories, Eli Lilly, Regado, Roche, Takeda and Vivus through his institution.