BACKGROUND: Insulin-resistant states, including type 2 diabetes (T2D) and 
prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar 
is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable 
insulin-sensitizing and glucose-lowering actions, favorable effects on blood 
lipids, and an acceptable safety profile in short-time studies. Therefore, it 
was hypothesized that aleglitazar would reduce CV morbidity and mortality in 
patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin 
≥5.7% to <6.5%) with previous CV complications.
STUDY DESIGN: ALEPREVENT was a phase III, multicenter, randomized, double-blind, 
trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or 
prediabetes with established, stable CV disease. The intended sample size was 
19,000 with a primary efficacy measure of major adverse CV events. However, the 
trial was halted prematurely after 1,999 patients had been randomized because of 
futility and an unfavorable benefit risk ratio in another CV outcomes trial 
evaluating aleglitazar.
RESULTS: At study termination after 58 ± 38 days of treatment, data had been 
collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the 
brief duration of treatment, aleglitazar induced favorable changes in 
glycosylated hemoglobin and blood lipids, similar for participants with T2D or 
prediabetes. However, compared with placebo, aleglitazar increased the incidence 
of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012).
CONCLUSIONS: Even within a short duration of exposure, aleglitazar was 
associated with excess adverse events, corroborating the findings of a larger 
and longer trial in T2D. Coupled with the previous failure of several other 
peroxisome proliferator-activated receptor α/γ activators, this class now holds 
little promise for CV therapeutics.