Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study

Summary Background Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-α and PPAR-γ agonist aleglitazar. Methods In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with ≤two oral agents) were enrolled from 47 sites in seven countries. After a single-blind, 4–5-week placebo run-in period, 332 patients were randomised double-blind (via an interactive voice-response system) to 16 weeks' treatment with aleglitazar at once-daily doses of 50 μg, 150 μg, 300 μg, or 600 μg, or matching placebo (n=55 in each group), or to open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated haemoglobin (HbA1c ) concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable post-baseline HbA1c measurement were included in the efficacy analysis. This study is registered with ClinicalTrials.gov , number NCT00388518. Findings The efficacy analysis excluded six patients (n=0 in pioglitazone group; n=1 in each of placebo, 50 μg, 150 μg, and 600 μg aleglitazar groups; and n=2 in 300 μg aleglitazar group). Aleglitazar significantly reduced baseline HbA1c versus placebo in a dose-dependent manner, from −0·36% (95% CI 0·00 to −0·70, p=0·048) with 50 μg to −1·35% (−0·99 to −1·70, p