Effects of high dose aleglitazar on renal function in patients with type 2 diabetes

Background

Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects.

Methods

SESTA R was a 26-week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 μg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m²).

Results

In 118 patients with evaluable GFR measurements, baseline mean (± SD) mGFR was 97.6 ± 17.5 ml/min/1.73 m² in the aleglitazar group and 101.9 ± 21.6 ml/min/1.73 m² in the pioglitazone group. Mean percent change from baseline mGFR was −16.9% (90% confidence interval −22.0 to −11.5) with aleglitazar and −4.6% (−10.15 to 1.35) with pioglitazone, a mean treatment difference of −13.0% (−19.0 to −6.5). The 17% decrease from baseline in mGFR was consistent with the 19% decrease in eGFR Modification of Diet in Renal Disease (MDRD) observed with aleglitazar, which reached a plateau after 4 weeks, with no further progression until treatment discontinuation. Following aleglitazar withdrawal, eGFR values returned to pretreatment levels within the 4-8-week follow-up, which suggests reversible hemodynamic changes in renal function.

Conclusions

Despite the increased incidence of expected, dose-dependent PPAR class side effects (e.g., peripheral edema, weight gain, and congestive heart failure) limiting further development of this supratherapeutic dosage of aleglitazar (600 μg/day), these data, together with the data from the dose-ranging SYNCHRONY study, suggest aleglitazar may be a potential new treatment for cardiovascular risk reduction in post-acute coronary syndrome patients at the therapeutic 150 μg daily dose.