Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study

Abstract

BackgroundType 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist.MethodsPatients were randomized to 52 weeks’ double-blind treatment with aleglitazar 150 μg/day (n = 150) or pioglitazone 45 mg/day (n = 152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment.ResultsMean estimated glomerular filtration rate change from baseline to end of follow-up was –2.7% (95% confidence interval: –7.7, 2.4) with aleglitazar versus –3.4% (95% confidence interval: –8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: –4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified.ConclusionsThe primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks’ treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone.Trial registrationNCT01043029 January 5, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2369-15-180) contains supplementary material, which is available to authorized users.

Efficacy, safety and tolerability of aleglitazar in patients with type 2 diabetes: pooled findings from three randomized phase III trials

“…It is probable that the glucose-lowering effects of aleglitazar and sulphonylurea were potentiated by concomitant use, accounting for the higher rate of hypoglycaemic events in this group compared with placebo-treated patients who received sulphonylurea. Weight gain and a small reduction in eGFR were observed with aleglitazar versus placebo, consistent with previous studies of aleglitazar [5,7,14], and of PPAR- [15] and PPAR-agonists [16], respectively. Importantly, there was no heart failure and little peripheral oedema with aleglitazar.…”

“…Importantly, there was no heart failure and little peripheral oedema with aleglitazar. Neither were there any unexpected safety events compared with previous studies of aleglitazar .…”

“…Metformin and/or sulphonylurea dose could be reduced in case of hypoglycaemia. The dose of 150 µg aleglitazar was based on findings from the phase II SYNCHRONY dose‐finding trial , which found similar glycaemic effects with this dose compared with 45 mg pioglitazone (consistent with 1‐year data from the phase II ALENEPHRO trial ), with the most favourable safety profile.…”

Renal Outcomes of Pioglitazone Compared with Acarbose in Diabetic Patients: A Randomized Controlled Study

“…In the PROactive study, which enrolled diabetic patients with documented macrovascular disease, the post hoc analysis showed pioglitazone group had a greater decline of eGFR as compared with the control group [18]. A randomized controlled trial showed a 5.4% decrease in eGFR after 52 weeks of pioglitazone treatment in stage 3 chronic kidney disease with type 2 diabetes mellitus [19]. They found that the decline in eGFR plateaued after 8 weeks of treatment and improved to a 3.4% decrease from baseline eGFR after 8 weeks of treatment [19].…”

“…A randomized controlled trial showed a 5.4% decrease in eGFR after 52 weeks of pioglitazone treatment in stage 3 chronic kidney disease with type 2 diabetes mellitus [19]. They found that the decline in eGFR plateaued after 8 weeks of treatment and improved to a 3.4% decrease from baseline eGFR after 8 weeks of treatment [19]. In our study, the mean eGFR had a non-significant decrement (95% CI -1.04 to 14.77, p = 0.09) in the pioglitazone group compared with the acarbose group.…”