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

Background: Type 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.

Methods: Patients 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.

Results: Mean 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.

Conclusions: The 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 registration: NCT01043029 January 5, 2010.

Figure 1

Patient disposition and study populations. Safety analysis population: all patients who received at least one dose of the study drug. Full analysis population: all patients who received at least one dose of study drug, and had an evaluable baseline and at least one evaluable post-baseline measurement of serum creatinine. Completer population: all patients included in the full analysis population who completed 52 weeks of double-blind treatment. Per-protocol population: completers without major protocol violations (defined prior database lock and unblinding). * 140 patients on aleglitazar and 132 patients on pioglitazone included in the full analysis population had at least one follow-up measurement of serum creatinine ≥ 21 days after last treatment intake, and therefore were included in the primary analysis.

Figure 2

LS mean percentage change in eGFR. (A) Change from baseline over time (full analysis population). Last-observation-carried-forward principle was applied to missing values of continuous variables. eGFR = estimated glomerular filtration rate; LS = least squares; EOT = end of treatment; EOF = end of follow-up. (B) Change from baseline over time, by eGFR strata (full analysis population). Last-observation-carried-forward principle was applied to missing values of continuous variables.

Figure 3

LS mean percentage change in eGFR from baseline at end of follow-up by analysis population. Circles = aleglitazar; squares = pioglitazone. LS mean change from baseline and ± 95% CI. Analysis of covariance of percentage change from baseline. Missing data imputed using last-observation-carried-forward principle applied only to follow-up measurements of serum creatinine ≥ 21 days after last treatment intake. CI = confidence interval; eGFR = estimated glomerular filtration rate; EOF = end of follow-up; EOT = end of treatment; LS = least squares. *Numbers reflect patients included in the full analysis population who had at least one follow-up measurement of serum creatinine ≥ 21 days after last treatment intake.

Figure 4

LS mean percentage change in UACR from baseline over time (patients with macroalbuminuria at baseline). Median baseline UACR values (interquartile range) were 75.4 mg/mmol (55.7–133.8) for aleglitazar (n = 21) and 89.6 mg/mmol (43.3–116.0) for pioglitazone (n = 27). Analysis on log-transformed scale, geometric means ratio expressed as percentage change. Patients analyzed at end of treatment (using last-observation-carried-forward principle): n = 20 for aleglitazar and 26 for pioglitazone, and at end of follow-up: n = 19 for aleglitazar and 25 for pioglitazone. LS = least squares; UACR = urine albumin-to-creatinine ratio.