Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria : A Randomized, Controlled Trial

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Abstract

Background and objectives

Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.

Design, setting, participants, & measurements

This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.

Results

Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), −16% (imarikiren 5 mg), −27% (imarikiren 20 mg), −38% (imarikiren 40 mg), −39% (imarikiren 80 mg), and −31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo ( P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo ( P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated.

Conclusions

Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.