Efficacy and safety of esaxerenone (CS-3150) for the treatment of type 2 diabetes with microalbuminuria A randomized, double-blind, placebo-controlled, phase ii trial

Background and objectives The progression of kidney disease in some patients with type 2 diabetes mellitus may not be adequately suppressed by renin-angiotensin system inhibitors. Esaxerenone (CS-3150) is a nonsteroidalmineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is apotential add-ontherapyto treatdiabetic kidney disease.Thisphase 2 studyevaluatedthe efficacy andsafetyof esaxerenone in Japanese patients with type 2 diabetes mellitus and microalbuminuria. Design, setting, participants, & measurements This multicenter, randomized, double-blind, placebo-controlled trial enrolled 365 hypertensive or normotensive patients with type 2 diabetes mellitus and microalbuminuria (urinary albumin-to-creatinine ratio ≥45 to <300 mg/g creatinine) treated with renin-angiotensin system inhibitor who had eGFR≥30 ml/min per 1.73 m². Participants were randomized to receive 0.625, 1.25, 2.5, or 5 mg/d esaxerenone or placebo for 12 weeks. The primary end point was the change in urinary albumin-tocreatinine ratio from baseline to week 12 (with last observation carried forward). Results Esaxerenone treatment at 1.25, 2.5, and 5mg/d significantly reduced urinary albumin-to-creatinine ratio by the end of treatment (38%, 50%, and 56%, respectively) compared with placebo (7%; all P<0.001). The urinary albumin-to-creatinine ratio remission rate (defined as urinary albumin-to-creatinine ratio <30mg/g creatinine at the end of treatment and ≥30% decrease from baseline) was 21% in the 2.5- and 5-mg/d groups versus 3% for placebo (both P<0.05). Adverse events occurred slightly more frequently with esaxerenone versus placebo, but the frequencies of drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d groups.Drug-related adverse events and treatment discontinuationsweremarginally higher in the 5-mg/d group. The most common drug-related adverse event was hyperkalemia, which was dose proportional. Conclusions Adding esaxerenone at 1.25, 2.5, and 5 mg/d for 12 weeks to an ongoing renin-angiotensin system inhibitor significantly reduces urinary albumin-to-creatinine ratio in patients with type 2 diabetes mellitus and microalbuminuria.