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

Abstract

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 nonsteroidal mineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is a potential add-on therapy to treat diabetic kidney disease. This phase 2 study evaluated the efficacy and safety of 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-to-creatinine ratio from baseline to week 12 (with last observation carried forward).

Results: Esaxerenone treatment at 1.25, 2.5, and 5 mg/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 <30 mg/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 discontinuations were marginally 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.

Keywords: Esaxerenone; Urine albumin-to-creatinine ratio; microalbuminuria; mineralocorticoid receptor antagonist; placebo-controlled; randomized; remission; type 2 diabetes mellitus.

Graphical abstract

Figure 1.

Esaxerenone dose dependently reduced mean changes in urinary albumin-to-creatinine ratio (UACR) from baseline to the end of treatment (A) and higher UACR remission rates were observed with esaxerenone 2.5- and 5-mg/d groups at the end of treatment (B). Data are geometric mean (point estimates) ±95% confidence interval (A); point estimate ± exact 95% CI (B). Among the participants in the full analysis set, those with UACR measurements at both weeks 11 and 12 were included in the calculation of the achievement rate of remission. ***P<0.001 versus placebo (A); ***P=0.004 versus placebo (B).

Figure 2.

Esaxerenone groups show numerically greater reductions in mean changes in systolic BP and diastolic BP compared with the placebo group at the end of treatment. Data are least square means ±95% confidence interval. *P<0.05 versus placebo; ***P<0.001 versus placebo.

Figure 3.

Serum potassium (K⁺; A) and serum K⁺ from baseline (B) increased dose dependently with esaxerenone during treatment visits but returned to baseline during the follow-up (safety analysis set). Data are means ± SD.

Figure 4.

Mean change in eGFR from baseline decreased with esaxerenone administration but returned to baseline during the follow-up. Data are least square means ±95% confidence interval.