Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial

Abstract

Background and objectives: Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group.

Design, setting, participants, & measurements: In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (n=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions).

Results: Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; P<0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (-58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation.

Conclusions: Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.

Keywords: diabetes mellitus; esaxerenone; microalbuminuria.

Graphical abstract

Figure 1.

Esaxerenone improved the time to and duration of the first remission. Kaplan–Meier analyses of the (A) time to first remission and (B) duration of remission. HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 2.

Esaxerenone decreased urinary albumin-to-creatinine ratio (UACR) slowly until week 24. The UACR remained stable until the end of treatment and was still significantly reduced versus baseline at 4 weeks post-treatment. Time course of UACR values (A) and geometric mean percent change from baseline in UACR (B). End-of-treatment (EOT) values were calculated by taking the average of measurements at the last two visits in the treatment period. Data are shown as geometric mean±95% confidence intervals.

Figure 3.

Esaxerenone increased serum potassium levels over the first 2 weeks. These remained stable during treatment and then decreased to near-baseline levels after the end of treatment. Time course of serum potassium (A) and mean change from baseline in serum potassium (B). Data are shown as mean±SD.

Figure 4.

In the esaxerenone group, eGFR decreased until week 24, then remained stable and recovered to a level similar to the placebo group at the post-treatment follow-up. Time course of eGFR values (A) and geometric mean percent change from baseline in eGFR (B).Data are shown as geometric mean±95% confidence intervals.