Sadayoshi Ito1,2, Naoki Kashihara3, Kenichi Shikata4, Masaomi Nangaku5, Takashi Wada6, Yasuyuki Okuda7, Tomoko Sawanobori8. 1. Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University School of Medicine, Sendai, Japan db554@med.tohoku.ac.jp. 2. Katta General Hospital, Shiroishi, Japan. 3. Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan. 4. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan. 5. Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 6. Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan. 7. Biostatistics and Data Management Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan. 8. Clinical Development Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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.
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.
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