Adding the nonsteroidal mineralocorticoid receptor blocker esaxerenone to renin-angiotensin system inhibitor (RASi) therapy can reduce the urinary albumin-to-creatinine ratio (UACR) in patients with type 2 diabetes and microalbuminuria, according to new study findings published in the Clinical Journal of the American Society of Nephrology.
The existing mineralocorticoid receptor blockers spironolactone and eplerenone can reduce albuminuria, but they increase the risk for hyperkalemia, lead author Sadayoshi Ito, MD, PhD, of Tohoku University in Japan, and colleagues explained. Eplerenone is also contraindicated in type 2 diabetes.
The phase 2 double-blind trial included 365 hypertensive or normotensive Japanese patients with an estimated glomerular filtration rate of 30 mL/min/1.73 m2 or higher. The investigators randomly assigned patients to receive oral esaxerenone (formerly CS-3150) at dosages of 0.625, 1.25, 2.5, and 5 mg/d or placebo for 12 weeks.
Patients who received the 1.25, 2.5, and 5 mg/d esaxerenone dosages experienced significant 38%, 50%, and 56% reductions in UACR, respectively, compared with placebo recipients (7% reduction). In addition, 21% of the 2.5 and 5 mg/d esaxerenone groups experienced significant UACR remission to less than 30 mg/g compared with just 3% of the placebo group. UACR declined 38% to 56% from baseline with intervention.
Drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d esaxerenone groups, but they occurred more often in the 5 mg/d group. Serum potassium increases were the most common event resulting in discontinuation. The risk for serum potassium elevations increased with higher drug doses: 3%, 7%, 14%, and 21% of the esaxerenone 0.625-, 1.25-, 2.5- and 5 mg/d groups, respectively, compared with 3% of the placebo group. Cases were usually mild and did not require treatment. Hyperkalemia, however, occurred in 10% of the 5 mg/d group, 3% of the other drug groups, and 1% of the placebo group. The maximum serum potassium level was 6.9 mEq/L in an intervention patient receiving 5 mg/d.
“This study showed that esaxerenone as add-on therapy to RASi in Japanese participants for 12 weeks reduced UACR by approximately one half in a dose-dependent manner,” the authors wrote. “This is the first study to clearly demonstrate a dose-response effect of a mineralocorticoid receptor blocker as an add-on therapy to RASi in Japanese patients with type 2 diabetes mellitus.”
This study was funded by the drug manufacturer, Daiichi-Sankyo.
Ito S, Shikata K, Nangaku M, et al. 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. Clin J Am Soc Nephrol. 2019.