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Aldosterone synthase inhibition dose-dependently reduced albuminuria by up to 40% in participants with CKD, according to study results presented at ASN Kidney Week 2023.
Results from a phase 2 clinical trial are providing an overview of the potential benefit of aldosterone synthase inhibition when added to SGLT2 inhibition for patients with chronic kidney disease (CKD) with or without type 2 diabetes.
Katherine Tuttle, MD, executive director for research at Providence Health Care, presented trial data at the American Society of Nephrology Kidney Week 2023, which showed the selective aldosterone synthase inhibitor BI 690517 dose-dependently reduced albuminuria by up to 40% in participants with CKD regardless of concurrent SGLT2 inhibition.
“This is the first clinical trial with randomized use of SGLT2 inhibition in the background, not drop-in use, and it also has a control without SGLT2 inhibition, which gives us the opportunity in a controlled fashion to be able to demonstrate the potential for additive efficacy,” said Tuttle.
Despite treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and SGLT2 inhibitors, patients with CKD are still at risk of disease progression. Excess aldosterone accelerates this progression but is not addressed by most CKD treatments, highlighting the need for a treatment to block the effects of aldosterone and decrease the risk of hyperkalemia in patients with CKD.
In the present study, investigators sought to assess the impact of aldosterone synthase inhibitors on aldosterone production and the subsequent therapeutic efficacy of CKD treatment. To do so, they examined the safety and efficacy of BI 690517 with or without empagliflozin in patients with CKD. Patients with and without diabetes were included, but were required to be receiving stable background treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for > 4 weeks prior to screening.
In total, 714 patients were enrolled in the study. Among the cohort, 356 participants were assigned to empagliflozin 10 mg and 358 were assigned to empagliflozin-matching placebo for an 8-week run-in period prior to baseline, with investigators pointing out baseline characteristics were similar between the groups. Patients were then assigned to receive BI 690517 placebo, BI 690517 3 mg, BI 690517 10 mg, or BI 690517 20 mg in addition to empagliflozin or empagliflozin-matching placebo for the 14-week treatment period.
The primary outcome of interest was change in urine albumin-creatinine ratio measured in FMV urine from baseline to week 14. Secondary endpoints included the proportion of patients with > 15% and > 30% FMV urine albumin-creatinine ratio at week 14. Investigators also measured changes from baseline to week 14 in estimated glomerular filtration rate (eGFR), serum potassium, blood pressure, plasma aldosterone, and morning serum cortisol, and conducted a safety analysis.
Upon analysis, patients taking BI 690517 with empagliflozin in the background experienced a greater mean change in urine albumin-creatinine ratio from baseline to week 14 than patients without background empagliflozin, especially among those assigned to BI 690517 10 mg (-46 with empagliflozin vs -39 without empagliflozin, respectively).
Additionally, investigators pointed out a greater proportion of patients with empagliflozin achieved > 30% reduction in urine albumin-creatinine ratio from baseline (33% for BI 690517 3 mg, 70% for BI 690517 10 mg, and 58% for BI 690517 20 mg) compared to those without empagliflozin (29% for BI 690517 3 mg, 51% for BI 690517 10 mg, and 51% for BI 690517 20 mg).
Investigators noted BI 690517 was generally well tolerated with no unexpected safety findings. The discontinuation rate for hyperkalemia was 4% among patients on BI 690517 compared to 0% for placebo, although no fatal hyperkalemia events occurred and 86% of cases did not require treatment.
“Aldosterone synthase inhibition is a promising new therapy that may add benefit to SGLT2 inhibition for CKD with or without type 2 diabetes,” concluded Tuttle.