Efficacy and Safety of Aldosterone Synthase Inhibition With and Without Empagliflozin for Chronic Kidney Disease - ASi in CKD

Jan 11, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD, MPH, FACC
Trial Sponsor:
Boehringer Ingelheim
Date Published:
12/15/2023
Original Posted Date:
01/11/2024
References

Contribution To Literature:

In patients with CKD in the ASi in CKD trial, the aldosterone synthase inhibitor BI 690517 demonstrated a dose-dependent reduction in albuminuria both alone and in combination with empagliflozin.

Description:

The goal of the trial was to determine the effect on albuminuria of BI 690517, an investigational aldosterone synthase inhibitor, alone and in combination with empagliflozin compared with placebo in patients with chronic kidney disease (CKD).

Study Design

  • International
  • Randomized
  • Phase 2
  • 2x4 factorial design

Patients with CKD and albuminuria were first randomized in 1:1 fashion to initiate empagliflozin 10 mg daily or matching placebo. After an 8-week run-in period, participants were then randomized in 1:1:1:1 fashion to BI 690517 3 mg (+ empagliflozin n = 76, + placebo n = 71), 10 mg (+ empagliflozin n = 74, + placebo n = 72), 20 mg (+ empagliflozin n = 74, + placebo n = 72), or matching placebo (+ empagliflozin n = 74, + placebo n = 73) orally once daily for 14 weeks. Randomization was stratified by estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR).

  • Total number of enrollees: 586
  • Duration of follow-up: 18 weeks
  • Mean patient age: 64 years
  • Percentage female: 33%

Inclusion criteria:

  • Age ≥18 years
  • eGFR ≥30 and <90 mL/min/1.73 m2
  • Spot UACR ≥200 and <5000 mg/g
  • Stable, maximally tolerated dose of renin-angiotensin-aldosterone system (RAAS) inhibitor ≥4 weeks
  • Serum potassium ≤4.8 mmol/L

Exclusion criteria:

  • Active or planned sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy
  • Other active or planned anti-aldosterone therapy or potassium-sparing diuretic ≤7 days prior
  • CKD due to type 1 diabetes
  • Glycated hemoglobin (HbA1c) ≥10.0%

Other salient features/characteristics:

  • Mean baseline eGFR: 52 mL/min/1.73 m2
  • Median baseline UACR: 426 mg/g
  • Percentage with type 2 diabetes: 71%

Principal Findings:

The primary endpoint, absolute and BI 690517 placebo-corrected change from baseline UACR at 14 weeks, was:

  • Empagliflozin placebo + BI 690517 placebo: -3% (95% confidence interval [CI] -19 to 17)
  • Empagliflozin placebo + BI 690517 3 mg: -22% (95% CI -36 to -7), corrected -20% (95% CI -39 to 3)
  • Empagliflozin placebo + BI 690517 10 mg: -39% (95% CI -50 to -26), corrected -37% (95% CI -52 to -18)
  • Empagliflozin placebo + BI 690517 20 mg: -37% (95% CI -49 to -22), corrected -35% (95% CI -51 to -14)
  • Empagliflozin 10 mg + BI 690517 placebo: -11% (95% CI -23 to 4)
  • Empagliflozin 10 mg + BI 690517 3 mg: -19% (95% CI -31 to -5), corrected -9% (95% CI -27 to 13)
  • Empagliflozin 10 mg + BI 690517 10 mg: -46% (95% CI -45 to -36), corrected -40% (95% CI -52 to -24)
  • Empagliflozin 10 mg + BI 690517 20 mg: -40% (95% CI -49 to -30), corrected -33% (95% CI -47 to -17)

Key secondary outcomes:

  • ≥30% reduction in baseline UACR, BI 690517 10 mg vs. placebo at 14 weeks:
  • Empagliflozin placebo: 51% vs. 14%, OR 6.09 (95% CI 2.64-14.08)
  • Empagliflozin 10 mg: 70% vs. 22%, OR 8.42 (95% CI 3.73-19.02)
  • Change in plasma aldosterone, BI 690517 vs. placebo at 14 weeks:
  • Empagliflozin placebo: -41% (3 mg), -49% (10 mg), -62% (20 mg)
  • Empagliflozin 10 mg: -39% (3 mg), -56% (10 mg), -66% (20 mg)
  • Change in morning serum cortisol, BI 690517 vs. placebo at 14 weeks:
  • Empagliflozin placebo: 16% (3 mg), -5% (10 mg), 11% (20 mg)
  • Empagliflozin 10 mg: 7% (3 mg), 28% (10 mg), 6% (20 mg)

Key safety outcomes, pooled BI 690517 placebo vs. 3 vs. 10 vs. 20 mg at 14 weeks:

  • Adrenal insufficiency: 1% vs. 1% vs. 3% vs. 2%
  • Hyperkalemia: 6% vs. 10% vs. 15% vs. 18%
  • Hypotension: 1% vs. 1% vs. 3% vs. 1%
  • Acute kidney injury: 1% vs. 0% vs. 1% vs. 3%

Interpretation:

The current trial demonstrates a dose-dependent reduction in albuminuria associated with treatment with BI 690517, a novel aldosterone synthase inhibitor, in patients with CKD. These findings were observed on a background of maximally tolerated RAAS inhibition, which represents first-line treatment, and both independently of and additively with the SGLT2 inhibitor empagliflozin. Aldosterone selectivity was confirmed with ≥60% reduction in plasma aldosterone levels at 20 mg without a substantial effect on serum cortisol. The dose effect of BI 690517 on albuminuria plateaued at 10 mg with both placebo and empagliflozin. Adverse events were largely similar across doses and compared with placebo except for hyperkalemia, which predictably increased with greater levels of aldosterone synthase suppression. This effect was attenuated in the empagliflozin group, potentially due to the associated diuretic effect. The authors also note that the majority (86%) of hyperkalemic episodes did not require any treatment and resulted in study drug discontinuation in only 4% of patients.

Based on prior clinical trials, particularly of SGLT2 inhibitors and finerenone, the authors estimate that the albuminuria-reducing effect of BI 690517 may translate to a ≥30% reduction in clinical events related to CKD progression. The current data provide reassuring evidence to support phase 3 studies, which will be essential to confirm both any potential clinical benefit and long-term safety outcomes associated with BI 690517.

References:

Tuttle KR, Hauske SJ, Canziani ME, et al. Efficacy and Safety of Aldosterone Synthase Inhibition With and Without Empagliflozin for Chronic Kidney Disease: A Randomized, Controlled, Phase 2 Trial. Lancet 2024;403:379-90.

Clinical Topics: Diabetes and Cardiometabolic Disease

Keywords: Aldosterone, Kidney Failure, Chronic


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