Residual cardiorenal benefits after discontinuation of empagliflozin in CKD

08/11/2024

Post-trial observation of EMPA-KIDNEY among CKD patients at risk of progression showed empagliflozin had additional cardiorenal benefits over placebo for up to 12 months after it was discontinued.

This summary is based on the publication of The EMPA-KIDNEY Collaborative Group - Long-Term Effects of Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2024 Oct 25:10.1056/NEJMoa2409183 [Online ahead of print]. doi: 10.1056/NEJMoa2409183

Introduction and methods

Background

Recently, the EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) trial among patients with CKD at risk of disease progression showed empagliflozin reduced the incidence of the primary endpoint of kidney disease progression or CV death compared with placebo [1]. The trial was stopped prematurely for shown efficacy—after a median follow-up time of 2 years. Post-trial follow-up allows for evaluation of additional benefits and/or harms of the study drug after its discontinuation.

Aim of the study

The authors examined the effects of treatment with empagliflozin on the risk of kidney disease progression and mortality during the active phase of the EMPA-KIDNEY trial and 2 years post-trial.

Methods

In the international, double-blind, placebo-controlled, phase 3 EMPA-KIDNEY trial, 6609 CKD patients with eGFR 20–44 mL/min/1.73 m² or eGFR 45–89 mL/min/1.73 m² plus urinary albumin-to-creatinine ratio ≥200 mg/g were randomized to empagliflozin 10 mg once daily or placebo. Median follow-up duration of the active trial period was 2.0 years (Q1–Q3: 1.5–2.4; range: 0.3–3.1). Of the randomized patients in the active trial, 4891 (74%) were enrolled in the post-trial period (empagliflozin: n=2472; placebo: n=2419). During this period, no trial empagliflozin or placebo was administered, but local practitioners could prescribe open-label SGLT2 inhibitors, including open-label empagliflozin. Median follow-up duration of the post-trial period was 2.0 years (Q1–Q3: 2.0–2.1).

Outcomes

The prespecified primary endpoint was a composite outcome of time to kidney disease progression (i.e., sustained eGFR decline ≥40% from randomization, end-stage kidney disease (ESKD), sustained eGFR <10 mL/min/1.73 m², or kidney failure death) or CV death, assessed from the start of the active trial period to the end of the post-trial period. Prespecified key secondary endpoints were kidney disease progression and a composite outcome of all-cause mortality or ESKD. The other secondary endpoint was ESKD. The safety endpoint was non-CV death.

Main results

• During the post-trial period, the use of open-label SGLT2 inhibitors was similar in the empagliflozin and placebo groups (43% vs. 40%).

• During the entire follow-up period (i.e., active trial plus post-trial observation periods), the primary endpoint of kidney disease progression or CV death occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and 1001 of 3305 patients (30.3%) in the placebo group (HR: 0.79; 95%CI: 0.72–0.87).

• This comprised a risk reduction of 28% during the active trial period (HR: 0.72; 95%CI: 0.64–0.82) and a 13% risk reduction during the post-trial period (HR: 0.87; 95%CI: 0.76–0.99).

• The post-trial benefit was greatest early after discontinuation of the study drug (HR during first 6 months: 0.60; 95%CI: 0.38–0.93; HR during first year: 0.76; 95%CI: 0.60–0.96; HR during second year: 0.90; 95%CI: 0.75–1.07).

• During the combined periods, patients treated with empagliflozin versus placebo had lower risks of kidney disease progression (23.5% vs. 27.1%; HR: 0.79; 95%CI: 0.72–0.87), the composite outcome of all-cause mortality or ESKD (16.9% vs. 19.6%; HR: 0.81; 95%CI: 0.72–0.90), and ESKD (9.0% vs. 11.3%; HR: 0.74; 95%CI: 0.64–0.87).

• The risk of CV death during the entire follow-up period was also lower in empagliflozin-treated patients than placebo-treated patients (3.8% vs. 4.9%; HR: 0.75; 95%CI: 0.59–0.95), but there was no difference in the incidence of non-CV death (5.3% vs. 5.3%; HR: 0.97; 95%CI: 0.79–1.20).

Conclusion

Prospective observation of EMPA-KIDNEY trial patients, who had CKD and were at risk of disease progression, showed 2-year treatment with empagliflozin had residual cardiorenal benefits over placebo, for up to 12 months after discontinuation of the study drug.

Find this article online at N Engl J Med.

Reference

1. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023;388:117-27.

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