Effects of SGLT2i on renal function in patients hospitalized for acute HF
Renal effects of empagliflozin in patients hospitalized for acute heart failure: from the EMPULSE trial
Literature - Voors AA, Damman K, Teerlink JR, et al - Eur J Heart Fail. 2022 Sep 6. doi: 10.1002/ejhf.2681.Introduction and methods
Background
The EMPULSE trial showed that treatment with the SGLT2i empagliflozin for 90 days results in a statistically significant clinical benefit in patients hospitalized for acute HF, compared with placebo [1]. In patients with chronic HF, SGLT2i cause a decrease in eGFR of 2-4 ml/min per 1.73 m2 in the first weeks of treatment, followed by a slower decline in eGFR over time, compared with placebo [2-7]. However, the effect of SGLT2i on renal function is largely unknown in patients hospitalized for acute HF.
Aim of the study
The aim of this post hoc analysis of data from the EMPULSE trial of patients hospitalized for acute HF was twofold. First, the study examined the effect of empagliflozin on renal function, sodium and potassium levels and the occurrence of renal and urinary adverse events. Second, the study examined whether renal function at baseline affected the clinical benefit of empagliflozin.
Methods
The researchers conducted a post hoc analysis of data from the EMPULSE trial. This multicenter, double-blind, placebo-controlled phase 3 trial included 530 adults hospitalized for acute HF (de novo or decompensated chronic HF), with or without DM2 and regardless of ejection fraction. Participants were randomized (1:1) between once daily empagliflozin 10 mg (n=265) or placebo (n=265) for 90 days as early as possible after clinical stabilization, but no earlier than 24 hours and no later than 5 days after admission. Inclusion criteria were dyspnea on exertion or at rest and at least 2 of the following findings: congestion on chest radiograph, rales on auscultation of the lungs, clinically relevant edema or increased jugular venous pressure. Patients with an eGFR<20 ml/min per 1.73 m2 were excluded from participation. Renal function (eGFR) and sodium and potassium levels were measured at baseline and on days 15, 30 and 90 of treatment. Patients were divided into the following 3 subgroups based on eGFR at baseline: <45, ≥45 and <60, and >60 ml/min per 1.73 m2.
Outcomes
The researchers evaluated the effect of empagliflozin on eGFR and sodium and potassium levels over time and the influence of eGFR at baseline on the primary outcome. The primary outcome was clinical benefit, defined as a hierarchical composite of (i) time death from any cause, (ii) number of HF events, (iii) time to first HF event or (iv) a difference in KCCQ-TSS of 5 or more points from baseline to day 90 of treatment. Clinical benefit was assessed using a win ratio. Renal and urinary adverse events were also assessed.
Main results
Renal function
- On day 15 of treatment, eGFR in the empagliflozin group was on average 2 ml/min per 1.73 m2 lower than in the placebo group (P=0.0822).
- On day 90 of treatment, the eGFR was similar between the empagliflozin and placebo groups, with a mean difference of 0.9 ml/min per 1.73 m2 (P=0.5714).
- The clinical benefit of empagliflozin was not affected by eGFR at baseline; the win ratio for patients with an eGFR<45, ≥45 and <60, and >60 ml/min per 1.73 m2 was 1.56 (95%CI: 1.08-2.25), 1.14 (95%CI: 0.73-1.78) and 1.48 (95%CI: 1.04-2.13), respectively (P-interaction=0.5400).
Sodium and potassium levels
- The differences in sodium levels between the empagliflozin and placebo groups at baseline and on day 15 (P=0.0503), day 30 (P=0.1534) and day 90 (P=0.1314) of treatment were small and not statistically significant.
- The differences in potassium levels between the empagliflozin and placebo groups at baseline and on day 15 (P=0.0723), day 30 (P=0.7347) and day 90 (P=0.9618) of treatment were also small and not statistically significant.
Renal and urinary adverse events
- Renal and urinary adverse events occurred in 11.2% of patients in the empagliflozin group and in 17.0% of patients in the placebo group (P=0.0528).
- Renal and urinary adverse events occurred more frequently in patients with an eGFR<45 ml/min per 1.73 m2 at baseline, compared with patients with an eGFR ≥45 and <60 or an eGFR >60 ml/min per 1.73 m2, but this difference was not statistically significant (P-trend=0.6620).
- During the 90-day treatment period, investigator-reported acute kidney injury occurred in 3.8% of patients in the empagliflozin group and in 7.2% of patients in the placebo group (P=0.0935).
Conclusion
This post hoc analysis of data from the EMPULSE trial showed that in patients hospitalized for acute HF, treatment with empagliflozin resulted in a modest, not statistically significant decline in renal function after 15 days, compared with placebo. After 90 days, this difference had virtually disappeared. The clinical benefit of empagliflozin was independent of renal function at baseline and the frequency of renal and urinary adverse events was similar in both groups.
References
1. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28:568-74.
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