Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function

Insights From EMPEROR-Reduced

Faiez Zannad, MD, PhD; João Pedro Ferreira, MD, PhD; Stuart J. Pocock, PhD; Cordula Zeller, Dipl Math; Stefan D. Anker, MD, PhD; Javed Butler, MD; Gerasimos Filippatos, MD; Sibylle Jenny Hauske, MD; Martina Brueckmann, MD; Egon Pfarr, Dipl Stat; Janet Schnee, MD; Christoph Wanner, MD; Milton Packer, MD

Disclosures

Circulation. 2021;143(4):310-321. 

In This Article

Abstract and Introduction

Abstract

Background: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin reduced cardiovascular death or heart failure (HF) hospitalization and total HF hospitalizations, and slowed the progressive decline in kidney function in patients with HF and a reduced ejection fraction, with and without diabetes. We aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.

Methods: In this prespecified analysis, patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or albumin-to-creatine ratio >300 mg/g). The primary and key secondary outcomes were: (1) a composite of cardiovascular death or HF hospitalization (primary outcome); (2) total HF hospitalizations; and (3) eGFR slope. The direct impact on kidney events was investigated by a prespecified composite kidney outcome (defined as a sustained profound decline in eGFR, chronic dialysis, or transplant). The median follow-up was 16 months.

Results: Of 3730 patients who were randomized to empagliflozin or placebo, 1978 (53%) had CKD. Empagliflozin reduced the primary outcome and total HF hospitalizations in patients with and without CKD: hazard ratio (HR)=0.78 (95% CI, 0.65–0.93) and HR=0.72 (95% CI, 0.58–0.90), respectively (interaction P=0.63). Empagliflozin slowed the slope of eGFR decline by 1.11 (0.23–1.98) ml/min/1.73 m2/yr in patients with CKD and by 2.41 (1.49–3.32) ml/min/1.73 m2/yr in patients without CKD. The risk of the composite kidney outcome was reduced similarly in patients with and without CKD: HR=0.53 (95% CI, 0.31–0.91) and HR=0.46 (95% CI, 0.22–0.99), respectively. The effect of empagliflozin on the primary composite outcome and key secondary outcomes was consistent across a broad range of baseline kidney function, measured by clinically relevant eGFR subgroups or by albuminuria, including patients with eGFR as low as 20 ml/min/1.73 m2. Empagliflozin was well tolerated in CKD patients.

Conclusions: In EMPEROR-Reduced, empagliflozin had a beneficial effect on the key efficacy outcomes and slowed the rate of kidney function decline in patients with and without CKD, and regardless of the severity of kidney impairment at baseline.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Introduction

The incidence and prevalence of both heart failure (HF) and kidney disease are increasing.[1] Patients with HF with reduced ejection fraction have a poor quality of life and a high risk of adverse cardiovascular events and death, particularly in those with kidney impairment.[2,3] Additionally, patients with chronic kidney disease (CKD) commonly develop heart failure, and the most common cause of demise is cardiovascular death.

For nearly 2 decades, both angiotensin converting enzyme inhibitors and angiotensin receptor blockers have been used for the treatment of both HF and reduced ejection fraction, as well as for the management of albuminuric CKD.[4–7] In both conditions, initiation of treatment with these drugs is commonly accompanied by mild transient worsening of kidney function attributable to their hemodynamic effects on the intraglomerular pressure in the kidneys. This early azotemia frequently leads clinicians to withhold or fail to up-titrate these drugs to achieve the target doses in HF with reduced ejection fraction, and may therefore deprive patients of the clinical benefit associated with their optimal use.[8,9] More recently, sacubitril/valsartan was shown to slow the decline in estimated glomerular filtration rate (eGFR) in patients with both a reduced and preserved ejection fraction.[10,11]

Sodium glucose contransporter-2 (SGLT2) inhibitors have been shown to reduce eGFR decline, progression of kidney disease, or kidney failure (including renal death, the need for dialysis, or kidney transplantation), as well as the risk of HF hospitalizations and cardiovascular death in patients with type 2 diabetes.[12–17] In patients with type 2 diabetes and albuminuric CKD enrolled in the CREDENCE trial (Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy), canagliflozin reduced the risk of kidney failure and serious cardiovascular events compared with placebo.[17] Most recently, in the DAPA-CKD trial (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in patients with Chronic Kidney Disease), which enrolled patients with albuminuric kidney disease with or without diabetes, dapagliflozin reduced the rate of serious kidney outcomes, hospitalizations for HF, and mortality.[18]

In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction), empagliflozin reduced the composite of cardiovascular death or HF hospitalization and first and recurrent hospitalizations for HF, slowed the progressive decline in kidney function, and reduced the risk of serious kidney events in patients with and without diabetes.[19] Importantly, in EMPEROR-Reduced, patients were eligible for enrollment with an eGFR as low as 20 ml/min/1.73 m2 and more than half of the patients had prevalent CKD at baseline. Thus, the trial afforded the opportunity of investigating the efficacy and safety of empagliflozin on cardiac and kidney outcomes according to CKD and across a wide range of kidney function; these findings were a prespecified analysis of EMPEROR-Reduced.

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