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Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced. Circulation. 2021 Jan 26;143(4):310-321. doi: 10.1161/CIRCULATIONAHA.120.051685. Epub 2020 Oct 23. (Original study)

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.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 6 / 7
Cardiology 6 / 7
Nephrology 6 / 7
Comments from MORE raters

Cardiology rater

The essence of this publication's message is available in the original NEJM publication (figure 2).

Family Medicine (FM)/General Practice (GP) rater

Big Pharma study showing benefit of empagliflozin in HFrEF. Very interesting.

General Internal Medicine-Primary Care(US) rater

More good news about the impact of this agent on cardiovascular and renal outcomes in our patients with DM. Important to know the impact across a range of kidney diseases.

Internal Medicine rater

This seems to be a recurring message with the SGLT-2 agents. The main question now: Is this a class effect?

Internal Medicine rater

These are becoming part of CHF treatment. It's very important to keep up with these outcome trials.

Internal Medicine rater

The SGLT2-i continue to force our respect with integration in treatment beyond those with T2DM. In this report, we see the benefits of an area once thought to be untouchable, the ability to reduce the progression of CKD (outside of ACEI) and reduce progression to CKD.

Nephrology rater

Well done pre-specified subgroup analysis of the EMPEROR-Reduced study.
Comments from EvidenceAlerts subscribers

Mr. Olli Kantola (3/2/2021 3:30 AM)

Perhaps it remains to be seen whether this is a class effect as ertugliflosin has been shown to be only non-inferior compared with placebo.