Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced)

Authors, Journal, Affiliations, Type, DOI

• Authors: Milton Packer, Stefan D. Anker, Javed Butler, Gerasimos Filippatos, Stuart J. Pocock, and the EMPEROR-Reduced Trial Investigators
• Journal: New England Journal of Medicine
• Affiliations: Baylor Heart and Vascular Institute; Imperial College London; London School of Hygiene and Tropical Medicine; and 520 centres in 20 countries
• Type: Phase 3 randomised, double-blind, placebo-controlled, event-driven trial
• DOI: https://doi.org/10.1056/NEJMoa2022190
• Funding: Boehringer Ingelheim and Eli Lilly

Overview

EMPEROR-Reduced randomised 3,730 patients with HFrEF (LVEF ≤40%, NYHA II–IV) to empagliflozin 10 mg OD or placebo, deliberately enriched for more severe disease than DAPA-HF (73% LVEF ≤30%; 79% NT-proBNP ≥1,000 pg/mL). Empagliflozin reduced the primary composite of CV death or HF hospitalisation (HR 0.75; 95% CI 0.65–0.86; P<0.001; NNT=19) and significantly slowed eGFR decline (−0.55 vs −2.28 mL/min/1.73m²/year; P<0.001), halved the composite renal outcome (HR 0.50), and this renal benefit persisted after drug discontinuation. The primary composite benefit was driven predominantly by HF hospitalisations; CV death and all-cause death individually were not statistically significant. Together with DAPA-HF, EMPEROR-Reduced forms the trial basis for Class I / COR 1A SGLT2i recommendation in HFrEF GDMT, and provides the strongest evidence to date for SGLT2i renal protection in established HFrEF.

Keywords

Empagliflozin; SGLT2 inhibitor; heart failure with reduced ejection fraction; cardiovascular death; heart failure hospitalisation; renal protection; eGFR; diabetes-independent; EMPEROR-Reduced

Key Takeaways

Trial Design

• Phase 3 RCT; n=3,730; 520 centres; 20 countries; enrolment April 2017 – November 2019; median follow-up 16 months
• Enriched population: Patients with LVEF 31–35% required prior HF hospitalisation within 12 months OR NT-proBNP ≥1,000 pg/mL; LVEF 36–40% required NT-proBNP ≥2,500 pg/mL; LVEF ≤30% required only NT-proBNP ≥600 pg/mL — designed to capture more advanced HF than DAPA-HF
• Baseline characteristics: 73% LVEF ≤30%; 79% NT-proBNP ≥1,000 pg/mL; 48% eGFR <60 mL/min/1.73m²; ~50% T2DM; ~20% on sacubitril-valsartan
• Exclusion: Prior use of or intolerance to SGLT2i; T1DM; severe renal impairment

Primary Outcome

• Composite CV death or first HF hospitalisation:
  • Empagliflozin: 361/1,863 (19.4%) vs placebo: 462/1,867 (24.7%)
  • HR 0.75 (95% CI 0.65–0.86; P<0.001); NNT=19 (95% CI 13–37)
• CV death component: HR 0.92 (95% CI 0.75–1.12) — not statistically significant
• First HF hospitalisation component: HR 0.69 (95% CI 0.59–0.81)

Secondary Outcomes

• Total (first + recurrent) HF hospitalisations: 388 vs 553 events; HR 0.70 (95% CI 0.58–0.85; P<0.001)
• eGFR decline rate (double-blind treatment period): −0.55 vs −2.28 mL/min/1.73m²/year; between-group difference +1.73 mL/min/1.73m²/year (95% CI 1.10–2.37; P<0.001)
• Composite renal outcome (chronic dialysis / renal transplantation / profound sustained GFR decline): 1.6% vs 3.1%; HR 0.50 (95% CI 0.32–0.77)
• Post-discontinuation eGFR (measured 23–45 days after stopping drug, n=966 with paired data): −0.93 vs −4.21 mL/min/1.73m² — persistent renal benefit independent of drug presence, confirming disease-modifying renal protection
• All-cause death: 13.4% vs 14.2%; HR 0.92 (95% CI 0.77–1.10) — not statistically significant

Diabetes-Independent Benefit

• Benefit of empagliflozin was consistent in patients with and without T2DM (non-significant interaction term)
• Confirms class effect established by DAPA-HF: SGLT2i benefit in HFrEF is glucose-independent

Subgroup Analyses

• Consistent benefit across prespecified subgroups including LVEF, eGFR, NYHA class, aetiology, geography
• Sacubitril-valsartan subgroup: HR 0.64 (95% CI 0.45–0.89) vs HR 0.77 (95% CI 0.66–0.90) among those not on ARNi — suggests consistent or possibly enhanced benefit on ARNi background (contrast with DAPA-HF ARNi subgroup: HR 0.75, NS)

Safety

• Uncomplicated genital tract infection: Higher with empagliflozin (the only significant safety difference)
• No significant difference: hypoglycaemia, lower limb amputation, bone fracture, volume depletion, renal dysfunction, bradycardia, hyperkalemia
• Safety profile consistent with prior SGLT2i trials

Limitations of the Document

• Median follow-up only 16 months — relatively short for assessing mortality trends
• All-cause and CV death not significantly reduced; trial not powered as primary mortality trial (event-driven for composite endpoint)
• ~20% ARNi use at baseline — higher than DAPA-HF but still not reflecting contemporary full quadruple GDMT; incremental benefit on top of optimised quadruple therapy remains extrapolated
• Post-discontinuation eGFR data available in only ~966/3,730 patients (26%) — selective measurement may introduce bias in the renal benefit estimates
• Operationally, 21 patients (0.6%) had unknown vital status partly due to COVID-19 operational challenges during the trial's final months

Key Concepts Mentioned

• concepts/Diuretic-Resistance — empagliflozin's SGLT2-mediated natriuresis (~5% proximal Na⁺) contributes to volume reduction; distinct from acetazolamide's NHE3 blockade (~60%)

Key Entities Mentioned

• entities/HFrEF — primary trial context; EMPEROR-Reduced with DAPA-HF forms the dual-trial evidence base for Class I SGLT2i recommendation
• entities/Heart-Failure — broader HF syndrome; SGLT2i benefit diabetes-independent across HF aetiology

Wiki Pages Updated

• wiki/sources/empagliflozin-hfref-nejm-2020.md — created (this file)
• wiki/entities/HFrEF.md — EMPEROR-Reduced data added to SGLT2i section; contradiction added; source_count updated
• wiki/entities/Heart-Failure.md — EMPEROR-Reduced citation added to HFrEF SGLT2i bullet
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — HFrEF entry updated
• log.md — entry appended