Long-Term Effects of Empagliflozin in Patients with Chronic Kidney Disease (EMPA-KIDNEY Post-Trial)

Authors, Journal, Affiliations, Type, DOI

• Authors: William G. Herrington, Natalie Staplin, et al. (EMPA-KIDNEY Collaborative Group; writing committee ~30 members)
• Journal: New England Journal of Medicine
• Affiliations: Renal Studies Group, Nuffield Department of Population Health, University of Oxford (coordinating centre); 185 of 241 original trial centres in 7 of 8 countries (Japan excluded from post-trial)
• Type: Phase 3 double-blind placebo-controlled RCT (active trial) + prospective post-trial observational follow-up
• DOI: https://doi.org/10.1056/NEJMoa2409183
• Funding: Boehringer Ingelheim and Eli Lilly (grant to University of Oxford)

Overview

The EMPA-KIDNEY active trial randomised 6,609 CKD patients to empagliflozin 10 mg vs placebo for a median of 2 years; this paper reports on 2 additional years of prospective post-trial follow-up without trial drug in 4,891 consenting survivors. Over the combined ~4-year period, the primary composite of kidney disease progression or cardiovascular death was reduced (HR 0.79; 95% CI 0.72–0.87; 26.2% vs 30.3%). Significant residual cardiorenal benefits persisted in the post-trial period (HR 0.87; 95% CI 0.76–0.99), strongest in the first 6 months (HR 0.60) and attenuating by year 2 (HR 0.90, NS) — establishing a disease-modifying "legacy effect" of approximately 12 months after stopping. Benefits were consistent regardless of diabetes status, eGFR level, albuminuria category, and primary kidney disease aetiology, and no effect on non-cardiovascular death was observed.

Keywords

Empagliflozin; SGLT2 inhibitor; chronic kidney disease; kidney disease progression; end-stage kidney disease; cardiovascular death; post-trial follow-up; legacy effect; cardiorenal; eGFR; UACR; albuminuria; EMPA-KIDNEY

Key Takeaways

Trial Design and Population

• Double-blind RCT: empagliflozin 10 mg OD vs matching placebo; active trial median 2.0 years (IQR 1.5–2.4); post-trial observation median 2.0 years (IQR 2.0–2.1)
• Inclusion criteria: eGFR 20–44 mL/min/1.73m² (any albuminuria) OR eGFR 45–89 with UACR ≥200 mg/g; on clinically appropriate RAS inhibitor unless contraindicated
• Population profile: mean eGFR 36.9±14.1 mL/min/1.73m²; median UACR 317 mg/g (IQR 44–1063); 56.9% without diabetes; 71.3% non-diabetic kidney disease aetiology; mean age 63±14 years; 34% women
• 4,891 of 6,253 surviving patients (74%) enrolled in post-trial follow-up at 185 sites in 7 countries
• Trial blinding maintained in 99.5% of all patients throughout; no additional trial drug provided post-trial
• During post-trial period: open-label SGLT2i use was similar in both groups (43% empagliflozin group vs 40% placebo group), diluting the observed post-trial effect estimates

Primary Outcome (Combined Active + Post-Trial)

• Kidney disease progression or CV death: 26.2% empagliflozin vs 30.3% placebo; HR 0.79 (95% CI 0.72–0.87)
• Absolute benefit at end of combined periods: 45±14 fewer events per 1,000 patients (vs 57±14 at end of active trial)
• Active-trial component HR 0.72 (95% CI 0.64–0.82); post-trial component HR 0.87 (95% CI 0.76–0.99)

Legacy / Carry-Over Effect (Post-Trial Period)

• Carryover benefits attenuate progressively after stopping:
  • First 6 months post-trial: HR 0.60 (95% CI 0.38–0.93) — strongest residual benefit
  • Year 1 post-trial: HR 0.76 (95% CI 0.60–0.96) — significant
  • Year 2 post-trial: HR 0.90 (95% CI 0.75–1.07) — not significant
• Conclusion: carryover effect is real but lasts ~12 months; maximising benefit requires uninterrupted long-term treatment

Secondary and Tertiary Outcomes (Combined Periods)

• Kidney disease progression: 23.5% vs 27.1%; HR 0.79 (95% CI 0.72–0.87)
• End-stage kidney disease: 9.0% vs 11.3%; HR 0.74 (95% CI 0.64–0.87); absolute 25±10 fewer per 1,000
• ESKD or death from any cause: 16.9% vs 19.6%; HR 0.81 (95% CI 0.72–0.90)
• CV death: 3.8% vs 4.9%; HR 0.75 (95% CI 0.59–0.95)
• Non-CV death: 5.3% both groups; HR 0.97 (95% CI 0.79–1.20; NS) — no harm signal
• All-cause death: 9.1% vs 10.2%; HR 0.86 (95% CI 0.74–1.01; NS, trending)
• Post-trial period alone: ESKD HR 0.80 (95% CI 0.66–0.98); ESKD or death HR 0.82 (95% CI 0.70–0.96)

Subgroup Analyses

• Primary outcome benefit consistent across all prespecified subgroups:
  • Diabetes status: benefit in both diabetic and non-diabetic patients
  • eGFR categories: benefit across all strata including lowest (eGFR 20–29)
  • Albuminuria: benefit in all categories including low/normal UACR in the low-eGFR group
  • Primary kidney disease aetiology: benefit regardless of underlying diagnosis
• eGFR slope analyses from active trial show empagliflozin slows progression in ALL albuminuria subgroups

Exploratory: eGFR at Final Measurement

• Mean last eGFR (excluding ESKD patients): 31.4 mL/min empagliflozin vs 30.6 mL/min placebo; difference +0.8 mL/min (95% CI 0.1–1.4)
• The acute eGFR dip with SGLT2i reverses within 4 weeks of stopping; part of post-trial eGFR advantage reflects this reversal; but ESKD benefit persists, suggesting true nephroprotection beyond haemodynamic mechanism

Proposed Mechanisms for Residual Post-Trial Benefit

• Nephron preservation during active treatment → reduced hyperfiltration per nephron → sustained protection post-treatment
• Preserved kidney function during active trial may mediate post-trial reduction in CV death
• Reversal of initial eGFR dip does not explain the persistent ESKD reduction

Limitations

• Japan excluded from post-trial follow-up (logistic); active-trial effects in Japan were similar to other regions
• Post-trial relied on local creatinine measurements; active-trial results were similar with both local and central values
• Hospitalisation data not collected during post-trial (deliberate protocol decision to streamline follow-up)
• ~26% of surviving patients did not enter post-trial (non-participating sites or patient refusal); those who entered were slightly younger, with slightly lower eGFR and higher predicted kidney failure risk
• Open-label SGLT2i uptake ~40–43% in both groups post-trial — convergence dilutes true carryover treatment effect (actual residual benefit likely greater than estimated)
• Patients who did not start open-label SGLT2i post-trial had twice the predicted risk of kidney failure, creating prognostic imbalance that confounds on-treatment post-hoc comparisons
• Active trial was stopped early for efficacy, limiting accrual of hard ESKD events in active period

Key Concepts Mentioned

• concepts/SGLT2-Inhibitors-in-CKD — primary intervention; disease-modifying cardiorenal effects with legacy effect after stopping
• concepts/Cardiorenal-Syndrome — EMPA-KIDNEY data extend understanding of SGLT2i in CRS Type 4 (chronic renocardiac)

Key Entities Mentioned

• entities/Heart-Failure — CV death was a primary outcome component; empagliflozin significantly reduced CV death (HR 0.75)
• entities/Hypertension — major CKD comorbidity; RAS inhibitor co-treatment was required at trial entry

Wiki Pages Updated

• Created wiki/sources/empagliflozin-empakidney-nejm-2025.md
• Created wiki/concepts/SGLT2-Inhibitors-in-CKD.md
• Updated wiki/concepts/Cardiorenal-Syndrome.md
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md