Finerenone reduced HF events regardless of SGLT2 inhibitor use.

Background

In heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), both sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone reduce cardiovascular risk. Whether benefits are maintained when these therapies are used together had not been established.

Patients

• N=6001 adults with symptomatic HF and left ventricular ejection fraction (LVEF) ≥40% across 37 countries
• Mean age 72.0±9.6 years; 45.5% women; median NT-proBNP 1041 pg/mL
• Key inclusion: structural heart disease, elevated natriuretic peptides, loop diuretic use ≥30 days
• Key exclusion: eGFR <25 mL/min/1.73 m², serum potassium >5.0 mmol/L
• Baseline SGLT2i use: 13.6% (817/6001)

Intervention

• Finerenone once daily, dose targeted by baseline eGFR:
  • 20 mg if eGFR ≤60 mL/min/1.73 m²
  • 40 mg if eGFR >60 mL/min/1.73 m²
• Given in addition to usual care; steroidal MRAs were prohibited

Control

• Matching placebo plus usual care

Outcome

• Primary: Composite of total (first and recurrent) worsening HF events and cardiovascular (CV) death
• Secondary:
  • Total worsening HF events
  • CV death; all-cause death
  • Renal composite (sustained ≥50% eGFR decline, eGFR <15 mL/min/1.73 m², dialysis, or transplant)
  • Change in symptom burden via Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score
  • Time to first CV death or worsening HF event; and first CV death or HF hospitalization
• Safety: adverse events, hyperkalemia, renal function changes, blood pressure

Study Design

• Randomized, double-blind, placebo-controlled, parallel-group trial (FINEARTS-HF)
• 1:1 allocation; stratified by geographic region and baseline LVEF (<60% vs ≥60%)
• Prespecified subgroup by baseline SGLT2i use; independent blinded endpoint adjudication
• Intention-to-treat efficacy analyses; time-updated analyses accounting for baseline and during-trial SGLT2i use
• ClinicalTrials.gov: NCT04435626

Level of Evidence

Level 1b (individual randomized, double-blind, placebo-controlled trial; Oxford CEBM).

Follow up period

Median 2.6 years.

Results

• Primary outcome (total worsening HF events + CV death)
  • With baseline SGLT2i: Rate ratio (RR) 0.83 (95% CI, 0.60–1.16); absolute rate reduction 4.7 events per 100 patient-years
  • Without baseline SGLT2i: RR 0.85 (95% CI, 0.74–0.98); absolute rate reduction 2.5 events per 100 patient-years
  • No evidence of heterogeneity by baseline SGLT2i use; time-updated analyses yielded similar finerenone benefit
• Secondary outcomes
  • Total worsening HF events: RR 0.80 (0.55–1.15) with SGLT2i; 0.83 (0.71–0.97) without SGLT2i
  • CV death: HR 1.03 (0.65–1.62) with SGLT2i; 0.92 (0.76–1.11) without SGLT2i
  • All-cause death: HR 0.90 (0.64–1.27) with SGLT2i; 0.94 (0.82–1.07) without SGLT2i
  • Renal composite: No clear benefit observed (low event rates)
  • Symptoms (KCCQ total symptom score): Between-arm improvement +2.0 points (−0.2 to +4.3) with SGLT2i; +1.5 points (+0.7 to +2.3) without SGLT2i
• Clinically important dichotomous endpoints (NNT)
  • CV death or first worsening HF event:
    • With SGLT2i: 24.2% (finerenone) vs 28.8% (placebo) → absolute risk reduction (ARR) 4.6% → NNT ≈ 22
    • Without SGLT2i: 20.3% vs 23.2% → ARR 2.9% → NNT ≈ 35
  • CV death or first HF hospitalization:
    • With SGLT2i: 23.9% vs 27.1% → ARR 3.2% → NNT ≈ 31
    • Without SGLT2i: 19.3% vs 21.3% → ARR 2.0% → NNT ≈ 50
• SGLT2i use during follow-up
  • New SGLT2i initiation in nonusers occurred less often with finerenone than placebo (17.7% vs 20.1%; HR 0.86, 95% CI 0.76–0.97)
  • Accounting for baseline and time-updated SGLT2i use did not materially change finerenone’s benefit (HR 0.85, 95% CI 0.76–0.95 for first primary event)
  • SGLT2i discontinuation among baseline users was similar between arms
• Safety
  • Serious adverse events were similar between groups, irrespective of SGLT2i use
  • Hyperkalemia (laboratory >5.5 mmol/L) was more frequent with finerenone both with and without SGLT2i; hypokalemia was less frequent
  • Hyperkalemia leading to hospitalization was uncommon; no hyperkalemia-related deaths
  • Expected small early eGFR decline and modest blood pressure lowering with finerenone; no new additive safety concerns with concomitant SGLT2i

Limitations

• Prespecified subgroup analysis not powered for treatment-by-SGLT2i interaction; baseline SGLT2i use was modest
• Potential indication bias for during-trial SGLT2i initiation; unequal SGLT2i “drop-in” favored placebo
• Selective trial population may limit generalizability; reasons for SGLT2i use or discontinuation not systematically captured
• Low renal event rates and relatively short follow-up for kidney endpoints

Funding

Sponsored by Bayer AG.

Citation

Vaduganathan M, Claggett BL, Kulac IJ, Miao ZM, Desai AS, Jhund PS, Henderson AD, Brinker M, Lay-Flurrie J, Viswanathan P, Scheerer MF, Lage A, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, McMurray JJV, Solomon SD. Effects of the Nonsteroidal MRA Finerenone With and Without Concomitant SGLT2 Inhibitor Use in Heart Failure. Circulation. 2025;151:149–158. DOI: 10.1161/CIRCULATIONAHA.124.072055. ClinicalTrials.gov: NCT04435626.