Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity

Authors, Journal, Affiliations, Type, DOI

• Milton Packer, Michael R. Zile, Christopher M. Kramer, Seth J. Baum, Sheldon E. Litwin, Venu Menon, Junbo Ge, Govinda J. Weerakkody, Yang Ou, Mathijs C. Bunck, Karla C. Hurt, Masahiro Murakami, Barry A. Borlaug; for the SUMMIT Trial Study Group
• N Engl J Med 2025;392:427-437
• Baylor University Medical Center; Imperial College London; Medical University of South Carolina; University of Virginia; Flourish Research; Cleveland Clinic; Fudan University; Eli Lilly; Mayo Clinic
• International, double-blind, randomised, placebo-controlled Phase 3 RCT
• DOI: https://doi.org/10.1056/NEJMoa2410027
• Funded by Eli Lilly

Overview

The SUMMIT trial is the first randomised trial to demonstrate a significant reduction in hard cardiovascular outcomes (CV death or worsening HF) in patients with obesity-phenotype HFpEF. Tirzepatide (dual GIP/GLP-1 receptor agonist, up to 15 mg SC weekly) was compared against placebo in 731 patients with HFpEF (LVEF ≥50%) and obesity (BMI ≥30) over a median follow-up of 104 weeks at 129 centres in 9 countries. Both pre-specified primary endpoints were met: the composite of CV death or worsening HF event (HR 0.62; P=0.026) and improvement in KCCQ-CSS at 52 weeks (+6.9 points; P<0.001). All three key secondary endpoints were also significant: weight loss (−11.6pp), 6MWT (+18.3m), and CRP reduction (−34.9pp). This builds on and extends the semaglutide STEP-HFpEF evidence, adding longer follow-up, greater weight loss, and the first hard composite endpoint benefit in this population.

Keywords

Heart failure with preserved ejection fraction, obesity, tirzepatide, GIP receptor agonist, GLP-1 receptor agonist, KCCQ, worsening heart failure, Kansas City Cardiomyopathy Questionnaire, epicardial adipose tissue, body weight

Key Takeaways

Background and Rationale

• Obesity is strongly linked to HFpEF through visceral adiposity-mediated systemic inflammation, epicardial adipose tissue (EAT) paracrine signalling, plasma volume expansion, and myocardial fibrosis
• Prior semaglutide (GLP-1 RA) trials (STEP-HFpEF 2023 and STEP-HFpEF DM 2024) improved symptoms and exercise capacity at 52 weeks with ~8–9% weight loss, with exploratory (not powered) signal toward fewer HF events (HR 0.08, 13 events only)
• Tirzepatide is a dual GIP and GLP-1 receptor agonist producing 12–21% weight loss in obesity — exceeding the weight loss of GLP-1 RA monotherapy; SUMMIT was designed to prospectively test the effect on hard HF outcomes

Study Design and Patients

• International double-blind RCT; 731 patients (364 tirzepatide / 367 placebo); 129 centres; 9 countries; randomisation April 2021–June 2023
• Inclusion: age ≥40, chronic HF NYHA II–IV, LVEF ≥50%, BMI ≥30, 6MWT 100–425m, KCCQ-CSS ≤80, plus ≥1 of: elevated NT-proBNP (>200 pg/mL SR; >600 pg/mL AF), LA enlargement, elevated filling pressures; AND prior HF decompensation within 12 months OR eGFR <70 mL/min/1.73m²
• Notably: NT-proBNP elevation was NOT mandatory — recognising that obese HFpEF patients may have suppressed natriuretic peptides despite elevated filling pressures
• Dose escalation: 2.5 mg weekly → increased 2.5 mg every 4 weeks → target 15 mg at 20 weeks; maximum tolerated dose maintained thereafter
• Median follow-up: 104 weeks; trial continued until last patient completed 52 weeks
• Baseline: mean age 65.2 years; 53.8% women; mean BMI 38.3; mean KCCQ-CSS 53.5; mean 6MWT 302.8m; 46.9% had HF hospitalisation/urgent care in prior 12 months; median NT-proBNP <200 pg/mL
• Primary endpoint revision: endpoints were formally amended ~1 year before trial end (prior to any unblinded efficacy review) following FDA discussion; original hierarchical composite split into two stand-alone primary endpoints

Primary Endpoints

• Composite CV death or worsening HF (time-to-first event): 36 (9.9%) tirzepatide vs 56 (15.3%) placebo; HR 0.62 (95% CI 0.41–0.95; P=0.026)
  • Worsening HF events: 29 (8.0%) vs 52 (14.2%); HR 0.54 (95% CI 0.34–0.85)
  • Worsening HF requiring hospitalisation: HR 0.44 (95% CI 0.22–0.87)
  • CV death: 8 (2.2%) vs 5 (1.4%); HR 1.58 (95% CI 0.52–4.83) — NS, numerically higher with tirzepatide
  • When diuretic-only intensification events removed: HR 0.57 (95% CI 0.34–0.95) — consistent
• KCCQ-CSS at 52 weeks: Mean change +19.5±1.2 tirzepatide vs +12.7±1.3 placebo; between-group difference 6.9 (95% CI 3.3–10.6; P<0.001)

Key Secondary Endpoints (all P<0.001)

• Body weight: −13.9% vs −2.2%; between-group difference −11.6 percentage points (95% CI −12.9 to −10.4)
• 6-minute walk distance: +26.0m vs +10.1m; between-group median difference +18.3m (95% CI 9.9–26.7)
• High-sensitivity CRP: −38.8% vs −5.9%; between-group difference −34.9pp (95% CI −45.6 to −22.2)

Mortality Signal

• All-cause death: 19 tirzepatide vs 15 placebo; HR 1.25 (95% CI 0.63–2.45) — NS; numerically higher with tirzepatide
• Of 15 total CV/undetermined deaths (adjudicated), 11 were not preceded by worsening HF — consistent with the premise that CV death in HFpEF often does not reflect HF progression
• 2 tirzepatide deaths occurred after >15 months off trial medication
• Authors note: in long-term GLP-1 RA cardiovascular outcome trials (SUSTAIN-6, SELECT), GLP-1 RA reduced CV and all-cause death in obesity/T2DM — the SUMMIT population and duration may be insufficient to capture mortality benefit

Mechanism of Benefit

• Tirzepatide reduces fat mass → decreasing plasma volume expansion and inflammatory response underlying obesity-HFpEF pathogenesis
• Decline in high-sensitivity CRP (−38.8%) mirrors semaglutide anti-inflammatory effect
• GIP receptors are abundant in epicardial adipocytes — GIP receptor agonism may suppress local epicardial inflammation and adjacent myocardial fibrosis beyond GLP-1 alone
• Systolic blood pressure lowering and modest heart rate increase may contribute additional hemodynamic benefit in HFpEF
• GLP-1 receptor agonism independently reverses proinflammatory adipocyte biology, muting microvascular rarefaction and myocardial fibrosis

Safety

• Adverse events leading to discontinuation: 23 (6.3%) tirzepatide vs 5 (1.4%) placebo
• GI-related discontinuations: 15 (4.1%) tirzepatide vs 0 placebo — GI symptoms generally dissipated over time
• Serious adverse events: similar frequency between groups
• 91.2% tirzepatide and 90.2% placebo patients attended final trial visit — high retention

Comparison with Semaglutide (STEP-HFpEF)

Limitations of the Document

• Primary endpoint revision approximately 1 year before trial end — though authors affirm no unblinded data access prior to amendment, this introduces analytical concern; FDA discussions informed the revision
• BMI ≥30 eligibility criterion excludes patients with excess visceral adiposity but BMI <30; waist-to-height ratio >0.5 may be a more reliable indicator and would capture additional HFpEF patients who might benefit
• All-cause and CV deaths numerically higher with tirzepatide (19 vs 15; 10 vs 5), both non-significant and study underpowered for mortality — cannot exclude a mortality signal from this trial alone
• Median follow-up 104 weeks with trial not designed for mortality as primary endpoint — hard mortality benefit requires longer, larger trials
• No active comparator — benefit is vs placebo (usual care), not vs semaglutide or SGLT2 inhibitor
• NT-proBNP median <200 pg/mL at baseline — lower-risk population than STEP-HFpEF trials; subgroup analyses reassuring that benefit persists at low NT-proBNP
• 9 countries, 129 centres — possible selection bias toward motivated, clinic-attending patients; 46.9% with prior HF hospitalisation enriches for higher-risk patients

Key Concepts Mentioned

• entities/HFpEF — primary patient population; obesity-HFpEF phenotype
• concepts/Visceral-Adiposity — epicardial adipose tissue as mechanistic mediator; GIP receptor expression in epicardial adipocytes
• concepts/Obesity-Paradox — SUMMIT extends refutation of obesity paradox in HFpEF to hard outcomes

Key Entities Mentioned

• entities/Tirzepatide — investigational agent (dual GIP/GLP-1 RA); primary subject of trial
• entities/Semaglutide — comparator context; prior GLP-1 RA trials in HFpEF
• entities/Obesity — mandatory eligibility criterion; mechanistic driver

Wiki Pages Updated

• wiki/sources/tirzepatide-hfpef-summit-nejm-2025.md — created
• wiki/entities/Tirzepatide.md — created
• wiki/entities/HFpEF.md — SUMMIT section added under Management; contradictions updated
• wiki/entities/Semaglutide.md — comparative context with SUMMIT added
• wiki/sourceindex.md — entry added
• wiki/wikiindex.md — Tirzepatide entity entry added