SUMMIT trial deep-dive: tirzepatide for HFpEF and obesity (Packer 2025 NEJM)
Last verified 2026-05-28 · Phase 3 · Completed (results published Nov 2024 / Jan 2025 NEJM) · NCT04847557 ↗
SUMMIT (NCT04847557) is the pivotal phase-3 trial that tested whether tirzepatide, Eli Lilly's long-acting GLP-1 and GIP receptor co-agonist, could improve cardiovascular outcomes and symptoms in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. The international double-blind study randomized 731 adults with an ejection fraction of at least 50 percent and a body-mass index of at least 30 in a 1:1 ratio to weekly subcutaneous tirzepatide (titrated up to 15 mg) or matching placebo for a minimum of 52 weeks, with a median follow-up of 104 weeks. Results, published by Packer and colleagues in the New England Journal of Medicine on January 30, 2025 (online November 16, 2024), showed a 38 percent relative reduction in the composite of adjudicated cardiovascular death or worsening heart-failure event and a 6.9-point greater improvement in the Kansas City Cardiomyopathy Questionnaire clinical summary score on tirzepatide versus placebo. The trial was the principal evidence supporting the FDA's subsequent expansion of the Zepbound label to include reduction of the risk of worsening heart failure in adults with HFpEF and obesity.
- Enrollment
- 731
- Duration
- Minimum 52 weeks of treatment with a median follow-up of 104 weeks; primary endpoints assessed at 52 weeks (KCCQ-CSS) and time-to-first-event up to 160 weeks (composite CV outcome)
- Drug
- Tirzepatide
- Population
- Adults with chronic heart failure, left-ventricular ejection fraction at least 50 percent, body-mass index at least 30 kg/m², elevated NT-proBNP or evidence of structural heart disease on imaging, and NYHA functional class II to IV symptoms. Diabetes was permitted and used as a stratification variable; mean baseline weight was approximately 105 kg, mean BMI roughly 38 kg/m², mean age 65 years, and about 54 percent of participants were women. Enrollment spanned Argentina, Brazil, China, India, Israel, Mexico, Russia, Taiwan, the United Kingdom, and the United States.
Primary endpoint
Composite of adjudicated cardiovascular death or worsening heart-failure event (time to first event, median follow-up 104 weeks)
Treatment arm
36/364 (9.9%)
Comparator
56/367 (15.3%)
Treatment difference: Hazard ratio 0.62 (95% CI 0.41 to 0.95; P=0.026)
The benefit was driven primarily by fewer worsening heart-failure events (8.0% vs 14.2%, HR 0.54, 95% CI 0.34 to 0.85); cardiovascular deaths were numerically uncommon in both arms (2.2% vs 1.4%; HR 1.58, 95% CI 0.52 to 4.83).
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Change from baseline in KCCQ Clinical Summary Score at 52 weeks (coprimary endpoint, range 0-100, higher = better quality of life) A between-group difference of approximately 5 points on the KCCQ-CSS is widely considered clinically meaningful in HFpEF trials; SUMMIT exceeded that threshold. | +19.5 points (SD 1.2) | +12.7 points (SD 1.3) | Between-group difference 6.9 points (95% CI 3.3 to 10.6; P<0.001) |
| Change from baseline in 6-minute walk distance at 52 weeks Mechanistic improvement in functional exercise capacity, consistent with the symptom-burden reduction captured by KCCQ-CSS. | Increased on tirzepatide | Smaller change on placebo | Between-group difference approximately 18 meters favoring tirzepatide (P<0.001) |
| Percent change from baseline in body weight at 52 weeks Weight loss in HFpEF participants mirrors the magnitudes seen in obesity-only SURMOUNT trials; the diabetes subgroup lost 10.4% versus 12.9% in the non-diabetes subgroup. | Approximately -13.9% | Approximately -2.2% | Between-group difference roughly -11.6 percentage points (P<0.001) |
| Percent change from baseline in high-sensitivity C-reactive protein at 52 weeks Anti-inflammatory effect was tightly correlated with reductions in troponin T and improved 6-minute walk distance in mechanistic analyses. | Reduced | Smaller change | Estimated treatment difference -37.2% (95% CI -45.7 to -27.3; P<0.001) |
| Percent change from baseline in NT-proBNP at 52 weeks Numerical reduction in the canonical heart-failure biomarker that fell just short of statistical significance, consistent with concurrent reductions in blood volume and filling pressures. | Reduced | Smaller change | Estimated treatment difference -10.5% (95% CI -20.7 to 1.0; P=0.07) |
| Change from baseline in systolic blood pressure at 52 weeks Modest blood-pressure reduction contributing to the volume-pressure offloading hypothesis advanced in the Borlaug mechanistic companion. | Reduced | Smaller change | Estimated treatment difference -5 mmHg (95% CI -7 to -3; P<0.001) |
| Percent change from baseline in troponin T at 52 weeks Reduction in a marker of myocardial injury, supporting a structural rather than purely hemodynamic benefit. | Reduced | Smaller change | Estimated treatment difference -10.4% (95% CI -16.7 to -3.6; P=0.003) |
| NYHA functional-class improvement at 52 weeks | Higher proportion improved | Lower proportion improved | Favors tirzepatide; magnitude similar in patients with and without diabetes in prespecified subgroup analysis |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Adverse event leading to discontinuation of trial drug Predominantly gastrointestinal. | 23/364 (6.3%) | 5/367 (1.4%) |
| Nausea (gastrointestinal events were the most common AE class) Consistent with the GI profile across the SURMOUNT and SURPASS programs. | Higher on tirzepatide than placebo | Lower |
| Serious adverse events No new safety signal identified relative to prior tirzepatide cardiovascular and obesity programs. | Similar between arms | Similar |
Subgroup analyses
- Patients with type 2 diabetes: Composite primary endpoint HR 0.64 (95% CI 0.35 to 1.15)
Pinteraction = 0.95 versus the non-diabetes subgroup; the diabetes subgroup lost 10.4% of body weight versus 12.9% in the non-diabetes subgroup, but KCCQ-CSS, 6MWD, and functional-class improvements did not differ.
- Patients without type 2 diabetes: Composite primary endpoint HR 0.61 (95% CI 0.33 to 1.10)
Effect on the primary cardiovascular outcome was indistinguishable from the diabetes subgroup, indicating the benefit is not contingent on the magnitude of weight loss.
- By body-mass index tertile and central adiposity: Benefit on the composite endpoint and KCCQ-CSS was preserved across BMI tertiles in the prespecified analysis
Reported in the Packer 2025 JACC companion (PMID 40701669).
Clinical significance
SUMMIT is the first phase-3 cardiovascular outcomes trial to show that a GLP-1-based therapy reduces a composite of cardiovascular death and worsening heart-failure events in HFpEF, the heart-failure phenotype that has historically lacked disease-modifying therapy beyond SGLT2 inhibitors. The dual primary win on both the hard composite outcome and the patient-reported KCCQ-CSS, the consistency across the diabetes and non-diabetes strata, and the mechanistic congruence with reductions in blood volume, blood pressure, hsCRP, troponin T, NT-proBNP, and paracardiac fat from the cardiac-MRI substudy collectively reframe obesity-related HFpEF as a directly treatable disease. SUMMIT supported the FDA's expansion of the Zepbound label to include reduction of the risk of worsening heart failure in adults with HFpEF and obesity, parallel to the earlier Wegovy HFpEF-symptom indication from STEP-HFpEF.
Frequently asked questions
How is SUMMIT different from STEP-HFpEF, the semaglutide HFpEF trial?
STEP-HFpEF (Kosiborod 2023 NEJM, semaglutide 2.4 mg) and STEP-HFpEF DM (Kosiborod 2024 NEJM, the diabetes-cohort companion) showed improvements in patient-reported symptoms (KCCQ-CSS), 6-minute walk distance, hsCRP, and weight in HFpEF and obesity but were not powered to reduce hard cardiovascular outcomes. SUMMIT enrolled 731 patients (larger and longer than STEP-HFpEF's two trials of about 529 and 616 patients), tested tirzepatide instead of semaglutide, and was the first to demonstrate a statistically significant reduction in the composite of cardiovascular death or worsening heart-failure event (HR 0.62, P=0.026) in addition to the KCCQ-CSS improvement. The two programs are complementary rather than head-to-head.
Does the SUMMIT result apply to heart failure with reduced ejection fraction (HFrEF)?
No. SUMMIT enrolled only patients with an ejection fraction of at least 50 percent, the HFpEF phenotype. HFrEF (ejection fraction below 40 percent) has a separate evidence base built on ACE inhibitors and ARBs, beta blockers, mineralocorticoid antagonists, sacubitril-valsartan, and SGLT2 inhibitors. There is no completed phase-3 trial of tirzepatide in HFrEF, and clinicians should not extrapolate the SUMMIT result to that population. Ongoing programs such as Lilly's broader cardiovascular outcomes trial portfolio may eventually address HFrEF separately.
Does the Zepbound HFpEF FDA label require the patient to also have obesity?
Yes. The FDA-expanded indication, like the SUMMIT eligibility criteria, applies to adults with HFpEF and obesity, defined in the trial as a body-mass index of at least 30 kg/m². A patient with HFpEF but a BMI in the normal range is outside the studied population and outside the label. Patients should consult their cardiologist or endocrinologist about whether the label criteria apply to their specific situation; the trial did not study patients with BMI below 30.
Was the cardiovascular benefit larger in patients without diabetes, given they lost more weight?
No, and that is one of the most clinically important findings from the prespecified diabetes-stratified analysis. Patients with type 2 diabetes lost roughly 10.4 percent of body weight on tirzepatide versus 12.9 percent in patients without diabetes, but the hazard ratio for the composite cardiovascular endpoint was effectively identical in the two strata (HR 0.64 with diabetes versus 0.61 without; Pinteraction 0.95). Improvements in KCCQ-CSS, 6-minute walk distance, quality of life, and NYHA functional class were also similar between strata. This suggests the heart-failure benefit is not simply a function of weight-loss magnitude and may reflect mechanisms beyond weight loss, including reductions in blood volume, inflammation, and myocardial injury.
Should a patient with HFpEF currently on Wegovy switch to Zepbound based on SUMMIT?
There is no head-to-head comparison of Wegovy and Zepbound in HFpEF, and the two drugs are now both supported by phase-3 evidence in this population through different programs (semaglutide via STEP-HFpEF and STEP-HFpEF DM; tirzepatide via SUMMIT). SUMMIT showed a hard cardiovascular outcomes benefit that the STEP-HFpEF program was not designed to detect, while STEP-HFpEF demonstrated KCCQ-CSS and 6-minute walk benefits in line with what SUMMIT later confirmed for tirzepatide. The decision to switch is a clinical one that should weigh symptom control on the current regimen, tolerability, insurance coverage, and the patient's cardiovascular risk profile. Patients should not switch GLP-1 medications without consulting their prescriber.
What was the absolute risk reduction in SUMMIT, and what is the number needed to treat?
The composite of cardiovascular death or worsening heart-failure event occurred in 9.9 percent of the tirzepatide group versus 15.3 percent of the placebo group over a median follow-up of 104 weeks, an absolute risk reduction of about 5.4 percentage points. That corresponds to a number needed to treat (NNT) of approximately 19 over roughly two years to prevent one composite cardiovascular event. The NNT for the KCCQ-CSS improvement is more difficult to express because it is a continuous quality-of-life measure rather than a binary outcome, but the 6.9-point between-group difference exceeds the 5-point threshold widely used as a clinically meaningful within-patient change.
References
- 1.Packer M, Zile MR, Kramer CM, et al.; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025. PMID: 39555826.
- 2.U.S. National Library of Medicine. A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity: The SUMMIT Trial. ClinicalTrials.gov, NCT04847557. 2025. https://clinicaltrials.gov/study/NCT04847557
- 3.Borlaug BA, Zile MR, Kramer CM, et al. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med. 2025. PMID: 39551891.
- 4.Packer M, Zile MR, Kramer CM, et al.; SUMMIT Trial Study Group. Influence of Type 2 Diabetes on the Effects of Tirzepatide in Patients With Heart Failure and a Preserved Ejection Fraction With Obesity: A Prespecified Stratification-Based Analysis. J Am Coll Cardiol. 2025. PMID: 40903131.
- 5.Kramer CM, Borlaug BA, Zile MR, et al. Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy. J Am Coll Cardiol. 2025. PMID: 39566869.
- 6.Packer M, Zile MR, Borlaug BA, et al. Impact of Body Mass Index, Central Adiposity, and Weight Loss on the Benefits of Tirzepatide in HFpEF: The SUMMIT Trial. J Am Coll Cardiol. 2025. PMID: 40701669.