Tirzepatide and Heart Failure: What the SUMMIT Trial Showed
In the SUMMIT trial, tirzepatide cut the combined risk of cardiovascular death or worsening heart failure by 38% (HR 0.62) in adults with HFpEF and obesity, but neither Zepbound nor Mounjaro is approved for heart failure in the US or EU.
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The SUMMIT trial found that tirzepatide (the drug in Zepbound and Mounjaro) reduced the combined risk of cardiovascular death or worsening heart failure by 38% compared with placebo in adults with heart failure with preserved ejection fraction (HFpEF) and obesity — a hazard ratio of 0.62, with events in 9.9% of the tirzepatide group versus 15.3% of the placebo group [1][3][7]. Tirzepatide also improved symptoms, walking distance, and quality of life in the same trial [1][3]. But no regulator has approved tirzepatide for heart failure. Lilly withdrew its US application in May 2025 after the FDA said another confirmatory trial was required [8], and the European Medicines Agency decided on 30 January 2026 that a separate HFpEF indication was not needed, though it added the SUMMIT data to Mounjaro’s European product information [9]. The US Zepbound label (revised 08/2026) lists only weight reduction and obstructive sleep apnea [11].
One more distinction matters: in August 2026 the FDA approved Mounjaro to lower the risk of major cardiovascular events in adults with type 2 diabetes at high cardiovascular risk, based on a separate trial called SURPASS-CVOT — but that approval does not cover heart failure [14].
What is HFpEF in plain English?
HFpEF stands for heart failure with preserved ejection fraction. In this form of heart failure, the heart muscle becomes too stiff and cannot relax and fill properly between heartbeats, so the heart pumps out less blood than the body needs [9]. The result is difficulty breathing, tiredness, and swelling, usually in the ankles and feet [9].
Ejection fraction measures how much blood the left ventricle pumps out with each contraction. A normal reading is between 55% and 70% [4]. In HFpEF, that number is preserved — it looks normal — but the heart is still failing because it cannot fill properly. Over half of all heart failure patients have HFpEF, and roughly two-thirds of them have obesity [5].
Obesity-related HFpEF tends to come with a particular set of features: high blood pressure, chronic kidney disease, expanded blood volume, and chronic whole-body inflammation [5]. Drugs already used for HFpEF — angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and SGLT2 inhibitors — provide generally modest benefit, and none of them target obesity, one of the main drivers of the condition [6].
The European Society of Cardiology’s updated heart failure guideline, released at its congress in Munich and reported on 31 August 2026, simplified the categories: heart failure with reduced ejection fraction (HFrEF) is now defined as a left ventricular ejection fraction of 50% or less, and HFpEF as anything above 50%, with the “mildly reduced” category removed [15].
How was the SUMMIT trial designed, and who was in it?
SUMMIT enrolled 731 adults, randomized 1:1 to tirzepatide (364 people) or placebo (367 people), at 129 centers in nine countries including the US, Argentina, Brazil, China, India, Israel, Mexico, Russia, and Taiwan [1][2][4][7]. It was a double-blind, placebo-controlled Phase 3 trial funded by Eli Lilly, registered as NCT04847557 [1][2]. Screening ran from April 20, 2021 to June 30, 2023, with 1,494 people screened [4][7].
To enter, participants had to be at least 40 years old with NYHA class II to IV heart failure, a left ventricular ejection fraction of at least 50%, and a BMI of at least 30 [6][7]. They also needed either a heart failure flare-up (decompensation) in the previous 12 months or an eGFR below 70, plus a six-minute walk distance of 100 to 425 meters and a KCCQ-CSS score of 80 or less [6][7].
The trial started everyone at 2.5 mg once weekly and increased by 2.5 mg every four weeks as tolerated, up to a maximum tolerated dose of 5, 10, or 15 mg, on top of each person’s usual heart failure medications [3][4][6]. Median follow-up was 104 weeks, with a maximum of 3.0 years [1][6].
At baseline, participants had a mean age of 65.2, 53.8% were women, mean BMI was 38.2, and 53% had a worsening heart failure event in the prior 12 months [6]. Mean KCCQ-CSS was 53.5 and mean six-minute walk distance was 302.8 meters; 28% were NYHA class III or IV, 26% had atrial fibrillation, 17% were on an SGLT2 inhibitor, and 74% were on a diuretic [6][7]. About 20% of participants came from the US and 53% from Latin America [4][7].
SUMMIT was the first trial in HFpEF with obesity to use heart failure outcomes as a prespecified primary endpoint [4][6]. Results were published in the New England Journal of Medicine online on November 16, 2024, and presented the same day at the American Heart Association Scientific Sessions in Chicago [1][4][7].
What were the primary endpoint results?
SUMMIT had two primary endpoints: time to first cardiovascular death or worsening heart failure event, and the change in KCCQ-CSS (a 23-question patient survey scored 0 to 100, higher is better) at 52 weeks [1][4][6]. A worsening heart failure event meant a hospitalization, intravenous drugs in an urgent care setting, or intensification of oral diuretics with symptoms — all judged by a blinded committee [6].
The composite of cardiovascular death or worsening heart failure occurred in 36 patients (9.9%) on tirzepatide versus 56 (15.3%) on placebo: a hazard ratio of 0.62, with a 95% confidence interval of 0.41 to 0.95 and P=0.026 [1][7]. That is the 38% relative risk reduction [1][3][7].
The KCCQ-CSS improved by 19.5 points with tirzepatide versus 12.7 with placebo at 52 weeks — a between-group difference of 6.9 points (95% CI, 3.3 to 10.6; P<0.001) under the treatment-regimen estimand [1][3]. Under the efficacy estimand, which counts only people still on treatment, the improvement was 24.8 versus 15.0 points [3].
Did tirzepatide reduce heart failure hospitalizations?
Yes, hospitalizations dropped in the tirzepatide group. Worsening heart failure events overall occurred in 29 patients (8.0%) on tirzepatide versus 52 (14.2%) on placebo, a hazard ratio of 0.54 (95% CI, 0.34 to 0.85) [1][7].
Breaking that down: heart failure hospitalization happened in 12 patients (3.3%) on tirzepatide versus 26 (7.1%) on placebo, which Lilly describes as a 56% relative risk reduction [3]. Urgent heart failure visits occurred in 5 (1.4%) versus 12 (3.3%), and oral diuretic intensification in 17 (4.7%) versus 21 (5.7%) [3].
For heart failure events requiring hospitalization or intravenous drugs in urgent care, the hazard ratio was 0.41 (95% CI, 0.22 to 0.75; P=0.004) [6]. Across all composites of death and worsening heart failure, hazard ratios ranged from 0.41 to 0.67 [6]. The composite of all-cause death or worsening heart failure occurred in 11.8% versus 16.9% (HR 0.67, 95% CI, 0.46 to 0.99) [7].
| Outcome | Tirzepatide | Placebo | Hazard ratio |
|---|---|---|---|
| CV death or worsening HF | 36 (9.9%) | 56 (15.3%) | 0.62 (0.41–0.95) [1][7] |
| Worsening HF event | 29 (8.0%) | 52 (14.2%) | 0.54 (0.34–0.85) [1][7] |
| HF hospitalization | 12 (3.3%) | 26 (7.1%) | 56% relative reduction (Lilly) [3] |
| Urgent HF visit | 5 (1.4%) | 12 (3.3%) | — [3] |
| All-cause death or worsening HF | 11.8% | 16.9% | 0.67 (0.46–0.99) [7] |
What about walking, weight, inflammation, and blood pressure?
At 52 weeks, six-minute walk distance improved by 26.0 meters with tirzepatide versus 10.1 meters with placebo under the treatment-regimen estimand — an 18.3-meter between-group difference (95% CI, 9.9 to 26.7) [3][6][7]. Under the efficacy estimand it was 38.2 versus 7.9 meters [3].
Body weight fell 13.9% with tirzepatide versus 2.2% with placebo under the treatment-regimen estimand, and 15.7% versus 2.2% under the efficacy estimand — about 11.9 percentage points more weight loss [3][4][7]. High-sensitivity CRP, a marker of inflammation, fell 38.8% versus 5.9% (treatment-regimen), or 43.4% versus 3.5% (efficacy) [3][7]. Systolic blood pressure dropped 4.6 mmHg with tirzepatide versus a 0.1 mmHg rise with placebo [7].
Other measures also favored tirzepatide: the EQ-5D-5L quality-of-life index gained 0.12 versus 0.06 (between-group 0.06, 95% CI, 0.03 to 0.09) [6][7]; participants shifted toward better overall health impressions (proportional odds ratio 1.99) and better NYHA class (2.26); they needed fewer heart failure medications (P=0.015); and a hierarchical composite win ratio was 1.63 (95% CI, 1.17 to 2.28) [6].
Did tirzepatide reduce deaths in SUMMIT?
SUMMIT did not show a reduction in deaths, and the trial was not large enough to settle the question. Adjudicated cardiovascular death occurred in 8 patients (2.2%) on tirzepatide versus 5 (1.4%) on placebo — a hazard ratio of 1.58 with a confidence interval of 0.52 to 4.83, which crosses 1 and is not statistically significant [1][7]. All-cause mortality was 5.2% versus 4.1% (HR 1.25, 95% CI, 0.63 to 2.45) [7].
There were 34 deaths from any cause in the whole trial and 15 cardiovascular deaths total; 11 were not preceded by worsening heart failure, and 2 tirzepatide-group deaths occurred after patients had been off the drug for more than 15 months [4]. Lilly’s table counts 10 cardiovascular deaths in the tirzepatide group including 2 of undetermined cause, and notes 7 of those 10 people had been off the drug more than 30 days [3].
The American College of Cardiology’s interpretation is that the composite reduction was driven primarily by fewer heart failure events, not by fewer deaths [7]. The EMA likewise concluded that Mounjaro did not reduce cardiovascular deaths in this population [9].
What side effects did SUMMIT participants report?
The most common adverse events were gastrointestinal and mostly mild to moderate [3]. Diarrhea occurred in 18.4% of the tirzepatide group versus 6.3% on placebo, nausea in 17.0% versus 6.5%, and constipation in 14.8% versus 6.0% [3].
Adverse events led to discontinuation of the trial drug in 23 patients (6.3%) on tirzepatide versus 5 (1.4%) on placebo, mainly gastrointestinal [1]. The American Heart Association’s release puts it at about 4% stopping for GI symptoms [4]. Lilly states the overall safety profile was consistent with prior tirzepatide studies [3].
How might tirzepatide have helped the heart?
A secondary analysis published in Nature Medicine looked at what changed in participants’ bodies at 52 weeks. Tirzepatide lowered systolic blood pressure by an estimated 5 mmHg (95% CI, −7 to −3), reduced estimated blood volume by 0.58 liters, and cut CRP by 37.2% compared with placebo [5].
Kidney and heart-injury markers moved too. eGFR increased (estimated treatment difference 2.90 mL/min/1.73m² per year, P=0.004); urine albumin-creatinine ratio fell 25.0% at 24 weeks and 15% at 52 weeks (P=0.051); and troponin T fell 10.4% (P=0.003) [5]. NT-proBNP fell 10.5%, but with a confidence interval of −20.7 to 1.0 and P=0.07, that change was not statistically significant [5]. Diastolic blood pressure effects were minimal and not significant, while pulse pressure was reduced [5].
In exploratory post hoc analyses, the drop in blood volume correlated with lower blood pressure, less microalbuminuria, and better KCCQ-CSS and walking distance, and the fall in CRP correlated with the fall in troponin T [5]. At baseline, participants had a mean eGFR of 55.3, over half had stage 3 or worse chronic kidney disease, median CRP was 3.2 mg/L, and 41% had elevated troponin T [5]. A post hoc analysis presented in March 2025 found the effect was similar with and without CKD, though CKD patients had about double the risk of worsening heart failure [7].
One question remains open: whether the benefit is independent of weight loss. The ACC flags this as a limitation, and the EMA calls it an uncertainty [7][9].
Why is there no US heart failure indication for Zepbound?
Lilly submitted applications for HFpEF with obesity to the FDA and EMA, announced on November 16, 2024 [3]. On May 1, 2025, at an investor briefing, Lilly’s Chief Scientific Officer Dan Skovronsky disclosed that the company had withdrawn the US application after the FDA indicated an additional confirmatory clinical trial would be required [8].
Skovronsky said Lilly believes the SUMMIT data do support an indication, but noted that patients in the trial are already covered under the obesity indication — so it would be a new benefit for an existing population, not a new population to treat. He said the FDA position could have a curtailing effect on investment in HFpEF, and that additional data from other trials could support a resubmission [8].
Novo Nordisk went through something similar: it withdrew its Wegovy HFpEF application to the FDA in 2024 and resubmitted in early 2025 with a pooled analysis of heart failure outcomes from four prior studies [8]. Lilly pointed out in November 2024 that no treatments were available specifically for obesity-related HFpEF in the US [3].
What did Europe decide?
On 30 January 2026, the EMA finalized its assessment (document EMA/18704/2026) of an application to extend Mounjaro to symptomatic chronic HFpEF in adults with obesity [9]. The agency concluded that although Mounjaro did not reduce cardiovascular deaths, it significantly reduced heart failure hospitalizations and improved quality of life [9].
Even so, the EMA decided a separate indication was not needed, for two reasons: uncertainty about whether the effect is independent of weight loss, and the fact that this group of people is already covered by Mounjaro’s approved weight-management indication [9]. The agency agreed to add the SUMMIT data to the product information so healthcare professionals have access to it, and said there are no consequences for patients in clinical trials [9]. Endpoints News reported on January 30, 2026 that the CHMP opposed Mounjaro in heart failure [10].
Mounjaro has been authorized in the EU since September 2022, with a weight indication covering BMI of 30 or more, or 27 to 30 with a weight-related health problem [9].
What does the ESC 2026 guideline say, and how does that differ from the labels?
The European Society of Cardiology’s updated heart failure guideline, introduced at its congress in Munich and reported on 31 August 2026, recommends semaglutide and tirzepatide for patients with HFpEF and obesity [15]. The same guideline backs finerenone and other mineralocorticoid receptor antagonists in chronic heart failure regardless of ejection fraction [15].
A guideline recommendation is not the same as a regulatory approval. The US Zepbound label, revised 08/2026, lists only two uses: reducing excess body weight and keeping it off, and treating moderate to severe obstructive sleep apnea in adults with obesity [11]. Its clinical studies section covers weight and sleep apnea studies only [11].
What is the difference between SUMMIT and SURPASS-CVOT?
SURPASS-CVOT was a different trial asking a different question. It enrolled 13,299 people with type 2 diabetes and established atherosclerotic cardiovascular disease, randomized to tirzepatide (up to 15 mg) or dulaglutide (1.5 mg) — an active comparator, not placebo, making it the first cardiovascular outcomes trial to compare two incretin drugs head-to-head [12][14]. It is registered as NCT04255433 [12][14].
The modified intention-to-treat population was 6,586 versus 6,579, with a mean age of 64.1, 29.0% women, mean BMI 32.6, A1c 8.4%, and diabetes duration of 14.7 years [12]. The primary endpoint — cardiovascular death, heart attack, or stroke — occurred in 801 patients (12.2%) on tirzepatide versus 862 (13.1%) on dulaglutide: a hazard ratio of 0.92 (95.3% CI, 0.83 to 1.01), meeting noninferiority (P=0.003) but not superiority (P=0.09) [12][14]. Median follow-up was 210.1 weeks across 640 sites in 30 countries, and results were published in the New England Journal of Medicine on December 17, 2025 [12][14]. Gastrointestinal adverse events were more common with tirzepatide, but overall adverse event rates were similar [12].
On August 28, 2026, the FDA approved Mounjaro to lower the risk of major adverse cardiovascular events in adults with type 2 diabetes at high cardiovascular risk, based on this trial [14]. Heart failure is not part of that indication; the approval covers Mounjaro, for type 2 diabetes only, and SURPASS-CVOT data are included in the EU product information [14].
What is still being studied?
A trial called SURMOUNT-MMO (NCT05556512) is studying tirzepatide’s effect on reducing morbidity and mortality in adults with obesity [13]. Lilly said in November 2024 that studies in chronic kidney disease and in morbidity and mortality in obesity were ongoing [3], and Skovronsky has said additional data from other trials could support a resubmission of the heart failure application in the US [8].
What does this mean if you have HFpEF and obesity?
In the US, Zepbound is approved for weight reduction in adults with obesity, or overweight with at least one weight-related condition, and for moderate to severe obstructive sleep apnea in adults with obesity — not for heart failure [11]. The label carries a boxed warning about thyroid C-cell tumors based on rat studies, and the drug is contraindicated for anyone with a personal or family history of medullary thyroid carcinoma or MEN 2 syndrome [11]. Label warnings include severe gastrointestinal reactions, acute kidney injury from volume depletion, gallbladder disease, pancreatitis, hypoglycemia when combined with insulin or insulin secretagogues, and aspiration of food or liquid during deep sedation or anesthesia [11].
One limitation worth knowing: SUMMIT used BMI as its measure of body size, so people with a high waist-to-height ratio but a BMI under 30 were excluded — even though many HFpEF patients carry belly fat without meeting the BMI threshold for obesity [4]. Decisions about any medication for heart failure belong with a cardiologist or other treating clinician.
Sources
- New England Journal of Medicine. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.
- PubMed. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.
- Eli Lilly and Company. Lilly’s tirzepatide reduced the risk of worsening heart failure events by 38% in adults with heart failure with preserved ejection fraction (HFpEF) and obesity. November 16, 2024.
- American Heart Association. Tirzepatide lowered risk of worsening heart failure and CVD death for obese adults. November 16, 2024.
- Nature Medicine. 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.
- Circulation. Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity.
- American College of Cardiology. A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity - SUMMIT. March 31, 2025.
- ConscienHealth. Lilly Withdraws Tirzepatide Application to FDA for Heart Failure. May 3, 2025.
- European Medicines Agency. Outcome of assessment on use of Mounjaro in treatment of heart failure with preserved ejection fraction in adults with obesity. January 30, 2026.
- Endpoints News. CHMP opposes Lilly’s Mounjaro in heart failure, backs Novo’s Kayshild. January 30, 2026.
- US Food and Drug Administration. ZEPBOUND (tirzepatide) Injection, for subcutaneous use: prescribing information. 2026.
- New England Journal of Medicine. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.
- ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity (NCT05556512).
- PR Newswire. FDA approves Lilly’s Mounjaro (tirzepatide) to reduce cardiovascular risk in adults with type 2 diabetes. August 28, 2026.
- pharmaphorum. ESC26: Heart attack reclassification rights gender imbalance.
Frequently asked questions
Is Zepbound FDA approved for heart failure?
No. The US Zepbound label, revised 08/2026, lists only weight reduction and maintenance, and moderate to severe obstructive sleep apnea in adults with obesity. Lilly withdrew its heart failure application in May 2025 after the FDA indicated an additional confirmatory trial was required.
Is Mounjaro approved for heart failure in Europe?
No. On 30 January 2026 the EMA concluded a separate HFpEF indication was not needed, because the population is already covered by the weight-management indication and it is uncertain whether the benefit is independent of weight loss. The agency did add SUMMIT data to the product information.
What does HFpEF stand for, and how is it different from reduced ejection fraction?
HFpEF is heart failure with preserved ejection fraction: the heart is too stiff to relax and fill between beats, so it pumps out less blood than the body needs, causing breathlessness, tiredness, and swelling. In HFrEF, the pumping fraction itself is reduced. The ESC's 2026 guideline sets the dividing line at 50%.
Did tirzepatide reduce deaths in SUMMIT?
SUMMIT did not show a death reduction. Cardiovascular death occurred in 2.2% on tirzepatide versus 1.4% on placebo (HR 1.58, 95% CI 0.52 to 4.83), and all-cause mortality was 5.2% versus 4.1% (HR 1.25) — both confidence intervals cross 1, so neither is statistically significant. The EMA also noted no reduction in cardiovascular deaths.
How much weight did SUMMIT participants lose?
At 52 weeks, body weight fell 13.9% with tirzepatide versus 2.2% with placebo under the treatment-regimen estimand, and 15.7% versus 2.2% under the efficacy estimand — about 11.9 percentage points more weight loss than placebo.
What does the 38% figure mean in absolute terms?
The 38% is the relative reduction in the composite of cardiovascular death or worsening heart failure (HR 0.62). In absolute terms, that composite occurred in 9.9% of the tirzepatide group versus 15.3% of the placebo group over a median of 104 weeks. The 38% applies to the composite, not to hospitalizations alone, which Lilly reports as a 56% reduction.
Why did Lilly withdraw the FDA heart failure application?
Lilly's Chief Scientific Officer Dan Skovronsky said on May 1, 2025 that after discussions with the FDA, the agency indicated an additional confirmatory clinical trial was required. He noted patients were already covered under the obesity indication, and said data from other trials could support a resubmission.
What does the ESC 2026 guideline say about GLP-1 drugs in heart failure?
The updated ESC guideline, presented at the congress in Munich and reported on 31 August 2026, recommends semaglutide and tirzepatide for patients with HFpEF and obesity. A guideline recommendation is distinct from regulatory approval; the US Zepbound label still lists only weight and sleep apnea uses.
This article summarizes FDA labeling, published research and company information current as of September 14, 2026. It is not medical advice and does not replace a conversation with your own healthcare provider. How we research and verify.