Heart failure with preserved ejection fraction, usually shortened to HFpEF, is the most common form of heart failure in adults with obesity, and for many years it had very few treatments that changed how people felt from one day to the next. In HFpEF the heart pumps a normal share of blood, yet the muscle has become stiff, and ordinary tasks such as climbing stairs bring on breathlessness and fatigue.
The SUMMIT trial tested tirzepatide in exactly this group. This article explains what SUMMIT measured and where its evidence stops. It is educational information rather than medical advice, tirzepatide is not FDA approved as a treatment for heart failure, and heart failure care should always be directed by a cardiologist or heart failure team.
Key Takeaways
- The SUMMIT trial enrolled 731 adults with HFpEF (an ejection fraction of 50 percent or higher) and a BMI of 30 or more, and followed them for a median of about two years.
- In SUMMIT, cardiovascular death or a worsening heart failure event occurred in 9.9 percent of people taking tirzepatide versus 15.3 percent taking placebo, a hazard ratio of 0.62, or roughly a 38 percent relative reduction.
- SUMMIT participants taking tirzepatide improved their Kansas City Cardiomyopathy Questionnaire clinical summary score by about 19.5 points at 52 weeks, compared with about 12.7 points on placebo.
- At 52 weeks in SUMMIT, body weight fell by about 13.9 percent with tirzepatide versus about 2.2 percent with placebo, and high sensitivity C-reactive protein fell by about 39 percent versus about 6 percent.
- SUMMIT was not designed to show a reduction in cardiovascular death on its own and excluded people with reduced ejection fraction, so its findings apply specifically to HFpEF with obesity.
- Tirzepatide is not FDA approved to treat heart failure, and people with heart failure should start or change tirzepatide only with their cardiologist involved.
What is HFpEF, and why is obesity so closely linked to it?
HFpEF is a form of heart failure in which the left ventricle still ejects a normal share of blood, but the heart muscle fills poorly because it has stiffened, which raises pressure in the lungs and causes breathlessness, fatigue and swelling. HFpEF accounts for roughly half of all heart failure, and published estimates suggest that around four in five people living with HFpEF also have overweight or obesity.
Cardiologists increasingly describe an obesity phenotype of HFpEF. In this pattern, visceral fat and fat surrounding the heart release inflammatory signals, expand blood volume and physically constrain the heart. Because so many of these drivers are metabolic, researchers began asking whether a medication that reduces body fat and inflammation might change the course of HFpEF itself, rather than only the number on the scale.
Figure 1
A Metabolic Heart Condition: Estimated Share of People With HFpEF Who Also Have Overweight or Obesity
Sources: Published HFpEF registry and trial population estimates, summarized in Borlaug et al., Circulation 2023. Individual results vary.
What was the SUMMIT trial, and who took part?
SUMMIT was a randomized, double blind, placebo controlled trial sponsored by Eli Lilly and led by cardiologist Milton Packer, and its full results were published in the New England Journal of Medicine after a first presentation in November 2024. The trial enrolled 731 adults with symptomatic heart failure (NYHA class II to IV), a left ventricular ejection fraction of 50 percent or higher and a BMI of 30 or more.
Participants received once weekly tirzepatide, increased in 2.5 mg steps to a maximum of 15 mg, or a matching placebo on top of their usual heart failure care, and they were followed for a median of about 104 weeks. The trial had two primary outcomes, and the first was a composite of cardiovascular death or a worsening heart failure event, such as a hospitalization, an urgent visit requiring intravenous diuretics or an intensified oral diuretic regimen, and the second was the change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 52 weeks, a validated measure of symptoms and physical limitation.
Did tirzepatide reduce heart failure events in SUMMIT?
Tirzepatide was associated with fewer heart failure events in SUMMIT. Cardiovascular death or a worsening heart failure event occurred in 9.9 percent of participants taking tirzepatide and 15.3 percent of those taking placebo, a hazard ratio of 0.62 (95 percent confidence interval 0.41 to 0.95), which corresponds to roughly a 38 percent lower relative risk over the study period.
Figure 2
Events Accumulated More Slowly on Tirzepatide: Cumulative Rate of Cardiovascular Death or Worsening Heart Failure Over 104 Weeks
Sources: Packer et al., SUMMIT, New England Journal of Medicine 2025. Individual results vary.
The difference came mostly from fewer worsening heart failure events, which occurred in about 8.0 percent of the tirzepatide group and about 14.2 percent of the placebo group. Cardiovascular deaths were uncommon in both groups (about 2.2 percent with tirzepatide and 1.4 percent with placebo), and those numbers were too small to support a conclusion in either direction, so SUMMIT does not show that tirzepatide lowers the risk of dying from heart failure.
Figure 3
Where the Difference Came From: SUMMIT Event Rates by Component Over a Median of 104 Weeks
Sources: Packer et al., SUMMIT, New England Journal of Medicine 2025. Individual results vary.
Did people in SUMMIT feel better on tirzepatide?
People taking tirzepatide in SUMMIT reported better symptoms and physical function on average. The KCCQ clinical summary score rose by about 19.5 points at 52 weeks with tirzepatide and by about 12.7 points with placebo, a difference of roughly 7 points, and heart failure researchers generally regard a change of 5 points as one that patients can notice. Six minute walk distance also rose further with tirzepatide, by roughly 26 meters compared with about 10 meters on placebo.
The placebo group also improved, which is common in heart failure trials, and the tirzepatide group improved on top of that baseline effect.
Figure 4
Symptoms and Function at 52 Weeks: Change in KCCQ Clinical Summary Score and Six Minute Walk Distance
Sources: Packer et al., SUMMIT, New England Journal of Medicine 2025. Individual results vary.
How might tirzepatide help a stiff heart?
The mechanism is still being studied, but SUMMIT and its imaging substudy point to several overlapping effects of tirzepatide on the heart and circulation.
Less fat around the heart. A cardiac MRI substudy of SUMMIT, published in the Journal of the American College of Cardiology in 2025, reported that tirzepatide reduced left ventricular mass and the fat surrounding the heart compared with placebo, which may allow the heart to fill at lower pressure.
Lower inflammation. High sensitivity C-reactive protein, a blood marker of systemic inflammation, fell by about 39 percent with tirzepatide versus about 6 percent with placebo, and inflammation is thought to contribute to stiffening of heart muscle in obesity related HFpEF.
Lower blood pressure and blood volume. Systolic blood pressure fell by roughly 5 mm Hg more with tirzepatide than with placebo, and weight loss tends to reduce circulating blood volume, which eases the load on a stiff heart. Weight loss probably explains a large share of the benefit, although researchers have not yet separated it from effects on inflammation and blood vessels.
Figure 5
Beyond the Heart: Percent Reduction in Body Weight and hsCRP at 52 Weeks in SUMMIT
Sources: Packer et al., SUMMIT, New England Journal of Medicine 2025. Individual results vary.
How does SUMMIT compare with the semaglutide heart failure trials?
SUMMIT is the tirzepatide counterpart to the STEP-HFpEF and STEP-HFpEF DM trials, which tested semaglutide 2.4 mg in similar patients and also reported better KCCQ scores (roughly 7 to 8 points more than placebo), longer walking distance and lower inflammation markers. The two medications have never been compared head to head in HFpEF, so current evidence cannot say that one is better for heart failure than the other.
| Question | What SUMMIT tells us |
|---|---|
| HFpEF with BMI of 30 or more | Fewer heart failure events, better symptoms |
| Cardiovascular death | Too few events to draw a conclusion |
| Reduced ejection fraction (HFrEF) | Not studied; excluded from the trial |
| HFpEF with BMI below 30 | Not studied |
| Preventing heart failure in people without it | Outside the scope of SUMMIT |
| Benefit after stopping tirzepatide | Unknown |
Summary of the SUMMIT population and outcomes for educational purposes. Packer et al., New England Journal of Medicine 2025.
What safety issues matter for people with heart failure on tirzepatide?
The side effect profile of tirzepatide in SUMMIT resembled other tirzepatide trials and was dominated by nausea, diarrhea, constipation and vomiting, with about 6.3 percent of tirzepatide participants stopping treatment because of adverse events compared with about 1.4 percent on placebo.
Diuretic doses. As weight and blood volume fall, a diuretic dose that suited someone at the start may become too strong, and vomiting or diarrhea can add to the resulting risk of dehydration, dizziness and kidney strain, so heart failure teams often review diuretics more frequently during dose escalation.
Blood pressure and heart rate. Weight loss combined with blood pressure medications, SGLT2 inhibitors or mineralocorticoid receptor antagonists can occasionally push blood pressure too low, and GLP-1 based medications modestly raise resting heart rate, which is worth monitoring in people with arrhythmias.
Muscle and kidney function. Many people with HFpEF are older and already deconditioned, so adequate protein and supervised activity or cardiac rehabilitation help protect muscle, while regular kidney and electrolyte labs catch problems caused by fluid shifts. Tirzepatide also carries a boxed warning about thyroid C-cell tumors seen in rodents and is not recommended for people with a personal or family history of medullary thyroid carcinoma or MEN 2.
What should someone with HFpEF ask a cardiologist about tirzepatide?
Useful questions for a cardiologist include whether their echocardiogram and symptoms match the kind of HFpEF studied in SUMMIT, how diuretics and blood pressure medications will be monitored during weight loss, how often kidney function and electrolytes should be checked, and whether cardiac rehabilitation would help preserve strength.
The bottom line
The SUMMIT trial suggests that, in adults with HFpEF and obesity, tirzepatide was associated with fewer worsening heart failure events, better symptoms, longer walking distance and lower inflammation over about two years. Because the findings do not extend to reduced ejection fraction or show fewer cardiovascular deaths, anyone with heart failure should weigh tirzepatide together with their cardiologist.
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