Tirzepatide and Heart Failure: The SUMMIT Trial Explained

There is a strange gap in the tirzepatide story. A major trial showed the drug cut heart failure events by 38 percent in a group of people who have almost no good treatment options. The result was published in the New England Journal of Medicine, presented as late-breaking science at the American Heart Association, and described by its lead investigator as the first time a medication has been shown to change the clinical trajectory of the disease.

And there is still no approved heart failure indication for tirzepatide anywhere. This page explains what the trial found, and why that gap exists.

What is HFpEF, and why is it hard to treat?

Heart failure with preserved ejection fraction — HFpEF, usually said as “heff-peff” — is heart failure where the pumping function looks normal on an ultrasound. The ejection fraction, the percentage of blood pushed out with each beat, is 50 percent or above. The problem is on the filling side: the heart muscle has become stiff and cannot relax properly between beats, so it does not take in enough blood to send out.

The symptoms are breathlessness, exhaustion and swelling, usually in the ankles and feet. It accounts for roughly half of all heart failure cases, it is strongly linked to obesity, and until recently the list of treatments shown to change outcomes was close to empty.

That is the context for SUMMIT. It was the first trial in obesity-related HFpEF to make heart failure events a prespecified primary endpoint rather than just measuring how people felt [4].

What did SUMMIT actually find?

SUMMIT randomized 731 adults with stable heart failure (New York Heart Association class II to IV), an ejection fraction of at least 50 percent, and a BMI of at least 30, to tirzepatide titrated up to a maximum tolerated dose of 5, 10 or 15 mg weekly, or to placebo, on top of their usual heart failure medications. Median follow-up was 104 weeks, with some people treated for up to three years [1].

The participants were not a mild group. Average age 65, 54 percent women, average BMI 38.2, and 53 percent had already had a worsening heart failure event in the previous 12 months.

The trial had two primary endpoints, and both were met [1][7]:

Heart failure events. Cardiovascular death or a worsening heart failure event occurred in 36 people (9.9 percent) on tirzepatide and 56 people (15.3 percent) on placebo — a hazard ratio of 0.62, meaning a 38 percent relative reduction (95% CI 0.41–0.95, P=0.026).

Symptoms and physical limitation. Scores on the Kansas City Cardiomyopathy Questionnaire, a standard heart failure quality-of-life measure, improved by 19.5 points on tirzepatide versus 12.7 on placebo at 52 weeks — a difference of 6.9 points (95% CI 3.3–10.6, P<0.001).

The secondary results filled in the picture [7]:

• Worsening heart failure events alone: 8.0 percent versus 14.2 percent (hazard ratio 0.54)
• Hospitalization for heart failure: reduced 56 percent [3]
• 6-minute walk distance: improved 26.0 meters versus 10.1
• Systolic blood pressure: −4.6 versus +0.1 mmHg
• hsCRP, a marker of inflammation: −38.8 percent versus −5.9 percent
• Body weight: −13.9 percent versus −2.2 percent

Side effects were mostly gastrointestinal — diarrhea in 18.4 percent versus 6.3 percent, nausea 17.0 versus 6.5, constipation 14.8 versus 6.0 — and led 23 people on tirzepatide and 5 on placebo to stop the study drug [3].

What about deaths?

Here is the part that headlines usually skip, and it matters.

There were 15 cardiovascular deaths in the entire trial: 8 in the tirzepatide group (2.2 percent) and 5 in the placebo group (1.4 percent). The hazard ratio was 1.58 with a confidence interval running from 0.52 to 4.83 — which is another way of saying the trial had no ability to detect a difference in either direction [1][7]. All-cause mortality was 5.2 percent versus 4.1 percent, also not distinguishable.

Eleven of the 15 cardiovascular deaths were not preceded by a worsening heart failure event, and two in the tirzepatide group happened more than 15 months after the person had stopped taking the drug [4].

So the honest description of SUMMIT is: fewer people got sicker, felt better and walked further. It did not show that fewer people died. Both halves belong in the summary.

How did tirzepatide appear to work?

Two companion analyses tried to answer that.

A Nature Medicine mechanistic analysis found a coherent pattern: tirzepatide reduced systolic blood pressure by about 5 mmHg, cut estimated blood volume by 0.58 liters and lowered C-reactive protein by 37 percent. At the same time, kidney filtration rate improved, urine albumin fell, and both NT-proBNP and troponin T — markers of cardiac strain and injury — went down [5]. In plain terms: less fluid and pressure loading on a stiff heart, less systemic inflammation, and less measurable damage to the heart and kidneys.

A Circulation analysis showed the benefit was not narrow. Across walking distance, quality-of-life scores, patients’ own global impression of their health, New York Heart Association class and even the number of heart failure medications needed, tirzepatide came out ahead, with a hierarchical composite win ratio of 1.63 [6].

What none of this settles is whether the benefit is a weight effect or a drug effect. Everyone in the trial had a BMI of at least 30 and lost roughly 12 percentage points more weight than placebo. Losing that much weight would be expected to help obesity-related HFpEF on its own. That ambiguity turned out to be decisive for regulators.

Why is tirzepatide not approved for heart failure?

Lilly filed with both the FDA and the European Medicines Agency after SUMMIT [3]. Neither application produced an indication.

In the United States, Lilly withdrew the application. In an investor briefing at the start of May 2025, chief scientific officer Dan Skovronsky said the company had withdrawn the US HFpEF application after discussions with the FDA, which “indicated an additional confirmatory clinical trial is required.” He added something revealing about the economics: “all the patients in this trial and for this indication are already covered under the obesity indication. So it’s not a new population to treat. It’s rather a new benefit for people that might already be understood to doctors today.” He also warned the decision “could have a curtailing effect on investments in HFpEF” [8].

A European guideline body has since gone the other way. At the European Society of Cardiology Congress in Munich (August 28-31, 2026), the ESC issued updated heart failure guidelines recommending semaglutide and tirzepatide for patients with HFpEF and obesity [15]. Guideline endorsement and US labeling have now diverged: a major European cardiology society recommends the drugs for the indication the FDA declined to grant without a confirmatory trial. US prescribers reading European guidance should note that the recommendation is not a US indication and does not change what Lilly may promote. (updated 2026-09-14)

In Europe, regulators reached a similar destination by a different route. On January 30, 2026 the EMA published its assessment. It acknowledged that tirzepatide significantly reduced heart failure hospitalizations and improved quality of life. But it noted the drug did not reduce cardiovascular deaths, and that uncertainty remained over whether the benefit was independent of weight loss. Since these patients are already covered by the approved weight management indication, the agency concluded a separate HFpEF indication was not needed. It did agree to add the SUMMIT data to the product information so clinicians can see it [9][10].

Both decisions rest on the same two objections: no mortality benefit, and no proof the effect is anything more than what weight loss would do.

The current US Zepbound prescribing information, verified on September 14, 2026, lists only weight management and obstructive sleep apnea [11]. There is no heart failure indication.

This is not unique to tirzepatide. Novo Nordisk hit the same wall with semaglutide’s HFpEF filing, withdrawing it in 2024.

What does SURPASS-CVOT change?

SURPASS-CVOT is a different trial asking a different question, and it is worth keeping the two straight.

It enrolled 13,299 adults with type 2 diabetes and established atherosclerotic cardiovascular disease and followed them for a median four years. There was no placebo arm — researchers judged that unethical in this population — so tirzepatide was compared head to head against dulaglutide (Trulicity), a drug already shown to reduce cardiovascular events [12].

The combined rate of cardiovascular death, heart attack or stroke was 12.2 percent on tirzepatide and 13.1 percent on dulaglutide, a hazard ratio of 0.92. That met the prespecified bar for noninferiority (P=0.003) but not for superiority (P=0.09). Death from any cause was 16 percent lower on tirzepatide (hazard ratio 0.84), a secondary finding the investigators described as exploratory [12].

This is the trial behind the August 28, 2026 FDA approval of Mounjaro to lower the risk of major adverse cardiovascular events in adults with type 2 diabetes at high risk for them [14]. Note the boundaries: type 2 diabetes only, Mounjaro only, and nothing about heart failure.

A later post hoc analysis widened the endpoint to six components including kidney outcomes and heart failure, and found a hazard ratio of 0.84 favoring tirzepatide, with a number needed to treat of 27. Every component contributed. But post hoc composites are exploratory by definition.

What would settle the question?

SURMOUNT-MMO is the trial to watch. It enrolled 15,374 adults aged 40 and older with a BMI of at least 27, without diabetes, who either have cardiovascular disease or are at risk of it. Its primary endpoint is a five-component composite: death from any cause, non-fatal heart attack, non-fatal stroke, coronary revascularization, and heart failure events requiring hospitalization or urgent care [13].

Two things make it different from everything above. It includes people who have not yet developed cardiovascular disease — the first incretin outcome trial to cover primary prevention. And it is large enough and long enough to detect a mortality difference if one exists. Completion is estimated for October 2027.

A note of caution on sourcing: several websites describe SURMOUNT-MMO as a 17,604-participant trial with a three-point MACE primary endpoint. The registry record and the peer-reviewed design paper both say 15,374 participants and a five-component composite. Use the registry.

The bottom line

SUMMIT was a real result. In people with obesity-related HFpEF — a condition with very little to offer them — tirzepatide reduced worsening heart failure, cut hospitalizations, improved how people felt and how far they could walk, and lowered markers of strain on the heart and kidneys.

It did not show a mortality benefit, and regulators on both sides of the Atlantic concluded that the effect could not be distinguished from what the weight loss alone would do — and that the patients in question already qualify for treatment under the obesity indication anyway.

For someone living with HFpEF and obesity, the practical upshot is that the SUMMIT data exist and can inform a conversation with a cardiologist, but tirzepatide is not an approved heart failure treatment. Whether that changes probably depends on what SURMOUNT-MMO reports in 2027 or later.

Sources

1. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity — New England Journal of Medicine, November 2024
2. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity — PubMed record — PubMed
3. Lilly’s tirzepatide reduced the risk of worsening heart failure events by 38% in adults with HFpEF and obesity — Eli Lilly and Company, November 2024
4. Tirzepatide lowered risk of worsening heart failure and CVD death for obese adults — American Heart Association Newsroom, November 2024
5. Effects of tirzepatide on circulatory overload and end-organ damage in HFpEF and obesity: a secondary analysis of the SUMMIT trial — Nature Medicine, November 2024
6. Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity — Circulation, November 2024
7. SUMMIT trial summary — American College of Cardiology
8. Lilly Withdraws Tirzepatide Application to FDA for Heart Failure — ConscienHealth, May 2025
9. Outcome of assessment on use of Mounjaro in treatment of heart failure with preserved ejection fraction in adults with obesity — European Medicines Agency, January 2026
10. CHMP opposes Lilly’s Mounjaro in heart failure — Endpoints News, January 2026
11. ZEPBOUND (tirzepatide) injection prescribing information — US Food and Drug Administration, 2026
12. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes — New England Journal of Medicine, December 2025
13. SURMOUNT-MMO registry record (NCT05556512) — ClinicalTrials.gov
14. FDA approves Lilly’s Mounjaro to reduce cardiovascular risk in adults with type 2 diabetes — Eli Lilly and Company, August 2026
15. ESC 2026: heart attack reclassification, rights, gender imbalance — and the updated heart failure guideline — pharmaphorum, ESC Congress 2026 (Munich, August 28-31, 2026)