SUMMIT: tirzepatide cuts heart failure events by 38 percent in obesity-related HFpEF

Eli Lilly's tirzepatide reduced heart failure events in people with obesity and heart failure with preserved ejection fraction (HFpEF), according to the SUMMIT trial presented November 16, 2024 at the American Heart Association Scientific Sessions in Chicago and published the same day in the New England Journal of Medicine ^[1][2][3]. Tirzepatide is the molecule sold as Mounjaro for type 2 diabetes and Zepbound for weight management ^[3].

SUMMIT randomly assigned 731 adults — 364 to tirzepatide, 367 to placebo — at 129 centers across nine countries including the United States ^[1][2]. Participants had to have an ejection fraction of at least 50% and a body mass index of at least 30 ^[1]. The average age was 65.2 years, 53.8% were women, and mean BMI was 38.3 ^[2]. Doses started at 2.5 mg once weekly and rose by 2.5 mg every four weeks to a maximum tolerated dose of 5, 10 or 15 mg ^[3]. Median follow-up was 104 weeks, with some patients treated up to three years ^[1][3].

What the trial found

The first primary endpoint — adjudicated cardiovascular death or a worsening heart failure event — occurred in 36 patients (9.9%) on tirzepatide versus 56 (15.3%) on placebo, a hazard ratio of 0.62 (95% CI, 0.41 to 0.95; P=0.026), described as a 38% relative risk reduction ^[1][3].

Most of that difference came from heart failure events rather than deaths. Worsening heart failure events happened in 29 patients (8.0%) versus 52 (14.2%), a hazard ratio of 0.54 (95% CI, 0.34 to 0.85) ^[1]. Hospitalization for heart failure occurred in 12 patients (3.3%) on tirzepatide versus 26 (7.1%) on placebo, which Lilly described as a 56% reduction ^[3]. Adjudicated cardiovascular deaths were numerically higher on tirzepatide — 8 (2.2%) versus 5 (1.4%) — with a hazard ratio of 1.58 and a wide confidence interval from 0.52 to 4.83, meaning the trial could not tell whether that difference was real or chance ^[1]. There were 15 cardiovascular deaths in total; two in the tirzepatide group happened after patients had been off the drug for more than 15 months, and 34 patients died from any cause ^[2][3].

The second primary endpoint was symptom burden on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, a 23-question survey scored 0 to 100 ^[1][2]. Scores rose 19.5 points on tirzepatide versus 12.7 on placebo, a difference of 6.9 points (95% CI, 3.3 to 10.6; P<0.001) ^[1].

Secondary results at 52 weeks: body weight fell 15.7% on tirzepatide versus 2.2% on placebo in one analysis, six-minute walk distance improved by 38.2 meters versus 7.9 meters, and high-sensitivity C-reactive protein, an inflammation marker, fell 43.4% versus 3.5% ^[3]. The AHA release, using a different statistical approach, reported an 11.9% greater weight loss and an 18.3-meter greater walking distance versus placebo ^[2] — the same data analyzed two ways, so the figures differ depending on the source ^[2][3].

Side effects were mainly gastrointestinal: diarrhea (18.4% vs 6.3%), nausea (17.0% vs 6.5%) and constipation (14.8% vs 6.0%) ^[3]. Adverse events led 23 patients (6.3%) on tirzepatide and 5 (1.4%) on placebo to stop the study drug ^[1].

Why it matters for patients

HFpEF is a form of heart failure where the heart pumps normally but stiffens, and it is strongly tied to obesity. Investigators called SUMMIT the first trial to test any medication's effect on major heart failure outcomes in this specific group ^[2]. Lilly said no treatment is currently approved specifically for obesity-related HFpEF in the U.S. ^[3].

Some caveats belong alongside the headline number. The trial enrolled 731 people and counted 92 primary events total, so it was not large enough to settle questions about death rates ^[1]. The AHA noted a key limitation: BMI was used to define obesity, and many people with HFpEF carry excess belly fat while having a BMI under 30, so they would not have qualified ^[2]. The trial was funded by Eli Lilly, and several authors are Lilly employees ^[1].

What happens next

Lilly said it submitted tirzepatide for HFpEF with obesity to the FDA and the European Medicines Agency and planned filings elsewhere ^[3]. The sources do not give a decision date, so the timing and outcome of U.S. review are not yet known. The NEJM paper appeared online November 16, 2024 and in print January 30, 2025 ^[1].