Tirzepatide cut heart failure events by 38% in obesity-related HFpEF, SUMMIT trial finds

Tirzepatide reduced the combined risk of cardiovascular death or a worsening heart failure event by 38 percent compared with placebo in adults with heart failure with preserved ejection fraction and obesity, according to results from 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].

SUMMIT is described as the first trial to test the effect of any medication on major heart failure outcomes in patients with HFpEF and obesity ^[2]. Researchers screened 1,494 people between April 2021 and June 2023 at 129 health centers in nine countries and randomized 731 of them ^[2]. Every participant was 40 or older, had an ejection fraction of at least 50 percent, and had a body-mass index of at least 30 ^[1]. Their mean age was 65.2 years, 53.8 percent were women, and mean BMI was 38.3 ^[2].

Participants received weekly injections of tirzepatide or placebo. The dose started at 2.5 mg and was increased every four weeks up to a maximum tolerated dose of 5, 10 or 15 mg ^[3]. All continued their usual medications, including heart failure drugs ^[2]. Median follow-up was 104 weeks, with some patients treated for up to three years ^[1][2].

The composite of cardiovascular death or a worsening heart failure event occurred in 36 patients (9.9 percent) taking tirzepatide and 56 patients (15.3 percent) taking placebo, a hazard ratio of 0.62 (95 percent confidence interval, 0.41 to 0.95; P=0.026) ^[1]. Worsening heart failure events alone occurred in 8.0 percent versus 14.2 percent, a hazard ratio of 0.54 (95 percent CI, 0.34 to 0.85) ^[1]. Adjudicated cardiovascular death occurred in 8 patients (2.2 percent) on tirzepatide and 5 (1.4 percent) on placebo, a difference the trial was not sized to settle (hazard ratio, 1.58; 95 percent CI, 0.52 to 4.83) ^[1]. Eli Lilly, which funded the trial, reported that hospitalization for heart failure fell 56 percent, from 7.1 percent to 3.3 percent ^[3].

On the second primary endpoint, the Kansas City Cardiomyopathy Questionnaire clinical summary score rose 19.5 points with tirzepatide versus 12.7 with placebo at 52 weeks, a between-group difference of 6.9 points (95 percent CI, 3.3 to 10.6; P<0.001) ^[1]. Lilly reported average weight change at 52 weeks of −15.7 percent versus −2.2 percent and a drop in high-sensitivity C-reactive protein of 43.4 percent versus 3.5 percent, both using its efficacy estimand; the treatment-regimen figures were −13.9 percent versus −2.2 percent for weight and −38.8 percent versus −5.9 percent for hs-CRP ^[3]. Six-minute walk distance improved by 38.2 meters versus 7.9 meters under the efficacy estimand and 26.0 versus 10.1 meters under the treatment-regimen estimand ^[3], while the American Heart Association's release described an 18.3-meter between-group difference at one year ^[2].

Side effects were mostly gastrointestinal. Adverse events led to discontinuation in 23 patients (6.3 percent) on tirzepatide and 5 (1.4 percent) on placebo ^[1]. The most common side effects reported were diarrhea (18.4 percent versus 6.3 percent), nausea (17.0 percent versus 6.5 percent) and constipation (14.8 percent versus 6.0 percent) ^[3].

One limitation the investigators noted: the trial used BMI to define obesity. Some people with HFpEF have a high waist-to-height ratio but a BMI below 30, so they did not meet the study's entry criteria, and more research is needed to identify who can benefit ^[2].

Why it matters for patients

Tirzepatide is sold as Mounjaro for type 2 diabetes and as Zepbound for adults with obesity or overweight plus at least one weight-related condition; it is not FDA-approved to treat HFpEF ^[3]. Lilly said no treatments are currently available specifically for obesity-related HFpEF in the United States ^[3]. Whether the heart failure benefits depend on weight loss, inflammation reduction, or something else has not been established.

People with HFpEF and obesity who took the drug in this trial were also on standard heart failure medications, and the trial compared tirzepatide against placebo, not against another weight-loss drug ^[2]. Effects in people with HFpEF and a BMI under 30 were not studied ^[2]. Cost and insurance coverage of tirzepatide for a heart failure indication are not addressed in these sources.

What happens next

Lilly says it has submitted tirzepatide to the FDA and the European Medicines Agency for the treatment of HFpEF and obesity and plans submissions to other agencies ^[3]. No decision date has been disclosed. The results appeared in the January 30, 2025 print issue of the New England Journal of Medicine ^[1], and Lilly said additional SUMMIT data would be presented at the AHA meeting and published in peer-reviewed journals ^[3].