Lilly says tirzepatide cut heart failure events by 38% in phase 3 trial

Eli Lilly said on Aug. 1, 2024 that tirzepatide reduced the risk of heart failure events by 38% compared with placebo in adults with heart failure with preserved ejection fraction (HFpEF) and obesity, in topline results from the phase 3 SUMMIT trial ^[1][2].

The main composite endpoint combined the first occurrence of an urgent heart failure visit, heart failure hospitalization, oral diuretic intensification or cardiovascular death. Tirzepatide cut that risk by 38% over a median follow-up of 104 weeks, with a hazard ratio of 0.62 and a 95% confidence interval of 0.41 to 0.95 (P=0.026) ^[1].

SUMMIT enrolled 731 participants in 10 countries and assigned them in a 1:1 ratio to tirzepatide or placebo. Participants received weekly injections of the highest dose they could tolerate, up to 15 mg ^[1][2]. Dosing started at 2.5 mg and rose by 2.5 mg every four weeks until the maximum tolerated dose was reached ^[1].

The trial had two primary goals. The second was change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), a measure of heart failure symptoms and physical limitations, from baseline to week 52. Under one analysis method, called the efficacy estimand, the score improved by 24.8 points with tirzepatide and 15.0 points with placebo. Under a second method, the treatment-regimen estimand, the improvement was 19.5 points with tirzepatide and 12.7 points with placebo ^[1].

Weight change also differed. Under the efficacy estimand, tirzepatide led to a 15.7% body weight reduction versus 2.2% for placebo. Under the treatment-regimen estimand, the figures were 13.9% and 2.2% ^[1]. The two results were described differently in the coverage: Reuters reported the 13.9% figure as weight loss among patients without type 2 diabetes, while Lilly's announcement attributed it to the treatment-regimen estimand rather than to a subgroup ^[1][2].

All key secondary endpoints were met, Lilly said, including exercise capacity as measured by the 6-Minute Walk-Test Distance and a reduction in the inflammation marker high-sensitivity C-reactive protein (hsCRP) ^[1].

The most common side effects were gastrointestinal — diarrhea, nausea, constipation and vomiting — and were generally mild to moderate, the company said. Lilly said the overall safety profile was consistent with earlier tirzepatide trials, including SURMOUNT and SURPASS ^[1].

Why it matters for patients

HFpEF, in which the heart's left pumping chamber becomes stiff and cannot fill properly, accounts for nearly half of all heart failure cases, and in the U.S. almost 60% of people with it also live with obesity, according to Lilly ^[1][2]. Symptoms include fatigue, shortness of breath, reduced ability to exercise and swelling of the extremities ^[1]. Lilly described treatment options for this group as limited ^[1].

Tirzepatide is not currently approved for HFpEF. The FDA approved it as Mounjaro for type 2 diabetes on May 13, 2022, and as Zepbound for adults with obesity, or with excess weight plus a weight-related condition, on Nov. 8, 2023 ^[1]. The SUMMIT results are data that regulatory agencies will review; any approval would be a separate step. Whether insurers would cover the drug for a heart failure indication has not been disclosed.

Reuters noted that Novo Nordisk has reported data showing its GLP-1 drug Wegovy reduces heart failure symptoms, so tirzepatide is not the only drug in this class being studied for that condition ^[2].

What happens next

Lilly said it plans to submit the SUMMIT results to the FDA and other regulatory agencies starting later this year, and to present them at an upcoming medical meeting and in a peer-reviewed journal ^[1][2]. The dates of that meeting and of publication have not been disclosed. Lilly also said studies of tirzepatide in chronic kidney disease and in morbidity and mortality in obesity are ongoing ^[1].