SUMMIT Trial Proves Tirzepatide's Benefit in HFpEF with Obesity

Use of tirzepatide (Zepbound/Mounjaro) reduces risk of worsening heart failure among patients with obesity and heart failure with preserved ejection fraction (HFpEF), according to research presented at the American Heart Association (AHA) Scientific Sessions 2024.

Coming less than 4 months after Eli Lilly and Company announced topline results from the trial in August 2024, SUMMIT trial data from AHA 2024 demonstrate use of tirzepatide was associated with a 38% reduction in risk for heart failure hospitalization or cardiovascular death as well as a 12 to 21% reduction in body weight during the trial.^1,2

“These results indicate tirzepatide produced meaningful benefits for people living with heart failure with preserved ejection fraction and obesity,” said principal investigator Milton Packer, MD, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas and a visiting professor at Imperial College in London.² “The patients experienced a lower combined risk of worsening heart failure events and cardiovascular disease death, along with improved health status and exercise tolerance. This is the first trial to demonstrate that a medication can change the clinical trajectory of the disease in patients with HFpEF and obesity.”

The first dual GIP/GLP-1 receptor agonist to receive approvals from the US Food and Drug Administration (FDA) for type 2 diabetes and obesity, tirzepatide has set itself apart from other agents and classes gaining province during the ongoing revolution of cardiometabolic disease management. Eli Lilly and Company’s August 2024 announcement of topline results came less than a year after Novo Nordisk debuted their STEP-HFpEF program, which included 2 trials examining use of semaglutide against placebo for symptom scores and functional outcomes. Unlike these trials, the phase 3 SUMMIT trial included heart failure outcomes as a primary endpoint.1,2,3

A multicenter, randomized, double-blind, parallel, placebo-controlled phase 3 trial, SUMMIT enrolled 731 adult patient adults with HFpEF and obesity, with or without type 2 diabetes, from 10 countries across 4 continents. These patients were randomized in a 1:1 ratio to tirzepatide or placebo therapy, with 364 receiving tirzepatide and 367 receiving placebo therapy.¹

The trial leveraged a pair of primary outcomes of interest. The first was a composite of time-to-first occurrence of urgent heart failure visit, heart failure hospitalization, oral diuretic intensification and cardiovascular death to study completion and the second primary endpoint was change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) from baseline to week 52.¹

Results of the trial suggested death from cardiovascular causes or a worsening heart failure event occurred among 9.9% of the tirzepatide group and 15.3% of the placebo group (HR, 0.62; 95% CI, 0.41 to 0.95; P = .026). Further analysis indicated use of tirzepatide was associated with a 46% relative reduction in risk of worsening heart failure events(HR, 0.54; 95% CI, 0.34 to 0.85). However, investigators pointed out adjudicated death from cardiovascular causes occurred among 2.2% of the tirzepatide group and 1.4% of the placebo group (HR, 1.58; 95% CI, 0.52 to 4.83).¹

Analysis of KCCQ-CSS at 52 weeks favored tirzepatide, with a mean change of 19.5 (SD, 1.2) among the tirzepatide group and 12.7 (SD, 1.3) in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P <.001). Safety analysis suggested adverse events leading to discontinuation of the trial drug occurred among 6.3% of the tirzepatide group and among 1.4% of the placebo group.¹

In a November 16, 2024 press release announcing the presentation of results at AHA 2024, Eli Lilly and Company pointed out they had submitted tirzepatide for the treatment of HFpEF and obesity to the US FDA and the European Medicines Agency and plans to submit to other regulatory agencies starting later this year.³

"Cardiometabolic diseases, such as heart failure and obesity, are closely linked and often coexist. New approaches are needed to address the interrelated nature of these diseases. At Lilly, we want to better understand the root causes of these conditions and how they impact each other so we're better able to treat them," said Jeff Emmick, MD, PhD, senior vice president of product development, at Eli Lilly and Company.³ "Currently, no treatments are available specifically for obesity-related HFpEF in the US. The SUMMIT data suggest that, if approved, tirzepatide could provide a significant advancement for these patients, potentially setting a new standard of care."

References:

1. Packer M. Tirzepatide for Patients with Heart Failure with Preserved Ejection Fraction and Obesity: the SUMMIT Trial. Paper presented at: American Heart Association Scientific Sessions 2024; November 15 - 18; Chicago, Il. Accessed November 16, 2024.
2. American Heart Association. Tirzepatide lowered risk of worsening heart failure and CVD death for obese adults. American Heart Association. November 16, 2024. Accessed November 16, 2024. https://newsroom.heart.org/news/tirzepatide-lowered-risk-of-worsening-heart-failure-and-cvd-death-for-obese-adults.
3. Eli Lilly and Company. Lilly’s tirzepatide reduced the risk of worsening heart failure events by 38% in adults with heart failure with preserved ejection fraction (HFPEF) and obesity. Eli Lilly and Company. November 16, 2024. Accessed November 16, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-reduced-risk-worsening-heart-failure-events.