Tirzepatide Reduces Risk of Heart Failure Outcomes in Adults with HFpEF and Obesity: Phase 3 SUMMIT Trial

Tirzepatide reduced the relative risk of heart failure outcomes by 38% vs placebo in the phase 3 SUMMIT trial that evaluated adults with heart failure with preserved ejection fraction (HFpEF) and obesity, both with and without type 2 diabetes (T2D).¹

The injectable "twincretin," dosed at 5 mg, 10 mg, and 15 mg, was also associated with statistically significant improvements in HF symptoms and physical limitations, according to a news release from Lilly.1 SUMMIT met all key secondary study endpoints, according to Lilly, including improvement in exercise capacity, reduction in systemic inflammation, and mean weight loss of 15.7% compared with 2.2% seen with placebo.¹

"HFpEF accounts for nearly half of all heart failure cases, and in the US almost 60% of those impacted also live with obesity. Despite a continuing increase in the number of people with both HFpEF and obesity, treatment options remain limited," Jeff Emmick, MD, PhD, senior vice president, product development, Lilly, said in the company announcement.¹ "Previous incretin studies in this population focused on symptoms and physical limitations." Emmick notes SUMMIT is a first-of-its-kind trial, ie, focused on the effect of tirzepatide on HF symptom severity on specific HF outcomes in adults with HFpEF and obesity.

Lilly plans to submit SUMMIT study results to the US FDA and other regulatory agencies later this year.

Tirzepatide is a dual once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist currently approved by the FDA for reduction of hyperglycemia in adults with T2D (Mounjaro, May 2022)² and for chronic weight management in adults with obesity or overweight with related comorbidities (Zepbound, November 2023).³

SUMMIT, a multicenter, randomized, double-blind, parallel, placebo-controlled phase 3 study, enrolled 731 adults across 9 countries and randomly assigned them 1:1 to receive "tirzepatide maximum tolerated dose" of 5 mg, 10 mg or 15 mg or placebo once weekly. The study's coprimary endpoints were to reduce the risk of a composite HF endpoint (time-to-first occurrence of urgent HF visit, HF hospitalization, oral diuretic intensification and cardiovascular [CV] death to study completion) for which median follow up was 104 weeks and the change in score from baseline to week 52 on the Kansas City Cardiomyopathy Questionnaire Clinical Summary (KCCQ-CSS).

Investigators reported, relative to placebo, statistically significant improvements with tirzepatide for risk of the composite HF endpoint(HR, 0.62; 95% CI, 0.41 to 0.95; P = .026) and also for mean change in baseline score for KCCQ-CSS (24.8 vs 15.0). Leading the improvements from baseline for SUMMIT secondary endpoints were increased exercise capacity based on 6-Minute Walk-Test Distance score, reduction in hs-CRP level, and mean body weight reductions.

Lilly described ongoing studies of tirzepatide used in the treatment of CKD and morbidity/mortality in obesity in the news release. Earlier this year the company announced data from the phase 3 SURMOUNT-OSA program,⁴ demonstrating a reduction in the apnea-hypopnea of nearly 63%in individuals with obesity. These findings were submitted to US and other global regulatory bodies. In June, tirzepatide was reported superior to placebo for resolution of metabolic dysfunction-associated steatohepatitis without worsening of fibrosis, findings from the phase 2 SYNERGY-NASH study. And in July, weight loss with tirzepatide was found significantly greater than with semaglutide (Ozempic; Novo Nordisk)

The SUMMIT results join the growing body of evidence for the pleiotropic effects of the incretin mimetic class, particularly in the reduction of risk for CV and renal disease. GLP-1 receptor agonist semaglutide was granted a label expansion in March, broadening the original indication to include reducing risk of CV death, heart attack, and stroke in adults with overweight or obesity with ASCVD. The FDA submission was based on results from the phase 3 SELECT trial. Also in March, Novo Nordisk announced topline results from the phase 3 FLOW study that showed a 24% reduction in the risk of renal disease progression, major adverse CV events and death from renal disease n adults with T2D and chronic kidney disease (CKD).

Lilly scientists will continue to evaluate the SUMMIT data and plan to present results at an upcoming medical meeting and also submit them for publication in a peer-reviewed journal.

References
1. Lilly's tirzepatide successful in phase 3 study showing benefit in adults with heart failure with preserved ejection fraction and obesity. News release. Lilly. August 1, 2024. Accessed August 1, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-successful-phase-3-study-showing-benefit
2. Halsey G. First-In-Class Tirzepatide Wins FDA Approval for Treatment of Type 2 Diabetes. Patient Care. May 16, 2022. https://www.patientcareonline.com/view/first-in-class-tirzepatide-wins-fda-approval-for-treatment-of-type-2-diabetes
3. Halsey G. Tirzepatide approved by FDA for chronic weight management in adults. Patient Care. November 9, 2023. https://www.patientcareonline.com/view/tirzepatide-approved-by-fda-for-chronic-weight-management-in-adults