Tirzepatide (Eli Lilly) significantly reduced the risk of cardiovascular mortality and worsening heart failure events by nearly 40% in patients with obesity and heart failure with preserved ejection fraction (HFpEF) over a median follow-up of roughly 2 years, according to results from the SUMMIT trial presented at the American Heart Association (AHA) 2024 Scientific Sessions.
The treatment benefit was primarily driven by a significant reduction in the risk of worsening HF events requiring hospitalization or urgent intravenous medication, with benefits emerging after 3 to 4 months. Milton Packer, MD (Baylor University Medical Center), emphasized the growing epidemic of obesity and its serious cardiovascular complication, HFpEF.
Impact on HFpEF Treatment
The SUMMIT trial included 731 patients with a mean age of 65.2 years and a mean BMI of 38 kg/m2. Nearly half of the patients had experienced HF decompensation within the previous 12 months, and high-sensitivity C-reactive protein (hs-CRP) levels were significantly elevated. Patients were randomized to receive either tirzepatide or a placebo for up to 3 years.
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist, is already approved for chronic weight management and type 2 diabetes. The study's findings suggest a potential expansion of its therapeutic role in cardiology.
Key Findings from SUMMIT
The primary endpoint, a composite of deaths from cardiovascular causes or worsening HF events, occurred in 9.9% of patients in the tirzepatide group compared to 15.3% in the placebo group (HR 0.62; 95% CI 0.41-0.95). Hospitalizations for HF alone were significantly lower in the tirzepatide arm (3.3%) versus the placebo arm (7.1%), with a hazard ratio of 0.44 (95% CI 0.22-0.87).
There was also a significant improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, with a between-group difference of 6.9 points at 52 weeks favoring tirzepatide (P < 0.001). Additionally, tirzepatide led to an 18-m placebo-corrected improvement in the 6-minute walk distance and a significant 13.9% reduction in body weight compared to a 2.2% reduction in the placebo group (P < 0.001).
Expert Commentary
Sanjiv Shah, MD (Northwestern Feinberg School of Medicine), noted that the SUMMIT trial reinforces the benefits observed with semaglutide in previous STEP-HFpEF trials, solidifying the role of these drugs in HFpEF treatment. Jennifer Ho, MD (Beth Israel Deaconess Medical Center), described SUMMIT as a "practice-changing trial," emphasizing its potential to affect the management of the majority of HFpEF patients who have obesity or are overweight.
Robert Mentz, MD (Duke University School of Medicine), highlighted that SUMMIT provides data showing a benefit in terms of HF hospitalizations beyond the improvement in symptoms and function seen in STEP-HFpEF. He cautioned, however, that the relatively modest number of events in the trial should be kept in context.
Challenges and Future Directions
Despite the promising results, challenges remain in ensuring patient access to these medications. Ho noted that GLP-1 receptor agonist discontinuation is a significant problem, with many patients stopping the medication within a year. Packer emphasized that patients need to stay on the medication to maintain its benefits, while Shah called for healthcare community advocacy to reduce prices and improve coverage for these drugs.
Further research is needed to address the residual risk in HFpEF patients and to explore alternative mechanisms for improving outcomes. Studies from STEP-HFpEF and SUMMIT suggest that weight loss is a major mechanism of benefit, but other factors may also be involved.
