Tirzepatide, a long-acting GIP/GLP-1 receptor agonist, has demonstrated significant clinical benefits for individuals with obesity and heart failure with preserved ejection fraction (HFpEF). The SUMMIT trial revealed that tirzepatide (Zepbound, Mounjaro) reduced the incidence of cardiovascular death or worsening heart failure events compared to placebo.
SUMMIT Trial Results
In the SUMMIT trial, conducted over a median follow-up of 104 weeks, patients treated with tirzepatide experienced a notable decrease in cardiovascular death or worsening heart failure events (9.9% vs 15.3%, HR 0.62, 95% CI 0.41-0.95). This translated to 5.5 vs 8.8 events per 100 patient-years, primarily driven by a reduced risk of worsening heart failure events requiring hospitalization or urgent intravenous drug therapy. The findings were presented at the American Heart Association (AHA) annual meeting and simultaneously published in the New England Journal of Medicine.
Expert Commentary
Dr. Jennifer Ho of Harvard Medical School commented that this trial could change clinical practice and solidify incretin-based therapies as a key treatment for obesity-HFpEF. Dr. Milton Packer of Baylor University Medical Center and Imperial College London, who presented the study, emphasized that SUMMIT is the first GLP-1 receptor agonist trial specifically powered to assess major heart failure outcomes in HFpEF patients with obesity.
Additional Benefits Observed
Tirzepatide demonstrated superiority over placebo in several other endpoints:
- Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ-Clinical Summary Score), improved by +6.9 points from baseline to 52 weeks (P < 0.001).
- Functional capacity, assessed by the 6-minute walk distance, increased by +18.3 meters (P < 0.001).
- Weight reduction showed a between-group difference of 11.6% (P < 0.001).
- Systemic inflammation decreased by a between-group difference of 34.9% (P < 0.001).
Safety Profile and Considerations
In the SUMMIT trial, 4.1% of participants in the tirzepatide group discontinued treatment due to gastrointestinal side effects, aligning with the known safety profile of GLP-1 receptor agonists. There were small, non-significant increases in cardiovascular death (2.2% vs 1.4%) and all-cause mortality (5.2% vs 4.1%) in the tirzepatide group, which researchers attributed to chance.
Context within HFpEF Treatment Landscape
HFpEF is a prevalent form of heart failure, particularly affecting women, with obesity being a significant contributing factor. While sacubitril/valsartan (Entresto) and SGLT2 inhibitors like empagliflozin (Jardiance) and dapagliflozin (Farxiga) are already approved for HFpEF, tirzepatide offers a novel approach by targeting obesity, a key driver of the condition. Tirzepatide is currently FDA-approved for type 2 diabetes and chronic weight management.
Challenges and Future Directions
Despite the promising results, challenges remain in implementing GLP-1 receptor agonists in clinical practice. These include access barriers, health inequities, and the need for provider expertise in initiating and managing these therapies. Payers may also be hesitant due to the large number of eligible patients and the associated costs.
The SUMMIT trial included 731 participants with HFpEF and obesity (BMI ≥ 30), randomized to weekly tirzepatide or placebo for up to 3 years. The average age was 65 years, with over 50% being women and approximately 30% non-white. The observed clinical benefit was largely due to fewer instances of worsening heart failure requiring hospitalization or IV drugs (HR 0.41, 95% CI 0.22-0.75) and hospitalizations for heart failure (HR 0.44, 95% CI 0.22-0.87).
While the precise mechanism of benefit remains unclear, researchers suggest that tirzepatide's effects may be related to its ability to reduce fat mass, thereby reducing plasma volume expansion and the inflammatory response associated with HFpEF.
