SUMMIT Subanalysis: Tirzepatide Reduces Symptom Burden in Patients with Obesity-Related HFpEF

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By Lucas Marinacci on

Key Points

  • Patients with heart failure with preserved ejection fraction (HFpEF) and obesity often have significant functional limitations.
  • The SUMMIT trial demonstrated that tirzepatide (TZP), a dual GIP/GLP-1 receptor agonist, improved clinical outcomes, reduced symptom burden, and enhanced functional status in patients with HFpEF and obesity.
  • These benefits were likely driven by reductions in cardiac filling pressures, volume overload, and heart failure medication requirements.

Obesity-related heart failure with preserved ejection fraction (HFpEF) can cause significant limitations in health status, exercise capacity, and quality of life. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, may help improve functional status in this disease state.

On November 18th  2024, findings from “Effects of Tirzepatide on the Clinical and Symptom Burden of Patients with Heart Failure and a Preserved Ejection Fraction, Results from the SUMMIT Trial” were presented at AHA Scientific Sessions 2024 and simultaneous publication on Circulation..

The SUMMIT trial randomized  731 patients with NYHA class II-IV heart failure, ejection fraction ≥50%, and a body mass index ≥30 kg/m² were to tirzepatide (n=364) or placebo (n=367) for a median of 104 weeks. The primary focus of this substudy was a four-level hierarchical composite win ratio assessing time to all-cause mortality, time to and number of heart failure events (HFE), change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), and change in 6-minute walk distance (6MWD) over 52 weeks. Other endpoints included changes in NYHA functional class, NT-proBNP levels, and heart failure medications. At baseline, mean body mass index was 38 kg/m², KCCQ-CSS was 54, and 6MWD was 303 meters. Half of the participants had experienced a worsening heart failure event within the prior 12 months.

At the end of the study, the win ratio significantly favored tirzepatide, with 63% more “wins” compared to placebo (p = 0.004). Improvements were seen across all hierarchical levels, including heart failure events, KCCQ-CSS, and 6MWD. NYHA functional class also improved significantly in the tirzepatide group (OR 2.28, 95% CI 1.53-3.40, p < 0.001), and patients receiving tirzepatide also required fewer increases in diuretic doses (50% fewer intensifications) and more frequent dose reductions compared to placebo. NT-proBNP levels, a marker of cardiac filling pressures, decreased in the tirzepatide group, particularly among patients with elevated baseline levels, but this improvement did not reach statistical significance (p = 0.072).

These results indicate that tirzepatide not only reduces clinical events but also enhances the quality of life and functional status in HFpEF patients with obesity. This study suggests tirzepatide reduced volume overload and likley cardiac filling pressures, key drivers of HFpEF symptom burden. Overal, these findings support tirzepatide as a potential therapeutic strategy for HFpEF and obesity, demonstrating improvement in both clinical outcomes and the underlying pathophysiology.