A secondary analysis of the SUMMIT trial has found that the benefits of tirzepatide on reducing the risk of cardiovascular death or worsening heart failure (HF) are consistent across all levels of obesity in patients with heart failure with preserved ejection fraction (HFpEF).¹ However, patients with a higher baseline body mass index (BMI) experienced greater improvements in exercise capacity and other secondary measures.
Tirzepatide is a long-acting dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, which has previously been shown to be effective in this patient population.²
This secondary analysis examined data from the SUMMIT trial, a randomised, placebo-controlled study involving 731 patients with New York Heart Association (NYHA) functional class II–IV HFpEF and a BMI of ≥30 kg/m².¹ Patients were assigned to receive either once-weekly tirzepatide (n=364) or placebo (n=367) for 52 weeks.
The primary outcomes were the time to cardiovascular death or worsening HF, and the change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks. Key secondary outcomes included changes in 6-minute walk distance (6MWD), C-reactive protein (CRP), and body weight. For this analysis, outcomes were stratified by baseline BMI and waist-height ratio (WHR) tertiles.
The analysis confirmed that patients with higher baseline BMI were typically younger, more likely to be female, and presented with more severe HF symptoms, greater volume expansion, and more pronounced systemic inflammation.
The effect of tirzepatide on the primary composite outcome of cardiovascular death or worsening HF was consistent across all BMI and WHR tertiles, showing no evidence of heterogeneity.
However, the magnitude of benefit for several secondary endpoints was greater in patients with more severe obesity. Compared with placebo, the estimated treatment difference for improvement in 6MWD with tirzepatide increased across baseline BMI tertiles (9.9 m vs 26.3 m vs 37.5 m; P=0.025). Similarly, greater reductions were observed in body weight (–10.7% vs –11.8% vs –14.4%; P=0.006) and systolic blood pressure (–1.00 mmHg vs –6.65 mmHg vs –6.62 mmHg; P=0.035) in those with higher baseline BMI. A trend towards greater improvement in KCCQ-CSS was also noted (P=0.097).
Among patients receiving tirzepatide, a greater degree of weight loss at 52 weeks was significantly associated with larger improvements in 6MWD, KCCQ-CSS, and CRP levels.
These findings from the SUMMIT trial reinforce the efficacy of tirzepatide in the obesity-related HFpEF phenotype, regardless of the initial severity of obesity. While the crucial benefit of reducing HF events and cardiovascular death is consistent, the results suggest that patients with higher BMI may derive additional, more pronounced functional and symptomatic benefits. As stated by the authors, “Tirzepatide consistently reduced the risk of HF or cardiovascular death regardless of baseline BMI, but there was evidence suggesting greater improvement in 6MWD in those with higher BMI at baseline.”¹ This highlights that the degree of weight loss achieved with tirzepatide is a key mediator of improvements in exercise capacity, symptoms, and inflammation.
References
1. Borlaug BA, Zile MR, Kramer CM, et al. Impact of Body Mass Index, Central Adiposity, and Weight Loss on the Benefits of Tirzepatide in HFpEF: The SUMMIT Trial. JACC. 2025;86(4):242–255. https://doi.org/10.1016/j.jacc.2025.04.059
2. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392:427-437. https://doi.org/10.1056/nejmoa2410027
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