Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity

The SUMMIT trial was an international, randomized, double-blind, placebo-controlled study that evaluated whether tirzepatide could improve clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF) and obesity — a very high-risk population with few effective therapeutic options. 731 patients with BMI >=30 kg/m² and HFpEF (EF >=50%) were randomized to tirzepatide (maximum dose 15 mg weekly) or placebo, with median follow-up of 104 weeks (2 years).

The dual primary endpoint included (1) adjudicated cardiovascular death or worsening heart failure event; and (2) change in KCCQ-CSS score (quality of life) at 52 weeks. Results were positive for both:

• Cardiovascular composite endpoint: 9.9% with tirzepatide vs. 15.3% with placebo (HR 0.62; 95% CI 0.41-0.95; P=0.026)
• KCCQ-CSS score: improvement of +19.5 points with tirzepatide vs. +12.7 with placebo (difference 6.9; P<0.001)
• 6-minute walk distance: increase of 18.3 m vs. -2.5 m with placebo
• Weight loss: 13.9% with tirzepatide vs. 2.2% with placebo

Relevant secondary analyses included reductions in high-sensitivity C-reactive protein (hsCRP) and NT-proBNP, suggesting improvements in both systemic inflammation and circulatory overload. Imaging substudies demonstrated reductions in left ventricular mass and paracardiac adipose tissue.

SUMMIT consolidated tirzepatide as a therapeutic option for HFpEF associated with obesity — a phenotype increasingly recognized as a distinct clinical entity. Combined with results from the semaglutide STEP-HFpEF program, these data establish GLP-1/GIP agonists as a new therapeutic class for HFpEF, an area historically refractory to pharmacological intervention.