Abstract Body (Do not enter title and authors here): Background: Obesity contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Tirzepatide, a long-acting agonist of gastric inhibitory polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss and may have clinical benefits in HFpEF.
Methods: We randomly (double-blind) assigned 731 patients with class II-IV heart failure, ejection fraction ≥50% and body mass index ≥30 kg/m² to tirzepatide (titrated to 15 mg subcutaneously weekly) (n=364) or placebo (n=367), added to background therapy, for a median of 104 weeks. The dual primary outcomes were (1) cardiovascular death or worsening heart failure events (α=0.04) and (2) change in health status at 52 weeks, assessed by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), α=0.01.
Results: The mean body mass index was »38 kg/m², and patients exhibited substantial limitations of health status (mean KCCS-CSS=54) and exercise capacity (mean 6-minute walk distance=307 meters), and half the patients had a worsening heart failure event in the prior 12 months. Cardiovascular death or worsening heart failure occurred in 36 patients in the tirzepatide group and 56 patients in the placebo group — 5.5 and 8.8 events per 100 patient-years of follow-up, respectively — hazard ratio, 0.62; 95% CI, 0.45 to 0.95; P=0.026. This effect was driven by a reduced risk of worsening heart failure events requiring hospitalization and intravenous diuretic intensification (hazard ratios ≈0.40-0.45), without a reduction in cardiovascular death. At 52 weeks, KCCQ-CSS score increased more in the tirzepatide than the placebo group (between-group difference 6.9 (3.3-10.6), P<0.001. For all key secondary endpoints, as compared with the placebo group at 52 weeks, the tirzepatide group showed a loss of body weight (by 11.6%), an increase in 6-minute walk distance (by 18.3 [9.9-26.7] meters), and a decrease in high-sensitivity C-reactive protein (by 35%), all P<0.001. Generally mild-to-moderate gastrointestinal adverse events were seen in the tirzepatide group, and 2% of patients discontinued treatment due to gastrointestinal adverse events.
Conclusions: Tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure events and improved health status in patients with HFpEF and obesity.