Abstract Body (Do not enter title and authors here): Background: Patients with heart failure and a preserved ejection fraction (HFpEF) have severe clinical and symptomatic disability. We hypothesized that tirzepatide (TZP), a long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist, would improve the clinical and symptom burden of patients with HFpEF and obesity.
Methods: In this double-blind trial, 731 patients with class II-IV heart failure, ejection fraction ≥ 50% and body mass index ≥ 30 kg/m² were randomized to TZP (titrated to a maximum tolerated dose of up to 15 mg subcutaneously weekly) (n=364) or placebo (n=367), added to background therapy, for a median of 104 weeks. Clinical and symptomatic endpoints included a stratified 4 level hierarchical composite win ratio: time to all-cause mortality, time to and number of heart failure events (HFE), change from baseline to 52 weeks in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and 6-minute walk distance (6MWD). In addition, a change in New York Heart Association (NYHA) class , N-terminal pro B type natriuretic peptide (NT-proBNP) and heart failure medications from baseline to 52 weeks were examined.
Results: At randomization, mean body mass index was 38 kg/m², and patients exhibited substantial limitations of health status (mean KCCQ-CSS=54) and exercise capacity (mean 6-minute walk distance=303 meters), and half the patients had a worsening HFE in the prior 12 months. The win ratio markedly favored TZP (1.63, 95% CI 0.73, 3.67; p = 0.004) with 63% more wins in TZP treated patients. TZP had more wins in each of the HFE, KCCQ, and 6 MWD hierarchical levels. NYHA class was significantly improved in TZP group (OR 2.28 (95% CI 1.53, 3.40, p< 0.001). HF medication intensification was decreased more often in the TZP group, especially the use of diuretics (50% fewer increases and 50% more frequent decreases in dose in TZP group). NT-proBNP decreased in TZP (p=0.072) particularly in patients with baseline values ≥ 175 pg/ml. The decrease in HF medications and NT-proBNP, likely reflecting a reduction in filling pressure and volume overload, contributed to reduced symptomatic burden produced by TZP.
Conclusions: Tirzepatide reduced clinical events, improved health status, and reduced symptom burden in patients with HFpEF and obesity. One mechanism underlying these outcomes likely reflects a reduction in the increased filling pressure and volume overload commonly found in HFpEF.