Effects of Tirzepatide in Obesity-Related HFpEF by Sex

BACKGROUND The SUMMIT trial showed that the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide decreased risk of cardiovascular death or worsening heart failure (HF) in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Women outnumber men with HFpEF, and there are sexual dimorphisms in the relationships between body fat and pathophysiology that could influence response to tirzepatide. OBJECTIVES This study aims to compare baseline characteristics and effects of tirzepatide on primary and other endpoints in women and men with obesity-related HFpEF. METHODS In the SUMMIT trial, 731 patients with NYHA functional class II-IV HFpEF and body mass index (BMI) ≥30 kg/m2 were randomly assigned to tirzepatide (n = 364) or placebo (n = 367). The primary outcomes were time to cardiovascular death or worsening HF and change in 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, and body weight at 52 weeks. Baseline characteristics and effects of tirzepatide on primary and secondary endpoints were contrasted by sex. RESULTS Compared with men (n = 338, 46.2%), women with obesity-related HFpEF (n = 393, 53.8%) had greater BMI, waist to height ratio (WHtR), symptom severity (higher NYHA functional class, lower KCCQ-CSS), and poorer exercise capacity (lower 6MWD), whereas men had greater left ventricular remodeling and paracardiac fat. Greater baseline BMI or WHtR were correlated with lower KCCQ-CSS and 6MWD in women and men, with no interaction, but higher WHtR was associated with poorer kidney function exclusively in women (interaction P = 0.043). The effect of tirzepatide on the risk of worsening HF or cardiovascular death did not differ in women and men (HR: 0.66 and 0.61, respectively, interaction P = 0.81), with no heterogeneity of effect on KCCQ-CSS at 52 weeks (8.1- and 5.5-point placebo-corrected improvement, respectively, interaction P = 0.43) or 6MWD (18 m and 15 m placebo-corrected improvement, respectively, interaction P = 0.76). Among patients randomized to tirzepatide, decreases in body weight on treatment were more strongly associated with improvements in KCCQ-CSS in women than men (interaction P = 0.0058). CONCLUSIONS Compared with men, women with obesity-related HFpEF have greater adiposity, symptom severity, and poorer exercise capacity but lower left ventricular mass and paracardiac fat deposition. Despite these differences, tirzepatide resulted in consistent benefits across multiple domains of HF severity that did not differ by sex. (A Study of Tirzepatide LY3291876 in Participation With Heart Failure With Preserved Ejection Fraction HFpEF and Obesity SUMMIT; NCT04847557).