Tirzepatide's benefits on cardiovascular death or worsening HF in obesity-related HFpEF are consistent across sexes

Heart failure with preserved ejection fraction (HFpEF) is a growing concern, particularly in women, often exacerbated by obesity. Current therapies struggle to address the complex interplay of metabolic dysfunction and cardiac remodeling in this population. Given known sexual dimorphisms in body composition and disease pathophysiology, understanding how treatments like tirzepatide, a dual GIPR and GLP-1R agonist, perform across sexes is crucial for optimizing patient outcomes and personalizing care. The SUMMIT trial previously showed tirzepatide's benefit, but sex-specific responses were unknown.

This prespecified secondary analysis of the SUMMIT trial enrolled 731 patients with NYHA functional class II-IV HFpEF and BMI ≥30 kg/m2. Participants were randomized to receive tirzepatide (n = 364) or placebo (n = 367). Primary endpoints included 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 assessed changes in 6-minute walk distance (6MWD), C-reactive protein, and body weight over the same 52-week period. Baseline characteristics and treatment effects were rigorously contrasted between women and men.

Women constituted 53.8% (n = 393) of the cohort, while men comprised 46.2% (n = 338). At baseline, women presented with greater BMI, waist-to-height ratio (WHtR), more severe symptoms (higher NYHA functional class, lower KCCQ-CSS), and poorer exercise capacity (lower 6MWD) compared to men. Conversely, men exhibited greater left ventricular remodeling and paracardiac fat. While higher baseline BMI or WHtR correlated with lower KCCQ-CSS and 6MWD in both sexes without interaction, a higher WHtR was uniquely associated with poorer kidney function in women (interaction P = 0.043). > Crucially, the beneficial effect of tirzepatide on the risk of worsening HF or cardiovascular death did not significantly differ between women and men (HR: 0.66 for women and 0.61 for men, interaction P = 0.81). Furthermore, no heterogeneity of effect by sex was observed for changes in KCCQ-CSS, 6MWD, C-reactive protein, or body weight, indicating consistent improvements across both groups.