Obesity-related heart failure with preserved ejection fraction is characterised by symptom burden, impaired mobility, and reduced health status. Direct comparative evidence between incretin-based therapies and sodium-glucose cotransporter 2 inhibitors is lacking.

We conducted a PRISMA-guided systematic review and programme-level meta-analysis, using the independent parent randomised trial programme as the unit of analysis to avoid double-counting linked reports. The primary endpoint was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, and the secondary endpoint was the six-minute walk distance. Random-effects models used restricted maximum likelihood estimation with Knapp-Hartung inference.

Six parent programmes were included: STEP-heart failure with preserved ejection fraction, STEP-heart failure with preserved ejection fraction DM, SUMMIT, PRESERVED-HF, EMPEROR-Preserved, and DELIVER. In obesity-focused incretin programmes, pooled mean differences were 7.38 Kansas City Cardiomyopathy Questionnaire Clinical Summary Score points (95% confidence interval, 6.29 to 8.48; I2 = 0.00%) and 17.60 m for six-minute walk distance (95% confidence interval, 10.69 to 24.52; I2 = 0.00%). The secondary sodium-glucose cotransporter 2 Kansas City Cardiomyopathy Questionnaire Clinical Summary Score synthesis showed a pooled mean difference of 2.53 points (95% confidence interval, −1.97 to 7.03; I2 = 82.21%). No parent programme was judged to be at high risk of bias.

Incretin-based therapies showed consistent patient-centred improvements in obesity-related heart failure with preserved ejection fraction, whereas sodium-glucose cotransporter 2 inhibitor evidence was derived from broader heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction populations and was more heterogeneous. Cross-class comparisons remain exploratory because of population differences, follow-up differences, limited six-minute walk distance availability, and the absence of direct comparative trials; these findings do not establish class superiority.