Published online Jun 18, 2026. doi: 10.13105/wjma.v14.i2.121918
Revised: April 21, 2026
Accepted: May 13, 2026
Published online: June 18, 2026
Processing time: 69 Days and 8.2 Hours
Heart failure with preserved ejection fraction (HFpEF) is a growing global health burden with historically limited disease-modifying therapies. Patient-reported outcomes (PROs) and health-related quality of life (QoL) are central therapeutic targets, particularly in obesity-related HFpEF where symptom burden is substan
To systematically review and quantitatively pool the evidence on PRO measure
Following PRISMA 2020 guidelines, MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception through January 2026. Eligible studies included randomised controlled trials (RCTs) and prospective cohort studies enrolling adults with HFpEF receiving semaglutide that reported validated QoL or PRO instruments. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool for RCTs and the ROBINS-I framework for the cohort study. A fixed-effects meta-analysis using inverse-variance weighting was performed for the two design-homogeneous RCTs (identical dose, endpoint, and follow-up). A qualitative synthesis additionally appraised the methodological comparability of PRO measurement across all included studies.
Three studies met inclusion criteria: Two double-blind, placebo-controlled, multicentre RCTs [semaglutide treatment effect in people with obesity and HFpEF (STEP-HFpEF), n = 529; STEP-HFpEF and diabetes mellitus, n = 616] and one prospective propensity score-matched cohort study (n = 406 after matching). Fixed-effects meta-analysis of the two RCTs yielded a pooled KCCQ-Clinical Summary Score (CSS) treatment effect of 7.36 points (95%CI: 5.32-9.40; P < 0.001; I² = 0%), exceeding the 5-point MCID. The open-label observational cohort reported a 21-point absolute KCCQ-Total Symptom Score improvement, substantially larger than the RCT estimates-most plausibly attributable to expectation bias, residual confounding, subscale non-equivalence, and dose heterogeneity. Methodological evaluation revealed important gaps in KCCQ psychometric reporting, missing data handling, MCID justification, and standardisation of PRO data collection procedures. Generalisability is constrained by exclusive enrolment of obesity-related HFpEF phenotypes, predominantly White Western populations, and industry-sponsored trial designs.
Semaglutide produces consistent, clinically meaningful PRO improvements in obesity-related HFpEF. The pooled RCT effect of 7.36 KCCQ-CSS points constitutes the most methodologically reliable estimate of pharmacologic benefit. Significant methodological gaps remain across PRO instrument standardisation, psychometric reporting, population diversity, and prospective trial registration, which future HFpEF trials must address.
Core Tip: This systematic review demonstrates that semaglutide improves patient-reported quality of life in obesity-related heart failure with preserved ejection fraction, with blinded randomised trials showing approximately 7-8 Kansas City Cardiomyopathy Questionnaire points of benefit over placebo. The threefold larger effect in the open-label observational cohort reflects expectation bias and residual confounding rather than genuine superiority. Methodological heterogeneity across instruments, doses, and study designs limits cross-study comparisons and highlights the urgent need for standardised patient-reported outcome sets and prospective trial registration in this field.