Abstract
OBJECTIVE: To identify comorbidities associated with incident heart failure with preserved ejection fraction (HFpEF) and quantify their HRs for early risk stratification and prevention. DESIGN: PROSPERO-registered (CRD42024505533) systematic review and meta-analysis. Primary analysis prioritised unadjusted HRs; exploratory analysis incorporated adjusted HRs. DATA SOURCES: Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials through 15 June 2025. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Cohort studies of adults (≥18 years) without prior HF reporting HRs for incident HFpEF-associated comorbidities. EXCLUSIONS: non-English publications, reviews, non-clinical studies and studies without HR data. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed quality (Newcastle-Ottawa Scale). Random-effects models pooled HRs. Heterogeneity was investigated using Galbraith/Baujat plots, meta-regression and subgroup analyses. Publication bias assessed via funnel plots, Egger's and Begg's tests. RESULTS: Among 61 eligible studies, 22 reporting unadjusted HRs formed the primary analysis, identifying five comorbidities with significant incident HFpEF risk: atrial fibrillation (AF) (HR 2.92, 95% CI 1.94 to 4.37, I²=86.6%), hypertension (HR 2.28, 95% CI 1.35 to 3.84, I²=96.9%), diabetes (HR 1.88, 95% CI 1.54 to 2.30, I²=58.2%), obesity (HR 1.70, 95% CI 1.45 to 2.00, I²=69.7%) and myocardial infarction (MI) (HR 1.62, 95% CI 1.18 to 2.23, I²=72.1%). Conversely, chronic kidney disease (CKD) (HR 1.44, 95% CI 0.68 to 3.06, I²=86.6%) and cerebrovascular disease (HR 1.72, 95% CI 0.93 to 3.18, I²=77.2%) showed non-significant associations. Exploratory analysis integrating unadjusted HRs from primary studies and adjusted HRs from 39 additional studies confirmed these five comorbidities as significant risk factors, with CKD again demonstrating non-significant association. CONCLUSION: AF, hypertension, diabetes, obesity and MI constitute evidence-based targets for HFpEF risk stratification and preventive management. The CKD-HFpEF association requires validation in larger cohorts. PROSPERO REGISTRATION NUMBER: CRD42024505533.