Heart failure with preserved ejection fraction (HFpEF) is increasingly understood as a heterogeneous syndrome in which cardiometabolic and functional phenotypes may influence treatment response beyond ejection fraction alone. This systematic review synthesized recent clinical and trial-derived evidence published from June 2025 to May 2026 evaluating cardiometabolic phenotypes and therapeutic response in adults with HFpEF or closely related heart failure with mildly reduced or preserved ejection fraction populations. PubMed/MEDLINE, Scopus, and Web of Science were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 principles using terms related to HFpEF, diabetes, obesity, adiposity, frailty, exercise function, sodium-glucose cotransporter 2 inhibitors, incretin-based therapies, and treatment outcomes. Six studies met the eligibility criteria, including randomized trials, prespecified secondary analyses, pooled participant-level analyses, stratification-based analyses, and randomized crossover trial evidence. The included studies evaluated tirzepatide, semaglutide, dapagliflozin, and dapagliflozin plus spironolactone across phenotypes including type 2 diabetes, body mass index (BMI), central adiposity, achieved weight loss, epicardial or paracardiac fat, exercise limitation, frailty, and renal-electrolyte profile. Overall, contemporary cardiometabolic therapies were associated with improvements in heart failure outcomes, patient-reported health status, exercise capacity, body weight, natriuretic peptides, adiposity measures, cardiac remodeling markers, and frailty burden. Diabetes did not appear to uniformly attenuate heart failure benefit despite less weight loss, while adiposity distribution, functional limitation, frailty, and local cardiac fat may represent clinically relevant, hypothesis-generating domains for interpreting treatment response. Sodium-glucose cotransporter 2 inhibitor-based therapy also showed potential cardiometabolic, renal, hemodynamic, and structural effects, although combination therapy required careful renal and potassium monitoring. These findings suggest the potential value of a phenotype-informed framework for evaluating cardiometabolic treatment response in HFpEF; however, they are insufficient to support phenotype-guided treatment selection because the evidence was derived predominantly from secondary, pooled, or subgroup analyses rather than prospective phenotype-guided trials. Prospective studies are needed to determine whether integrating diabetes status, adiposity distribution, exercise capacity, frailty, renal profile, and imaging-based fat depots can improve treatment selection beyond ejection fraction and body mass index alone.
