Diabetes, Adiposity, and Functional Phenotypes in HFpEF: A Systematic Review of Recent Treatment-Response Evidence
- Design
- Systematic review · Unknown outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.
- Could weight loss explain it?
- Possibly[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.
- Study tier
- Study tier 2[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; last sentences of abstract] 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.
01Findings
What the study reported
- Drugs
- Semaglutide, Tirzepatide
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- Not stated
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Obesity status
- obesity/overweight present (all or most)
- Diabetes status
- diabetes mentioned
- Cvd status
- cardiovascular disease present in population (see abstract)
- Baseline condition
- heart failure with preserved ejection fraction
Study quality details
- Study design
- Systematic review
- Sample size
- not extracted
- Randomization
- n/a
- Blinding
- not stated
- Comparator
- not stated
- Follow up duration
- not stated
- Outcome type
- unknown
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- not extracted
- Risk of bias
- not assessed (auto)
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- None identified
- Sponsor role
- not reported in abstract
- Author conflicts
- Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
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.