Effects of semaglutide in obesity-related heart failure with preserved ejection fraction across the age spectrum: Findings from the STEP-HFpEF programme
- Design
- Randomized trial · 573 participants · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Participants had obesity/overweight (age/BMI not reported in abstract).
- 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] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).
- 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; quoted from abstract conclusions] In patients with HFpEF enrolled across the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide improved disease-specific symptoms, physical function and reduced body weight across the age spectrum. The safety profile of semaglutide was consistent in older and younger patients.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg once weekly
- Comparator
- placebo
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- 52 weeks
- 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)
- Cvd status
- cardiovascular disease present in population (see abstract)
- Baseline condition
- heart failure with preserved ejection fraction
- Sample size
- 573
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 573
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- 52 weeks
- Outcome type
- mixed
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- not extracted
- Funding conflicts
- no
- Peer review status
- yes
01bRisk of bias
How much the result can be relied on
Risk of bias is judged per result, not per paper: the same study can report one marker at low risk and another at high. Two reviewers assess each result independently against a written guide, and every domain judgment below carries its reasoning and the sentences it rests on.
These words are not quality scores. On the RoB 2 scale, High risk of bias is the worst rating a result can receive and Low risk of bias is the best — the opposite of how the same words read on some other scales. Levels are always written out in full here for that reason.
C-reactive protein (CRP), log-transformed; treatment ratio semaglutide vs placebo · baseline to 52 weeks
Some concerns about risk of bias · RoB 2 · Two reviewers differed; settled by a recorded ruling
How the overall was reached: Two domains at Some concerns and none at High. D1 is Some concerns only because the bundle omits sequence generation, concealment and an arm-wise baseline table; D5 is Some concerns because prespecification of this derived, age-stratified CRP analysis is asserted but unverifiable from the available sources, with no multiplicity adjustment. D2, D3 and D4 are Low. The subgroup character of the result (the assessed 65-74 stratum is a non-randomized partition of the randomized population, and the p-interaction of 0.20 does not establish stratum-specific effects) is carried here per ruling 4 and keeps the result from being Low overall. Obtaining the STEP-HFpEF protocols/SAPs and the parent-trial randomization description would likely move both D1 and D5 to Low.
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Random 1:1 allocation to semaglutide or matching placebo is stated for both parent trials, but the bundle contains no description of the sequence-generation method or of allocation concealment (no IVRS/IWRS statement), and no arm-wise baseline table is presented (Table 1 is stratified by age, not by treatment arm), so baseline balance cannot be checked. Concealment is therefore NI rather than the PY the collection rule permits for a documented central/IVRS system. Per ruling 4, D1 is kept trial-level; the derived, age-stratified character of the assessed result is carried at D5 and overall.Eligible participants were randomized 1:1 to receive once‐weekly semaglutide 2.4 mg or matching placebo in addition to standard care for 52 weeks. We performed a pre‐specified, age‐stratified analysis of the pooled participant‐level data from the randomized, double‐blind, placebo‐controlled STEP‐HFpEF programme (STEP‐HFpEF and STEP‐HFpEF DM) |
| D2 · Deviations from intended interventions Low risk of bias | Per the collection rule, D2 is judged on discontinuation imbalance and ITT handling, not on unblinding. The analysis is explicitly by intention-to-treat with a defined, pre-stated imputation scheme applied identically to both arms, and the appropriate (assignment) effect is estimated. Numbers discontinuing study drug by arm are not reported in the bundle (NI), but gastrointestinal serious adverse events are closely similar between arms in every age stratum, giving no signal of differential drug-exposure-driven withdrawal; the trial was double-blind and placebo-controlled.The efficacy endpoints were examined according to the intention‐to‐treat principle. For other endpoints, missing observations at week 52 were imputed irrespective of death or prior HF events using the same imputation method. |
| D3 · Missing outcome data Low risk of bias | Analysis denominators in Table 2 total 1053 of the 1145 randomized (8.0% without a week-52 observation): semaglutide 532/573 (7.2% missing), placebo 521/572 (8.9% missing), a 1.7-point arm difference. Neither prong of the collection threshold trips (missingness <= 20%, arm difference <= 5 points), so by calibration ruling 2, D3 is Low absent specific contrary evidence, and multiple imputation was applied in any case. No MNAR sensitivity analysis is reported; per ruling 2 that is a limitations note, not a downgrade. Caveat recorded in limitations: the paper states per-outcome n varies and lists only one set of arm-level n's, so these denominators are taken as the CRP denominators.Among 1145 randomized participants, 8.8% ( N = 101) were <55, 23.3% ( N = 267) were aged between 55–64, 42.4% ( N = 485) were between 65–74, and 25.5% ( N = 292) were 75 years or over. Semaglutide ( n = 36) Placebo ( n = 52) Semaglutide ( n = 131) Placebo ( n = 110) Semaglutide ( n = 240) Placebo ( n = 218) Semaglutide ( n = 125) Placebo ( n = 141) |
| D4 · Measurement of the outcome Low risk of bias | CRP is an objective laboratory biomarker measured identically in both arms under a double-blind, placebo-controlled design, and was handled by a single pre-stated transformation (log) for all strata. Per the collection rule, measurement bias for CRP is Low unless the assay changed partway through or measurement differed between arms; the bundle reports no such change. Assay vendor/central-laboratory details are not stated in the bundle, which is a reporting gap rather than evidence of differential measurement.the randomized, double‐blind, placebo‐controlled STEP‐HFpEF programme (STEP‐HFpEF and STEP‐HFpEF DM) NT‐proBNP and CRP were log‐transformed; hence, the treatment ratio with the corresponding 95% CI is reported. |
| D5 · Selection of the reported result Some concerns about risk of bias | The paper asserts that the pooled age-stratified analysis is pre-specified, and CRP is a confirmatory secondary endpoint of the parent programme rather than a newly invented outcome, so this is not the "affirmatively absent prespecification" situation that ruling 3 makes High: no protocol or SAP is in the bundle, so prespecification could not be checked in either direction. Under the D5 domain rule, prespecification unverifiable is at least Some concerns. Two further selection pressures push to the same place and no further: the age cut-points (<55/55-64/65-74/>=75) and the choice to report CRP as a treatment ratio on the log scale are not traceable to a protocol here, and the paper states that no multiplicity adjustment was made across the reported endpoints and four strata.In this pre‐specified pooled subanalysis of the STEP‐HFpEF trials, we evaluated the efficacy of semaglutide across the age spectrum. The confirmatory secondary endpoints were changes in 6‐min walk distance (6MWD) and C‐reactive protein (CRP), and a hierarchical composite endpoint |
02Funding
Funding and conflicts
- Funding
- NIA NIH HHS; NHLBI NIH HHS; NIMHD NIH HHS
- Industry funded
- No
- Manufacturer
- None identified
- Sponsor role
- no manufacturer funding identified
- Author conflicts
- not available in metadata
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[BACKGROUND] The prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age, and older adults with HFpEF have worse physical function, quality of life, and clinical outcomes. Semaglutide demonstrated efficacy in the treatment of obesity-related HFpEF in the STEP-HFpEF trials. Some have speculated that older patients may have less to gain from incretin therapies (and perhaps more to lose) than younger patients. [AIMS] In this pre-specified pooled subanalysis of the STEP-HFpEF trials, we evaluated the efficacy of semaglutide across the age spectrum. [METHODS] The STEP-HFpEF and STEP-HFpEF DM trials enrolled participants with obesity-related HFpEF and randomized them to semaglutide 2.4 mg once weekly (n = 573) or placebo (n = 572) for 52 weeks. Dual primary outcomes (change in Kansas City Cardiomyopathy Questionnaire clinical summary score [KCCQ-CSS] and change in body weight) and secondary outcome measures (6-minute walk distance [6MWD], C-reactive protein, hierarchical composite endpoint containing all-cause death, heart failure events, changes in KCCQ-CSS and 6MWD) were compared across specific age groups; <55 years, 55-64 years, 65-74 years and ≥75 years. [RESULTS] Among 1145 randomized participants, 8.8% (N = 101) were <55, 23.3% (N = 267) were aged between 55-64, 42.4% (N = 485) were between 65-74, and 25.5% (N = 292) were 75 years or over. The efficacy of semaglutide on the dual primary endpoints was consistent across the age spectrum, KCCQ-CSS (p-interaction = 0.80), and body weight (p-interaction = 0.41). Similar benefits were observed for the key secondary endpoints, with no treatment effect heterogeneity across age groups. Moreover, the safety of semaglutide was consistent across age groups. [CONCLUSION] In patients with HFpEF enrolled across the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide improved disease-specific symptoms, physical function and reduced body weight across the age spectrum. The safety profile of semaglutide was consistent in older and younger patients.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 41290376 first ingestion |