Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity
- Design
- Randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase 3 trial; 52-week treatment period · 529 participants · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationParticipants had HFpEF and BMI >= 30. Outcomes were symptoms, walking distance and CRP, not events.
- Could weight loss explain it?
- LikelyWeight loss was a co-primary endpoint (-13.3%); symptom and CRP improvements were not separated from weight loss in the abstract.
- Study tier
- Study tier 2Well-conducted RCT but symptom/functional outcomes over one year; not an event trial.
- Assessment
- Version 3 · ai:two-pass · 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.
In 529 people with heart failure with preserved ejection fraction and obesity, semaglutide improved symptoms, walking distance and CRP while producing 13% weight loss over a year. Whether the heart-failure improvement is separate from weight loss was not tested.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg once weekly
- Route
- subcutaneous
- Treatment duration
- 52 weeks
- Comparator
- placebo
- Primary outcome
- Dual: change in KCCQ-CSS and change in body weight at 52 weeks
- Effect
- KCCQ-CSS +7.8 points; weight -10.7 percentage points; 6MWD +20.3 m; CRP treatment ratio 0.61
- 95% confidence interval
- KCCQ 4.8 to 10.9; CRP 0.51 to 0.72
- P value
- <0.001
- Follow-up
- 52 weeks treatment period (plus 5-week follow-up; hierarchical composite endpoint assessed to week 57)
- Adverse events
- Serious adverse events 13.3% vs 26.7% (fewer with semaglutide).
- Limitations
- Obese HFpEF only; one year; no event outcomes.
Who was studied
- Condition
- Heart failure with preserved ejection fraction and obesity
- Mean age
- NI
- Sex
- NI
- Bmi criterion
- BMI >= 30.0 kg/m^2
- Diabetes status
- not reported (trial excluded HbA1c >=6.5%; overall diabetes prevalence/status of randomized participants not given in available sources)
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 529
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo
- Follow up duration
- 52 weeks
- Outcome type
- patient-reported and functional; CRP biomarker
- Replication
- STEP-HFpEF DM and SUMMIT (tirzepatide) consistent
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% confidence interval [CI], 4
- Funding conflicts
- yes
- Peer review status
- yes
- Rob2
- O1: {"D1":{"judgment":"Low","rationale":"Large industry-sponsored, multicentre phase 3 trial using a central interactive web response system (IWRS) for screening and randomisation, stratified by BMI; per the collection's domain rule this supports presumed allocation concealment (PY) absent contradicting evidence, and no baseline imbalance data were available to contradict it."},"D2":{"judgment":"Low","rationale":"Per the guide, D2 for this lab-biomarker outcome is judged on discontinuation imbalance and ITT handling rather than on unblinding awareness. Treatment discontinuation ('NOT COMPLETED') was only modestly imbalanced (7/263, 2.7% semaglutide vs 12/266, 4.5% placebo), and the confirmatory analysis is performed on the Full Analysis Set (= all randomised participants) under a treatment-policy estimand,"},"D3":{"judgment":"Low","rationale":"CRP was analysed in 241/263 (91.6%) semaglutide and 243/266 (91.4%) placebo participants who had an observed week-52 value — missingness of 8.4% vs 8.6% (difference 0.2 points), below both the guide's >20%-missing and >5-point-differential thresholds, so the default is 'data available for nearly all' (PY) rather than PN. In addition, the prespecified primary analysis does not rely on observed case"},"D4":{"judgment":"Low","rationale":"CRP (hs-CRP) is an objective, centrally-assayed laboratory measurement per the guide's domain rule (central-lab hs-CRP is Low risk unless the assay changed or differed between arms); the protocol specifies central-laboratory testing for the trial's laboratory panel including CRP, applied identically to both arms, with no evidence of a mid-trial assay change."},"D5":{"judgment":"Low","rationale":"CRP is explicitly prespecified as a confirmatory secondary endpoint in both the protocol (Section 3.2.2.1 / 9.4.3.1) and the SAP (Section 5.4.1), with its analysis method (log-transformed ANCOVA on ratio-to-baseline, same imputation approach as the primary endpoints) fully specified in advance, and its place in the alpha-preserving graphical multiplicity/gatekeeping procedure explicitly defined. O"},"overall":{"judgment":"Low"},"result":"CRP (high-sensitivity C-reactive protein), percentage/ratio change from baseline (week -2) to week 52, semaglutide vs placebo; confirmatory secondary endpoint; log-scale ANCOVA yielding estimated treatment (geometric-mean) ratio 0.61 (95% CI 0.51-0.72, P<0.001); numbers appear in the abstract RESULTS paragraph (no table/figure available — full text not provided) and are cross-referenced by the registry's 'Change in C-Reactive Protein (CRP): Ratio to Baseline' outcome measure.","passes":[{"pass":"A","model":"claude-sonnet"},{"pass":"B","model":"claude-opus"}],"guide_version":"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)","label":"AI: two passes agreed","resolution":"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)"}
Methodological notes
Calibration two-pass assessment 2026-09-13 (drafts in data/assessments/37622681/); sources: abstract, registry, public protocol/SAP where available; no paper full text.
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.
O1
Low risk of bias · RoB 2 · Two reviewers agreed on every domain
How the overall was reached: RoB 2 algorithm: overall judgment is the worst domain judgment; all five domains (D1-D5) were judged Low for this result, so the overall judgment is Low risk of bias — noting this rests on abstract, registry, protocol and SAP text only (full text and supplement unavailable), which limited some fields (e.g., baseline imbalance data, GI-adverse-event-specific unblinding evidence) to NI rather than direct confirmation.
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Large industry-sponsored, multicentre phase 3 trial using a central interactive web response system (IWRS) for screening and randomisation, stratified by BMI; per the collection's domain rule this supports presumed allocation concealment (PY) absent contradicting evidence, and no baseline imbalance data were available to contradict it.All subjects will be centrally screened and randomised using an IWRS and assigned to the next available treatment according to randomisation schedule. Randomisation will be stratified by BMI into two subgroups (BMI <35.0 and BMI ≥35.0). |
| D2 · Deviations from intended interventions Low risk of bias | Per the guide, D2 for this lab-biomarker outcome is judged on discontinuation imbalance and ITT handling rather than on unblinding awareness. Treatment discontinuation ('NOT COMPLETED') was only modestly imbalanced (7/263, 2.7% semaglutide vs 12/266, 4.5% placebo), and the confirmatory analysis is performed on the Full Analysis Set (= all randomised participants) under a treatment-policy estimand, i.e. an ITT-consistent approach that retains data collected after intercurrent events.NOT COMPLETED Full Analysis Set (FAS) |
| D3 · Missing outcome data Low risk of bias | CRP was analysed in 241/263 (91.6%) semaglutide and 243/266 (91.4%) placebo participants who had an observed week-52 value — missingness of 8.4% vs 8.6% (difference 0.2 points), below both the guide's >20%-missing and >5-point-differential thresholds, so the default is 'data available for nearly all' (PY) rather than PN. In addition, the prespecified primary analysis does not rely on observed cases alone: it uses a multiple-imputation approach for non-retrieved subjects (imputing from retrieved subjects by timing of last on-treatment observation) intended to address missingness related to treatment discontinuation, plus a prespecified nonparametric sensitivity analysis, which mitigates concern that missingness depends on the true CRP value."value": "241" "value": "243" |
| D4 · Measurement of the outcome Low risk of bias | CRP (hs-CRP) is an objective, centrally-assayed laboratory measurement per the guide's domain rule (central-lab hs-CRP is Low risk unless the assay changed or differed between arms); the protocol specifies central-laboratory testing for the trial's laboratory panel including CRP, applied identically to both arms, with no evidence of a mid-trial assay change.high sensitivity C-Reactive Protein (hsCRP) The tests detailed in Table 10-1 will be performed by the central laboratory except otherwise stated. |
| D5 · Selection of the reported result Low risk of bias | CRP is explicitly prespecified as a confirmatory secondary endpoint in both the protocol (Section 3.2.2.1 / 9.4.3.1) and the SAP (Section 5.4.1), with its analysis method (log-transformed ANCOVA on ratio-to-baseline, same imputation approach as the primary endpoints) fully specified in advance, and its place in the alpha-preserving graphical multiplicity/gatekeeping procedure explicitly defined. Only one CRP transformation (ratio to baseline / log scale, reported as % change) is used — there is no evidence of multiple competing CRP metrics with one chosen for emphasis. The abstract reports the full prespecified endpoint hierarchy (both primary endpoints, 6MWD, the hierarchical composite, and CRP) together rather than CRP in isolation, consistent with prespecified, non-selective reporting.The confirmatory secondary endpoints are change in CRP and 6MWD (metres) from baseline (week 0) to end of treatment (week 52) as well as the hierarchical composite endpoint as listed in Section 3. The secondary confirmatory endpoints CRP and 6MWD will be analysed using the primary imputation approach used for the primary endpoint and to address the primary estimand. The statistical model for change in CRP and 6MWD will be the same as for the primary endpoints. The linear regression for CRP will be based on the log-transformed values at week 52 and log-transformed baseline values. |
02Funding
Funding and conflicts
- Funding
- Novo Nordisk
- Industry funded
- Y
- Manufacturer
- Novo Nordisk A/S (also lead sponsor)
- Sponsor role
- not reported in available sources (no explicit statement of sponsor's role in design/conduct/analysis/reporting was found in the abstract or provided protocol/SAP excerpts); registry lists sponsor as the trial's responsible party
- Author conflicts
- Authors report Novo Nordisk relationships; sponsor co-authors.
- Independent replication
- no independent; consistent industry trials (SUMMIT)
- Notes
- Authors declare relationships with the drug's manufacturer: Novo Nordisk
Funding is shown on every study and never used to score it.
03Claims
Claims this study bears on
- GLP-1 receptor agonist treatment reduces systemic inflammatory markers beyond what can be explained by treatment-associated weight loss.Mixed
STEP-HFpEF: CRP -43.5% vs -7.3% alongside -13.3% weight loss; mediation not separated.
- Incretin therapies improve outcomes in heart failure with preserved ejection fraction and obesity.Supports
STEP-HFpEF: KCCQ-CSS +7.8 points; weight -13.3%.
04Source
The source, as retrieved
Abstract
[BACKGROUND] Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. [METHODS] We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. [RESULTS] The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. [CONCLUSIONS] In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).