Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial
- Design
- Randomized trial · 130 participants · Biomarker 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 3[Auto] Small or short randomized trial (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; last sentences of abstract] Liraglutide alone shows no such improvements. Overall, regular physical activity, with or without GLP-1R agonists, is essential for promoting vascular health in adults with obesity.
01Findings
What the study reported
- Drugs
- Liraglutide
- 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)
- Sample size
- 130
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 130
- Randomization
- yes
- Blinding
- not stated
- Comparator
- not stated
- Follow up duration
- 52 weeks
- Outcome type
- biomarker
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- not extracted
- Funding conflicts
- partial
- 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.
IL-6, liraglutide alone vs placebo (estimated treatment ratio, log-scale LMM, back-transformed % change) · 52 weeks of weight-loss maintenance (after the 8-week LCD run-in)
Some concerns about risk of bias · RoB 2 · Two reviewers differed; settled by a recorded ruling
How the overall was reached: Algorithmic: highest domain is Some concerns (D1, D2, D3), none High. The result is a prespecified, double-blind, objectively measured biomarker contrast; the residual concerns are undescribed allocation concealment, a per-protocol analysis population for an assignment effect, and unverifiable missingness.
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Some concerns about risk of bias | Sequence generation is adequately described (computer-generated list, stratified by sex and age). Allocation concealment is not described: participants were assigned sequentially from a randomization list implemented by an unblinded study nurse, with no statement of a central/IVRS system or sealed opaque envelopes. This is a small academic trial, so under the D1 collection rule concealment cannot be assumed PY. Baseline characteristics are well balanced, so no evidence of a failed randomization.in a 1:1:1:1 ratio to one of four treatment arms using a computer-generated randomization sequence provided by Novo Nordisk Within each stratum, participants were assigned sequentially according to the randomization list. Allocation was implemented by a qualified, unblinded study nurse who was not otherwise involved in trial conduct. |
| D2 · Deviations from intended interventions Some concerns about risk of bias | Participants and study personnel were blinded to study medication, so the liraglutide- versus-placebo contrast is double-blind; under the collection rule, unblinding is not the basis for judgment here. The concern is the analysis population: the reported estimate is per-protocol, defined by >=75% medication adherence, which is not an appropriate analysis to estimate the effect of assignment. The paper states ITT results are in Supplementary Table 7 and "generally support the main findings", but that table is not in the available sources and no discontinuation counts by arm are visible (the CONSORT flow chart is a figure caption only). Not High, because the same n = 130 is described both as randomized and as the per-protocol population, so large differential exclusion is not demonstrated; not Low, because it cannot be verified.Study participants and study personnel were blinded to the study medication. The analyses were performed in the per-protocol population (defined as participants who performed at least 75% of the exercise programme and/or had taken at least 2.4 or 3.0 mg d −1 of liraglutide or placebo for at least 75% of the intervention period). |
| D3 · Missing outcome data Some concerns about risk of bias | The proportion of randomized participants with an IL-6 measurement at 52 weeks is not reported in any available source (Supplementary tables and the CONSORT figure are not in the bundle), so neither prong of the 20% / 5-point rule can be evaluated - the thresholds are decisive only when they can be read. Missingness is handled by maximum likelihood under an assumed MAR mechanism with no sensitivity analysis for value-dependent missingness. Answer to "data available for nearly all" is NI, not PN.All missing data were assumed to be missing at random and handled implicitly in the mixed model by maximum likelihood estimation. CONSORT flow diagram of the participants enrolled in the S-LiTE trial. |
| D4 · Measurement of the outcome Low risk of bias | IL-6 was measured on a central multiplex immunoassay platform in duplicate, from fasting samples collected identically in all arms, with reported CVs and detection limits; the outcome is objective and the assay is not reported to have changed mid-trial or to have differed between arms. Detection rate for IL-6 exceeded 75% and no values fell below the detection limit.Pro-inflammatory cytokines were measured in duplicates using a V-PLEX MSD Proinflammatory Panel 1 (human), K15049D No measurements of the five cytokines reported had measurements below the detection limit |
| D5 · Selection of the reported result Some concerns about risk of bias | IL-6 is named as a prespecified supportive outcome in the trial protocol, and the model used is the one prespecified in the original SAP. Under calibration ruling 1, D5 judges this result, not the paper's wider analysis suite (the exploratory 2x2 pooled contrasts are flagged as exploratory and go to limitations). The paper is titled and described as a prespecified secondary analysis. The protocol/SAP themselves are not in the available sources, but the prespecification statement is specific and the analysis model is stated to follow the original SAP, so this is not "unverifiable" in the sense of the domain rule.Supportive outcomes were changes during the weight maintenance period in markers of general inflammation (IL-6, IL-8, IL-10, TNF and IFNγ) and endothelial function (sICAM-1, sVCAM-1, vWF and tPA), which were prespecified objectives in the trial protocol as prespecified in the statistical analysis plan for the original trial |
TNF (TNF-alpha), liraglutide alone vs placebo (estimated treatment ratio, log-scale LMM) · 52 weeks of weight-loss maintenance
Some concerns about risk of bias · RoB 2 · Two reviewers differed; settled by a recorded ruling
How the overall was reached: Highest domain Some concerns (D1, D2, D3); no domain High.
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Some concerns about risk of bias | Same randomization as O2: sequence generation described, allocation concealment not described, baseline balance adequate.Within each stratum, participants were assigned sequentially according to the randomization list. Allocation was implemented by a qualified, unblinded study nurse who was not otherwise involved in trial conduct. TNF (pg ml −1 ) 1.3 (1.0–1.6) 1.2 (0.9–1.5) 1.2 (1.0–1.4) 1.4 (1.2–1.6) |
| D2 · Deviations from intended interventions Some concerns about risk of bias | Same as O2: double-blind medication, but the reported estimate is per-protocol and the ITT table is not in the available sources; no by-arm discontinuation counts visible.Study participants and study personnel were blinded to the study medication. The analyses were performed in the per-protocol population (defined as participants who performed at least 75% of the exercise programme and/or had taken at least 2.4 or 3.0 mg d −1 of liraglutide or placebo for at least 75% of the intervention period). |
| D3 · Missing outcome data Some concerns about risk of bias | Same as O2: proportion with a 52-week TNF measurement is not reported in available sources; MAR assumed, no sensitivity analysis. NI on availability.All missing data were assumed to be missing at random and handled implicitly in the mixed model by maximum likelihood estimation. |
| D4 · Measurement of the outcome Low risk of bias | Central multiplex immunoassay in duplicate, identical across arms, detection rate above 75%, no values below detection limit.only IL-6, IL-8, IL-10, TNF and IFNγ displayed detection rates above 75%; therefore, only these five cytokines were included in the analyses see Supplemental Table 6 for a table of the coefficient of variation and limits of detection and quantification of the measured biomarkers |
| D5 · Selection of the reported result Some concerns about risk of bias | TNF is named among the prespecified supportive outcomes and among the outcomes on which significance testing was planned; the null result is reported rather than suppressed. Ruling 1 applies: the exploratory pooled 2x2 framing is a limitations note, not a D5 downgrade for this result.Supportive outcomes were changes during the weight maintenance period in markers of general inflammation (IL-6, IL-8, IL-10, TNF and IFNγ) We found that the initial weight loss induced a 10% increase in TNF, with no change in IL-6 or IFNγ |
Inflammatory marker change (IL-6, TNF, IFNγ) attributed to liraglutide independently of weight change - the paper's claim that the weight trajectories of the arms permit a weight-loss-independent reading of the treatment effects · 52 weeks of weight-loss maintenance
High risk of bias · RoB 2 · Two reviewers differed; settled by a recorded ruling
Why the overall is not simply the worst domain: rob2-guide v1.3 item 7 limit: no weight-adjusting analysis exists at all, which is carried in the overall rather than in D5. data/assessments/Q-020-D5-resolution-2026-09-14.md
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Some concerns about risk of bias | Trial-level judgment, identical to O2/O3 (ruling 4: the derived character of the contrast is carried in D5 and overall, not in D1).in a 1:1:1:1 ratio to one of four treatment arms using a computer-generated randomization sequence provided by Novo Nordisk |
| D2 · Deviations from intended interventions Some concerns about risk of bias | As O2/O3: double-blind medication, per-protocol analysis population, ITT table not available.The analyses were performed in the per-protocol population |
| D3 · Missing outcome data Some concerns about risk of bias | As O2/O3: availability of 52-week biomarker and weight data by arm is not reported in available sources; total weight loss is referred to Supplementary Table 2, which is not in the bundle.Total weight loss across the duration of the trial is presented in Supplementary Table 2 . |
| D4 · Measurement of the outcome Low risk of bias | The underlying markers are central-lab multiplex assays, objective and identical across arms; weight is an objective measurement.Pro-inflammatory cytokines were measured in duplicates using a V-PLEX MSD Proinflammatory Panel 1 (human), K15049D |
| D5 · Selection of the reported result Some concerns about risk of bias | No weight-independence analysis is listed among the prespecified outcomes or in the statistical methods; the outcomes section names only marker change, and the statistical section names no weight-adjusted or mediation model. Prespecification is therefore absent from everything visible - but ruling 3's High requires the protocol and SAP to have been fully searchable and the specific analysis affirmatively absent, and neither the protocol nor the SAP is in the available sources, so the floor of "at least Some concerns" applies rather than the escalation.This observation enabled us to investigate weight-loss-independent effects of exercise or liraglutide treatment alone. The prespecified main outcome in this analysis was the change in cIMT 11 in persons with obesity after 52 weeks of weight maintenance with exercise and liraglutide treatment. |
02Funding
Funding and conflicts
- Funding
- Novo Nordisk Fonden (Novo Nordisk Foundation); Helsefonden (Health Foundation); Novo Nordisk; EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020); Hjerteforeningen (Heart Foundation)
- Industry funded
- Partial
- Manufacturer
- Novo Nordisk, AstraZeneca, Sanofi, Boehringer Ingelheim
- Sponsor role
- mixed industry and public/foundation funding
- Author conflicts
- Competing interests: J.J.H. is on the advisory board of Novo Nordisk. L.M.O. currently works at Novo Nordisk and was employed after data collection and the end of the study. The spouse of T.B. works at Novo Nordisk; T.B. and spouse own Novo Nordisk stocks. In the last 5 years, S.M. has been on the advisory boards of AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Sanofi and Bayer; received lecture fees from AstraZeneca and Novo Nordisk; been a research grant recipient from Novo Nordisk and Boehringer Ingelheim; and received support for attending meetings and/or travel from Novo Nordisk and Boehringer Ingelheim. S.S.T. has received research grants and honoraria for lectures and has had a membership on an advisory panel for Novo Nordisk. The other authors declare no competing interests.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Novo Nordisk
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
Obesity and inactivity are linked to endothelial dysfunction and atherosclerosis. In this secondary analysis of the S-LiTE trial (ClinicalTrials.gov identifier: NCT04122716 ; EudraCT identifier: 2015-005585-32 ), 130 adults with obesity completed a diet-induced weight loss plan, followed by randomization to weight maintenance with exercise and/or liraglutide for 52 weeks. We show that exercise, alone or in combination with liraglutide, reduces carotid intima-media thickness and systemic pro-inflammatory cytokine levels (interleukin-6 and interferon-γ). Combination treatment also improves endothelial function biomarkers (sICAM-1, sVCAM-1 and tPA). Liraglutide alone shows no such improvements. Overall, regular physical activity, with or without GLP-1R agonists, is essential for promoting vascular health in adults with obesity.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 42342869 first ingestion |