Effect of Semaglutide on the Inflammatory Biomarker High-Sensitivity CRP in Patients With Established Cardiovascular Disease and Overweight or Obesity in SELECT: A Prespecified Secondary Analysis
- Design
- Prespecified secondary (sub-study) analysis of a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial (select) · 17604 participants · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationObese secondary-prevention population; but the early, weight-loss-independent hs-CRP fall is the most relevant human inflammation signal available. Biomarker, not outcome.
- Could weight loss explain it?
- Specifically testedmethod: Combination of (1) temporal analysis — hsCRP reduction with semaglutide was 'evident by 4 and 8 weeks,' i.e., preceding the period of major weight loss; (2) subgroup analysis — hsCRP reduction 'occurred among those without weight loss' (non-losers); and (3) statistical modeling described only as 'modeling suggests decreased inflammation as contributing in part to the benefits seen with semaglutide' linking hsCRP change to MACE risk reduction. The abstract does not name a specific mediation-analysis method (e.g., causal mediation, formal weight-adjusted Cox model) beyond 'multiple approaches, including Cox modeling.'; prespecified: NI; key limitation: None of these specific weight-independence analyses (early 4-/8-week hsCRP timepoints, non-weight-loser subgroup, or the mediation/modeling statement) could be located in the protocol or SAP text provided — only the standard week 0-to-week 104 hsCRP ratio-to-baseline endpoint is documented there — so whether they were prespecified, and their full methodology (denominators, handling of missing early timepoints, adjustment set), is not verifiable from the sources available to this pass; full text and any dedicated biomarker-substudy protocol/SAP would be needed to confirm.
Adjusted for: weight loss (time-varying), LDL cholesterol, statin use - Study tier
- Study tier 2Prespecified analysis of a large RCT; biomarker endpoint with modelled mediation.
- Assessment
- Version 3 · manual · 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 SELECT, semaglutide lowered hs-CRP by 38% and the fall began within weeks, before meaningful weight loss and even in people who did not lose weight. This is the best human evidence for a weight-independent anti-inflammatory effect, but it is a blood marker in people with obesity and heart disease, analysed by the manufacturer.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg weekly
- Route
- subcutaneous
- Comparator
- placebo
- Primary outcome
- Prespecified: baseline hs-CRP as MACE predictor; hs-CRP change vs weight loss and MACE
- Effect
- hs-CRP -37.8% at 104 weeks; reductions evident by 4-8 weeks, before major weight loss, and in those without weight loss; hs-CRP reduction prognostic of lower MACE
- 95% confidence interval
- Not extracted
- Follow-up
- 104-208 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
- Condition
- Established/known atherosclerotic cardiovascular disease with overweight or obesity, without diabetes
- Diabetes status
- No diabetes (history of type 1 or type 2 diabetes was an exclusion criterion)
Study quality details
- Study design
- Unknown
- Sample size
- 604
- Randomization
- yes (parent trial)
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- 39.8 months
- Outcome type
- biomarker plus association with MACE
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- UNKNOWN
- Statistical precision
- not extracted
- Funding conflicts
- unclear
- Peer review status
- yes
- Rob2
- O1: {"D1":{"judgment":"Low","rationale":"Large industry-sponsored Phase 3 trial (17,604 randomized) using a centralized IWRS for randomization and allocation, double-blind with visually identical active/placebo product; baseline hsCRP was near-identical between arms (1.96 vs 1.91 mg/L geometric mean), consistent with adequate concealment/randomization. Per the domain rule this pattern warrants PY on allocation concealment absent contradi"},"D2":{"judgment":"Low","rationale":"Per the domain rule, D2 for this lab biomarker outcome is judged on discontinuation imbalance and ITT handling rather than unblinding. Trial-completion imbalance between arms was modest (NOT COMPLETED 259/8803 semaglutide vs 284/8801 placebo), and the SAP specifies an intention-to-treat estimand (FAS, irrespective of adherence) for all objectives, with the hsCRP imputation model fitted on data 'ir"},"D3":{"judgment":"Low","rationale":"7472/8803 (84.9%) semaglutide and 7400/8801 (84.1%) placebo participants contributed to the week-104 hsCRP result: about 15% of randomised participants lack the outcome and the between-arm difference in availability is 0.8 percentage points, i.e. below both of the guide's thresholds (>20% missing, or >5-point between-arm gap), so \"data available for nearly all\" is PY. Missing values were handled b"},"D4":{"judgment":"Low","rationale":"hsCRP is a central-lab, objective biomarker measurement. The protocol specifies that laboratory analyses (including the panel containing hsCRP) are performed by a central laboratory throughout the trial, with no evidence in the available sources of an assay change partway through or of differential measurement procedures between arms. Per the domain rule, this defaults to Low."},"D5":{"judgment":"Low","rationale":"The outcome, timepoint, transformation, model and missing-data handling were all prespecified in the protocol (v7.0, 09 Feb 2022) and SAP (v3.0, 22 Apr 2022), both finalised well before primary completion (21 Jun 2023) and before any unblinded data; the emphasised timepoint (104 weeks) is exactly the prespecified one, and the corresponding result is posted in the registry, so there is no sign of s"},"overall":{"judgment":"Low"},"result":"Change in hsCRP (ratio to baseline), semaglutide vs placebo, at week 104; registered secondary continuous endpoint 'Change in High Sensitivity C-Reactive Protein (hsCRP) - Ratio to Baseline' (FAS, n=7472 semaglutide / 7400 placebo; geometric mean ratio 0.61 vs 1.00); abstract reports this as '-37.8% [104 weeks]' in the RESULTS section, no table/figure identifiable (full text not available).","passes":[{"pass":"A","model":"claude-sonnet"},{"pass":"B","model":"claude-opus"}],"guide_version":"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)","label":"Human-reviewed","resolution":"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)"}
O4: {"D1":{"judgment":"Low","rationale":"Same trial-level randomization/allocation infrastructure as O1 (central IWRS, double-blind, identical-appearing product); no result-specific randomization concern for the weight-independence analyses."},"D2":{"judgment":"Some concerns","rationale":"The weight-independence claims rest on a non-loser subgroup and early (4-/8-week) hsCRP trajectories; no protocol/SAP text was found defining an intercurrent-event/estimand strategy for these specific sub-analyses, so it is unclear how deviations (discontinuation, non-adherence, dose interruption during up-titration through week 4-8) were handled for them specifically, beyond the trial's general I"},"D3":{"judgment":"Some concerns","rationale":"No information in the abstract, registry, protocol, or SAP on the number of participants contributing to the week 4/week 8 hsCRP measurements or to the 'without weight loss' subgroup used for O4; denominators and missingness for these specific analyses are not stated anywhere in the available sources. Given O1's overall hsCRP missingness is already ~15%/arm, and week 4/8 draws would be additional/"},"D4":{"judgment":"Low","rationale":"hsCRP measurement itself is via the same central laboratory used for the week-104 endpoint (per protocol, all specified lab tests are run centrally); no evidence of a different/changed assay for the earlier (4-/8-week) draws. Objective biomarker measurement defaults to Low per the domain rule."},"D5":{"judgment":"High","rationale":"The paper is titled a \"prespecified secondary analysis\", but the only hsCRP analysis prespecified anywhere in the protocol or SAP is change from randomisation to year 2 (week 104), on the log scale, by MI + ANCOVA. Neither document contains any week-4 or week-8 hsCRP analysis, any subgroup defined by weight change, or any mediation analysis, and the SAP's subgroup list is entirely baseline-defined"},"overall":{"judgment":"High"},"result":"Weight-independence of the hsCRP effect: (a) temporal precedence of hsCRP reduction over weight loss, 'evident by 4 and 8 weeks'; (b) hsCRP reduction 'occurred among those without weight loss' (implied non-weight-loser subgroup); (c) mediation-type modeling statement that 'decreased inflammation [is] contributing in part to the benefits seen with semaglutide in SELECT' on MACE. All from the abstract METHODS/RESULTS; no table/figure identifiable (full text not available), and none of these specific analyses (4-/8-week hsCRP timepoints, non-loser subgroup, mediation model) appear in the available protocol or SAP text.","passes":[{"pass":"A","model":"claude-sonnet"},{"pass":"B","model":"claude-opus"}],"guide_version":"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)","label":"Human-reviewed","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/42610271/); 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.
Assessed, not settled (2)
Recorded rather than omitted. Leaving these out would make the appraisal look cleaner than it is, and a disagreement between two careful readers is itself worth knowing.
O1
Assessed, not settled · RoB 2 · Two reviewers reached different judgments and nothing has settled it
This result has no overall judgment, because the two independent reviews did not reach one. Both readings are shown. The domains they did agree on are below.
| Where they differ | The two readings |
|---|---|
| D3 · Missing outcome data | One reviewer: Some concerns about risk of bias The other: Low risk of bias |
| D5 · Selection of the reported result | One reviewer: Some concerns about risk of bias The other: Low risk of bias |
| Overall | One reviewer: Some concerns about risk of bias The other: Low risk of bias |
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Large industry-sponsored Phase 3 trial (17,604 randomized) using a centralized IWRS for randomization and allocation, double-blind with visually identical active/placebo product; baseline hsCRP was near-identical between arms (1.96 vs 1.91 mg/L geometric mean), consistent with adequate concealment/randomization. Per the domain rule this pattern warrants PY on allocation concealment absent contradicting evidence.All s u bj e cts will b e c e ntr all y r a n d o mis e d usi n g a n I W R S a n d assi g n e d t o t h e n e xt a v ail a bl e T his is a r a n d o mis e d, d o u bl e -bli n d, p ar all el gr o u p, pl a c e b o -c o ntr oll e d tri al c o m p ari n g s e m a gl uti d e |
| D2 · Deviations from intended interventions Low risk of bias | Per the domain rule, D2 for this lab biomarker outcome is judged on discontinuation imbalance and ITT handling rather than unblinding. Trial-completion imbalance between arms was modest (NOT COMPLETED 259/8803 semaglutide vs 284/8801 placebo), and the SAP specifies an intention-to-treat estimand (FAS, irrespective of adherence) for all objectives, with the hsCRP imputation model fitted on data 'irrespective of adherence to randomised treatment'. No arm-specific GI-adverse-event rates were available in the provided sources to assess unblinding directly (NI on that sub-question), but the guide states awareness alone rarely biases a lab biomarker result."type": "NOT COMPLETED" T h e esti m a n d f or all o bj e cti v es is a n i nt e nti o n-t o-tr e at esti m a n d, e v al u ati n g t h e eff e ct of t h e |
| D3 · Missing outcome data Some concerns about risk of bias | hsCRP was analyzed in 7472/8803 (84.9%) semaglutide and 7400/8801 (84.1%) placebo randomized participants — about 15% missing in each arm, below the guide's 20% bright-line and the arm difference (~0.8 points) below its 5-point threshold, so strictly 'data available for nearly all' could be answered PY. However, missingness of this magnitude is non-trivial, and the SAP's missing-data handling for hsCRP is a standard per-arm regression multiple-imputation (MAR-type), not a mechanism (e.g., the J2R-MI approach used specifically for body weight) that addresses missingness plausibly related to treatment-driven discontinuation. Because GLP-1 RA discontinuation for GI events correlates with drug exposure and could relate to the true hsCRP trajectory, and no hsCRP-specific sensitivity analysis addressing this dependency was found, the guide's default (PY on 'could depend on true value' absent an addressing sensitivity analysis) pulls the domain judgment to Some concerns rather than Low."groupId": "OG000", "value": "7472" "groupId": "OG001", "value": "7400" |
| D4 · Measurement of the outcome Low risk of bias | hsCRP is a central-lab, objective biomarker measurement. The protocol specifies that laboratory analyses (including the panel containing hsCRP) are performed by a central laboratory throughout the trial, with no evidence in the available sources of an assay change partway through or of differential measurement procedures between arms. Per the domain rule, this defaults to Low.T h e l a b or at or y a n al ys es will b e p erf or m e d b y a c e ntr al l a b or at or y, u nl ess ot h er wis e Hi g h s e nsiti vit y C -R e a cti v e Pr ot ei n ( hs C R P) ( m g/ L) |
| D5 · Selection of the reported result Some concerns about risk of bias | hsCRP change (ratio to baseline, week 104) IS a registered/protocol-specified supportive secondary endpoint (added via protocol/SAP amendment, analyzed on a log scale as planned), which supports prespecification of the core O1 result. However, the paper's title/abstract additionally frames the whole biomarker analysis as a 'prespecified SELECT substudy,' and the abstract reports several hsCRP transformations/framings (geometric-mean baseline levels, subgroup categories <2/2-<10/≥10 mg/L, ratio-to-baseline percent change, and Cox-modeled prognostic associations) — a multiplicity of CRP presentations that the guide flags as at least 'Some concerns' when one estimate (the -37.8% figure) is emphasized. We could not locate the specific analytic plan for these framings in the protocol/SAP text provided (only the baseline-to-week-104 ratio endpoint itself is described), so full prespecification of the exact reported estimate/analysis is not verifiable from available sources.Hi g h s e nsiti vit y C -R e a cti v e Pr ot ei n ( hs C R P) ( m g/ L) hs C R P will b e a n al ys e d usi n g a l o g -n or m al distri b uti o n i nst e a d of a n or m al distri b uti o n (s e cti o n |
O4
Assessed, not settled · RoB 2 · Two reviewers reached different judgments and nothing has settled it
This result has no overall judgment, because the two independent reviews did not reach one. Both readings are shown. The domains they did agree on are below.
| Where they differ | The two readings |
|---|---|
| D1 · Randomisation process | One reviewer: Low risk of bias The other: Some concerns about risk of bias |
| D5 · Selection of the reported result | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Overall | One reviewer: Some concerns about risk of bias The other: High risk of bias |
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Same trial-level randomization/allocation infrastructure as O1 (central IWRS, double-blind, identical-appearing product); no result-specific randomization concern for the weight-independence analyses.All s u bj e cts will b e c e ntr all y r a n d o mis e d usi n g a n I W R S a n d assi g n e d t o t h e n e xt a v ail a bl e T h e I W R S is us e d f or bli n d -br e a ki n g i nstr u cti o ns. |
| D2 · Deviations from intended interventions Some concerns about risk of bias | The weight-independence claims rest on a non-loser subgroup and early (4-/8-week) hsCRP trajectories; no protocol/SAP text was found defining an intercurrent-event/estimand strategy for these specific sub-analyses, so it is unclear how deviations (discontinuation, non-adherence, dose interruption during up-titration through week 4-8) were handled for them specifically, beyond the trial's general ITT/FAS approach. Per the guide, D2 is judged on discontinuation/ITT handling rather than unblinding; the general trial-level ITT approach is documented, but its specific application to these substudy analyses is NI.T h e esti m a n d f or all o bj e cti v es is a n i nt e nti o n-t o-tr e at esti m a n d, e v al u ati n g t h e eff e ct of t h e No information — no protocol/SAP section describing intercurrent-event handling for the 4-/8-week hsCRP or non-weight-loser subgroup analyses was found |
| D3 · Missing outcome data Some concerns about risk of bias | No information in the abstract, registry, protocol, or SAP on the number of participants contributing to the week 4/week 8 hsCRP measurements or to the 'without weight loss' subgroup used for O4; denominators and missingness for these specific analyses are not stated anywhere in the available sources. Given O1's overall hsCRP missingness is already ~15%/arm, and week 4/8 draws would be additional/earlier timepoints not listed among the registered outcome measures at all, missingness for O4 could plausibly be as large or larger; absent any data, the guide's principle that NI on a key question usually means Some concerns (not Low) applies.No information — n analyzed for the 4-/8-week hsCRP timepoints or for the non-weight-loss subgroup is not reported in the abstract, registry, protocol, or SAP |
| D4 · Measurement of the outcome Low risk of bias | hsCRP measurement itself is via the same central laboratory used for the week-104 endpoint (per protocol, all specified lab tests are run centrally); no evidence of a different/changed assay for the earlier (4-/8-week) draws. Objective biomarker measurement defaults to Low per the domain rule.T h e l a b or at or y a n al ys es will b e p erf or m e d b y a c e ntr al l a b or at or y, u nl ess ot h er wis e |
| D5 · Selection of the reported result Some concerns about risk of bias | None of the specific O4 analyses — 4-/8-week hsCRP timepoints, subgroup restricted to participants without weight loss, or the mediation-style modeling statement linking hsCRP change to MACE benefit — appear anywhere in the protocol or SAP text made available for this assessment; the registered hsCRP outcome measure lists only week 0 and week 104 timepoints, with no week-4/week-8 hsCRP outcome registered. The abstract's title claims the overall substudy was 'prespecified,' but this specific set of weight-independence analyses is not independently verifiable from the sources checked, which per the guide means at least Some concerns."title": "Change in High Sensitivity C-Reactive Protein (hsCRP) - Ratio to Baseline" Greater reductions in ratio-to-baseline hsCRP with semaglutide were associated with greater weight loss, but preceded major weight loss, evident by 4 and 8 weeks, and occurred among those without weight loss. |
02Funding
Funding and conflicts
- Funding
- Novo Nordisk A/S (trial sponsor)
- Industry funded
- Yes
- Manufacturer
- Novo Nordisk A/S
- Sponsor role
- Sponsor analysed.
- Author conflicts
- Authors report Novo Nordisk relationships; sponsor co-authors.
- Independent replication
- no (single trial dataset)
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.Supports
SELECT prespecified analysis: hs-CRP -37.8% at 104 weeks; reduction preceded weight loss and occurred in non-losers. Biomarker only; population had obesity and CVD; Novo Nordisk funded.
- The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss.Supports
hs-CRP reduction prognostic of MACE reduction; modelling attributes part of benefit to inflammation.
04Source
The source, as retrieved
Abstract
[BACKGROUND] In SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity), among 17 604 patients with known atherosclerotic cardiovascular disease and overweight or obesity, but not diabetes, randomization to the glucagon-like peptide-1 receptor antagonist semaglutide significantly reduced the primary outcome of major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo (mean follow-up, 39.8 months). Inflammation, as indicated by plasma hsCRP (high-sensitivity C-reactive protein) level, is implicated as a biomarker predicting cardiovascular risk in obesity and atherosclerotic cardiovascular disease. SELECT provides a unique opportunity to study the relationship among hsCRP, obesity, weight loss, and MACE outcomes in semaglutide versus placebo groups. [METHODS] In this prespecified SELECT substudy, we evaluated whether baseline hsCRP levels predicted MACE risk and examined the relationships between changes in hsCRP levels and time to first MACE, baseline body weight, weight loss, and other clinical measures among treatment groups over time (104-208 weeks) using multiple approaches, including Cox modeling. [RESULTS] Baseline hsCRP level, which was similar in the semaglutide (geometric mean 1.96 mg/L) and placebo (geometric mean 1.91 mg/L) groups, was prognostic of future MACEs. The risk of MACEs increased across baseline hsCRP level <2, 2-<10, and ≥10 mg/L subgroups, including significant associations with cardiovascular and all-cause death. Semaglutide reduced hsCRP levels (-37.8% [104 weeks]) and risk of MACEs across all hsCRP subgroups. Greater reductions in ratio-to-baseline hsCRP with semaglutide were associated with greater weight loss, but preceded major weight loss, evident by 4 and 8 weeks, and occurred among those without weight loss. Semaglutide-associated changes in hsCRP were independent of low-density lipoprotein cholesterol levels, statin use, and atherosclerotic cardiovascular disease entry criteria. hsCRP reductions were found to be prognostic of decreased risk of MACEs. Modeling suggests decreased inflammation as contributing in part to the benefits seen with semaglutide in SELECT. [CONCLUSIONS] In SELECT, hsCRP data at baseline and in response to treatment with semaglutide support inflammation as a potential prognostic factor associated with cardiovascular risk in these generally well-treated patients with atherosclerotic cardiovascular disease and overweight or obesity but not diabetes. These findings suggest that the MACE reduction observed with semaglutide versus placebo in SELECT may have partially involved a decrease in inflammation. [REGISTRATION] URL: https://clinicaltrials.gov; Unique identifier: NCT03574597.