Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-Analysis
- Design
- Meta-analysis · 1991 participants · Biomarker outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationType 2 diabetes trials; biomarkers only; heterogeneity moderate to high.
- Could weight loss explain it?
- PossiblyTrials in diabetes with concurrent weight and glycaemic change; meta-analysis did not adjust for weight loss.
- Study tier
- Study tier 3Meta-analysis of small RCTs with biomarker endpoints and high heterogeneity.
- Assessment
- Version 6 · Checked against the source by AI · Oct 19, 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.
Pooling 41 randomized trials in people with type 2 diabetes, GLP-1 drugs modestly lowered CRP and raised adiponectin, but did not consistently change IL-6 or TNF-alpha, and MCP-1 was not significantly changed. In two tirzepatide trials IL-6 fell but CRP showed only a non-significant trend. Biomarkers only, in diabetes, with much variation between trials.
What the study reported
- Drugs
- Class unspecified, Tirzepatide
- Comparator
- placebo or active therapy
- Primary outcome
- CRP/hs-CRP, IL-6, TNF-alpha, MCP-1, MDA, adiponectin in RCTs in type 2 diabetes
- Effect
- CRP SMD -0.37 (27 studies); adiponectin +0.30; MDA -0.98; IL-6 and TNF-alpha not significant; tirzepatide IL-6 SMD -0.28
- 95% confidence interval
- -0.59 to -0.14 (CRP)
- Follow-up
- Not stated
- Adverse events
- Not extracted
- Limitations
- Risk-of-bias judgments (RoB 2, Table S2) are reported but not carried into the interpretation of results; registry/grey-literature search absent and English-only limit unjustified (item 4 Partial Yes).
Who was studied
- Diabetes status
- type 2 diabetes (all trials)
- Sample size
- 1991
Study quality details
- Study design
- Meta-analysis
- Sample size
- 1991
- Randomization
- n/a
- Blinding
- not stated
- Comparator
- placebo or active therapy
- Follow up duration
- not stated
- Outcome type
- biomarker
- Replication
- 41 RCTs
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: -0.59 to -0.14 (CRP)
- Risk of bias
- high heterogeneity; small trials; biomarker outcomes
- Funding conflicts
- unclear
- Peer review status
- yes
- Included trials
- 0: [21] Ahmad 2021 (LYDIA trial)
1: [22] Ahmadi 2019 (MDI-Liraglutide Study 5)
2: [23] Bouchi 2017
3: [24] Bunck 2010
4: [25] Caruso 2025
5: [26] Derosa 2010 (exenatide vs glibenclamide)
6: [27] Derosa 2012 (exenatide plus metformin)
7: [28] Dutour 2016
8: [29] Fan 2013
9: [30] Forst 2012
10: [31] Gurkan 2014
11: [32] Jensen 2021 (LIRAFLAME trial)
12: [33] Kang 2021
13: [34] Lambadiari 2018
14: [35] Lambadiari 2021 (yields pairwise comparisons "Lambadiari 2021a"/"2021b" vs insulin and empagliflozin)
15: [36] Li 2019
16: [37] Liang 2013
17: [38] Lin 2015
18: [39] Liu 2019
19: [40] Pastel 2017
20: [41] Quan 2017
21: [42] Ripa 2021
22: [43] Rosenstock 2025 (orforglipron)
23: [44] Sathyanarayana 2011
24: [45] Savvidou 2016
25: [46] Shao 2024
26: [47] Shi 2017
27: [48] Suzuki 2014
28: [49] Takeshita 2015
29: [50] Wang J. 2019
30: [51] Wang Q. 2020
31: [52] Wu 2011
32: [53] Xie 2022
33: [54] Yan 2019 (yields pairwise comparisons "Yan 2019a"/"2019b" vs sitagliptin and insulin glargine)
34: [55] Yao 2020
35: [56] Ying 2023
36: [57] Zhang W.-q. 2018
37: [58] Zhang J. 2020
38: [59] FLAT-SUGAR Trial Investigators 2016 ("Investigators TF-ST")
39: [60] Sattar 2024 (SURMOUNT-1 and SURMOUNT-2 post-hoc, tirzepatide)
40: [61] Wilson 2022 (tirzepatide post hoc)
Methodological notes
AMSTAR 2 from full text 2026-09-13, two passes: Low confidence (critical flaw at item 13). All 41 included RCTs listed from the text (40 of 41 author-year tokens machine-verified; the FLAT-SUGAR group-author entry verified by its reference entry). Included-trial list recorded to prevent double-counting: none of this review's trials may be separately graded in an outcome body that also uses its pooled estimate.
How far the review's own results can be trusted
This record is a systematic review, so it is appraised with AMSTAR 2, which rates how far the review's own pooled results can be trusted. It does not grade the trials inside the review; those are appraised one by one.
On this scale High is the best rating. The levels run High, Moderate, Low, Critically low: Critically low confidence in the review is the worst rating a review can receive, and means it should not be relied on for an accurate summary. That is the opposite direction to the risk-of-bias scale used for single trials, where High is the worst.
Low confidence in the review · AMSTAR 2 · AI: two passes agreed
Why: one critical flaw: item 13 — risk-of-bias results are not brought into the interpretation of the pooled estimates.
What it is used for here: Used only to find trials. A review at this level does not supply a pooled result to any outcome in this collection; the trials it lists are appraised on their own.
A: 9 Yes / 3 Partial Yes / 4 No; B: 10 Yes / 2 Partial Yes / 4 No; one item differs (item 2: Partial Yes vs Yes — both non-flaws, rating unaffected; recorded in the inbox)
Two reviewers assessed the review independently against a written guide, from the full text (PMC HTML), 2026-09-13; supersedes the abstract-only assessment.
Funding and conflicts
- Funding
- Not stated
- Industry funded
- Unclear
- Manufacturer
- None identified
- Sponsor role
- not reported in abstract
- Author conflicts
- Authors declare no conflicts.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
Claims this study bears on
- GLP-1 receptor agonist treatment reduces systemic inflammatory markers beyond what can be explained by treatment-associated weight loss.Consistent, but doesn't test the claim
Meta-analysis of 41 RCTs in adults with type 2 diabetes: GLP-1 RAs reduced CRP/hs-CRP (SMD -0.37), while pooled IL-6, TNF-alpha and MCP-1 effects were not significant; two tirzepatide trials lowered IL-6 with a non-significant CRP trend. It does not separate any effect from weight loss.
The source, as retrieved
Abstract
[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM), but their effects on inflammatory and oxidative biomarkers are not fully defined. [MATERIALS AND METHODS] We searched PubMed, Ovid MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to 19 February 2026 for randomised controlled trials (RCTs) in adults with T2DM comparing a GLP-1RA or dual GIP/GLP-1 agonist with placebo or active therapy, and reporting C-reactive protein (CRP or high-sensitivity CRP [hs-CRP]), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), malondialdehyde (MDA) or adiponectin. Random-effects meta-analyses were conducted using standardised mean differences (SMDs). [RESULTS] Forty-one RCTs were included. GLP-1RAs significantly reduced CRP/hs-CRP (27 studies, 1991 participants; SMD -0.37, 95% CI -0.59 to -0.14) and MDA (3 studies, 272 participants; SMD -0.98, 95% CI -1.65 to -0.30), and increased adiponectin (16 studies, 1327 participants; SMD 0.30, 95% CI 0.13 to 0.46). Pooled effects on IL-6 (17 studies, 1068 participants; SMD -0.14, 95% CI -0.37 to 0.10), TNF-α (16 studies, 1164 participants; SMD -0.25, 95% CI -0.61 to 0.12) and MCP-1 (7 studies, 450 participants; SMD -0.27, 95% CI -0.58 to 0.03) were not statistically significant, although MCP-1 decreased in sensitivity analyses. Across biomarkers, heterogeneity was moderate to high. Two tirzepatide RCTs (562 participants) showed a significant reduction in IL-6 (SMD -0.28, 95% CI -0.47 to -0.09) and a non-significant trend towards lower CRP/hs-CRP. [CONCLUSIONS] In adults with T2DM, incretin-based therapies consistently lower CRP/hs-CRP, reduce oxidative stress (MDA) and increase adiponectin, while effects on IL-6 and TNF-α are more variable. These data support a selective anti-inflammatory and metabolic regulatory profile of GLP-1-based therapy, but heterogeneity and limited data for some biomarkers warrant cautious interpretation and further mechanistic studies. [TRIAL REGISTRATION] PROSPERO number: CRD420261321430.