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 4 · 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.
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. Biomarkers only, in diabetes, with much variation between trials.
01Findings
What the study reported
- Drugs
- Class unspecified, Tirzepatide
- Comparator
- placebo
- 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
- 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: 95% CI -0
- Risk of bias
- high heterogeneity; small trials; biomarker outcomes
- Funding conflicts
- unclear
- Peer review status
- yes
- Amstar2
- Overall: Low confidence (AMSTAR 2, full text, two passes agreed)
Driver: one critical flaw: item 13 — risk-of-bias results are not brought into the interpretation of the pooled estimates
Items: 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)
Source: full text (PMC HTML), 2026-09-13; supersedes the abstract-only assessment
Passes: [{"pass":"A","model":"claude-sonnet"},{"pass":"B","model":"claude-opus"}]
Label: AI: two passes agreed - 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.
02Funding
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.
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
Meta-analysis of 41 RCTs in T2D: CRP/hs-CRP reduced (SMD -0.37); IL-6 and TNF-alpha not significantly changed. Biomarkers in diabetes only.
04Source
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.