The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis
- Design
- Randomized trial · 316 participants · Biomarker outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had type 2 diabetes (HbA1c 7.0%‐10.5%), with entry BMI 23‐50 kg/m2 and age 18‐75 years; mean BMI is not reported.
- Could weight loss explain it?
- Specifically testedLinear regression of biomarker change on body weight change found that weight change explained 0% of hsCRP and 6% of YKL-40 variability with tirzepatide, against 13% and 21% with dulaglutide, and 20% of leptin and 4% of ICAM-1 variability with tirzepatide (10 + 15 mg combined).
Adjusted for: body-weight change - Study tier
- Study tier 3LOW: post hoc, hypothesis-generating biomarker analysis of a 26-week randomised, double-blind phase 2b trial, with no clinical outcomes.
- Assessment
- Version 3 · Two reviewers differed; settled by a recorded ruling · 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.
This post hoc analysis of a 26-week randomised, double-blind phase 2b trial in adults with type 2 diabetes compared tirzepatide with placebo and dulaglutide; 316 people were analysed. At 15 mg, tirzepatide lowered several cardiovascular risk markers, including hsCRP by 36.2% (significant versus placebo but not versus dulaglutide). GlycA, IL-6, VCAM-1 and NT-proBNP did not change significantly in any group. These are blood markers, and the authors call the analysis hypothesis-generating.
01Findings
What the study reported
- Drugs
- Tirzepatide
- Dose
- 1, 5, 10 or 15 mg once weekly
- Comparator
- placebo; dulaglutide 1.5 mg
- Route
- subcutaneous
- Treatment duration
- 26 weeks
- Primary outcome
- change in inflammation, endothelial dysfunction and cellular stress biomarkers at 26 weeks (post hoc)
- Effect
- Tirzepatide 15 mg at 26 weeks: hsCRP −36.2% from baseline (significant versus placebo, not versus dulaglutide), YKL-40 −30.8%, ICAM-1 −11.2%, leptin −34.1%; GlycA, IL-6, VCAM-1 and NT-proBNP not significantly changed in any group
- 95% confidence interval
- Not extracted
- P value
- P < .001 for YKL-40 reductions with 10 and 15 mg versus baseline; other results marked P < .05 or not significant
- Follow-up
- 26 weeks (biomarkers at baseline, 4, 12 and 26 weeks)
- Adverse events
- not reported
- Limitations
- Post hoc, hypothesis-generating analysis with sample sizes set for the primary endpoints rather than these biomarkers; 26 weeks in people with type 2 diabetes; biomarker outcomes only.
Who was studied
- Age range
- 18‐75 years
- Age min
- 18
- Bmi min
- 23
- Obesity status
- mixed (BMI 23‐50 kg/m2 entry range)
- Diabetes status
- type 2 diabetes required (HbA1c 7.0%-10.5%)
- Baseline condition
- type 2 diabetes inadequately controlled with diet and exercise alone or stable metformin
- Sample size
- 316
- Inclusion exclusion
- aged 18-75; type 2 diabetes for 6 months or longer, HbA1c 7.0%-10.5%; diet and exercise alone or stable metformin; BMI 23-50
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 316
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo; dulaglutide 1.5 mg
- Follow up duration
- 26 weeks (biomarkers at baseline, 4, 12 and 26 weeks)
- Outcome type
- biomarker
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- LSM (SE) reported, no CI; 316 in the modified intention-to-treat population; post hoc, sample sizes set for the primary endpoints, not these biomarkers
- Risk of bias
- not assessed
- Funding conflicts
- yes
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Eli Lilly and Company
- Industry funded
- Yes
- Manufacturer
- Eli Lilly and Company (named as sponsor)
- Sponsor role
- Sponsored by Eli Lilly and Company; no separate sponsor-role statement, but the author contributions credit study design, medical oversight, data analysis and the statistical analysis to authors who are Lilly employees
- Author conflicts
- Nine of ten authors are employees and shareholders of Eli Lilly and Company; the tenth is a contractor who works with Lilly.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Eli Lilly and Company
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
Post hoc analysis of a 26-week phase 2 trial in type 2 diabetes: tirzepatide 15 mg lowered hsCRP vs placebo but not vs dulaglutide, the fall was evident by week 4, and body weight change explained 0% of hsCRP variability on tirzepatide 10 and 15 mg vs 13% on dulaglutide. IL-6 and GlycA did not change significantly.
04Source
The source, as retrieved
Abstract
In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.