Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide: A SURMOUNT-1 Post Hoc Analysis

Tirzepatide improved many cardiovascular risk biomarkers over 72 weeks in adults with overweight or obesity, with dose-related changes compared with placebo. Reductions were seen in markers of inflammation, insulin resistance, metabolic/adiposity/hepatic stress, and selected thrombosis markers, while fibrinogen, tissue plasminogen activator:Ag, and thrombomodulin did not change consistently.

Randomized controlled trial — Randomized double-blind placebo-controlled post hoc analysis. Population: Adults with overweight or obesity in the SURMOUNT-1 trial who completed assigned treatment. Sample size: 392 participants (100 randomly selected per treatment group, after low sample volumes excluded). Follow-up: 72 weeks (biomarkers measured at baseline, 24 weeks, and 72 weeks). Interventions: tirzepatide 5 mg once weekly; tirzepatide 10 mg once weekly; tirzepatide 15 mg once weekly. Cited by 1 other paper.

At week 72 versus placebo, tirzepatide 5/10/15 mg changed geometric means by: high-sensitivity C-reactive protein -36.9%/-46.9%/-54.6%; interleukin-6 -25.4%/-27.8%/-30.2%; homeostatic model assessment of insulin resistance -26.4%/-35.5%/-39.1%; leptin -44.4%/-59.3%/-61.4%; gamma-glutamyl transferase -18.6%/-21.6%/-32.7%; fibroblast growth factor-21 -27.4%/-27.6%/-39.9%; adiponectin +21.1%/+35.1%/+47.7%; E-selectin -12.6%/-20.0%/-26.4%; and plasminogen activator inhibitor-1:Ag -41.4%/-35.6%/-44.3%. Leukocytes were not significantly changed at the 5 mg dose but fell by 8.6% and 10.0% at 10 and 15 mg; free fatty acids were not significant at 5 or 10 mg but fell by 17.1% at 15 mg; soluble intercellular adhesion molecule-1 was not significant at 5 mg but fell by 9.7% and 11.1% at higher doses; platelets were not significant at 5 or 10 mg but fell by 6.0% at 15 mg. No consistent associations were observed for fibrinogen, tissue plasminogen activator:Ag, or thrombomodulin.

This paper gives researchers a comprehensive, randomized, placebo-controlled picture of tirzepatide's long-term effects on multiple cardiovascular biomarker pathways in obesity, including dose-response information. It does not establish that tirzepatide reduces clinical cardiovascular events, nor does it prove that the biomarker changes translate into improved cardiovascular outcomes.

Key findings

At week 72, tirzepatide 5, 10, and 15 mg reduced high-sensitivity C-reactive protein by 36.9%, 46.9%, and 54.6% versus placebo.
Interleukin-6 fell by 25.4%, 27.8%, and 30.2% across the three tirzepatide doses.
Homeostatic model assessment of insulin resistance decreased by 26.4%, 35.5%, and 39.1% for tirzepatide 5, 10, and 15 mg.
Leptin decreased by 44.4%, 59.3%, and 61.4%, while adiponectin increased by 21.1%, 35.1%, and 47.7%.
E-selectin declined by 12.6%, 20.0%, and 26.4%, and plasminogen activator inhibitor-1:Ag declined by 41.4%, 35.6%, and 44.3%.
Leukocytes, free fatty acids, soluble intercellular adhesion molecule-1, and platelets were significantly reduced only at higher tirzepatide doses.

Limitations

Post hoc analysis of a selected subsample of participants who completed treatment, not the full randomized cohort.
Restricted to participants with available plasma samples after low-volume exclusions, which may introduce selection bias.
Biomarker outcomes were exploratory and no clinical cardiovascular events were assessed.

The record

Journal: Journal of the American College of Cardiology 88(6): 652-666
Published: 2026-06-03
PMID: 42233927 — DOI: 10.1016/j.jacc.2026.04.044
MeSH terms: Humans, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Obesity, Double-Blind Method, Time Factors, Middle Aged, Female, Male, Biomarkers, Heart Disease Risk Factors, Tirzepatide
Funding: Eli Lilly and Company
Author countries: Austria, Canada, USA, United Kingdom

Peptide profiles: Tirzepatide.

All indexed evidence: Tirzepatide trials & papers.