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

Abstract

Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes and obesity. The effect of tirzepatide on cardiovascular risk biomarkers in people with overweight or obesity remains uncertain. The purpose of this study was to evaluate the association of tirzepatide compared to placebo on biomarkers that reflect inflammation (high-sensitivity C-reactive protein, interleukin-6, fibrinogen, leukocytes), metabolic/adiposity/hepatic stress (homeostatic model assessment of insulin resistance, leptin, gamma-glutamyl transferase, fibroblast growth factor-21, adiponectin, free fatty acids), endothelial dysfunction (soluble intercellular adhesion molecule-1, E-selectin), and hemostasis/thrombosis (plasminogen activator inhibitor-1:antigen [Ag], tissue plasminogen activator:Ag, thrombomodulin, platelets) in people with obesity. The aforementioned biomarkers were assayed from plasma samples, collected at baseline, 24 weeks, and 72 weeks, from 100 randomly selected participants from each group of the SURMOUNT-1 trial who completed treatment with once-weekly placebo or tirzepatide 5, 10, or 15 mg (n = 392 after low sample volumes excluded). The change in each log-transformed biomarker level over time was evaluated by a mixed model for repeated measures, with change at 72 weeks the primary outcome of interest. Model estimates were back-transformed to the original (geometric mean ratio) scale and expressed as percent change in geometric means. Pearson correlations between log change in biomarker levels and weight were done on pooled tirzepatide doses. At week 72, tirzepatide was associated with significantly greater reductions (negative values) or increases (positive values) in biomarker geometric means compared with placebo. For the 5-, 10-, or 15-mg doses, respectively, these included high-sensitivity C-reactive protein (-36.9%, -46.9%, -54.6%), interleukin-6 (-25.4%, -27.8%, -30.2%), leukocytes (not significant [NS], -8.6%, -10.0%), 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%), free fatty acids (NS, NS, -17.1%), soluble intercellular adhesion molecule-1 (NS, -9.7%, -11.1%), E-selectin (-12.6%, -20.0%, -26.4%), plasminogen activator inhibitor-1:Ag (-41.4%, -35.6%, -44.3%), and platelets (NS, NS, -6.0%) (all adjusted P < 0.05). No consistent associations were observed between tirzepatide and changes in fibrinogen, tissue plasminogen activator:Ag, or thrombomodulin. In this post hoc analysis, tirzepatide was associated with improvements in biomarkers of metabolic/adiposity/hepatic stress and endothelial dysfunction, as well as selected biomarkers of inflammation and hemostasis/thrombosis. This analysis provides a comprehensive, long-term, randomized assessment of biomarker changes across multiple cardiovascular pathways during tirzepatide treatment in obesity. (A Study of Tirzepatide [LY3298176] in Participants With Obesity or Overweight [SURMOUNT-1]; NCT04184622).