Abstract
Introduction: The dual GIP/GLP-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with obesity and type 2 diabetes (T2D) in a Phase 2 trial. Hypothesis: In this post hoc analysis, additional biomarkers of inflammation, endothelial dysfunction, and cellular stress were measured to better understand possible additional effects of tirzepatide treatment on cardiovascular risk factors. Methods: Patients with T2D were randomly assigned to receive either once-weekly subcutaneous injection of tirzepatide (1, 5, 10, or 15 mg), GLP-1 receptor agonist dulaglutide (1.5 mg), or placebo for 26 weeks. Soluble ICAM-1 and VCAM-1, IL-6, NT-proBNP, hsCRP and GDF-15 were assessed by immunoassay at baseline and 26 weeks in stored serum or EDTA plasma samples. Results were analyzed in a modified intent-to-treat population using a mixed effect model for repeated measures. Results: At 26 weeks, tirzepatide dose-dependently decreased ICAM-1 levels compared to baseline (Table). ICAM-1 levels were also significantly lower with tirzepatide 15 mg than placebo or dulaglutide. Moreover, tirzepatide 15 mg significantly decreased hsCRP levels from baseline compared with placebo. GDF-15 levels were decreased from baseline with all tirzepatide doses and with dulaglutide; however, changes in GDF-15 levels with tirzepatide were not significantly different from those with placebo or dulaglutide. Levels of IL-6, VCAM-1 or NT-proBNP were unchanged in all groups. Conclusions: In a 26-week study in patients with obesity and T2D, treatment with tirzepatide dose-dependently decreased circulating levels of specific biomarkers of inflammation and endothelial dysfunction previously associated with cardiovascular events, thus suggesting a net improvement in the cardiovascular risk profile of these patients. Clinical relevance of these changes will be assessed in the planned cardiovascular outcome study SURPASS-CVOT (NCT04255433).
Published Version
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