Tirzepatide significantly reduces comprehensive cardiovascular risk biomarkers in overweight/obese individuals over 72 weeks

Despite its approval for type 2 diabetes and obesity, the long-term impact of tirzepatide on a broad spectrum of cardiovascular risk biomarkers in people with overweight or obesity has remained largely undefined. Current obesity management strategies often fall short in comprehensively addressing the systemic inflammation, metabolic dysfunction, and endothelial damage that contribute to elevated cardiovascular risk. Understanding how a dual GLP-1R and GIPR agonist like tirzepatide influences these specific biomarkers is crucial for assessing its full therapeutic potential beyond weight and glycemic control.

This was a post hoc analysis of the SURMOUNT-1 trial, evaluating plasma samples from 392 randomly selected participants with overweight or obesity. Participants had completed 72 weeks of treatment with once-weekly placebo or tirzepatide 5 mg, 10 mg, or 15 mg. Biomarkers reflecting inflammation (e.g., high-sensitivity C-reactive protein, interleukin-6), metabolic/adiposity/hepatic stress (HOMA-IR, leptin, FGF-21), endothelial dysfunction (sICAM-1, E-selectin), and hemostasis/thrombosis (PAI-1:Ag, tPA:Ag) were assayed at baseline, 24 weeks, and 72 weeks. Changes in log-transformed biomarker levels were assessed using a mixed model for repeated measures.

At week 72, tirzepatide was associated with significantly greater reductions or increases in biomarker geometric means compared with placebo across all doses. For high-sensitivity C-reactive protein (hsCRP), the 5 mg, 10 mg, and 15 mg doses reduced levels by -36.9%, -46.9%, and -54.6%, respectively.

The 15 mg dose of tirzepatide achieved the most substantial reduction in high-sensitivity C-reactive protein (hsCRP), decreasing it by 54.6% at week 72 compared to placebo. Significant improvements were also observed across other biomarker categories. For instance, HOMA-IR (a measure of insulin resistance) and leptin (an adiposity marker) showed dose-dependent reductions. Endothelial dysfunction markers like soluble intercellular adhesion molecule-1 and E-selectin were also significantly decreased, indicating improved vascular health. Furthermore, markers of hemostasis and thrombosis, such as plasminogen activator inhibitor-1:antigen, demonstrated favorable changes, collectively pointing to a broad, positive impact on cardiovascular risk factors.