Title of project

High-risk coronary plaques and tirzepatide treatment in overweight and obesity: The influence of
metabolic clusters on mechanisms and therapeutic response

Abstract

With rising obesity rates and associated coronary artery disease (CAD), traditional treatments may not fully address underlying metabolic factors. Tirzepatide, a novel incretin-based therapy, has shown promising cardiovascular (CV) benefits but requires further investigation into its effects on coronary plaques and microcirculation.

This postdoctoral research aims to I) characterize metabolic phenotypes associated with high-risk coronary plaques and microvascular dysfunction; II) Delineate molecular mechanisms of tirzepatide during 52 weeks of tirzepatide treatment vs. placebo; and III) Distinguish and characterize responders and non-responders to the effects of tirzepatide on coronary plaque and microvascular circulation.

Individuals with overweight or obesity referred to coronary angiography (CAG) due to stable angina pectoris will undergo comprehensive evaluations (n ≈260). During CAG, advanced imaging techniques and measurements will be performed to assess coronary plaque lipid content and microvascular circulation. Participants will complete additional CV, metabolic, and molecular assessments. A subset with the highest coronary artery lipid content, will be enrolled in a randomized, placebo-controlled trial, evaluating effects of tirzepatide on coronary plaque lipid content and microvascular circulation vs placebo (n =124). Blood samples will be collected regularly to track changes in multi-omics profiles. Re-CAG will be performed after 52 weeks to assess plaque and circulation changes, followed by a followup visit for a comprehensive CV, metabolic and multi-omics profile analysis.

This study aims to profile individuals with overweight or obesity who have high-risk coronary plaques prone to rupture, delineate mode-of-action of incretin-based therapies in CAD, and characterize responders and non-responders to tirzepatide therapy, ultimately enhancing disease stratification and treatment efficacy.