The Effects of Tirzepatide in People with Overweight/obesity and Coronary Artery Disease

The objective of this study is to investigate, as a proof-of-principle, long-term (52 weeks) effects of tirzepatide once-weekly vs. placebo on changes in coronary plaque composition and progression (assessed by NIRS), plaque burden (assessed by IVUS) and microvascular function (assessed by invasively measured CFR) in overweight and obese individuals with stable coronary artery disease (CAD). In addition, the objective of a baseline cross-sectional sub-study is to explore potential metabolic and cardiovascular (CV) predictors for high arteriosclerotic plaque burden in overweight and obese individuals and to establish a cohort for future research projects.

The anti-atherogenic effect of tirzepatide has been studied in preclinical studies and seems to involve mechanisms related to a reduction in vascular inflammation and lipid accumulation. Any direct anti-atherogenic effect of tirzepatide may potentially reduce the incidence of major cardiovascular endpoints in individuals with overweight or obesity. As a proof of principle, it would be of scientific and clinical interest to explore the anti-atherogenic effect of tirzepatide in humans. IVUS-NIRS imaging is uniquely suited for this purpose, as it makes it possible to detect changes in not only atheroma burden by IVUS but also to detect progression within the plaques in the lipidic/necrotic core component by NIRS. LCBItotal allows for consecutive detection of small changes in the same individual, which is pivotal to explore the supposed antiatherogenic mechanism of tirzepatide with enough statistical power.

The investigators hypothesize that once-weekly sc. tirzepatide can reduce coronary lipid accumulation in the arterial wall and the progression of atheromatosis in individuals with overweight or obesity and established high-risk atherosclerosis. The investigators aim to investigate this hypothesis in a proof-of-principle study by investigating the change in coronary plaque composition in individuals with overweight or obesity and coronary artery disease (CAD) with high-risk characteristics by NIRS imaging randomised to 52-week treatment with tirzepatide or placebo.

Eligibility Criteria:
Inclusion Criteria:

* Informed written consent
* BMI equal to or above 27 kg/m2
* Age 18 years or older
* Referred to coronary angiogram (CAG) due to stable angina
* Coronary atheromatosis by angiography (obstructive or non-obstructive)
* LCBI4mm \>200 by NIRS in a vessel not subjected to coronary intervention

Exclusion Criteria:

* History of diabetes or HbA1c ≥48 mmol/mol (6.5%) at baseline
* Treatment with Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA)
* History of coronary artery bypass surgery (CABG)
* Planned CV intervention (including percutaneous coronary intervention, cardiac surgery or transcatheter valve intervention) at time of randomisation
* History of heart failure New York Heart Association (NYHA) class III or IV
* Left ventricular ejection fraction (LVEF) ≤35%
* eGFR \<30 ml/min/1.53 m2
* History of pancreatitis or plasma amylase \>2 times upper normal limit
* Impaired hepatic function at baseline (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 times the upper limit of normal)
* Pregnancy, planned pregnancy or breastfeeding
* Family or history of multiple endocrine neoplasia (MEN) type 2 or familial medullary thyroid carcinoma (FMTC)
* Hypersensitivity to the active substance (Tirzepatide) or to any of the excipients
* Left main stenosis (≥50% diameter or haemodynamically significant)
* Chronic total occlusion of any major coronary vessel
* Multi-vessel disease or complex anatomy potentially requiring coronary bypass surgery
* Coronary anatomy or pathology precluding the safe performance of intravascular imaging in all major coronary arteries not subjected to intervention