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

Phase 4

Recruiting

• Conditions: Coronary Artery Disease; Coronary Microvascular Dysfunction; Overweight or Obesity; Stable Angina Pectoris; Chronic Coronary Artery Disease; Atherosclerosis Cardiovascular Disease
• Interventions: Drug: Tirzepatide; Drug: Placebo

• Registration Number: NCT06606821
• Lead Sponsor: Tina Vilsbøll

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-04
• Study First Submitted QC: 2024-09-19
• Last Update Submitted: 2024-09-19
• Study First Posted: 2024-09-23
• Last Update Posted: 2024-09-23
• Study Start: 2024-10
• Primary Completion: 2027-03-20
• Study Completion: 2028-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 124

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tirzepatide	Tirzepatide	Tirzepatide is administered sc. once-weekly.
Placebo	Placebo	Placebo is administered sc. once-weekly.

Primary Outcome Measures

Name	Time	Method
Lipid core burden index	Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:	Lipid core burden index of the three major coronary vessels (LCBItotal) measured by NIRS imaging.

Secondary Outcome Measures

Name	Time	Method
Percent atheroma volume (PAV)	Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:	Total coronary plaque burden measured by coronary IVUS imaging assessed by Percent atheroma volume (PAV)
Number of high-risk coronary lesion	Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:	Number of high-risk coronary lesions characterized by maximum lipid core burden index of a 4 mm examined vessel (maxLCBI4mm) ≥325 and plaque burden ≥70%
Coronary flow reserve	Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo:	Coronary flow reserve (CFR) assessed by invasive coronary thermodilution technique during coronary angiogram measures the blood flow in the epicardial arteries and the microvasculature.

Trial Locations

Locations (3)

Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Gentofte Hospital; 🇩🇰 Gentofte, Denmark

Steno Diabetes Center Copenhagen; 🇩🇰 Herlev, Denmark