Atherosclerosis Cardiovascular Disease, Chronic Coronary Artery Disease, Coronary Artery Disease, Coronary Microvascular Dysfunction, Overweight or Obesity, Stable Angina Pectoris
Conditions
Keywords
NIRS, IVUS, GLP-1, Tirzepatide, Intravascular imagining, Stable Angina Pectoris
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.
Interventions
DRUGTirzepatide
Investigational drug will be administered as a sc. injection once-weekly.
DRUGPlacebo
Placebo containing the same excipients and volume as the active treatment arm but without tirzepatide will be administered as a sc. injection once-weekly.
Sponsors
Tina Vilsbøll
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Body composition assessed by DXA scan: | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Regional visceral adipose tissue (VAT) Bone density |
| Urine markers of oxidative stress | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | 8-oxo-7,8-dihydro2´-deoxyguanosine (8-oxodG) 8-oxo-7,8-dihydroguanosine (8-oxoGuo) |
| Myocardial work | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Assessed by pressure-strain loop analysis derived from speckle-tracking echocardiography |
| Seattle Angina Questionnaire-7 | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Seattle Angina Questionnaire-7 (SAQ-7) measures health status in patients with coronary artery disease. The SAQ-7 generates a summary score (scale 0-100, 100 = full health, 0 = worst health). |
| Thromboelastography | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Thromboelastography is a viscoelastic hemostatic assay that measures the global viscoelastic properties of whole blood clot formation under low shear stress The following parameters will be measured: * R value = reaction time (min) * K = kinetics (min) * alpha = angle (degrees) * MA = maximum amplitude (mm) Represents the ultimate strength of the fibrin clot; i.e. overall stability of the clot * LY30 = amplitude at 30 minutes (%) Percentage decrease in amplitude at 30 minutes post-MA |
| EuroQoL 5-Dimension 5-Level | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | The EuroQoL 5-Dimension 5-Level (EQ-5D-5L) is questionnaire of 5 health dimensions - mobility, self-care, usual activities, pain/discomfort, and anxiety/depression - and includes 5 response categories of no problem, slight problems, moderate problems, severe problems, and extreme problems. The 5 responses give a health state or profile represented by a 5-digit number (for example, 12231) corresponding to response categories reported by patients for successive dimensions, beginning with mobility. Health states are scored to give the EQ-5D-5L index using a scoring algorithm from a value set derived from valuation tasks typically undertaken with general population samples. Index scores range from -0.59 to 1; 1 is the best possible health state. |
| Controlled Attenuation Parameter | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Controlled Attenuation Parameter (CAP): This measurement is performed using a technology called Fibroscan. This measures the amount of fat in the liver, known as steatosis. The CAP score is expressed in decibels per meter (dB/m) and ranges from 100 to 400 dB/m. Higher CAP scores indicate greater levels of liver fat. |
| Plasma lipid profile | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Total cholesterol (TC) Triglyceride (TG) High-density lipoprotein cholesterol (HDL-C) LDL-C |
| Fibrosis-4 score | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Fibrosis-4 (FIB-4) score is a non-invasive scoring system used to estimate the amount of liver fibrosis in individuals. The score is calculated using the following formula: FIB-4 = (Age \* aspartate aminotransferase level U/L )/(Platelet count 10\^9/L \* squareroot(alanine aminotransferase level U/L )) The resulting score helps to stratify patients into different risk categories for liver fibrosis Low risk: FIB-4 under 1.3 Intermediate risk: FIB-4 between 1.3 and 2.67 High risk: FIB-4 above 2.67 |
| Glycaemic profile | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Glycaemic variability measured by continuous glucose monitoring (CGM) Fasting plasma glucose (FPG) Glycated haemoglobin A1c (HbA1c) |
| Change in glycaemic variability | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Glycaemic variability measured by continuous glucose monitoring (CGM) refers to the fluctuations in blood glucose levels over time. The following metrics are used to quantify glycaemic variability: Standard Deviation (SD): Measures the dispersion of glucose values around the mean. Coefficient of Variation (CV): The ratio of the standard deviation to the mean glucose level, expressed as a percentage. Mean Amplitude of Glycemic Excursions (MAGE): Captures the average of the absolute differences between consecutive peaks and nadirs in glucose levels. Continuous Overlapping Net Glycemic Action (CONGA): Measures the variability of glucose levels over a specified period. |
| Change in fasting plasma glucose | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Fasting plasma glucose (FPG) |
| Change in glycated haemoglobin A1c | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Glycated haemoglobin A1c (HbA1c) |
| Index of microcirculatory resistance | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo | Index of microcirculatory resistance (IMR) assessed by coronary thermodilution technique during coronary angiogram |
| Resistive Reserve Ratio | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo | Resistive Reserve Ratio (RRR) assessed by coronary thermodilution technique during coronary angiogram is a measure used to evaluate the vasodilatory capacity of the coronary microvasculature. |
| Homeostatic Model Assessment for Insulin Resistance | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Homeostatic model assessment of insulin resistance (HOMA-IR) evaluates systemic insulin resistance. HOMA-IR is calculated using fasting blood glucose and fasting insulin levels. The formula for HOMA-IR is: HOMA-IR = (Fasting Insulin uU/mL \* Fasting Glucose mmol/L)/22.5 HOMA-IR values between 0.5 and 1.4 are considered normal. ≥1.9 are indicative of early insulin resistance, and ≥2.9 indicate insulin resistance. |
| Liver stiffness measurement | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Liver Stiffness Measurement (LSM): This measurement is performed using a technology called Fibroscan. It measures the stiffness or hardness of the liver, which correlates with the degree of liver fibrosis (scarring). The result is expressed in kilopascals (kPa). Normal liver stiffness values typically range from 2 to 7 kPa, with higher values indicating more severe fibrosis. |
| Markers of inflammation | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | High-sensitive C-reactive protein (hsCRP) Interleukin-6 (IL-6) |
| Left ventricular systolic and diastolic function assessed by echocardiography: | Between-group difference in change from baseline to week 52 in participants treated with tirzepatide vs placebo: | Global longitudinal strain (GLS) measured by speckle tracking E/e' measured by tissue-Doppler |
Countries
Denmark
Contacts
Primary ContactDaniel Raaschou-Oddershede, MD
Backup ContactChristine Rode Schwarz, MD, PhD
Outcome results
None listed