The Effects of Tirzepatide in People With Overweight/Obesity and Coronary Artery Disease

Lipid core burden index of the three major coronary vessels (LCBItotal) measured by NIRS imaging.

Total coronary plaque burden measured by coronary IVUS imaging assessed by Percent atheroma volume (PAV)

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 (CFR) assessed by invasive coronary thermodilution technique during coronary angiogram measures the blood flow in the epicardial arteries and the microvasculature.

Total cholesterol (TC) Triglyceride (TG) High-density lipoprotein cholesterol (HDL-C) LDL-C

High-sensitive C-reactive protein (hsCRP) Interleukin-6 (IL-6)

Global longitudinal strain (GLS) measured by speckle tracking E/e' measured by tissue-Doppler

Regional visceral adipose tissue (VAT) Bone density

8-oxo-7,8-dihydro2´-deoxyguanosine (8-oxodG) 8-oxo-7,8-dihydroguanosine (8-oxoGuo)

Assessed by pressure-strain loop analysis derived from speckle-tracking echocardiography

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 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

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.

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.

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.

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.

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 variability measured by continuous glucose monitoring (CGM) Fasting plasma glucose (FPG) Glycated haemoglobin A1c (HbA1c)

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.

Fasting plasma glucose (FPG)

Glycated haemoglobin A1c (HbA1c)

Index of microcirculatory resistance (IMR) assessed by coronary thermodilution technique during coronary angiogram

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.