A placebo for Tirzepatide will be administered with a starting dose of 2.5 mg weekly, subcutaneously injected. The dose will increase by 2.5 mg every 4 weeks until reaching 15 mg.

Participants will be asked to follow lifestyle interventions:

• Low-calorie diet based on their predicted by Harris Benedict resting energy expenditure minus 500 kcal per day
• Physical activity: a goal of 10,000 steps or more per day
• Exercise: a goal of 150 minutes or more of moderate-intensity aerobic activity (cardiovascular exercise) per week
• Limited consumption of liquid calories (i.e. sodas, juices, alcohol, etc.).

Augmentation Index (AIx): AIX uses applanation tonometry of the radial artery pulse, calibrated to resting brachial systolic and diastolic pressures (SphygmoCor XCEL, Medtronic, Minneapolis, MN). Aortic systolic, diastolic, and pulse pressures will be derived from a synthesized aortic waveform using a validated mathematical transfer function. Augmentation pressure, reflecting the difference between aortic systolic pressure and the inflection point caused by the reflected wave, is influenced by arterial stiffness as well as factors like heart rate and ejection dynamics. AIx is calculated as augmentation pressure divided by aortic pulse pressure × 100%, adjusted to a heart rate of 75 bpm (AIx@75 bpm). Measurements will be performed in duplicate and averaged.

SphygmoCor estimates central arterial stiffness by calculating the speed at which the pressure wave travels between the carotid and femoral arteries using applanation tonometry and reported as the pulse wave velocity (PWV); PWV m/s

Change in cardiometabolic parameters including blood pressure from baseline to week 24 on treatment or placebo. Measured in mmhg

Change in cardiometabolic parameters including fasting glucose from baseline to week 24 on treatment or placebo. Measured in mg/dL

Change in cardiometabolic parameters including HbA1C from baseline to week 24 on treatment or placebo. Measured in %

Change in cardiometabolic parameters including Lipoprotein profile from baseline to week 24 on treatment or placebo. Measured in mg/dL

Change in cardiometabolic parameters including hsCRP from baseline to week 24 on treatment or placebo. Measured in mg/L

The SPPB is a standardized test that evaluates lower extremity function using three components: balance tests (standing in various positions), gait speed (walking a short distance), and chair stand (repeated standing from a seated position). Each component is scored from 0 to 4; the total score ranges from 0 to 12. Higher scores represent better physical function

The mCTSIB assesses balance under four sensory conditions: eyes open/closed on firm and foam surfaces. Testing is performed while standing on the RAPID foot pressure mat, which captures center of pressure and postural sway data. The primary measure is average sway area of the four sensory conditions. The sway area is the area which is required to correct equilibrium, representing the total area covered by postural sway, measured in square centimeters (cm²).

This test evaluates upper body muscular power. Participants perform a two-handed chest throw of a 2-kg medicine ball from a standing position. The MST is used to record throw distance, velocity, and related performance metrics. The primary measure is Peak Power Score (W).

This test assesses lower body strength and function. Participants are instructed to stand up from a chair and sit back down five times without using their arms. The MST measures movement dynamics. The primary measure is peak power score (W).

The 6MWT is a standardized submaximal exercise test used to assess functional aerobic capacity. Participants are instructed to walk as far as possible in six minutes along a flat, straight course. The total distance walked is recorded in feet. Longer walking distances indicate better aerobic capacity and endurance.

Participants are instructed to squeeze the dynamometer with maximum effort, measured in kilograms. The highest value from multiple trials is recorded.