The main purpose of this study is to determine if retatrutide can significantly lower the incidence of serious heart-related complications or prevent the worsening of kidney function. The trial will enroll adults with body mass index 27 kg/m^2 or higher and Atherosclerotic Cardiovascular Disease and/or chronic kidney disease. The study will last for about 5 years. Participants will have up to 27 clinic visits with the study doctor.

Inclusion Criteria:

• Participants may be without type 2 diabetes (T2D), or with T2D if their hemoglobin A1c (HbA1c) is 10% or lower

• Participants have established atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD), as evidenced at least one of the following:

  • Coronary artery disease

  • Cerebrovascular disease

  • Peripheral arterial disease

  • Chronic kidney disease defined as:

    • eGFR <45 millilitres/minute/1.73 meter squared (mL/min/1.73m^2) and UACR >30 milligram/gram (mg/g) (0.030 mg/mg)
    • eGFR <60 mL/min/1.73 m^2 and UACR >100 mg/g (0.100 mg/mg), or
    • eGFR <75 mL/min/1.73 m^2 and UACR >300 mg/g (0.300 mg/mg) (eGFR is calculated by central lab based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin c equation as determined by central lab)

• A Body Mass Index of ≥27.0 kilograms per meter squared (kg/m^2)

Exclusion Criteria:

Diabetes related:

• Participants have Type 1 Diabetes or any history of diabetic ketoacidosis

CV related:

• Participants have any of the following cardiovascular conditions ≤ 90 days prior to randomization:

  • Myocardial infarction
  • Acute coronary syndrome
  • Stroke, or
  • Coronary, peripheral, or carotid artery arterial revascularization procedure.

• Have acute decompensated heart failure requiring hospitalization.

• Have New York Heart Association (NYHA) Classification Class IV heart failure at screening

Kidney related:

• Participants have an eGFR <20 mL/min/1.73 m^2 at screening
• Have UACR >5000 mg/g (5.000 mg/mg) at screening
• Have received any form of dialysis ≤ 90 days from the date of randomization
• Have either undergone a kidney transplant or have a transplant procedure scheduled

Other medical conditions:

• Participants have had or plan to have a surgical treatment for obesity,
• Have a history of chronic or acute pancreatitis
• Have a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) syndrome type 2
• Have a known clinically significant gastric emptying abnormality, such as severe gastroparesis or gastric outlet obstruction

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later. Data will be indefinitely available for requesting.

research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.