The main purpose of this study is to evaluate the safety and efficacy of retatrutide once-weekly in participants who have obesity or are overweight and have osteoarthritis (OA) of the knee. The study will lasts about 77 weeks.

Inclusion Criteria:

• Have a body mass index (BMI) ≥27 kilogram/kg/m² at screening.
• Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight.
• Have index knee pain for >12 weeks prior to screening, and presence of index knee pain for >15 days over the previous month.
• Have knee X-ray with moderate radiographic changes (Kellgren-Lawrence Grade 2 or 3) per central reading at screening.
• Currently meets American College of Rheumatology (ACR) Criteria (clinical and radiological) for OA.

Exclusion Criteria:

• Have had steroid joint injections within 90 days of screening.
• Have had other joint injections and procedures within 6 months of screening.
• Have joint disease other than osteoarthritis.
• Have a self-reported or documented change in body weight >5 kg (11 pounds) within 90 days prior to screening.
• Have been taking weight loss drugs, including over-the-counter medications, within 90 days prior to screening.
• Have a prior or planned surgical treatment for obesity.
• Have diabetes mellitus.

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.

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