The purpose of this study is to evaluate the efficacy and safety of retatrutide in participants who have obesity or overweight (J1I-MC-GZBJ master protocol) including subsets of participants who have knee osteoarthritis (OA) (J1I-MC-GOA1) or who have obstructive sleep apnea (OSA) (J1I-MC-GSA1). This study will last about 89 weeks and will include up to 24 visits. Addendum (2) is optional and available to approximately 500 participants to continue treatment with retatrutide for up to an additional 24 weeks.

Inclusion Criteria:

• Have body mass index (BMI) ≥30.0 kilograms per square meter (kg/m²), or ≥27.0 kg/m² with at least one of the following:

  • hypertension
  • dyslipidemia
  • obstructive sleep apnea, or
  • cardiovascular disease

• History of of at least one unsuccessful dietary effort to reduce body weight

GOA1 Inclusion Criteria:

• 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.

GSA1 Inclusion Criteria:

• Previously diagnosed with OSA
• Have AHI ≥15 on polysomnography at screening (definition of moderate-to-severe OSA)
• For participants not on positive airway pressure (PAP) therapy: unable or unwilling to use PAP therapy and have not used PAP for at least 4 weeks prior to screening.
• If on PAP therapy, have been on PAP therapy for at least 3 consecutive months prior to screening, and willing to temporarily stop using PAP therapy for approximately 7 days prior to each of the sleep study (PSG) visits.

GZBJ Addenda (2) inclusion criteria:

• Have completed the final treatment visit of GZBJ Week 80.

Exclusion Criteria:

• Have a self-reported or documented change in body weight >5 kg (11 pounds) within 90 days.
• Have taken 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.
• Have family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2)
• Have had pancreatitis.

GOA1 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.

GSA1 exclusion criteria

• Use stimulants (for example, modafinil, armodafinil, solriamfetol, pitolisant, amphetamine) less than 3 months prior to screening.
• Use hypnotics, mirtazapine, opioids, trazodone, and zonisamide less than 3 months prior to screening.
• Use a dental appliance or other device to treat OSA other than PAP therapy.

GZBJ Addenda (2) exclusion criteria

• Have had study intervention discontinuation.
• Have had permanent dose reduction.

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.