This study will investigate the efficacy and safety of once daily oral orforglipron in adult participants with obesity or overweight with weight-related comorbidities. The study has two phases: a main phase and an extension phase. The main phase of the study lasted 72 weeks. Participants with prediabetes will continue in the extension for another 2 years.

Inclusion Criteria:

• Have a BMI

  • ≥30.0 kilogram/square meter (kg/m²),

  • ≥27.0 kg/m² and presence of at least 1 of the following weight-related comorbidities (treated or untreated) at screening:

    • Hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease (for example, ischemic cardiovascular disease, New York Heart Association Functional Class I-III heart failure).

• Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight.

Exclusion Criteria:

• Have Type 1 diabetes, Type 2 diabetes, or any other types of diabetes, history of ketoacidosis, or hyperosmolar state/coma
• Have a self-reported change in body weight >5 kg (11 pounds) within 90 days prior to screening.
• Have family (first-degree relative) or personal history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia (MEN)2 syndrome.
• Have had a history of chronic or acute pancreatitis.

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.