Study GZRA is a master protocol that will support 2 independent studies, GZ01 and GZ02. Participants will be assigned to the appropriate study prior to randomization. The purpose of the studies is to evaluate the efficacy and safety of orforglipron in participants who have moderate-to-severe OSA and obesity or overweight. Study GZ01 will include participants who are unable or are unwilling to use PAP therapy. Study GZ02 will include participants who are on PAP therapy for at least 3 months at time of screening and plan to continue PAP therapy during the study.

Inclusion Criteria:

Master GZRA inclusion criteria

• have AHI ≥15 on PSG as part of the trial at screening (V1).
• have body mass index (BMI) ≥27 kg/m²

Study 1 GZ01 inclusion criteria

• Participants who are unable or unwilling to use PAP therapy.
• Participants must not have used PAP for at least 4 weeks prior to screening.

Study 2 GZ02 inclusion criteria

• Participants who have been on PAP therapy for at least 3 consecutive months prior to study start and plan to continue PAP therapy during the study.

Exclusion Criteria:

Master GZRA exclusion criteria

• Have Type 1 diabetes (T1D) or Type 2 diabetes (T2D), history of ketoacidosis, or hyperosmolar state/coma
• Have HbA1c ≥6.5% (≥ 48 mmol/mol), as determined by the central laboratory at Visit 1.
• Had any previous or planned upper airway surgery for sleep apnea or major ear, nose or throat surgery
• Have diagnosis of Central or Mixed Sleep Apnea with % of mixed or central apneas/hypopneas ≥50%, or diagnosis of Cheyne Stokes Respiration
• Diagnosis of Obesity Hypoventilation Syndrome or daytime hypercapnia.
• Active device treatment of OSA other than PAP therapy
• Respiratory and neuromuscular diseases that could interfere with the results of the trial in the opinion of the investigator.
• Have a self-reported change in body weight >5 kg within 3 months prior to screening
• Have a prior or planned surgical treatment for obesity (excluding liposuction, abdominoplasty or cryolipolysis if performed more than 1 year prior to screening)
• Have a prior or planned endoscopic and/or present device-based therapy for obesity.
• Have obesity induced by other endocrinologic disorders or diagnosed monogenetic or syndromic forms of obesity.

Study 2 GZ02 exclusion criteria

• Have personal or job-related responsibilities, or in the opinion of the investigator have any situation that would make it unsafe to stop PAP therapy for 7 days prior to PSG testing during the study.
• Are unwilling to temporary discontinue PAP therapy for 7 days prior to PSG testing during the study.

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.