The primary objective of Study GZQG is to compare the effect of retatrutide and placebo on total clamp disposition index (cDI) after 28 weeks of treatment.

Inclusion Criteria:

• Have been diagnosed with Type 2 Diabetes Mellitus (T2DM) for at least 6 months prior to screening.

• Treated with diet and exercise and metformin daily, with or without other allowed oral antihyperglycaemia medications (OAMs), 3 months prior to screening. Allowed OAMs are dipeptidyl peptidase-4 inhibitors (DPP-IV) inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, glinides, and sulfonylureas.

• Have a HbA1c value at screening of:

  • 6.5% and ≤ 9.5 % if on metformin with or without SGLT2 inhibitors, or
  • 6% and ≤8.5% if on metformin in combination with allowed OAMs that require washout.

• Have venous access sufficient to allow for blood sampling as per the protocol.

• Have clinical laboratory test results within normal reference range for the population or investigative site or results with acceptable deviations that are judged to be not clinically significant by the investigator.

• Have a body mass index (BMI) between 25 kilograms per meter squared (kg/m²) and 45 kg/m², both inclusive, at screening.

• Have had a stable body weight that is less than 5% change during the 3-month period prior to screening.

Exclusion Criteria:

• Have Type 1 Diabetes Mellitus (T1DM)

• Have had more than 1 episode of severe hypoglycaemia, as defined by the American Diabetes Association criteria, within 6 months before screening or a history of hypoglycaemia unawareness or poor recognition of hypoglycaemic symptoms; any participant that cannot communicate an understanding of hypoglycaemic symptoms and the appropriate treatment of hypoglycaemia prior to the first dose of study drug should also be excluded.

• Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma requiring hospitalisation within the 6 months prior to screening.

• Are currently receiving, planning to receive, or in need of treatment, that is, intravitreal injections of Vascular Endothelial Growth Factor inhibitor or corticosteroids, focal/grid macular laser surgery, panretinal photocoagulation, or vitrectomy for diabetic retinopathy at screening.

• Have impaired renal estimated glomerular filtration rate <60.0 mL/min/1.73 m² calculated by Chronic Kidney Disease-Epidemiology (2021).

• Have acute or chronic pancreatitis or a history of acute idiopathic pancreatitis.

• Have elevations in:

  • serum aspartate aminotransferase (AST) >2.5X the upper limit of normal (ULN)
  • serum alanine aminotransferase (ALT) >2.5X ULN
  • total bilirubin level (TBL) >1.5X ULN (except, participants with Gilbert's syndrome), or
  • Alkaline phosphatase (ALP) level ≥1.5X ULN

• Show evidence of possible chronic or active hepatitis B, including hepatitis B core antibody and/or hepatitis B surface antigen positivity.

• Have a positive Hepatitis C virus (HCV) antibody (Ab) test. Participants with a positive HCV Ab test at screening can be included only if a confirmatory HCV ribonucleic acid (RNA) test is negative.

• Have a known clinically significant gastric emptying abnormality, have undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery or chronically take drugs that directly affect GI motility.

• Have had within 3 months prior to screening:

  • acute myocardial infarction
  • congestive heart failure New York Heart Association (NYHA) class III or IV, and/or
  • cerebrovascular accident [stroke]
  • coronary artery revascularisation
  • hospitalization hospitalisation for unstable angina
  • hospitalization hospitalisation due to congestive heart failure.

• Have a history of additional risk factors for Torsades de Pointes (for example, heart failure, hypokalaemia, family history of Long QT Syndrome), as judged by the investigator.

• Have a 12-lead ECG abnormality at screening that, in the opinion of the investigator, increases the risks associated with participating in the study or may confound electrocardiogram (ECG) data analysis.

• Have a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome Type 2 (MEN 2).

• Have an active or untreated malignancy or have been in remission from a clinically significant malignancy for <5 years prior to screening. Exceptions:

  • basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years
  • cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to baseline, or
  • in situ prostate cancer.

• Have, in the opinion of the investigator, evidence of significant, uncontrolled endocrine abnormality, for example, thyrotoxicosis or adrenal crisis.

• Have a prior or planned surgical treatment for obesity.

• Have a prior or planned endoscopic and/or device-based therapy for obesity.

• Have taken any glucose-lowering medications other than metformin, DPP IV inhibitors, sulfonylureas and/or SGLT-2 inhibitors, regardless of the indication for use, any time within the 3 months prior to screening.

• Have taken prescribed or over-the-counter (OTC) medications, either approved or unapproved, or alternative remedies, including herbal or nutritional supplements, intended to promote body weight reduction, within 3 months prior to screening.

• Have evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies.

• Have a calcitonin level at screening of ≥35.0 nanograms per liter (ng/L), [≥35.0 picograms per milliliter (pg/mL)].

Sponsor is blinded to Retatrutide/Placebo. Semaglutide is open-label.