PATHS-T2D: A Recall-by-Genotype Study of Physiologic and Pharmacologic Responses

Inclusion Criteria: * Adult male or non-pregnant female volunteers (Age 18-79) * Not currently taking more than two home oral antidiabetic agents, with or without a diagnosis of type 2 diabetes * Able and willing to stop home oral antidiabetic medications for 5 days prior to the start of the study, with approval from healthcare providers * Able and willing to give informed consent Exclusion Criteria: * Known contraindication for orforglipron (e.g., Personal or family history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia type 2 (MEN 2), allergies to any component) * Personal history of pancreatitis, gallbladder disease, intestinal malabsorption, severe gastroparesis, gastric outlet obstruction, or other clinically significant gastrointestinal motility disorder * History of liver disease or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 x upper limit of normal * Estimated glomerular filtration rate (eGFR) \< 45 mg/min/1.73m2 per the Modification of Diet in Renal Disease equation * Active gallbladder disease or cholecystectomy within the past 6 months * Current use of a strong CYP3A4 inducer (e.g., rifampin, carbamazepine, phenytoin, phenobarbital, rifabutin, or St. John's wort) or ritonavir, cobicistat, cyclosporine, or another strong CYP3A4 inhibitor that also inhibits OATP1B * Current simvastatin dose \>20 mg daily * Measured most recent HbA1c level greater than 7.5% in the last 6 months * Average glucose by fingerstick or contin…