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

We are conducting a research study to learn how the body responds to food through different genetic pathways and how these responses may change during a short course of orforglipron. Orforglipron is an oral glucagon-like peptide-1 (GLP-1) receptor agonist that was approved by the U.S. Food and Drug Administration (FDA) on April 1, 2026, for long-term weight management. In longer studies, it has helped people lose weight and improve blood sugar, blood pressure, and cholesterol. By taking part, you will receive detailed metabolic testing and may receive study results that provide additional information about your blood sugar and metabolic health.

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 continuous glucose monitor exceeding 180 mg/dL in the last 3 months * Current uses of any oral or injectable GLP-1 receptor agonists, insulin, or the use of two or more antidiabetic agents * Currently taking or planning to start other medication known to affect glycemic parameters, such as glucocorticoids, growth hormone, or fluoroquinolones during the study * Planned to change any prescribed medication during the study * Planned surgeries or procedures requiring general anesthesia during or within 10 days after completing the study * Participating in any other interventional study simultaneously * Dietary restrictions that prevent the consumption of the standardized liquid mixed meal * Pregnant, nursing, or postpartum in the last 6 months * Current suicidal ideation or suicide attempt within the past 5 years * Psychiatric illness, substance use disorder, or eating disorder that, in the opinion of the investigator, would compromise participant safety or study compliance