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

This is a clinical research study using a recall-by-genotype strategy to characterize physiologic responses associated with specific genetic pathways and to determine the physiologic responses under orforglipron challenge.

We will enroll approximately 100 adults aged 18-79 years who have previously agreed to be recontacted for future studies through the MGB biobank. The target sample size may be adjusted depending of funding availability and to power pharmacologic challenges. The study population will consist of four groups of high genetic risk for glycemic/insulinemic associations based on three pPS, along with controls selected from the interquartile range (IQR) across all pPS to provide a mechanism-agnostic comparator. Blood glucose, insulin, and incretin hormone levels will be measured during a baseline mixed-meal tolerance test (MMTT) at Visit 1. Individuals with diabetes or prediabetes determined through a previous HbA1c ≥ 5.7% or fingerstick glucose, during the MMTT (fasting glucose of ≥100 mg/dL, 1 hour glucose ≥155 mg/dL, or 2 hours glucose >=140 mg/dL. will be invited to participate in the acute orforglipron challenge and another MMTT at Visit 2.

Participants who are eligible for the orforglipron challenge will be provided with orforglipron 2.5mg daily for 11 days at home leading up to Visit 2, another MMTT, during which participants will take the final (12th) dose of orforglipron 2.5mg 30 minutes before starting another MMTT.

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