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

Phase 4Not Yet RecruitingNCT07739537

Massachusetts General Hospital100 enrolled

Overview

This research study aims to learn about 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, participants will receive detailed metabolic testing and may receive study results with additional information about their blood sugar and metabolic health.

This clinical research study uses a recall-by-genotype strategy to characterize physiologic responses associated with specific genetic pathways and to determine physiological responses and changes under orforglipron challenge. This study 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 on 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 levels during the MMTT (fasting glucose of ≥100 mg/dL, 1-hour glucose ≥155 mg/dL, or 2-hour glucose \>=140 mg/dL. will be invited to participate in the acute orforglipron challenge and another MMTT at Visit 2. Participants eligible for the orforglipron challenge will receive orforglipron 2.5mg daily for 13 days at home leading up to Visit 2, another MMTT, during which participants will take the final (14th) dose of orforglipron 2.5mg 30 minutes before starting another MMTT.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Eligibility

Sex: ALLMin age: 18 YearsMax age: 79 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Physiologic characterization by MMTT

The primary endpoint will be glucose area under the curve (AUCglc) over the timeframe. For β-cell function, we will assess the first phase of insulin secretion with the insulinogenic index. For insulin resistance, we will calculate HOMA-IR and Matsuda index of insulin sensitivity. We will also capture both phases of insulin secretion by calculating the insulin AUC (AUCins) divided by the AUCglc.

Time frame: 1 day

The acute drug challenges

The primary endpoint will be the difference in AUCglc over 180 minutes with drug administration vs. the MMTT without drug administration in Visit 1. We selected this endpoint because the decreased in post-prandial glucose is the most clinically relevant measure of drug response116. Secondary endpoints will include the difference between AUCins/AUCglc, the insulinogenic index (first phase of insulin secretion), and the Matsuda insulin sensitivity.

Time frame: 12 days

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

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Central Contacts