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

NCT07739537 | Not Yet Recruiting Phase 4 FDA Drug

• 2 other identifiers: 2026P0020011R01DK148455 - 01
• Study Type: interventional
• Target: 100
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Diabete Type 2; Pharmacogenomic Drug Interaction

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  12 days

Study Arms (2)

Drug challenge

EXPERIMENTAL

MMTT after 12 doses of orforglipron 2.5 mg

Drug: Orforglipron

Baseline

NO INTERVENTION

MMTT pre-drug challenge

Interventions

Orforglipron DRUG

Orforglipron challenge after baseline MMTT

Drug challenge

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

orforglipron

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Central Study Contacts

Nopporn Thangthaeng, PhD, DNP

CONTACT

617-726-8767; pathst2d@mgb.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinician Investigator, Assistant Professor

Study Record Dates

• First Submitted: July 28, 2026
• First Posted: July 31, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2030
• Last Updated: July 31, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share