GLUCOSE-MGH: Genetic Links Understood Through Challenge With Oral Semaglutide Exposure at MGH

Phase 4

Recruiting

• Conditions: Genetic Predisposition; Type 2 Diabetes; Metabolic Diseases
• Interventions: Drug: oral semaglutide; Other: Mixed Meal Tolerance Test (MMTT)

• Registration Number: NCT06003153
• Lead Sponsor: Massachusetts General Hospital

Brief Summary

The goal of this research study is to evaluate the pathophysiologic mechanisms by which genetic variation impacts response to an FDA-approved medication commonly used to treat type 2 diabetes called oral semaglutide (Rybelsus) and to characterize the physiological response to a mixed meal tolerance test (MMTT) before and after a 14-day treatment with oral semaglutide. The investigators will do this by measuring factors in the blood, such as sugars, fats, metabolites, and proteins, after eating a standardized breakfast meal at the first visit and after taking 14 doses of oral semaglutide over two weeks before the second study visit. The food (mixed meal breakfast) we will be studying is specially prepared to contain a set amount of protein, carbohydrates, and fat. The investigators hypothesize that understanding how the acute biochemical response to oral semaglutide differs by genetic variation will generate insight into drug mechanisms and type 2 diabetes pathophysiology.

Detailed Description

On day 1 (Visit 1), the research subject will present to the Translational and Clinical Research Center (TCRC) after an overnight fast. We will obtain informed consent, check vital signs, take anthropometric measurements, and draw fasting blood work through an intravenous catheter. The subject will then be provided a standard mixed meal to be consumed within 30 minutes. Additional blood will be drawn at the time of meal completion (0 minutes), as well as 5, 15, 30, 60, 90, and 120 minutes following the meal. During study days 3-15, the subject will take 7 mg of oral semaglutide once daily. On day 16 (Visit 2), the research subject will return to the TCRC. During this visit, the subject will take the final (14th) dose of semaglutide, receive fasting blood work, and receive another mixed meal with subsequent blood draws at several time points over 120 minutes.

Study Timeline

• Study First Submitted: 2023-08-09
• Study First Submitted QC: 2023-08-18
• Study First Posted: 2023-08-21
• Study Start: 2024-03-12
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-28
• Last Update Posted: 2025-05-01
• Primary Completion: 2027-05-31
• Study Completion: 2027-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 125

Inclusion Criteria

1. Males or non-pregnant females
2. Ages 18-50 (inclusive)
3. Able/willing to give consent
4. Span the metabolic range between normal glycemia and pre-diabetes (fasting glucose of 100-125 mg/dL based on chart review of existing laboratory data)

Exclusion Criteria

1. Currently taking medications or intending to take medications for diabetes
2. Currently taking medications or intending to take medications that affect glycemic parameters, such as glucocorticoids, growth hormone, or fluoroquinolones
3. Personal history of intestinal malabsorption, bariatric surgery, celiac disease, gallbladder disease, or pancreatitis
4. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2
5. Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 per the Modification of Diet in Renal Disease equation
6. History of cirrhosis and/or aspartate aminotransferase or alanine aminotransferase more than 3x upper limit of normal
7. Dietary restrictions preventing consumption of a MMTT
8. Women who are pregnant, nursing, or at risk of becoming pregnant
9. Participation in other interventional studies during the current study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GLUCOSE-MGH Study	oral semaglutide	Day 1: Mixed meal tolerance test Day 3-15: 7 mg oral semaglutide, once daily Day 16: 1 dose of 7 mg oral semaglutide, Mixed meal tolerance test in the presence of semaglutide
GLUCOSE-MGH Study	Mixed Meal Tolerance Test (MMTT)	Day 1: Mixed meal tolerance test Day 3-15: 7 mg oral semaglutide, once daily Day 16: 1 dose of 7 mg oral semaglutide, Mixed meal tolerance test in the presence of semaglutide

Primary Outcome Measures

Name	Time	Method
Insulin response to oral semaglutide treatment	15 days	Investigators will measure the change in insulin area under the curve (AUC) over 120 minutes of the MMTT, calculated using the trapezoidal method, between Visit 1 and Visit 2 as an index of response to oral semaglutide, and compare this outcome by genotype at selected loci.

Secondary Outcome Measures

Name	Time	Method
Fasting glucose response to oral semaglutide treatment	15 days	Investigators will measure the change in fasting glucose over 120 minutes of the MMTT, between the two visits, and compare this outcome by genotype at selected loci.
Cumulative glucose response to oral semaglutide treatment	15 days	Investigators will measure the change in glucose area under the curve (AUC) over 120 minutes of the MMTT, between the two visits, and compare this outcome by genotype at selected loci.
Baseline incretin level	120 minutes during Visit 1	Investigators will measure levels of GLP-1 during the length of the baseline MMTT (120 minutes) that takes place on Visit 1, and compare changes in the baseline levels by genotype at selected loci.

Trial Locations

Locations (1)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States