Oral Semaglutide for Type 2 Diabetes

(GLUCOSE-MGH Trial)

Overseen By Josephine Li

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Massachusetts General Hospital

Must not be taking: Diabetes medications, Glucocorticoids

Disqualifiers: Intestinal malabsorption, Thyroid cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 14 days

125 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications for diabetes or those that affect blood sugar levels, like glucocorticoids, growth hormone, or fluoroquinolones, to participate in this trial.

What data supports the effectiveness of the drug oral semaglutide for type 2 diabetes?

Research shows that oral semaglutide significantly lowers blood sugar levels (HbA1c) and helps with weight loss in people with type 2 diabetes. In clinical trials, it was more effective than some other diabetes medications, like empagliflozin and sitagliptin, and had a low risk of causing low blood sugar. ^{1 2 3 4 5}

Is oral semaglutide safe for humans?

Oral semaglutide is generally safe for humans, but it can cause mild-to-moderate stomach-related side effects like nausea, especially at higher doses. These side effects usually happen early in treatment and tend to decrease over time. Severe low blood sugar is rare and mostly occurs when taken with other diabetes medications. ^{3 6 7 8 9}

How is oral semaglutide different from other drugs for type 2 diabetes?

Oral semaglutide is unique because it is the first glucagon-like peptide-1 receptor agonist (GLP-1RA) available in a tablet form, making it more convenient than injectable options. It effectively lowers blood sugar and aids in weight loss with a low risk of causing dangerously low blood sugar levels (hypoglycemia). ^{1 3 8 10 11}

What is the purpose of this trial?

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.

Research Team

Josephine Li, MD

Principal Investigator

MGH

Eligibility Criteria

This trial is for adults aged 18-50 who can consent and have blood sugar levels indicating they are between normal health and pre-diabetes. It's not suitable for pregnant individuals or those outside the age range.

Inclusion Criteria

Able/willing to give consent

I am a male or a non-pregnant female.

My blood sugar levels are between 100-125 mg/dL, indicating pre-diabetes.

Exclusion Criteria

Dietary restrictions preventing consumption of a MMTT

I have a history of digestive system issues like celiac or gallbladder disease.

I or my family have a history of medullary thyroid cancer or MEN2.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Baseline Assessment

Participants undergo a mixed meal tolerance test and baseline measurements are taken

1 day

1 visit (in-person)

Treatment

Participants take 7 mg of oral semaglutide once daily for 14 days

14 days

Daily self-administration

Post-Treatment Assessment

Participants undergo a second mixed meal tolerance test and final measurements are taken

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Oral Semaglutide

Trial Overview The study tests how genetic differences affect responses to Rybelsus, a diabetes/obesity drug, by analyzing blood factors after a standard meal before and after two weeks of taking the drug.

Participant Groups

Group I: GLUCOSE-MGH Study Experimental Treatment 2 Interventions

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

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

Oral semaglutide, the first oral GLP-1 receptor agonist for type 2 diabetes, demonstrated the lowest cost of control for achieving key treatment targets compared to empagliflozin, sitagliptin, and liraglutide, based on data from the PIONEER clinical trials.

For endpoints like achieving HbA1c ≤ 6.5% and HbA1c < 7.0%, oral semaglutide was significantly more cost-effective, with savings of up to $15,036 compared to other medications, indicating its potential for better economic value in diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States. Hunt, B., Hansen, BB., Ericsson, Å., et al.[2022]

In a retrospective study of 782 patients using oral semaglutide for type 2 diabetes, there was a significant average reduction in HbA1c levels of -0.9% after about 6 months, indicating effective glycaemic control.

The study highlighted a treatment gap, as 37% of patients remained on the initial 3 mg dose instead of increasing to the recommended 7 mg after 30 days, suggesting that some patients may not be receiving optimal dosing for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insights into the early use of oral semaglutide in routine clinical practice: The IGNITE study. Aroda, VR., Faurby, M., Lophaven, S., et al.[2021]

Oral semaglutide, a new GLP-1 receptor agonist, significantly reduced glycated hemoglobin (HbA1c) levels by up to 1.4% after 26 weeks compared to placebo, indicating its efficacy in managing blood sugar levels in type 2 diabetes patients.

The treatment also led to greater body weight reductions compared to placebo and sitagliptin, with mild-to-moderate gastrointestinal side effects that typically decreased over time, suggesting it is a safe option with a low risk of severe hypoglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes compared with other oral antihyperglycemic agents and placebo. Lavernia, F., Blonde, L.[2022]

Oral semaglutide, the first oral GLP-1 receptor agonist, significantly reduced HbA1c levels by 1.1-1.5% and body weight by up to 5 kg in clinical trials, outperforming other diabetes medications like empagliflozin and liraglutide.

The most common side effects were mild-to-moderate gastrointestinal issues, primarily transient nausea, indicating a generally safe profile for patients with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Will oral semaglutide be a game-changer in the management of type 2 diabetes in primary care? Seidu, S., Mellbin, L., Kaiser, M., et al.[2021]

In a study of 32 patients with Type 2 Diabetes over 26 weeks, oral semaglutide significantly reduced body fat and improved metabolic parameters, including liver health indicators.

The treatment preserved muscle mass while decreasing visceral fat, leading to a better muscle-to-fat ratio, which is beneficial for overall health in T2D patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral semaglutide improves body composition and preserves lean mass in patients with type 2 diabetes: a 26-week prospective real-life study. Volpe, S., Lisco, G., Fanelli, M., et al.[2023]

In a study involving 2117 participants treated with semaglutide 2.4 mg for 68 weeks, gastrointestinal adverse events (AEs) like nausea and diarrhea were more common than in the placebo group, but these AEs were mostly mild and transient, with only 4.3% of participants discontinuing treatment due to them.

Weight loss with semaglutide was significant and similar in participants with and without GI AEs, indicating that the weight loss effects of semaglutide are largely independent of these gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Wharton, S., Calanna, S., Davies, M., et al.[2022]

A total of 5,442 cases of gastrointestinal adverse events (AEs) associated with semaglutide were identified, with 45 signals detected, indicating a range of gastrointestinal issues, including 17 new and unexpected signals.

The study found that patient age and body weight were significant factors influencing the severity of gastrointestinal AEs, with a median time-to-onset of 23 days for strong signals, suggesting that while risks exist, they may decrease over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system. Shu, Y., He, X., Wu, P., et al.[2023]

Oral semaglutide, a GLP-1 analogue, was found to be safe and well-tolerated in two clinical trials involving 135 healthy males and 23 males with type 2 diabetes, with most adverse events being mild and primarily gastrointestinal.

The pharmacokinetics showed that semaglutide exposure increased with higher doses and was consistent across healthy individuals and those with type 2 diabetes, supporting its suitability for once-daily dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes. Granhall, C., Donsmark, M., Blicher, TM., et al.[2020]

Semaglutide, a GLP-1 receptor agonist for type 2 diabetes, has a good safety profile but is associated with a high prevalence of gastrointestinal disorders, reported in over 3500 cases (53.2%).

Compared to other diabetes medications like sitagliptin and empagliflozin, semaglutide has a significantly higher number of reported gastrointestinal adverse events, indicating the need for careful monitoring in certain patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal disorders potentially associated with Semaglutide: an analysis from the Eudravigilance Database. Cabral Lopes, A., Roque, F., Lourenço, O., et al.[2023]

In a phase 3b trial involving 1606 adults with type 2 diabetes, higher doses of oral semaglutide (25 mg and 50 mg) significantly reduced HbA1c levels more than the approved 14 mg dose, with reductions of -1.8 and -2.0 percentage points respectively.

The study found that while gastrointestinal side effects were more common with the higher doses, no new safety concerns were identified, and all reported deaths were deemed unrelated to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Aroda, VR., Aberle, J., Bardtrum, L., et al.[2023]

Oral semaglutide 14 mg has been shown to be effective in lowering HbA1c levels and body weight in patients with type 2 diabetes mellitus, outperforming placebo and other active comparators in multiple phase 3 trials.

The most common side effects of oral semaglutide are gastrointestinal issues, which often lead to discontinuation of the medication, highlighting the need for monitoring patient tolerance during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral semaglutide in type 2 diabetes mellitus: Comprehensive review, critical appraisal and clinical consideration of its use in India. Singh, AK., Singh, R., Misra, A.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Insights into the early use of oral semaglutide in routine clinical practice: The IGNITE study. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes compared with other oral antihyperglycemic agents and placebo. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Will oral semaglutide be a game-changer in the management of type 2 diabetes in primary care? [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Oral semaglutide improves body composition and preserves lean mass in patients with type 2 diabetes: a 26-week prospective real-life study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal disorders potentially associated with Semaglutide: an analysis from the Eudravigilance Database. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. [2023]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Oral semaglutide in type 2 diabetes mellitus: Comprehensive review, critical appraisal and clinical consideration of its use in India. [2022]