GLP-1A + Metformin + Mediterranean Diet for Prediabetes

Overseen By Jasmine Yang, BA

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Stanford University

Must not be taking: Antihyperglycemics, Diabetogenics, Weight loss

Disqualifiers: CVD, Malignancy, Kidney/liver disease, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how different treatments can manage prediabetes and mild diabetes by focusing on the Mediterranean diet, metformin, and a GLP-1 agonist, a medication that lowers blood sugar. The researchers aim to determine if these treatments work better for people with varying metabolic profiles, such as those with insulin resistance or beta-cell issues. The goal is to identify which treatment combinations best control blood sugar, reduce heart disease risk, and manage weight. Suitable participants have prediabetes or mild diabetes with an HbA1c between 5.7 and 8.0% and do not currently use diabetes medication. Participants will try each treatment for four months with breaks in between. As a Phase 4 trial, the treatments are already FDA-approved and proven effective, and this research helps understand how they benefit more patients.

Will I have to stop taking my current medications?

If you are currently taking medications for blood sugar control, weight loss, or those that could affect blood sugar levels, you will need to stop them to participate in the trial. A washout period (time without taking certain medications) is allowed if approved by your primary doctor.

What is the safety track record for these treatments?

Research has shown that GLP-1 agonists are generally safe, but they can have some serious side effects. While they help control blood sugar and reduce prediabetes, they might also cause issues like sudden inflammation of the pancreas (acute pancreatitis) and gallstones, although these are less common. Most people tolerate them well, but awareness of these possible risks is important.

Metformin has proven safe and effective, especially for treating type 2 diabetes. It is usually easy to tolerate, with the most common side effects being mild stomach issues like nausea or diarrhea, which often improve over time as the body adjusts to the medication.

The Mediterranean diet is also part of this trial. It emphasizes plant-based foods, healthy fats like olive oil, and lean proteins such as fish. Studies have shown it is not only safe but also beneficial for heart health and weight management.

In summary, while all treatments in the trial offer known benefits, monitoring for any side effects and discussing them with a healthcare provider is crucial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about combining GLP-1 agonists, metformin, and a Mediterranean diet for prediabetes because it takes a comprehensive approach to tackling the condition. Unlike standard treatments that often focus on a single pathway, this combination aims to enhance insulin sensitivity, reduce appetite, and support healthy eating habits all at once. GLP-1 agonists work by mimicking a hormone that helps regulate blood sugar and appetite, while metformin improves insulin sensitivity and reduces glucose production in the liver. The Mediterranean diet complements these effects by providing a heart-healthy, nutrient-rich eating plan that is sustainable and easy to follow. This multifaceted strategy could offer a more effective way to manage and potentially reverse prediabetes.

What evidence suggests that this trial's treatments could be effective for prediabetes?

This trial will evaluate the effectiveness of different sequences of GLP-1 receptor agonists, Metformin, and the Mediterranean diet in managing prediabetes. Research has shown that GLP-1 receptor agonists effectively control blood sugar, aid in weight loss, and improve heart health. They help individuals with prediabetes return to normal blood sugar levels more effectively than lifestyle changes alone. Metformin, a well-known diabetes medication, reduces the risk of developing diabetes by about 31% compared to no intervention. It also lowers the risk of complications like strokes and heart problems. The Mediterranean diet, rich in plants, whole grains, and healthy fats, is linked to better blood sugar control and a reduced risk of prediabetes. These treatments are well-supported for managing prediabetes and improving overall health. ^{1 2 6 7 8}

Who Is on the Research Team?

Tracey L McLaughlin, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for individuals with prediabetes or mild diabetes (HbA1c levels between 5.7-7.0). It aims to identify different subtypes of type 2 diabetes and tailor treatments accordingly. Participants will undergo a series of tests and receive three first-line treatments: a Mediterranean diet, metformin, and a GLP-1 agonist over the course of five years.

Inclusion Criteria

My HbA1c level is between 5.7% and 8.0%, and I'm not taking diabetes medication.

My BMI is between 23 and 45, or between 22 and 45 if I'm Asian.

Exclusion Criteria

Physical activity >2 hours/day

I do not have a history of cancer, kidney/liver disease, pregnancy, chronic inflammation, eating disorders, or bariatric surgery.

I had a heart or blood vessel event in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Period 1

Participants follow a Mediterranean diet for 16 weeks

16 weeks

Regular visits for monitoring and dietary guidance

Washout Period 1

Participants undergo a washout period to clear previous treatment effects

12 weeks

Treatment Period 2

Participants use a GLP-1 agonist for 16 weeks

16 weeks

Regular visits for monitoring and dose adjustments

Washout Period 2

Participants undergo a washout period to clear previous treatment effects

12 weeks

Treatment Period 3

Participants use metformin for 16 weeks

16 weeks

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• GLP-1A
• Mediterranean Diet
• Metformin

Trial Overview The study is testing how well participants with varying underlying diabetic physiology respond to three interventions: dietary changes through the Mediterranean diet, the medication metformin, and GLP-1 agonists—a type of medication that affects insulin secretion. The goal is to see which treatment works best for specific diabetic subphenotypes.

How Is the Trial Designed?

Group I: Metformin/Mediterranean Diet/GLP1a Experimental Treatment 3 Interventions

1. 16 weeks of using metformin: Dosing will initiate at 500mg TID and increased to 1000mg BID after one week. 2. 3 months washout 3. 16 weeks of following a Mediterranean diet: a mostly plant-based diet that includes vegetables, whole grains, whole fruits, legumes, nuts and seeds, with fish being the primary animal protein, and olive oil the primary fat. 4. 3 months washout 5. 16 weeks using GLP1 agonist: Dosing will be titrated per clinical guidelines and as per FDA approved clinical protocols.

Group II: Mediterranean Diet/GLP1a/Metformin Experimental Treatment 3 Interventions

1. 16 weeks of following a Mediterranean diet: a mostly plant-based diet that includes vegetables, whole grains, whole fruits, legumes, nuts and seeds, with fish being the primary animal protein, and olive oil the primary fat. 2. 3 months washout 3. 16 weeks using GLP1 agonist: Dosing will be titrated per clinical guidelines and as per FDA approved clinical protocols. 4. 3 months washout 5. 16 weeks of using metformin: Dosing will initiate at 500mg TID and increased to 1000mg BID after one week.

Group III: GLP1a/Metformin/Mediterranean Diet Experimental Treatment 3 Interventions

1. 16 weeks using GLP1 agonist: Dosing will be titrated per clinical guidelines and as per FDA approved clinical protocols. 2. 3 months washout 3. 16 weeks of using metformin: Dosing will initiate at 500mg TID and increased to 1000mg BID after one week. 4. 3 months washout 5. 16 weeks of following a Mediterranean diet: a mostly plant-based diet that includes vegetables, whole grains, whole fruits, legumes, nuts and seeds, with fish being the primary animal protein, and olive oil the primary fat.

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

GLP-1 receptor agonists (RAs) like exenatide and liraglutide have been shown to effectively lower glycated hemoglobin (A1C) levels and promote weight loss in patients with type 2 diabetes, making them beneficial treatment options alongside metformin.

These medications have a low risk of causing hypoglycemia and can improve cardiovascular risk factors, although they may cause nausea initially, which tends to decrease over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current treatments and strategies for type 2 diabetes: can we do better with GLP-1 receptor agonists? Peterson, G.[2018]

GLP-1 receptor analogues (GLP-1RAs) are effective treatments for type 2 diabetes, improving blood sugar control and weight management while having a low risk of hypoglycemia.

These medications work by increasing insulin secretion and reducing glucagon release in a glucose-dependent manner, and they are generally well tolerated, with gastrointestinal issues being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Analogues in Type 2 Diabetes: Their Use and Differential Features. Lyseng-Williamson, KA.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11177512/

Efficacy and safety of glucagon-like peptide-1 receptor ... GLP-1 receptor agonists have been shown to improve glycemic control, decrease body weight, and cardiometabolic parameters [16–18], improve ...

2. dmsjournal.biomedcentral.com dmsjournal.biomedcentral.com/articles/10.1186/s13098-024-01371-3

Efficacy and safety of glucagon-like peptide-1 receptor ... GLP-1RAs combined with lifestyle modification proved to be a more effective therapy for managing prediabetic patients than lifestyle modification alone.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1871402124001309

A systematic review and meta-analysis of randomized trials The results of our meta-analysis indicated that GLP-1RA therapy was associated with higher odds of regression to normoglycemia (OR 4.80; 95%CI: 3.40–6.77, p < ...

4. bmj.com bmj.com/content/384/bmj-2023-076410

Comparative effectiveness of GLP-1 receptor agonists on ... Conclusions. Results for GLP-1RAs showed that these drugs were much more effective than placebo in treating adults with type 2 diabetes. ...

5. uchicagomedicine.org uchicagomedicine.org/forefront/research-and-discoveries-articles/2024/may/research-on-glp-1-drugs

Research shows GLP-1 drugs are effective but complex Different drugs performed better in different areas, but all 15 GLP-1RAs they analyzed were very successful in lowering blood glucose and ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2667368125000063

Comparative efficacy and safety of GLP-1 receptor agonists ... Additionally, large-scale real-world studies indicate that GLP-1 class drugs may cause severe adverse reactions, such as acute pancreatitis, cholelithiasis, and ...

7. nature.com nature.com/articles/s41598-025-09807-0

Efficacy and safety of GLP-1 agonists in the treatment ... To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in subjects with type 2 diabetes (T2DM).

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa2511774

Orforglipron, an Oral Small-Molecule GLP-1 Receptor ... In this phase 3, multinational, randomized, double-blind trial, we examined the safety and efficacy of once-daily orforglipron at doses of 6 mg, ...