Digital + Metformin for Prediabetes

Overseen By Stephanie Dixon, MD, MPH

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must be taking: Metformin

Must not be taking: Insulin, Oral glucose-lowering

Disqualifiers: Diabetes, Kidney disease, Cardiovascular, 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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in survivor, single-arm pilot study with the goal of establishing evidence of feasibility and safety of a combined pharmacologic (metformin) and lifestyle intervention (using an existing digital platform) to prevent diabetes in prediabetic adult survivors of childhood cancer. Primary Objective The primary aim of this proposal is to establish the feasibility and safety of a 24-week combined metformin + intensive lifestyle intervention among adult survivors with prediabetes (including a 12-week lifestyle alone run-in followed by 12-week combined intervention among survivors remaining prediabetic). Primary endpoints of this trial will be adherence to 1) daily metformin administration and 2) completion of required core-curriculum of the lifestyle change intervention. Safety will be assessed using the Global Rating of Side Effects Burden Secondary Objectives The secondary aim is to assess preliminary evidence for efficacy of the combined metformin + intensive lifestyle intervention on glycemic control and insulin resistance. Glycemic control will be measured by fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) and insulin resistance measured by the homeostatic model assessment (HOMA-IR) and IGF- binding protein 1 (IGF-BP1; a measure of insulin sensitivity strongly correlated with euglycemic insulin clamp testing). Exploratory Objectives To assess preliminary evidence for efficacy of the combined metformin + intensive lifestyle intervention on weight, other anthropometric measures, blood pressure and lipid profile, physical activity (self-reported and as measured by accelerometer), frailty measures, and health-related quality of life (HRQOL). We will also assess diabetes development at future SJLIFE visits. To assess measures of participation in the lifestyle change program as well as barriers to participation and medication adherence.

Will I have to stop taking my current medications?

The trial requires that you stop taking any current oral glucose-lowering medications, non-insulin injectable diabetes medications, or insulin. If you are currently using metformin, you cannot participate in the trial.

What data supports the effectiveness of the drug Metformin for prediabetes?

Metformin is commonly used to help manage blood sugar levels in people with type 2 diabetes, and it is often prescribed to prevent the progression from prediabetes to diabetes. It works by improving the body's response to insulin and reducing sugar production in the liver. ^{1 2 3 4 5}

Is the combination of digital intervention and metformin safe for humans?

Metformin, also known by brand names like Glucophage, Fortamet, and Glumetza, is generally considered safe for humans. Studies show it is well-tolerated, even at higher doses, with no increase in adverse effects. It has been used safely in combination with other diabetes medications. ^{6 7 8 9 10}

How is the drug Metformin unique for treating prediabetes?

Metformin is unique for treating prediabetes because it is often used as a first-line treatment to help control blood sugar levels by reducing glucose production in the liver and improving insulin sensitivity. Unlike some other treatments, it does not typically cause weight gain or low blood sugar (hypoglycemia). ^{6 11 12 13 14}

Research Team

Stephanie Dixon, MD, MPH

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

Adult survivors of childhood cancer aged 18-45 with prediabetes, part of the St. Jude Lifetime Cohort Study (SJLIFE), can join this trial. They must have a fasting plasma glucose level between 105-125 mg/dL or an HbA1c between 5.7-6.4%. Exclusions include severe health conditions like heart disease, kidney failure, liver dysfunction, and cognitive impairment.

Inclusion Criteria

You have slightly high blood sugar levels, but you are still eligible to participate in the study regardless of your gender or ethnic background.

The institution has a wide range of experience in this area.

I am 18-44 years old, part of the SJLIFE study, and have been diagnosed with prediabetes.

Exclusion Criteria

You are currently taking part in a program to change your lifestyle.

I have been diagnosed with schizophrenia or another psychotic disorder.

My kidney function is reduced (eGFR < 45 mL/min).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lifestyle Intervention Run-in

Participants engage in a 12-week digital lifestyle intervention program focusing on diet, exercise, and behavioral strategies

12 weeks

1 visit (in-person) at week 12

Combined Treatment

Participants who remain prediabetic receive metformin along with continued lifestyle intervention

12 weeks

2 visits (in-person) at weeks 12 and 24

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Digital Intervention
• Metformin

Trial Overview The trial is testing if metformin combined with a digital lifestyle intervention can prevent diabetes in adults who had cancer as children and now have prediabetes. It's a single-arm study lasting for 24 weeks where participants first try lifestyle changes alone then add metformin.

Participant Groups

Group I: Treatment Experimental Treatment 2 Interventions

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With Metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

St. Baldrick's Foundation

Collaborator

Trials

19

Recruited

9,100+

Conquer Cancer Foundation

Collaborator

Trials

22

Recruited

4,000+

Findings from Research

Long-acting GLP-1 receptor agonists (GLP-1RAs) like dulaglutide and semaglutide can reduce A1C levels by 1% to 1.5%, with some studies showing reductions close to 2%, making them effective treatments for type 2 diabetes.

These medications have a low risk of hypoglycemia due to their glucose-dependent action and have been shown to be safe, not increasing cardiovascular risk, while also promoting weight loss and improving patient adherence with convenient dosing options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting GLP-1RAs: An overview of efficacy, safety, and their role in type 2 diabetes management. Chun, JH., Butts, A.[2021]

Semaglutide, an oral GLP-1 receptor agonist, is effective for treating type 2 diabetes and is associated with significant weight loss and a low risk of hypoglycemia.

The PIONEER 6 trial confirmed the cardiovascular safety of oral semaglutide, showing it significantly reduces cardiovascular and overall mortality, making it a beneficial option for various diabetic populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral semaglutide - Rybelsus®, the first GLP-1 receptor agonist for oral use in clinical practice. Karásek, D.[2022]

Long-acting GLP-1 receptor agonists (GLP-1RAs) like dulaglutide and semaglutide can reduce A1C levels by 1% to 1.5%, with some studies showing reductions close to 2%, making them effective treatments for type 2 diabetes.

These medications have a low risk of hypoglycemia due to their glucose-dependent action and have been shown to be safe, not increasing cardiovascular risk, while also promoting weight loss and improving patient adherence with convenient dosing options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting GLP-1RAs: An overview of efficacy, safety, and their role in type 2 diabetes management. Chun, JH., Butts, A.[2022]

GLP-1 receptor agonists (GLP-1RAs) are effective injectable medications for adults with type 2 diabetes, significantly improving blood sugar levels and aiding in weight loss by enhancing insulin release and reducing appetite.

These medications have a low risk of causing hypoglycemia and are recommended as second-line treatments alongside other diabetes medications, making them a valuable option for managing type 2 diabetes effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

User's guide to mechanism of action and clinical use of GLP-1 receptor agonists. Shaefer, CF., Kushner, P., Aguilar, R.[2022]

Lifestyle interventions can effectively prevent type 2 diabetes (T2D), but awareness and tools for diabetes prevention among primary care physicians are lacking, contributing to the ongoing epidemic.

Oral semaglutide, the first FDA-approved oral GLP-1 receptor agonist, shows promise in improving glycemic control, promoting weight loss, and reducing cardiovascular risks, making it a significant advancement in diabetes treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral GLP1 Analog: Where Does the Tide Go? Gardner, H., Hamdy, O.[2021]

The combination tablet of sitagliptin and metformin (Janumet) has been approved by the FDA for patients with Type 2 diabetes who need better glycemic control, either when taking these medications separately or together.

Sitagliptin has been demonstrated to be safe and effective at a daily dose of 100 mg, and its combination with metformin is believed to enhance glycemic control through complementary mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janumet: a combination product suitable for use in patients with Type 2 diabetes. Reynolds, JK., Neumiller, JJ., Campbell, RK.[2019]

In a study of 78 patients with uncontrolled type 2 diabetes, dapagliflozin showed the most significant reduction in HbA1c levels after 24 months, with a mean change of -1.05%, compared to sitagliptin (-0.81%) and lobeglitazone (-1.08%).

Dapagliflozin also improved body composition by decreasing whole body fat percentage and increasing muscle percentage, while sitagliptin and lobeglitazone led to increases in body fat, suggesting dapagliflozin may be a better option for patients looking to improve their body composition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. Hong, JH., Moon, JS., Seong, K., et al.[2023]

In a study of 126 overweight and obese patients with type 2 diabetes, dulaglutide (DU) showed a significant and sustained reduction in HbA1c levels over 18 months, with a mean decrease of -0.85% at 6 months, indicating its effectiveness as an add-on therapy to metformin.

Dulaglutide was associated with a higher percentage of patients achieving glycemic targets (HbA1c ≤ 7.0%) compared to liraglutide (LIRA) at 18 months, with 64.8% of DU patients reaching this target versus 42.6% for LIRA, highlighting its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes. Mirabelli, M., Chiefari, E., Tocci, V., et al.[2021]

Metformin extended release (ER) provides effective glycaemic control with once-daily dosing, showing similar effectiveness to twice-daily dosing of immediate-release formulations over a 24-week period in clinical trials.

The metformin ER formulation was well tolerated at doses of 1500 and 2000 mg/day, with no increase in adverse events, indicating its safety for patients managing their blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. Schwartz, SL., Wu, JF., Berner, B.[2019]

In a 16-week study involving 169 adults with type 2 diabetes, all three medications (colesevelam, rosiglitazone, and sitagliptin) improved blood sugar control, as measured by reductions in HbA1c levels.

Colesevelam not only improved glycemic control but also significantly reduced LDL-cholesterol levels, while rosiglitazone and sitagliptin were associated with increases in LDL-cholesterol, highlighting colesevelam's unique benefit in managing both blood sugar and cholesterol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of colesevelam, rosiglitazone, or sitagliptin on glycemic control and lipid profile in patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy. Rigby, SP., Handelsman, Y., Lai, YL., et al.[2021]

Janumet, a combination of sitagliptin and metformin, effectively addresses multiple abnormalities in type 2 diabetes by enhancing insulin secretion and reducing glucose production, improving glucose control without causing hypoglycemia or weight gain.

The treatment is generally well-tolerated, though it may cause digestive side effects and has contraindications related to renal insufficiency, making it suitable for patients who have not achieved adequate control with metformin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Medication of the month. Sitagliptin-metformin fixed combination (Janumet)]. Scheen, AJ.[2015]

The fixed-dose combination of Remogliflozin Etabonate and Vildagliptin, when added to Metformin, was found to be effective in reducing HbA1c levels in patients with type 2 diabetes, showing a mean change of -1.46% compared to -1.38% with the active comparator, Empagliflozin and Linagliptin, indicating non-inferiority between the two treatments.

Both treatment regimens demonstrated comparable efficacy in reducing fasting plasma glucose, post-prandial plasma glucose, body weight, and blood pressure, with a low incidence of adverse events, suggesting that the new combination therapy is safe and well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of a Fixed Dose Combination of Remogliflozin Etabonate and Vildagliptin in Patients with Type-2 Diabetes Mellitus: A Randomized, Active-Controlled, Double-Blind, Phase III Study. Khaladkar, K., Mohan, B., Khaladkar, K., et al.[2022]

The combination of sitagliptin and pioglitazone effectively reduces HbA1c levels in type 2 diabetes patients, with reductions of over 2% when used as initial therapy and 0.7 - 1.4% when added to pioglitazone therapy.

This combination therapy is well tolerated, does not increase the risk of hypoglycemia, and may lead to similar or slightly more weight gain compared to pioglitazone alone, making it a suitable option for a fixed-dose single-tablet regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone. Bailey, CJ., Green, BD., Flatt, PR.[2018]

In a 24-week study involving 612 patients with type 2 diabetes who were not adequately controlled on metformin alone, remogliflozin etabonate (100 mg and 250 mg) demonstrated noninferior efficacy compared to dapagliflozin in reducing HbA1c levels, indicating it is an effective alternative treatment.

The safety profile of remogliflozin etabonate was comparable to dapagliflozin, with similar rates of treatment-emergent adverse events, most of which were mild to moderate, suggesting it is a well-tolerated option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial. Dharmalingam, M., Aravind, SR., Thacker, H., et al.[2020]

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Long-acting GLP-1RAs: An overview of efficacy, safety, and their role in type 2 diabetes management. [2021]

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Oral semaglutide - Rybelsus®, the first GLP-1 receptor agonist for oral use in clinical practice. [2022]

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Long-acting GLP-1RAs: An overview of efficacy, safety, and their role in type 2 diabetes management. [2022]

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Oral GLP1 Analog: Where Does the Tide Go? [2021]

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Janumet: a combination product suitable for use in patients with Type 2 diabetes. [2019]

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Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. [2023]

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

Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes. [2021]

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Metformin extended release for the treatment of type 2 diabetes mellitus. [2019]

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Effects of colesevelam, rosiglitazone, or sitagliptin on glycemic control and lipid profile in patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy. [2021]

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[Medication of the month. Sitagliptin-metformin fixed combination (Janumet)]. [2015]

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Efficacy and Safety of a Fixed Dose Combination of Remogliflozin Etabonate and Vildagliptin in Patients with Type-2 Diabetes Mellitus: A Randomized, Active-Controlled, Double-Blind, Phase III Study. [2022]

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Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial. [2020]