Metformin + Automated Insulin Delivery for Type 1 Diabetes

(MANATEE-T1D Trial)

Recruiting at2 trial locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Kalie Tommerdahl

Must be taking: Insulin

Must not be taking: ACE inhibitors, ARBs, NSAIDs

Disqualifiers: Hypertension, Anemia, Kidney disease, others

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests a device that automatically adjusts insulin levels and a medication called metformin in young people with type 1 diabetes. The goal is to see if this combination can better manage blood sugar and improve heart and kidney health. The use of metformin along with insulin therapy has been suggested as a means of improving diabetes control and alleviating weight gain in type 1 diabetes.

Will I have to stop taking my current medications?

The trial requires that participants do not use anti-diabetic agents other than insulin, ACE inhibitors, ARBs, diuretics, daily NSAIDs or aspirin, sulfonamides, procaine, thiazosulfone, or probenecid. If you are taking other anti-diabetic medications, you may need to stop them.

Is Metformin safe for use in humans?

Metformin, also known by names like Glucophage and Fortamet, is generally considered safe for humans when used as prescribed. It is commonly used to manage type 2 diabetes and is often combined with other medications to improve blood sugar control. The most common side effects are mild and include gastrointestinal issues like nausea and diarrhea. ^{1 2 3 4 5}

How does the drug Metformin + Automated Insulin Delivery differ from other treatments for Type 1 Diabetes?

This treatment is unique because it combines Metformin, a drug that improves insulin action, with an automated insulin delivery system, which uses a smartphone-based controller to manage insulin levels. This combination aims to improve blood sugar control in patients with Type 1 Diabetes who struggle with traditional insulin therapy alone. ^{6 7 8 9 10}

Research Team

Eligibility Criteria

This trial is for young people aged 12-21 with type 1 diabetes who use an automated insulin delivery system or injections plus a glucose monitor. They should weigh over 54 kg, have a BMI above the 5th percentile, and not have had recent severe diabetic complications. Participants must not be pregnant, taking certain medications (like ACE inhibitors), or have high blood pressure, kidney issues, or seafood/iodine allergies.

Inclusion Criteria

I am between 12 and 21 years old.

I haven't had recent severe diabetic complications.

I have been using an insulin pump or taking multiple daily insulin shots and a continuous glucose monitor for over 6 months.

Exclusion Criteria

My kidney function is reduced, shown by tests or past kidney injury.

I am not taking any diabetes medication except insulin, or specific blood pressure, water pills, daily pain relievers, or certain antibiotics.

I have anemia.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metformin or placebo for 4 months while using automated insulin delivery systems or multiple daily injections with continuous glucose monitoring

16 weeks

Regular visits for assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin Hcl (Biguanide)

Trial Overview The MANATEE-T1D study tests if metformin can improve kidney function and insulin sensitivity in youth with type 1 diabetes using automated insulin systems versus those on standard injections. It's a randomized trial where some get metformin and others get a placebo for four months to see effects on renal resistance and cardiometabolic health.

Participant Groups

Group I: Multiple daily insulin injections or manual insulin pump plus continuous glucose monitor Experimental Treatment 2 Interventions

Participants with type 1 diabetes using multiple daily injections or an insulin pump in manual mode plus a continuous glucose monitor will not be randomized to receive medication treatment but will undergo RPF (Aminohippurate Sodium Injections 20%), GFR (Iohexol Inj 300 MG/ML), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) assessments, in addition to assessments of cardiovascular and endothelial function.

Group II: Metformin plus automated insulin delivery system Active Control 3 Interventions

Some participants with type 1 diabetes using an automated insulin delivery system will be randomized to receive treatment with metformin and will undergo RPF (Aminohippurate Sodium Injections 20%), GFR (Iohexol Inj 300 MG/ML), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) assessments, in addition to assessments of cardiovascular and endothelial function.

Group III: Placebo plus automated insulin delivery system Placebo Group 3 Interventions

Some participants with type 1 diabetes using an automated insulin delivery system will be randomized to receive treatment with a placebo pill which is identical in appearance to the metformin pill and will undergo RPF (Aminohippurate Sodium Injections 20%), GFR (Iohexol Inj 300 MG/ML), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) assessments, in addition to assessments of cardiovascular and endothelial function.

Metformin Hcl is already approved in Canada for the following indications:

Approved in Canada as Glucophage for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Kalie Tommerdahl

Lead Sponsor

Trials

1

Recruited

60+

University of Colorado, Denver

Collaborator

Trials

1,842

Recruited

3,028,000+

Aviva Abosch

University of Colorado, Denver

Chief Medical Officer since 2019

MD

Uday B. Kompella

University of Colorado, Denver

Chief Executive Officer since 2015

PhD in Pharmaceutical Sciences

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Dr. Gary H. Gibbons

National Heart, Lung, and Blood Institute (NHLBI)

Chief Executive Officer since 2012

MD from Harvard Medical School

Dr. James P. Kiley

National Heart, Lung, and Blood Institute (NHLBI)

Chief Medical Officer since 2011

MD from University of California, San Francisco

Findings from Research

GLP-1 receptor agonists (like exenatide and liraglutide) can significantly lower hemoglobin A1C levels, plasma glucose, and body weight in patients with type 1 diabetes who are already on insulin, without increasing the risk of hypoglycemia.

The most common side effects of GLP-1 RAs are mild and transient gastrointestinal issues, making them a safe option for patients struggling with insulin side effects or those needing to lose weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus. Harris, KB., Boland, CL.[2022]

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]

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]

Semaglutide, an oral antidiabetic agent approved by the US-FDA, showed the highest efficacy in lowering HbA1c levels in Type 2 Diabetes Mellitus patients, with a significant reduction of 1.6% at a dose of 1.0 mg (p < 0.0001).

The safety profiles of the newer antidiabetic agents were generally similar to placebo, with no fatal adverse events reported; however, gastrointestinal issues and hypoglycemic events were the most common side effects, with alogliptin having the least frequency of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients. Palanisamy, S., Yien, ELH., Shi, LW., et al.[2020]

Tirzepatide, a novel GLP-1 receptor agonist, has been shown to significantly reduce A1C levels and body weight in patients with type 2 diabetes compared to placebo and other active treatments.

The safety profile of tirzepatide is similar to other GLP-1 receptor agonists, with the most common side effects being mild to moderate gastrointestinal issues, and it does not increase the risk of hypoglycemia, making it a promising treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers. Kushner, P., Anderson, JE., Simon, J., et al.[2023]

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]

In a study of 100 patients with type-1 diabetes and poor glycaemic control, metformin treatment for one year did not significantly improve HbA1c levels compared to placebo, indicating no enhancement in glycaemic control.

However, metformin was associated with a significant reduction in total daily insulin doses and body weight, suggesting potential benefits in insulin management and weight control for patients with type-1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. Lund, SS., Tarnow, L., Astrup, AS., et al.[2022]

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]

In a study of 688 patients with type 2 diabetes, Avandamet® (rosiglitazone/metformin) was found to be more effective than metformin alone in reducing blood sugar levels, achieving significant reductions in HbA1c and fasting plasma glucose over 18 months.

However, while Avandamet® improved glycaemic control, it was associated with a significant decrease in bone mineral density at the lumbar spine and total hip compared to metformin, indicating a potential safety concern regarding bone health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. Borges, JL., Bilezikian, JP., Jones-Leone, AR., et al.[2022]

References

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

Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus. [2022]

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

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

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients. [2020]

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

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers. [2023]

6. India 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. [2022]

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

Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. [2022]

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

Feasibility and Preliminary Safety of Smartphone-Based Automated Insulin Delivery in Adolescents and Children With Type 1 Diabetes. [2022]

9. Belgium pubmed.ncbi.nlm.nih.gov

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

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

A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. [2022]