Metformin + Automated Insulin Delivery for Type 1 Diabetes

(MANATEE-T1D Trial)

Recruiting at 3 trial locations

Overseen By Lucy Hall, MS

Age: < 65

Sex: Any

Trial Phase: Phase 1

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 This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how metformin (also known as Glucophage, Fortamet, Glumetza, Riomet, Riomet ER, Axpinet, Diagemet, Glucient, Metabet), combined with automated insulin delivery systems, might improve heart and kidney health in people with type 1 diabetes. It compares how the body processes insulin and how blood vessels function when using metformin with these systems. Participants are youth who have had type 1 diabetes for more than six months and are already using insulin delivery systems. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that automated insulin delivery (AID) systems are generally safe and effective for people with type 1 diabetes. These systems manage blood sugar levels without causing major side effects by using an insulin pump and a glucose monitor to track and adjust insulin levels.

Metformin, a drug often used for type 2 diabetes, has also been studied for type 1 diabetes. Studies have found that metformin can improve how the body uses insulin and may help keep blood vessels flexible in young people with type 1 diabetes. This suggests it might benefit heart and kidney health, but more studies are needed to confirm this.

While both treatments have been studied separately, combining them remains new. This trial is in its early stages, and researchers are still collecting initial safety data. However, since the FDA has already approved metformin for another use, it is generally considered safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Metformin, commonly known for treating type 2 diabetes, is being explored for type 1 diabetes in combination with automated insulin delivery. Unlike typical treatments that rely on multiple daily insulin injections or manual insulin pumps, this approach leverages metformin's potential to enhance insulin sensitivity and improve blood sugar control. Researchers are excited because this combination could offer better glucose management and possibly reduce cardiovascular risks, providing a more comprehensive treatment for individuals with type 1 diabetes.

What evidence suggests that this trial's treatments could be effective for type 1 diabetes?

Research has shown that metformin helps the body use insulin more effectively and maintains blood vessel flexibility, which is crucial for heart health in young people with type 1 diabetes. In this trial, some participants will receive metformin alongside an automated insulin delivery system. Automated insulin delivery systems have proven to control blood sugar levels better than other insulin treatments. They help maintain blood sugar within the desired range, reducing the risk of complications. Combining metformin with these automated systems might enhance these benefits, potentially improving heart and kidney health further. This trial studies whether this combination can better manage diabetes-related health issues. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Metformin Hcl

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.

How Is the Trial Designed?

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 European Union, United States, Canada for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes mellitus
• Polycystic ovary syndrome

Approved in United States as Glucophage for:

• Type 2 diabetes mellitus

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+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

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 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]

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 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]

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]

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 smartphone-based automated insulin delivery (AID) system was found to be safe for use in 20 pediatric participants with type 1 diabetes, with minimal instances of low blood glucose and no adverse events reported during a 48-hour trial.

The AID system maintained a similar percentage of time in the target glucose range compared to traditional sensor-augmented pump therapy, while also showing improved overnight glucose stability, indicating its efficacy in managing blood sugar levels in children and adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and Preliminary Safety of Smartphone-Based Automated Insulin Delivery in Adolescents and Children With Type 1 Diabetes. Deshpande, S., Weinzimer, SA., Gibbons, K., et al.[2022]

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]

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]

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