Metformin for Preventing Type 2 Diabetes After Gestational Diabetes

Overseen By Gianna Wilkie, MD

Age: 18+

Sex: Female

Trial Phase: Academic

Sponsor: University of Massachusetts, Worcester

Must not be taking: Systemic steroids

Disqualifiers: Pre-gestational diabetes, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

116 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are using systemic steroids, you would not be eligible to participate.

What data supports the effectiveness of the drug Metformin for preventing type 2 diabetes after gestational diabetes?

Metformin is widely used as a first-line treatment for type 2 diabetes due to its effectiveness in controlling blood sugar levels, its safety profile, and its cost-effectiveness. It is often combined with other diabetes medications to enhance its efficacy. ^{1 2 3 4 5}

Is metformin generally safe for humans?

Metformin is generally safe for humans when used as directed, but it can cause side effects like diarrhea, nausea, and vomiting. It is important to monitor liver and kidney function while taking it, and it may decrease vitamin B12 absorption. ^{6 7 8 9 10}

How does the drug metformin differ from other treatments for preventing type 2 diabetes after gestational diabetes?

Metformin is unique because it has been shown to effectively reduce the risk of developing type 2 diabetes in women with a history of gestational diabetes, and it is well tolerated. Unlike some other treatments, metformin has a long history of safe use for blood sugar control, and it can be used alone or alongside lifestyle changes, making it a flexible option for prevention. ^{11 12 13 14 15}

What is the purpose of this trial?

The overall goal of this proposal is to create and test an implementation protocol for in-hospital immediate postpartum diabetes screening for postpartum patients with pregnancies affected by GDM.

Research Team

Gianna Wilkie, MD

Principal Investigator

UMASS Memorial Healthcare

Eligibility Criteria

This trial is for postpartum patients who had gestational diabetes (GDM) and show signs of high blood sugar. They must have been diagnosed with GDM in their third trimester, be able to give consent, speak English or Spanish, and be capable of undergoing glucose testing immediately after delivery at UMASS Memorial.

Inclusion Criteria

Have evidence of impaired glucose metabolism defined as fasting glucose value of ≥126 mg/dL or 2-hour glucose value of ≥200 mg/dL

Pregnancy complicated by GDM as diagnosed with traditional two step testing in the third trimester according to Carpenter-Coustan Criteria

Able and willing to provide informed consent

Exclusion Criteria

I was diagnosed with diabetes before becoming pregnant.

I cannot undergo an oral glucose tolerance test due to past surgeries or conditions.

I am currently taking steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Postpartum day 1

1 visit (in-hospital)

Early Postpartum GDM Screening

Subjects are screened for GDM with a 2-hour glucose tolerance test during their postpartum hospitalization

Postpartum day 1

1 visit (in-hospital)

Standard of Care Postpartum Screening

Subjects receive the usual standard of care with a 2-hour glucose tolerance test at 6-12 weeks postpartum

6-12 weeks postpartum

1 visit (in-person)

Follow-up

Participants are monitored for glycemic outcomes and patient satisfaction after screening

6 weeks

1 visit (in-person)

Treatment Details

Interventions

• Metformin Hydrochloride

Trial Overview The study aims to test a protocol where new mothers who had GDM are screened right after giving birth and then treated with Metformin Hydrochloride if they have high blood sugar levels.

Participant Groups

Group I: Early Postpartum GDM Screening Experimental Treatment 1 Intervention

Subjects who are randomly assigned to this condition will be screened for GDM with the recommended 2-hour glucose tolerance test during their postpartum hospitalization.

Group II: Standard of Care Postpartum Screening Active Control 1 Intervention

Subjects randomized to the comparison condition will receive the usual standard of care. The standard of care will consist of screening with a 2 hour glucose tolerance test at 6-12 weeks postpartum.

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

Approved in European Union as Metformin Hydrochloride for:

• Type 2 diabetes
• Polycystic ovary syndrome

Approved in United States as Metformin Hydrochloride for:

• Type 2 diabetes
• Polycystic ovary syndrome
• Gestational diabetes

Approved in Canada as Metformin Hydrochloride for:

• Type 2 diabetes
• Polycystic ovary syndrome

Approved in Japan as Metformin Hydrochloride for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of Massachusetts, Worcester

Lead Sponsor

Trials

372

Recruited

998,000+

Findings from Research

A systematic review of 33 randomized controlled trials found that various third-line treatments for type 2 diabetes, including insulin and GLP-1 analogues, significantly reduced hemoglobin A1c levels when used alongside metformin and sulphonylureas, with reductions ranging from -0.89% to -1.17%.

While insulin treatments were linked to weight gain and increased risk of hypoglycemia, DPP-4 inhibitors and GLP-1 analogues were weight-neutral or associated with weight loss, highlighting the importance of considering side effects when choosing diabetes therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea: a systematic review and mixed-treatment comparison meta-analysis. McIntosh, B., Cameron, C., Singh, SR., et al.[2023]

In a randomized trial involving patients with type 2 diabetes, both metformin-vidagliptin (MF-VG) and metformin-glimepiride (MF-GP) combinations significantly reduced blood glucose levels and HbA1c after 12 weeks, showing similar efficacy.

Both treatment groups maintained normal liver and kidney function throughout the study, but the MF-GP group experienced numerically more cases of hypoglycemia, indicating a potential safety concern with this combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative evaluation of efficacy and safety of combination of metformin-vidagliptin versus metfromin-glimepiride in most frequently used doses in patients of type 2 diabetes mellitus with inadequately controlled metformin monotherapy-A randomised open label study. Gupta, S., Khajuria, V., Tandon, VR., et al.[2020]

The triple drug fixed-dose combination (FDC) of dapagliflozin, sitagliptin, and metformin significantly reduced HbA1c levels more than the dual combinations of sitagliptin with metformin or dapagliflozin with metformin in patients with type 2 diabetes, with a mean reduction of -1.73% compared to -1.28% and -1.33%, respectively.

All treatment regimens were well tolerated, indicating that the FDC of dapagliflozin, sitagliptin, and metformin is both effective and safe for improving glycemic control in patients poorly managed on metformin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations. Sahay, RK., Giri, R., Shembalkar, JV., et al.[2023]

Metformin is currently the best first-line treatment for type 2 diabetes due to its effectiveness, safety, weight neutrality, and low cost, and it can be combined with other antidiabetic medications.

Sulfonylureas are the preferred choice for combination therapy with metformin, although their effectiveness diminishes more quickly over time compared to other options like glitazones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Metformin role in the treatment of type 2 diabetes in 2008]. Spada, A., Philippe, J.[2013]

Metformin is an effective oral medication for treating non-insulin-dependent diabetes mellitus (type II diabetes) and does not cause hypoglycemia, which is a common side effect of other diabetes medications like sulfonylureas.

The drug is considered safe when proper precautions are taken, including monitoring liver and kidney function, and it has gained widespread use internationally, recently receiving FDA approval under the brand name Glucophage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin: a biguanide. Tanja, JJ., Langlass, TM.[2013]

A retrospective chart review of 471 patients showed that those switched from immediate-release metformin to extended-release metformin (metformin-XR) experienced significantly fewer gastrointestinal side effects, including diarrhea, indicating better tolerability of the extended-release formulation.

The study found that while the overall frequency of gastrointestinal adverse events was similar between both formulations, patients who switched to metformin-XR reported a reduction in gastrointestinal issues, with diarrhea rates dropping from 18.05% to 8.29%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Blonde, L., Dailey, GE., Jabbour, SA., et al.[2021]

In a study of 130 patients with type 2 diabetes treated with Metformin Hydrochloride, gastrointestinal adverse effects were the most common, with diarrhea affecting 30.77% of patients and leading to treatment discontinuation in 3.85%.

No cases of serious complications like lactic acidosis or allergic reactions were reported, indicating that while Metformin is generally safe, monitoring for digestive issues is important in managing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cross-Sectional Study on Adverse Effects of Metformin Hydrochloride on 130 Patients Type 2 Diabetic Admitted to Medical Center and Diabetes Home of Sidi Bel-Abbès]. Sakouhi, M., Matmour, D., Belakhdar, K., et al.[2023]

In two studies involving a total of 982 patients, metformin XR significantly reduced HbA1C levels compared to placebo, demonstrating its efficacy in improving glycemic control in patients with inadequate management despite diet and exercise.

A clear dose-response relationship was observed, with higher doses of metformin XR leading to greater reductions in HbA1C, and the medication was well tolerated, with minimal withdrawals due to gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Fujioka, K., Brazg, RL., Raz, I., et al.[2022]

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 has been shown to effectively reduce the incidence of diabetes after pregnancy (DAP) in women with a history of gestational diabetes mellitus (GDM), although the studies reviewed involved participants who were, on average, 12 years post-GDM pregnancy.

While troglitazone also demonstrated DAP prevention, it was withdrawn from the market due to safety concerns related to liver toxicity, highlighting the importance of safety in pharmacotherapy for DAP prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological intervention for diabetes after pregnancy prevention in women with prior gestational diabetes: A scoping review. Pancer, J., Wu, N., Mahmoud, I., et al.[2020]

Metformin is increasingly being recommended as a first-line treatment for gestational diabetes (GDM), showing similar outcomes to insulin for both mothers and their babies.

Despite its growing acceptance, there are still unresolved concerns regarding the safety and long-term effects of metformin use during pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The diversity of gestational diabetes: a therapeutic challenge. Qvigstad, E.[2019]

In a study of 150 women with gestational diabetes, those treated with metformin alone or metformin plus insulin experienced significantly less maternal weight gain and lower rates of preeclampsia compared to those treated with insulin alone.

Metformin treatment also resulted in lower mean birth weights and reduced neonatal morbidity, indicating it is an effective and safe option for managing gestational diabetes, with or without supplemental insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial. Ainuddin, J., Karim, N., Hasan, AA., et al.[2018]

References

1. Canada pubmed.ncbi.nlm.nih.gov

Choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea: a systematic review and mixed-treatment comparison meta-analysis. [2023]

2. India pubmed.ncbi.nlm.nih.gov

Comparative evaluation of efficacy and safety of combination of metformin-vidagliptin versus metfromin-glimepiride in most frequently used doses in patients of type 2 diabetes mellitus with inadequately controlled metformin monotherapy-A randomised open label study. [2020]

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

Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations. [2023]

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

[Metformin role in the treatment of type 2 diabetes in 2008]. [2013]

5. England pubmed.ncbi.nlm.nih.gov

A real world comparison of sulfonylurea and insulin vs. incretin-based treatments in patients not controlled on prior metformin monotherapy. [2018]

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

Metformin: a biguanide. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. [2021]

8. France pubmed.ncbi.nlm.nih.gov

[Cross-Sectional Study on Adverse Effects of Metformin Hydrochloride on 130 Patients Type 2 Diabetic Admitted to Medical Center and Diabetes Home of Sidi Bel-Abbès]. [2023]

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

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. [2022]

10. 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]

11. Ireland pubmed.ncbi.nlm.nih.gov

Pharmacological intervention for diabetes after pregnancy prevention in women with prior gestational diabetes: A scoping review. [2020]

12. England pubmed.ncbi.nlm.nih.gov

The diversity of gestational diabetes: a therapeutic challenge. [2019]

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

Metformin for Preventing Type 2 Diabetes Mellitus in Women with a Previous Diagnosis of Gestational Diabetes: A Narrative Review. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Preventing progression from gestational diabetes mellitus to diabetes: A thought-filled review. [2018]

15. Ireland pubmed.ncbi.nlm.nih.gov

Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial. [2018]