High-Dose Metformin for Type 2 Diabetes

(PRECISE_T2D Trial)

Recruiting at 2 trial locations

Overseen By Shylaja Srinivasan, MD

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of California, San Francisco

Must be taking: Metformin

Disqualifiers: Renal disease, Hepatic disease, Mental illness, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

20 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you must have a stable medication regimen for 2 weeks before the screening visit, meaning no changes in your medications during that time.

What data supports the effectiveness of the drug Metformin for Type 2 Diabetes?

Research shows that Metformin, when combined with other drugs like sitagliptin, can improve blood sugar control in people with Type 2 diabetes. This combination helps manage the disease by enhancing insulin secretion and reducing glucose production without causing weight gain or low blood sugar. ^{1 2 3 4 5}

Is high-dose metformin safe for humans?

Metformin, including its extended-release forms like Glumetza, has been shown to be well-tolerated in clinical trials for type 2 diabetes, even at higher doses of 1500 to 2000 mg per day, with no increase in adverse effects. However, it should not be used by people with kidney problems. ^{6 7 8 9 10}

How is high-dose metformin different from other drugs for type 2 diabetes?

High-dose metformin, particularly in its extended-release form, is unique because it allows for once-daily dosing while maintaining effective blood sugar control, similar to taking immediate-release metformin twice a day. This extended-release version also has a better absorption rate at higher doses compared to the immediate-release form, making it a convenient option for patients. ^{1 2 6 7 11}

What is the purpose of this trial?

The purpose of this study to compare the typically prescribed dose of metformin (1000mg twice a day) with a higher dose of metformin (1350mg twice a day).

Research Team

Shylaja Srinivasan, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for young people aged 8-21 with Type 2 Diabetes who speak English or Spanish. They must be able to wear a CGM device for 6 weeks, have been on a stable medication regimen for at least two weeks, and take regular metformin. Those with significant mental illness, ongoing renal or hepatic disease, or pancreatic autoantibody positivity cannot participate.

Inclusion Criteria

Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study

I can wear a continuous glucose monitor (CGM) for 6 weeks.

I have been diagnosed with type 2 diabetes.

Exclusion Criteria

You have specific antibodies related to pancreatic autoimmunity.

Known history of significant mental illness or developmental delay impacting the ability to complete study activities independently

I have a known ongoing kidney or liver disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 1000mg or 1350mg of metformin twice per day

12 weeks

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin

Trial Overview The study is testing the effects of two different doses of metformin in youth with Type 2 Diabetes: the standard dose (1000mg twice daily) versus a higher dose (1350mg twice daily). Participants will compare these dosages over the course of the study.

Participant Groups

Group I: Experimental Experimental Treatment 1 Intervention

1350mg metformin twice per day

Group II: Active Comparator Active Control 1 Intervention

1000mg metformin twice per day

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?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

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]

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 phase 4 trial involving patients with type 2 diabetes who were not adequately controlled on metformin and DPP4 inhibitors, low-dose lobeglitazone (0.25 mg/day) demonstrated non-inferior glycaemic control compared to standard-dose lobeglitazone (0.5 mg/day) after 24 weeks, with a mean difference in glycated hemoglobin levels of only 0.18%.

The low-dose lobeglitazone group experienced significantly fewer treatment-emergent adverse events, such as weight gain and hypoglycemia, compared to the standard-dose group, suggesting it may be a safer option for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, Randomized controlled trial on glucose-lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase-4 inhibitor therapy: REFIND study. Ryang, S., Kim, SS., Bae, JC., et al.[2022]

Saxagliptin significantly reduces glycosylated hemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM), with reductions ranging from -0.72% to -0.90% compared to -0.27% with placebo, based on data from 11 Phase III clinical trials.

Saxagliptin is well tolerated, with common side effects including upper respiratory infections and urinary tract infections, and it does not increase cardiovascular risk compared to other treatments, making it a safe option for managing T2DM, especially in combination with other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. Kania, DS., Gonzalvo, JD., Weber, ZA.[2022]

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]

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]

Glumetz (M-ER) is a newly approved extended-release formulation of metformin that provides effective and sustained glycemic control with once-daily dosing, showing similar bioavailability to immediate-release metformin taken twice daily.

In clinical trials lasting 24 weeks, M-ER demonstrated good efficacy and was well tolerated, with continued glycemic control maintained in an additional 24-week open-label extension study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. Schwartz, SL., Gordi, T., Hou, E., et al.[2013]

In a study of 150 patients with type 2 diabetes, extended-release metformin showed comparable efficacy to Glucophage (standard metformin) over 12 weeks, with no significant differences in fasting plasma glucose or HbA1c levels between the two treatments.

Both treatments had mild adverse effects, primarily gastrointestinal, with a slightly higher rate in the extended-release metformin group, but no serious adverse events were reported, indicating that both options are safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of extended-release metformin in treatment of type 2 diabetes mellitus]. Zhang, JP., Yang, WY., Hong, TP., et al.[2022]

A study analyzing 31,542 adverse event reports from the FDA found that semaglutide, a GLP-1 analogue, has a higher potential for misuse and abuse compared to other GLP-1 receptor agonists, with significant reporting odds ratios for issues like drug abuse and withdrawal syndrome.

The findings suggest that semaglutide may be misused as a weight-loss treatment in non-obese individuals, highlighting the need for further research to fully understand its safety profile and the implications of its use outside of approved indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is There a Risk for Semaglutide Misuse? Focus on the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) Pharmacovigilance Dataset. Chiappini, S., Vickers-Smith, R., Harris, D., et al.[2023]

The review highlights that while there are many innovative drugs being developed for type 2 diabetes, several have faced serious safety issues, leading to their withdrawal or halting of development.

It discusses the current state of treatments, including glitazones, incretin mimetics, SGLT-2 inhibitors, and new experimental drugs, emphasizing the need for better methods to predict and differentiate drug-related adverse events from natural disease occurrences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Benefits and risks of current pharmacotherapy in the treatment of type 2 diabetes]. Schindler, C., Barthel, A., Fischer, S., et al.[2021]

Sitagliptin, a DPP-4 inhibitor, effectively lowers glycosylated hemoglobin levels by 0.5-0.8% in patients with type 2 diabetes, making it a viable option for improving glycemic control either alone or in combination with other medications.

It has a favorable safety profile, with gastrointestinal side effects being the most common, and it does not significantly increase the risk of hypoglycemia or body weight gain compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sitagliptin: a novel drug for the treatment of type 2 diabetes. Choy, M., Lam, S.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. Belgium pubmed.ncbi.nlm.nih.gov

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

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

A double-blind, Randomized controlled trial on glucose-lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase-4 inhibitor therapy: REFIND study. [2022]

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

Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. [2022]

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. England pubmed.ncbi.nlm.nih.gov

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

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

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. [2013]

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of extended-release metformin in treatment of type 2 diabetes mellitus]. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Is There a Risk for Semaglutide Misuse? Focus on the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) Pharmacovigilance Dataset. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

[Benefits and risks of current pharmacotherapy in the treatment of type 2 diabetes]. [2021]

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

Sitagliptin: a novel drug for the treatment of type 2 diabetes. [2018]