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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a higher dose of metformin manages type 2 diabetes more effectively than the usual dose. Metformin is a common medication that controls blood sugar levels. Participants will take either the standard amount or a slightly higher dose to determine which manages blood sugar more effectively. Ideal candidates have had a type 2 diabetes diagnosis for at least a month and are already taking regular metformin. Participants should also be prepared to use a continuous glucose monitor (CGM) for six weeks. As an Early Phase 1 trial, this research aims to understand how a higher dose of metformin works in people, offering participants a chance to contribute to foundational diabetes treatment knowledge.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Studies have shown that metformin is generally a safe medication, often prescribed for managing type 2 diabetes. It is well-tolerated by many patients. Research indicates that metformin not only helps control blood sugar levels but also benefits the heart and aids in weight loss.

In trials, doses from 1,000 mg to 2,000 mg per day have been used safely. For the dose being studied here, 1,350 mg twice a day, higher doses can cause some side effects. For example, one study found that about 28% of patients taking metformin experienced side effects, compared to 15% of those taking a placebo. These side effects were mostly mild, such as stomach upset or diarrhea.

Overall, metformin has a strong track record and is approved by the FDA for treating type 2 diabetes. However, monitoring for any side effects is important, especially when using higher doses than usual. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for type 2 diabetes?

Researchers are excited about high-dose metformin for Type 2 diabetes because it offers a potentially more powerful approach to managing blood sugar levels. Unlike the standard treatment, which typically involves 1000mg of metformin taken twice daily, this new approach tests a higher dose of 1350mg taken twice per day. This increased dosage could enhance the drug’s effectiveness, potentially providing better control over blood glucose levels and improving outcomes for patients. This exploration of higher dosing is what sets this treatment apart from current options and could mark a significant advance in diabetes management.

What evidence suggests that this trial's treatments could be effective for Type 2 Diabetes?

Research shows that metformin helps manage type 2 diabetes. Studies have found that metformin lowers blood sugar levels and HbA1c, a measure of average blood sugar over time. This effect is dose-related, meaning higher doses can lead to greater reductions in blood sugar. In this trial, participants will receive either 1000 mg or 1350 mg of metformin twice per day to evaluate the effects of different dosages. Metformin is approved for treating type 2 diabetes and can reduce the need for insulin. In short, higher doses of metformin might offer more benefits for controlling blood sugar. ^{1 2 3 4 6}

Who Is on the Research Team?

Shylaja Srinivasan, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12295976/

Metformin's Overall Effectiveness and Combined Action with ... Conclusions: A 1700 mg dose of metformin daily is effective in preventing T2DM, especially in Caucasians, in women over 60 years, in prediabetes ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK518983/

Metformin - StatPearls - NCBI Bookshelf - NIH Metformin, an antidiabetic agent, was approved by the U.S. Food and Drug Administration (FDA) in 1994 for treating type 2 diabetes.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0002934397002544

Efficacy of Metformin in Type II Diabetes: Results of a ... CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin ...

4. dom-pubs.onlinelibrary.wiley.com dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15663

Metformin: Therapeutic profile in the treatment of type 2 diabetes Several large trials have shown that metformin (usually ≥ 1500 mg/day) can reduce the annual progression to T2D by approximately 30% and ...

5. diabetesjournals.org diabetesjournals.org/clinical/article/40/1/97/138890/Recommendations-for-Practical-Use-of-Metformin-a

Recommendations for Practical Use of Metformin, a Central ... Several studies have been performed using doses between 1,000 and 2,000 mg, and its use seems to be associated with reduced insulin requirements ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6243218/

Metformin and Type 2 Diabetes Prevention - PMC Metformin for prevention of diabetes in those at high risk of type 2 diabetes was shown to be safe and well tolerated in the DPP. Seventy-two percent of ...