Metformin for Exercise Capacity

Overseen By Emily E Grammer, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Virginia

Must not be taking: Metformin, Insulin, GLP-1, SGLT-2

Disqualifiers: Type 1 or 2 diabetes, Smoking, Severe liver or kidney disease, others

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 1

Duration: 19 days

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants do not use medications that significantly alter glucose regulation, such as metformin, insulin, or similar drugs. If you are taking any of these, you would need to stop before participating.

What evidence supports the effectiveness of the drug metformin for improving exercise capacity?

Research shows that metformin can enhance anaerobic capacity (the ability to perform short bursts of high-intensity exercise) and increase the time to exhaustion in rats, although it does not improve aerobic capacity (endurance). Additionally, metformin may protect muscles from exercise-induced damage, which could be beneficial for maintaining muscle health during physical activity. ^{1 2 3 4 5}

Is metformin generally safe for humans?

Metformin, including its extended-release forms like Glumetza, is generally well-tolerated and safe for humans, as shown in studies for type 2 diabetes. However, it should not be used by people with kidney problems. ^{1 3 6 7 8}

How does the drug metformin differ from other treatments for improving exercise capacity?

Metformin is unique because it may protect muscles from exercise-induced damage and improve metabolic efficiency during intense exercise, unlike other treatments that primarily focus on enhancing performance directly. It is commonly used for type 2 diabetes but shows potential benefits for exercise capacity by affecting muscle adaptation and reducing perceived exertion. ^{1 3 5 8 9}

What is the purpose of this trial?

Metformin is the most prescribed blood sugar (glucose)-lowering medication for patients diagnosed with type 2 diabetes mellitus (T2DM). Metformin stimulates glucose uptake in skeletal muscle similar to the effects of exercise, though, some studies report that metformin may decrease exercise capacity. The main question this study looks to answer is: • Does metformin alter exercise capacity? Participants will: * Complete 5 exercise tests on a stationary bike. * Undergo a body composition test. * Take metformin and placebo. * Complete food and symptom logs. The researchers hypothesize that: • Metformin will reduce aerobic capacity.

Research Team

Jason Allen, PhD

Principal Investigator

University of Virginia

Eligibility Criteria

This trial is for healthy, active adults aged 18-30 who have never taken Metformin, with a BMI under 30. Women must be premenopausal with regular menstrual cycles and all participants should be able to follow the study schedule.

Inclusion Criteria

I have never taken Metformin.

My BMI is under 30.

I exercise at least 3 days a week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Treatment

Participants undergo a 19-day treatment phase with metformin and placebo, including exercise tests and body composition assessments

19 days

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Metformin

Trial Overview The study tests whether Metformin affects exercise capacity in young adults. Participants will take both Metformin and a placebo at different times, complete bike exercises, body composition tests, and keep track of their food intake and any symptoms.

Participant Groups

Group I: Metformin (MET) Experimental Treatment 1 Intervention

At the end of the screening visit, participants will be randomized to either Condition A or Condition B (MET or PL first). Participants will begin the 19-day treatment phase of study the day after screening. During each treatment phase, participants will consume metformin as follows: 1x500 mg tablet/day for 5 days, 2x500 mg tablets/day for 5 days, and 3x500 mg tablets/day (or maximally tolerated dosage) for 9 days. Participants will then complete a VO2peak/LT test on day 16, rest for 48 hours, then complete a time-to-exhaustion test (day 19) during the final days of the treatment phase. After the time-to-exhaustion test, participants will begin the placebo treatment phase.

Group II: Placebo (PL) Placebo Group 1 Intervention

At the end of the screening visit, participants will be randomized to either Condition A or Condition B (MET or PL first). Participants will begin the 19-day treatment phase of study the day after screening. During each treatment phase, participants will consume placebo as follows: 1x500 mg tablet/day for 5 days, 2x500 mg tablets/day for 5 days, and 3x500 mg tablets/day (or maximally tolerated dosage) for 9 days. Participants will then complete a VO2peak/LT test on day 16, rest for 48 hours, then complete a time-to-exhaustion test (day 19) during the final days of the treatment phase. After the time-to-exhaustion test, participants will begin the metformin treatment phase.

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Findings from Research

In a systematic review of studies involving 388 participants, metformin did not significantly change overall oxygen consumption (VO2) or peak oxygen consumption (VO2peak), indicating it may not enhance exercise capacity in the general population.

However, metformin was associated with a significant decrease in heart rate and respiratory exchange ratio, along with an increase in perceived exertion during exercise, suggesting it may alter exercise response without improving performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of metformin on exercise capacity: A meta-analysis. Das, S., Behera, SK., Srinivasan, A., et al.[2018]

Chronic intake of metformin in healthy rats significantly increased anaerobic work capacity (AWC - W') and time until exhaustion during high-intensity swimming, indicating improved performance in anaerobic activities.

However, metformin did not affect aerobic capacity, as there was no difference in critical load (CL) between the metformin and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic metformin intake improves anaerobic but not aerobic capacity in healthy rats. de Araujo, GG., Learsi, S., Bastos-Silva, VJ., et al.[2020]

In a study involving 251 participants with type 2 diabetes, metformin users showed a significant reduction in HbA1c levels after aerobic training compared to control, while non-users did not show this benefit.

Metformin did not negatively impact changes in fitness, body weight, or waist circumference resulting from exercise, suggesting it does not hinder the positive effects of exercise on glycaemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does metformin modify the effect on glycaemic control of aerobic exercise, resistance exercise or both? Boulé, NG., Kenny, GP., Larose, J., et al.[2022]

In a study involving 15 healthy males, metformin (MET) increased the rate of perceived exertion (RPE) during fixed-intensity exercise, indicating that participants felt they were working harder when on MET compared to a placebo.

However, MET did not significantly reduce self-selected exercise intensity, as measured by oxygen consumption rate, suggesting that while it may affect perceived effort, it does not limit the intensity at which individuals choose to exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Metformin on Self-Selected Exercise Intensity in Healthy, Lean Males: A Randomized, Crossover, Counterbalanced Trial. Pilmark, NS., Petersen-Bønding, C., Holm, NFR., et al.[2022]

In a study involving healthy rats, Metformin (Met) did not enhance the benefits of exercise on physical performance, indicating it may not improve exercise outcomes despite its common use in diabetes management.

However, Metformin was found to protect muscle cells from damage caused by exercise and positively influence muscle adaptation, suggesting its potential therapeutic role in conditions where muscle function is impaired.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Protects Rat Skeletal Muscle from Physical Exercise-Induced Injury. Abbadessa, G., Maniscalco, E., Grasso, L., 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]

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 involving seven healthy swimmers, metformin intake (500 mg) was found to increase the anticipation of blood lactate peak concentration during high-intensity swimming intervals, suggesting a potential metabolic efficiency benefit.

However, metformin did not significantly affect neuromuscular responses, perceived exertion, or overall swimming performance, indicating that while it may influence certain metabolic parameters, it does not enhance athletic performance in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin anticipates peak of lactate during high-intensity interval training but no changes performance or neuromuscular response in amateur swimmers. Norberto, MS., De Arruda, TB., Cursiol, JA., et al.[2022]

In a study involving 90 individuals with overweight/obesity and prediabetes, metformin treatment did not lead to a reduction in free-living physical activity levels over 13 weeks, indicating that it does not negatively impact daily activity.

Despite increased perceived exertion during exercise on metformin, the treatment did not affect overall physical activity or sedentary behavior compared to a control group or those treated with dapagliflozin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of metformin treatment on volumes of free-living physical activity and sedentary behaviour: A post-hoc analysis of the PRE-D trial. Karstoft, K., Ried-Larsen, M., Bruhn, L., et al.[2023]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Effect of metformin on exercise capacity: A meta-analysis. [2018]

2. Canada pubmed.ncbi.nlm.nih.gov

Chronic metformin intake improves anaerobic but not aerobic capacity in healthy rats. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Does metformin modify the effect on glycaemic control of aerobic exercise, resistance exercise or both? [2022]

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

The Effect of Metformin on Self-Selected Exercise Intensity in Healthy, Lean Males: A Randomized, Crossover, Counterbalanced Trial. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Metformin Protects Rat Skeletal Muscle from Physical Exercise-Induced Injury. [2023]

6. England pubmed.ncbi.nlm.nih.gov

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

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

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

8. England pubmed.ncbi.nlm.nih.gov

Metformin anticipates peak of lactate during high-intensity interval training but no changes performance or neuromuscular response in amateur swimmers. [2022]

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

The effect of metformin treatment on volumes of free-living physical activity and sedentary behaviour: A post-hoc analysis of the PRE-D trial. [2023]