Metformin + Exercise for Metabolic Syndrome

Recruiting at 2 trial locations

Overseen By Jaclyn Dosik, MEd

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Rutgers, The State University of New Jersey

Must not be taking: Metformin, Heart rate medications

Disqualifiers: Morbid obesity, Type 1 diabetes, Smoking, others

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

Compensation: Varies

Number of Visits: 3

Duration: 16 weeks

80 Participants Needed

Trial Summary

What is the purpose of this trial?

Arterial disease is the leading cause of morbidity/mortality in Metabolic syndrome (MetS). This occurs early as evidenced by arterial dysfunction that, in turn, raises blood pressure and glucose. Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and cardiovascular risk. However, the optimal exercise dose to be combined with metformin for additive effects on vascular function is unknown. Based on the investigator's preliminary work, the overall hypothesis is that metformin blunts adaptation following high intensity exercise training (HiEx) by lowering mitochondrial derived oxidative stress signaling. The investigators further hypothesize that low intensity exercise (LoEx) training combined with metformin will promote additive effects on vascular function compared to LoEx or HiEx+metformin, and maintain/improve non-exercise physical activity patterns. In this double-blind trial, obese 30-60y MetS participants will be randomized to: 1) LoEx+placebo; 2) LoEx+metformin, 3) HiEx+placebo; or 4) HiEx+metformin for 16 weeks.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking medications that affect heart rate and rhythm or active weight suppression medications, you may not be eligible to participate.

What evidence supports the effectiveness of the treatment combining metformin and exercise for metabolic syndrome?

Research shows that exercise alone is more effective than metformin in improving insulin resistance and fat oxidation in overweight and obese adults. However, metformin is known to help with glucose tolerance and prevent diabetes progression in insulin-resistant patients. ^{1 2 3 4 5}

Is the combination of metformin and exercise safe for humans?

Research indicates that metformin and exercise are generally safe when used together in humans. Studies have not shown significant negative effects on muscle function or metabolic responses, suggesting that this combination is well-tolerated. ^{2 3 6 7 8}

How does the treatment of Metformin combined with exercise differ from other treatments for metabolic syndrome?

The combination of Metformin and exercise for treating metabolic syndrome is unique because it targets insulin resistance, a key factor in the condition, by using both a medication that improves glucose tolerance and physical activity that enhances fitness and body composition. However, there is conflicting evidence on whether Metformin might reduce the benefits of exercise, making this combination a novel area of study compared to using either treatment alone. ^{1 2 9 10 11}

Research Team

Steven K Malin, PhD

Principal Investigator

Rutgers, The State University of New Jersey

Eligibility Criteria

Adults aged 40-80 with Metabolic Syndrome, not currently on metformin or engaging in significant exercise, who have a BMI between 25 and 47. Participants should have risk factors like high blood pressure, large waist circumference, or a family history of diabetes but cannot be diabetic themselves. Excludes those with serious health conditions, non-English speakers, recent smokers, pregnant/nursing women, and anyone on certain heart medications.

Inclusion Criteria

I do not have Type 2 diabetes.

I am a man over 45 or a woman over 55.

My parent or sibling has type 2 diabetes.

Exclusion Criteria

I am currently on medication to help with weight loss.

You don't exercise regularly by doing moderate or high intensity activities for at least 30 minutes, at least 2 times a week.

You have a history of serious health issues that could affect the study results or your safety.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 16 weeks of exercise training combined with either metformin or placebo, with varying exercise intensities

16 weeks

3 supervised training sessions and 2 unsupervised training sessions per week

Follow-up

Participants are monitored for changes in vascular and metabolic insulin sensitivity

4 weeks

Treatment Details

Interventions

• Exercise
• Metformin
• Placebo

Trial Overview The trial is testing the combination of low (LoEx) or high intensity (HiEx) exercise with either metformin or placebo to see which improves vascular health in obese adults with Metabolic Syndrome. It's a double-blind study where participants are randomly assigned to one of four groups for 16 weeks.

Participant Groups

Group I: LoEx+Metformin Active Control 2 Interventions

Subjects randomly assigned to this group will participate in the same 3 supervised training sessions and 2 unsupervised training sessions, but they will be provided Metformin. Metformin is a common medication routinely used to treat high blood sugar and has secondary effects on vascular health. Subjects will not find out whether or not they are on Metformin until after the study is complete. If their doctor needs to know, the people doing this study can find out. Drug: Low Intensity Exercise + Metformin Low Intensity Exercise (LoEx) measured by a percentage of maximal heart rate in combination with placebo.

Group II: HiEx+Metformin Active Control 2 Interventions

Subjects randomly assigned to this group will participate in the same HiEx 3 supervised training sessions and 2 unsupervised training sessions, but they will be provided Metformin. Drug: High Intensity Exercise + Metformin High Intensity Exercise (HiEx) measured by a percentage of maximal heart rate in combination with placebo.

Group III: LoEx+Placebo Placebo Group 2 Interventions

Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions while receiving placebo. Drug: Low Intensity Exercise + Placebo Low Intensity Exercise (LoEx) measured by a percentage of maximal heart rate in combination with placebo.

Group IV: HiEx+Placebo Placebo Group 2 Interventions

Subjects will participate in 3 supervised training sessions and 2 unsupervised training sessions while receiving placebo. Drug: High Intensity Exercise + Placebo High Intensity Exercise (HiEx) measured by a percentage of maximal heart rate in combination with placebo.

Who Is Running the Clinical Trial?

Rutgers, The State University of New Jersey

Lead Sponsor

Trials

471

Recruited

81,700+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 75 insulin-resistant patients, exercise training alone or combined with metformin (MET) significantly improved maximal aerobic capacity (peak VO2), while MET alone showed no improvement.

Both exercise training groups (with and without MET) reported significant enhancements in quality of life, indicating that exercise should be prioritized as the primary therapy for insulin resistance, even when MET is included.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of metformin and exercise training, alone or in association, on cardio-pulmonary performance and quality of life in insulin resistance patients. Cadeddu, C., Nocco, S., Cugusi, L., et al.[2021]

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 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]

A 12-week concurrent training program significantly improved maximal fat oxidation by 308% in overweight and obese patients compared to a -30.3% change in those treated with metformin, indicating superior efficacy of exercise over medication for fat metabolism.

Both groups showed improvements in insulin resistance and glucose metabolism, but the exercise group had significantly better outcomes in HOMA-IR and fasting insulin levels, suggesting that concurrent training may be a more effective intervention for managing insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overweight and Obese Adult Patients Show Larger Benefits from Concurrent Training Compared with Pharmacological Metformin Treatment on Insulin Resistance and Fat Oxidation. Azócar-Gallardo, J., Ramirez-Campillo, R., Afonso, J., et al.[2023]

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 15 individuals, metformin significantly increased fat oxidation during exercise compared to a placebo, suggesting it enhances the body's ability to burn fat while exercising.

However, post-exercise, metformin slightly reduced fat oxidation, indicating that its effects on fat metabolism may vary depending on the timing relative to exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin's effect on exercise and postexercise substrate oxidation. Malin, SK., Stephens, BR., Sharoff, CG., et al.[2019]

In two clinical trials involving 29 glucose-intolerant individuals and 15 healthy males, metformin did not significantly alter the effects of acute exercise or 12 weeks of exercise training on key skeletal muscle factors like mitochondrial respiration, oxidative stress, or AMPK activation.

These findings suggest that metformin does not interfere with the beneficial adaptations of exercise in skeletal muscle, indicating that individuals taking metformin can still gain the full benefits of exercise training.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials. Pilmark, NS., Oberholzer, L., Halling, JF., et al.[2022]

Administering metformin 30 minutes before a meal significantly reduces total cholesterol and LDL-cholesterol levels in metabolic syndrome patients compared to taking it with the meal, based on a study involving 13 participants.

Combining pre-meal metformin with exercise improved postprandial plasma glucose and insulin levels, indicating that timing and physical activity can enhance the metabolic benefits of metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Pre-Meal Metformin With or Without an Acute Exercise Bout on Postprandial Lipemic and Glycemic Responses in Metabolic Syndrome Patients: A Randomized, Open Label, Crossover Study. Methnani, J., Hajbelgacem, M., Ach, T., et al.[2023]

Increased daily physical activity can prevent type 2 diabetes and help treat metabolic syndrome, showing effects on glycaemic control comparable to oral antidiabetic medications.

Exercise, whether endurance or strength training, improves insulin resistance and body composition, and when combined with a proper diet, can also help correct issues like dyslipidaemia and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Physical training in the treatment of metabolic syndrome]. Dela, F.[2017]

In a study of 99 adults with metabolic syndrome over 16 weeks, both metformin users and non-users showed similar rates of improvement in metabolic syndrome severity, indicating that metformin does not significantly hinder the benefits of exercise.

However, among those taking metformin, high-volume high-intensity interval training (HIIT) appeared to be less effective, with a higher proportion of non-responders compared to those not on metformin, suggesting that metformin may blunt the positive effects of intense exercise on metabolic syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial. Ramos, JS., Dalleck, LC., Keith, CE., et al.[2020]

Self-motivated individuals with type 2 diabetes can significantly improve their health and potentially reverse their condition through a combination of healthy eating, regular vigorous exercise (45-60 minutes daily), and newer medications that minimize hypoglycemia risk while promoting weight loss.

Effective medications for managing type 2 diabetes include metformin and GLP-1 receptor agonists, which support glucose control without the risk of low blood sugar during exercise, making them suitable for active patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes mellitus in self-motivated patients: optimized diet, exercise, and medication for weight loss and cardiometabolic fitness. Nadeau, DA.[2014]

References

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

Effects of metformin and exercise training, alone or in association, on cardio-pulmonary performance and quality of life in insulin resistance patients. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

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

3. 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]

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

Overweight and Obese Adult Patients Show Larger Benefits from Concurrent Training Compared with Pharmacological Metformin Treatment on Insulin Resistance and Fat Oxidation. [2023]

5. 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]

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

Metformin's effect on exercise and postexercise substrate oxidation. [2019]

7. Canada pubmed.ncbi.nlm.nih.gov

Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials. [2022]

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

Effect of Pre-Meal Metformin With or Without an Acute Exercise Bout on Postprandial Lipemic and Glycemic Responses in Metabolic Syndrome Patients: A Randomized, Open Label, Crossover Study. [2023]

9. Denmark pubmed.ncbi.nlm.nih.gov

[Physical training in the treatment of metabolic syndrome]. [2017]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes mellitus in self-motivated patients: optimized diet, exercise, and medication for weight loss and cardiometabolic fitness. [2014]