Metformin May Blunt Benefits of Exercise, Suggests Study
USA: A placebo-controlled study published in The Journal of Clinical Endocrinology & Metabolism found that the diabetes drug metformin may reduce the positive effects of exercise, such as improvements in blood pressure, physical fitness, and blood glucose control.
The research, led by Steven K. Malin from Rutgers University and colleagues, examined whether metformin interferes with vascular benefits typically achieved through exercise training in adults at risk for metabolic syndrome. Although the drug is widely used as first-line therapy to manage elevated blood sugar and lower cardiovascular risk, earlier research has hinted that it may counteract certain exercise-induced metabolic improvements. Until now, however, its impact on exercise-related vascular insulin sensitivity had not been directly tested.
To explore this, the team conducted a rigorous 16-week, double-blind, placebo-controlled trial in which participants were randomly allocated to one of four groups. These included low-intensity exercise with either placebo or metformin, and high-intensity exercise with either placebo or metformin. Exercise intensities ranged from about 55% of VO₂max for the low-intensity group to about 85% for the high-intensity group, with training conducted days a week. Those assigned to metformin received 2,000 mg daily.
Before and after the intervention, participants underwent a two-hour euglycemic-hyperinsulinemic clamp to assess vascular insulin sensitivity at both macrovascular and microvascular levels. This included measuring flow-mediated dilation of the brachial artery, as well as microvascular blood volume and blood flow using contrast-enhanced ultrasound. Researchers also evaluated fasting glucose, insulin levels, inflammatory markers such as endothelin-1 and TNF-α, nitric oxide availability, aerobic fitness, and body composition.
The following were the key findings of the study:
- Both low- and high-intensity exercise paired with a placebo led to significant improvements in aerobic capacity.
- Participants taking metformin showed no improvement in aerobic capacity despite performing the same exercise routines.
- Reductions in body fat occurred only in the high-intensity exercise groups, irrespective of metformin use.
- Metformin limited key vascular benefits typically gained from exercise.
- In the placebo groups, exercise enhanced insulin-stimulated flow-mediated dilation and boosted microvascular blood flow, reflecting healthier vascular function.
- These vascular improvements were substantially reduced in participants taking metformin across both exercise intensities.
- Metformin also diminished the reductions in fasting glucose that were observed in the placebo groups following exercise.
- The drug lessened the decrease in inflammatory markers such as endothelin-1 and TNF-α, indicating a blunted anti-inflammatory response to exercise.
- Overall, metformin weakened multiple metabolic and vascular benefits usually associated with regular exercise.
The investigators concluded that metformin hampers improvements in vascular insulin sensitivity induced by regular exercise, affecting both large conduit arteries and small capillaries. This attenuation coincided with reduced gains in glycemic control and reductions in inflammatory markers, raising important questions about how the drug interacts with exercise — a cornerstone of metabolic syndrome prevention and management.
"These findings highlight the need for further research to determine how best to combine pharmacological and lifestyle interventions in individuals at metabolic risk, ensuring that one does not unintentionally diminish the benefits of the other," the authors wrote.
Reference:
Malin, S. K., Heiston, E. M., Battillo, D. J., Ragland, T. J., Gow, A. J., Shapses, S. A., Shah, A. M., Patrie, J. T., & Barrett, E. J. Metformin Blunts Vascular Insulin Sensitivity After Exercise Training in Adults at Risk for Metabolic Syndrome. The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/clinem/dgaf551
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