New Metformin Side Effect Discovered

A new clinical trial published in The Journal of Clinical Endocrinology & Metabolism suggests that metformin, a first-line medication for high blood sugar, may come with a new side effect—weakening several of the benefits normally gained from regular exercise.

The research team found that when adults at risk for metabolic syndrome trained for 16 weeks, exercise improved blood vessel function, fitness, inflammation and fasting glucose, but when metformin was added, these effects were not there!

This emerging evidence raises important questions about how medications and lifestyle treatments interact, especially for people trying to prevent diabetes, those living with prediabetes and to lower long-term disease risk.

Metformin May Block Key Exercise Benefits

Alongside nutrition, exercise is one of the most reliable tools for improving blood glucose control, supporting heart health, and building physical fitness. For nearly two decades, clinical guidance has encouraged pairing metformin with lifestyle changes, under the assumption that the effects would reinforce one another.

But new work led by Rutgers researchers suggests the combination may not deliver the expected benefits.

The study enrolled 72 adults at risk of metabolic syndrome and assigned them to one of four groups:

1. high-intensity exercise with placebo
2. high-intensity exercise with metformin
3. low-intensity exercise with placebo
4. low-intensity exercise with metformin

Over 16 weeks, the researchers measured how well participants’ blood vessels responded to insulin, a response that helps move glucose into muscles, lower blood sugar after meals, and support cardiovascular health.

What the Study Found

Key Findings

• Exercise alone improved vascular insulin sensitivity. Both large arteries and small capillaries became more responsive to insulin, increasing blood flow and nutrient delivery to muscle.
• Metformin blunted these improvements. When metformin was taken, the usual vascular benefits of exercise were significantly smaller – an unknown side effect never before discovered!
• Fitness gains disappeared in the metformin groups. VO₂max improved in both placebo groups, but not in the groups combining metformin and exercise.
• Metformin reduced positive changes in relation to fasting blood glucose and inflammation.
• Exercise intensity did not change the outcome. Whether participants exercised at high or low intensity, metformin still dampened expected improvements.

Why This Matters

For people with prediabetes, this study adds an important layer to what recent research on metformin has already shown.

Large long-term studies such as the Diabetes Prevention Program Outcomes Study and the Framingham Offspring Study have demonstrated that most people with prediabetes do not progress to type 2 diabetes, even after many years.

In fact, most prediabetics using a proven prediabetes reversal program, return to normal blood sugar naturally, achieving prediabetes remission within around 6 months.

Against that backdrop, the finding that metformin can dampen the body’s normal response to exercise becomes especially relevant.

Alongside nutrition, exercise is one of the strongest lifestyle tools for improving insulin sensitivity, vascular health, and metabolic function.

If a medication reduces these natural gains, it becomes important to understand whether the benefits outweigh the trade-offs, particularly in a condition where medication doesn’t address the underlying metabolic issues.

And for those with living type 2 diabetes, we don’t know yet as there is limited research, but it adds a question as to whether metformin would have the same side effects or would be better left on the shelf!

Practical Takeaways

• High intensity or low intensity exercise can still provide blood sugar benefits, but the effects will be smaller when combined with metformin.
• Improvements in blood vessel function may be reduced, which could influence how effectively the body clears glucose after meals.
• Tracking glucose trends becomes more important when relying on both exercise and metformin.
• If you’re living with prediabetes, medication is usually not necessary, so taking metformin is probably not needed.
• If you’re living with type 2 diabetes and your A1c is 7% or below, consider talking to your doctor to get off metformin, as it’s probably not needed.
• Consider a natural supplement like berberine – it’s been clinically studied to work just as well as metformin in people with prediabetes and type 2 diabetes.

**Always make sure to consult with your medical doctor before stopping medications.

Limitations

The trial was relatively small with 72 participants, focused on adults at risk for metabolic syndrome, and lasted 16 weeks, so long-term outcomes remain unclear.

Participants completed structured and supervised exercise sessions, which may not reflect real-world habits. As with all clinical studies, replication is important. More research is needed to understand who is most affected and whether timing, dose, or type of activity influences the interaction.

Conclusion

Taking metformin while doing exercise reduces the metabolic and cardiovascular benefits.

If you’re living with prediabetes, medication is usually not necessary, so consider a natural supplement like berberine.

If you’re living with type 2 diabetes and your A1c is 7% or below, consider talking to your doctor to get off metformin, as it’s probably not needed. Berberine is also very effective for type 2 diabetes!

It will be interesting to see if further research emerges in this area, so be sure to subscribe to our enews for future research updates!

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Study Reference

Malin SK, Heiston EM, Battillo DJ, et al. Metformin Blunts Vascular Insulin Sensitivity After Exercise Training in Adults at Risk for Metabolic Syndrome. The Journal of Clinical Endocrinology & Metabolism, published October 7, 2025, doi:10.1210/clinem/dgaf551.