Metformin: A Good Drug, But Complicated

by Nima Afshar, MD
Private Medical San Francisco Physician

The French lilac plant (a.k.a. goat’s rue) has been a traditional herbal medicine in Europe for centuries, used for a variety of ailments, among them “conditions of thirst and frequent urination.”

Biochemists in the 19th and early 20th centuries isolated the active guanide molecule and fused it to itself, forming a non-toxic, glucose-lowering biguanide that came to be known as metformin. 

From French Lilac to First-Line Therapy

Metformin is a bedrock of modern medicine. It is the first-line treatment of choice for most people with diabetes, among the most prevalent and morbid diseases in the world. We’ve long known it’s an effective drug, but in 2014 a tantalizing possibility surfaced when a retrospective study showed that people with diabetes taking metformin lived longer than similar people without diabetes.

Given that even well-controlled diabetes is known to shorten lifespan, this finding generated the hypothesis that metformin might confer longevity benefits independent of its glucose-lowering effects. It took a few years for the word to get out, but once it did, metformin became a highly touted anti-aging medication.

When Better Data Temper Big Claims

Fortunately, as should be done in science, the study was repeated by a different group of investigators using more rigorous methodology, including the clever inclusion of discordant twins as a subgroup.

This study, published in 2022, showed what we would have expected from the beginning, even with a beneficial drug: people with diabetes on metformin had a 30-60% higher mortality than similar people without diabetes. This by no means proves that metformin does not have anti-aging benefits, but it does seem to pull us back closer to square one.

Metformin and the New Exercise Paradox

The metformin longevity narrative is further complicated by the drug’s impairment of adaptations to exercise. Aerobic exercise and strength training are among the most powerful interventions for extending healthspan and lifespan. Together they boost aerobic capacity (VO₂max), improve insulin sensitivity, and build skeletal muscle bulk and energy-processing capacity. Yet several well-designed studies in older adults have found that metformin can blunt these benefits, probably by inhibiting a major muscle enzyme involved in converting food energy into cellular energy.  

With all this in mind, a new study published late in 2025 caught my eye. Adults with at least three risk factors for metabolic disease (e.g. overweight, prediabetic, high cholesterol) were randomized to low vs high-intensity exercise + either metformin or placebo. The investigators found that metformin inhibited exercise-induced improvement in insulin sensitivity, a key determinant of cardiovascular and metabolic health, and reduced VO2max gains.

The data tables are more complex than the tidy conclusions, but the findings seem directionally accurate. 

The Case for Personalization

What do we make of all of this? It’s messy, but the one-liner is that while metformin undoubtedly benefits many with diabetes and reduces the risk that those with prediabetes progress to diabetes, it’s not clear whether it is net beneficial for relatively healthy people that exercise, even those at-risk for diabetes. 

This somewhat niche topic speaks to the importance of personalized care. We need to understand our patients’ risk profiles and, in this case, exercise regimens and goals in detail.

If we start a medication with question marks, we need to monitor the effects, with tools like continuous glucose monitors, device-estimated VO2max, and periodic glucose metabolism/insulin sensitivity testing. When we have all that data in hand, we should take the time to review it all with our patients and hear their perspective.

Through the fog of uncertainty, sometimes the answer to simple question “how do you feel?” provides clarity.