Research & Education

Does Metformin Interfere with Benefits of Exercise

Compared to many other commonly prescribed drugs used to treat type 2 diabetes, metformin is sometimes favored due to its relatively low adverse event and risk profile. Metformin may induce negative effects on the gut microbiome and lead to B12 deficiency and consequent peripheral neuropathy, but even these may be manageable compared to the potential for a rare but life-threatening necrotizing genital infection (Fournier’s gangrene) associated with the use of SGLT2 inhibiting drugs. Nevertheless, additional undesirable effects from metformin are being observed as the drug is more widely prescribed for conditions other than type 2 diabetes (such as PCOS, erectile dysfunction, acne, and other dermatological issues), and is also investigated for a potential role in promoting longevity and healthy aging. A recent study suggests metformin may blunt the desired physical adaptations to resistance training in older adults.

Maintaining muscle mass and strength during aging is absolutely critical for long-term health, mobility, and independent living. Sarcopenia (loss of muscle mass) and dynapenia (loss of strength) can have a massive impact on health outcomes and overall quality of life, so anything older individuals can do to build and maintain strong muscles may help to delay natural age-related declines and potentially reduce the risk for various conditions, including Alzheimer’s disease. With this in mind, we should be aware of the impact of medication on the effects of strength training, particularly a medication prescribed for conditions as prevalent as type 2 diabetes and prediabetes. (According to the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, 84 million US adults have prediabetes and another 30 million have diabetes [90–95% type 2]).

The study, published in Aging Cell, found that compared to placebo, 1700 mg per day of metformin led to smaller beneficial adaptations in skeletal muscle in subjects age 64–91. For a nice change, over 50% of study subjects in both the intervention and placebo cohorts were female. (Much research regarding resistance training, particularly in younger people, is conducted in males.) However, one weakness may be that out of a total of 109 subjects, 105 were Caucasian, with just three African Americans and one Asian subject. (Of the initial 109 who were randomized, 94 subjects completed the protocol: 46 in the metformin group, 48 in the placebo group.)  

Subjects participated in 14 weeks of supervised, variable intensity, bilateral, upper and lower body progressive resistance training. (This included an initial 2-week exercise familiarization and ramp‐up period.) They underwent an oral glucose tolerance test (OGTT), thigh CT scan, muscle biopsy and DXA (dual‐energy X‐ray absorptiometry) scans at baseline and at the end of the 14-week study (with a rest period of three days with no physical training before the final assessment). Metformin and placebo led to similar (small) results in body fat loss, but compared to placebo, subjects taking metformin gained less lean mass and less thigh muscle mass, with these differences reaching statistical significance.

It needs to be noted, however, that the two groups were significantly different at baseline with regard to relative strength, power output, knee extension one-rep max, maximum voluntary isometric contraction, and thigh muscle density. With this in mind, it is possible that metformin appeared to blunt some of the effects of the training because subjects taking metformin started off already substantially stronger and more muscular (at least in the thigh) and therefore may have had less room for improvement in the first place. More research should be conducted on subjects who are better matched at baseline to correct for this factor.

Mechanistically, activation of AMPK inhibits mTORC1, a key regulator of muscle growth. Study authors believe this may be one of the reasons for the blunting effect seen with metformin. It’s important to emphasize that nearly all study participants did experience at least some beneficial physiological adaptations from the training; the effects were just attenuated in those taking metformin.

Regarding adverse events, most of these were reported in the metformin arm, with the majority of these being related to GI discomfort, specified as nausea, diarrhea or flatulence. This is unsurprising considering the well-known effects of metformin on gut flora.

Whether they’re taking metformin or not, one thing most older subjects may benefit from—particularly if they’re participating in weight training but even if they’re not—is increased protein intake. Many older individuals don’t meet current recommendations for dietary protein intake, and a large body of evidence suggests these recommendations are inadequate anyway, so they need even more. Older individuals may have reduced mobility, compromised dental health, poor digestive function, or face other obstacles to increase their intake of whole-food proteins such as beef, poultry or seafood. In these cases, supplementation with protein shakes may be beneficial and can help contribute critical amino acids.