Metformin blunted exercise-induced improvements in vascular insulin sensitivity, aerobic fitness, inflammatory markers, and fasting glucose levels in adults at high risk for metabolic syndrome, according to the results of a new study.

“Metformin impaired the effect of exercise training to improve blood vessel function,” Steven K. Malin, PhD, professor, Division of Endocrinology, Metabolism, and Nutrition, 

Robert Wood Johnson Medical School, New Brunswick, New Jersey, told Medscape Medical News.

“Doctors and patients need to weigh the benefits of taking in metformin when engaged in exercise,” said Malin, also a professor in the Department of Kinesiology and Health, School of Arts and Sciences at Rutgers-New Brunswick, New Brunswick, New Jersey.

The study was published online in The Journal of Clinical Endocrinology & Metabolism.

Does Exercise Intensity Matter?

“About 25 years ago, the US Diabetes Prevention Program showcased that lifestyle — 7% weight loss via diet and exercise — was superior to metformin in reducing the progression from prediabetes to type 2 diabetes (T2D),” Malin said. “The difference in prevention effects prompted thoughts that maybe adding them together would product better effects.”

Previous research conducted by Malin and his group, using a high-intensity exercise regimen, found this wasn’t the case. But “we wondered whether low-intensity exercise would work differently when combined with metformin and whether insulin would act differently on blood vessels when metformin was combined with low- or high-intensity exercise,” he said.

In a double-blind, placebo-controlled trial, the researchers randomized sedentary adults at risk for metabolic syndrome into four groups: low- and high-intensity exercise plus placebo (n = 22 and n = 21, respectively) and low- and high-intensity exercise plus metformin (n = 24 for both). The intervention lasted for 16 weeks, with exercise consisting of ambulation.

There were no significant differences at baseline between the groups in age (approximately 56 for all), blood pressure, lipid medications, or postmenopausal status.

The researchers measured macrovascular and microvascular insulin sensitivity and microvascular blood flow (MBF). They also measured glucose, insulin, inflammatory markers, nitric oxide, aerobic fitness (VO2 max), and body composition.

Both Exercise and Metformin Act on Oxidative Stress

Low- and high-intensity exercise without metformin increased VO2 max, but the VO2 max was unchanged when each exercise regimen was combined with metformin. Moreover, metformin blunted the increase in vascular insulin sensitivity and MBF observed in both types of exercise and also attenuated the benefits both exercise regimens showed in reducing fasting glucose, endothelin-1, and TNF-alpha (P < .05 for all).

Body fat was reduced in both high-intensity regimens but not in either of the low-intensity regimens (P < .05).

“Our results show that people didn’t improve fitness, blood vessel health, or blood sugar as much as, or at all, when compared with [exercise] training alone,” Malin summarized.

This is “an important message,” he said, “as it shows exercise alone is an effective treatment for combating key risk factors related to T2D and cardiovascular disease.”

The mechanism responsible for this effect is “unclear,” although oxidative stress appears to play a role, he noted. “Although chronic oxidative stress is thought of as ‘bad’ because it promotes blood vessel and metabolic dysfunction, exercise works to improve health in part by raising oxidative stress,” he explained. After exercise, oxidative stress levels fall. The rising and falling of exercise-induced oxidative stress is beneficial because it “stresses the body to adapt and become more fit to handle future work.”

Metformin is thought to blunt oxidative stress, in part, through blunting the ability of cellular mitochondria to generate it, said Malin. “Taken by itself, that could be a good thing. But if metformin is combined with exercise, we wonder if this action to blunt mitochondrial oxidative stress…can oppose the exercise benefit we see.”

Mailin feels we need to “figure out how to best recommend exercise with metformin and also consider how other medications may interact with exercise so we can develop better guidelines for lowering chronic disease risk.”

Prescribe Judiciously

Commenting on the study, Marilyn Tan, MD, clinical professor of medicine and clinic chief, Endocrine Clinic, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Palo Alto, California, said, “Historically, the first-line therapy for type 2 diabetes has been metformin, due to cost, efficacy, lack of risk for hypoglycemia on its own, and long-term safety data.”

For most patients with T2D, “the metabolic and glucose benefits of metformin likely outweigh the small effect on the metabolic adaptation to exercise,” said Tan. “But more data is needed to assess whether this effect of metformin may influence actual clinical outcomes.”

Also commenting on the study, Lisa Chow, MD, MS, professor of medicine and division director, Diabetes, Endocrinology, and Metabolism, University of Minnesota, Minneapolis, said a take-home message of the findings is that “exercise is beneficial, and higher-intensity exercise is better.” Additionally, “be judicious about starting metformin when it isn’t clearly indicated clinically — type 2 diabetes and PCOS [polycystic ovary syndrome] are common indications — particularly if the patient is beginning an exercise program.”

This study was supported by a grant from the National Institutes of Health. Malin is on the editorial board for the Journal of Clinical Endocrinology & Metabolism. His coauthors and Chow disclosed no relevant financial relationships. Tan reported receiving consulting fees from Novo Nordisk.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).