Tens of millions of people with type 2 diabetes might actually be undermining their efforts to improve their health, with researchers demonstrating that the commonly prescribed metformin blocks the cardiovascular benefits normally gained through exercise.
In a study of 72 adults with an elevated risk of metabolic syndrome, Rutgers University researchers found that metformin has a way of stunting expected improvements in blood vessel function, blood sugar levels and overall fitness that comes with working out, compared with people not taking the drug. Doctors commonly advise patients to get regular exercise for a range of reasons that benefit diabetics: it helps insulin work better, lowers insulin resistance and blood glucose levels, and lowers the risk of obesity, heart disease and stroke.
“Most health care providers assume one plus one equals two,” said lead author Steven Malin, a professor in the Department of Kinesiology and Health in the School of Arts and Sciences at Rutgers. “The problem is that most evidence shows metformin blunts exercise benefits.”
Earlier research has hinted that metformin might be impeding the benefits of working out, but this study is the first to test whether the drug altered the effect that exercise has on vascular insulin sensitivity – a significant marker of glucose regulation and heart health. It indicates how well blood vessels respond to insulin to control blood sugar, and insulin resistance puts people at much higher risk of cardiovascular disease.
In the double-blind, placebo-controlled trial, participants were divided into four groups: people doing high-intensity exercise while taking a placebo, high-intensity exercise with metformin, low-intensity exercise with a placebo, and low-intensity exercise with metformin. Over the course of 16 weeks, the scientists tracked each person’s blood vessel function under insulin stimulation, which helps vessels dilate and take up oxygen, hormones and nutrients following meals.
“A 120-minute euglycemic-hyperinsulinemic clamp (40 mU/m2/min, 90 mg/dL) was conducted pre and post treatment to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation as well as microvascular insulin sensitivity using contrast-enhanced ultrasound,” the researchers explained. “Fasting and clamp-derived glucose, insulin, inflammatory measures, tumor necrosis factor α [TNF-α], soluble receptor for advanced glycation end products [sRAGE]), and nitric oxide (nitrite/nitrate) were assessed.”
The participants also had their aerobic fitness (maximal oxygen consumption) and body composition (dual-energy X-ray absorptiometry) was also analyzed.
After the 16 weeks, participants in the two placebo groups undertaking either high- or low-intensity exercise experienced a significant improvement in their aerobic fitness levels, while those in either metformin group saw no change. While there was a meaningful reduction in body fat across all of the groups except those taking metformin and doing low-intensity workouts, the high-intensity exercisers fared poorly in other key analyses. People taking metformin showed no sign of vascular insulin sensitivity, meaning exercise didn’t deliver the positive impact on blood vessels it did in the only-exercise cohorts. Inflammation and fasting glucose levels were also worse for those on the drug.
“Blood vessel function improved with exercise training, regardless of intensity,” Malin said. “Metformin blunted that observation, suggesting one type of exercise intensity is not better either with the drug for blood vessel health.”
Since 2006, medication and lifestyle changes have been doctors orders, under the assumption that regular exercise helps the body naturally change to better manage diabetes – and to make therapeutics more beneficial. However, it may not be the case for the more than 20 million Americans currently taking metformin and working hard to improve their health.
“If you exercise and take metformin and your blood glucose does not go down, that’s a problem,” Malin said. “People taking metformin also didn’t gain fitness. That means their physical function isn’t getting better and that could have long-term health risks.”
While we don’t yet understand how metformin is interfering, the researchers believe it may have something to do with how metformin works. The drug suppresses part of the cell’s mitochondria, which reduces oxidative stress and improves blood-sugar regulation. This impact might in turn undermine the expected benefits of exercise like better mitochondrial function and aerobic fitness, which boosts cardiovascular health and blood sugar control.
While the study was quite small and relatively short, the results nonetheless highlight that this two-pronged approach to managing diabetes may not be in a patient’s best interests, particularly in the long term. The researchers warn that it’s not a sign to either stop taking metformin – which has even shown promise in lowering risk of dementia – or exercising, but instead encourage clinicians to closely monitor patients who are not getting the benefits they should be from physical activity.
“We need to figure out how to best recommend exercise with metformin,” Malin said. “We also need to consider how other medications interact with exercise to develop better guidelines for doctors to help people lower chronic disease risk.”
More research is needed to understand this counterproductive interaction and to develop strategies that ensure people with diabetes are benefiting from their hard work.
The research was published in The Journal of Clinical Endocrinology & Metabolism.
Source: Rutgers University
