Twenty five years ago, two researchers tested two variables that are considered essential in treating insulin resistant diseases: metformin and exercise. They wanted to see if mild exercise (in this case, swimming) would boost metformin’s raison d’etre: to lower and/or control glucose levels, thereby reducing cardiovascular risk.

Independently, each treatment did so, by 15%-25%, respectfully, in mice models. So, the researchers thought: Combining the two would be even more efficacious in controlling glucose levels.

A logical assumption, yes?

Yet in the years since, particularly in the last 6 or so, researchers, primarily sports medicine experts, have published work showing that this assumption is highly questionable and suggesting just the opposite: metformin can blunt some of exercise’s gains in patients with insulin sensitivity, and hence can interfere with improvements to cardiovascular risk.

Researchers from Spain, the Robert Wood Johnson University Hospital in New Jersey, and others have all appeared within the last few months linking metformin with: modest drops in peak oxygen (V0₂) uptake and blood pressure; altered aortic waveforms and blood pressure on preinsulin- and postinsulin‐stimulation after exercise training; and increased lactate concentrations during exercise. These researchers have been studying the intersection of exercise, prescription therapies, and metabolism for a while.

Two points before proceeding. No one is saying physicians should stop prescribing metformin: All study authors stress that “More studies are needed.” Indeed, the dearth of robust studies in this field is hampering guidance.

“The seemingly conflicting findings from the literature may in part relate to doses of metformin, exercise prescriptions, and/or timing of treatments,” wrote Steven K. Malin, PhD, Department of Kinesiology and Health, Rutgers School of Arts and Science, New Brunswick, New Jersey, in a May editorial in Expert Review of Endocrinology and Metabolism. 

In an interview, Malin said, “Major health organizations [eg, American College of Sports Medicine or American Diabetes Association] do not have enough evidence to provide some guidance to healthcare providers.”

Emphasizing the point, two reviewers asked by Medscape Medical News to read the meta-analysis from Spain, had doubts about the results.

One questioned the low population (827 people) in the meta-analysis and the inclusion of other insulin resistant diseases, such as the metabolic syndrome, while the other didn’t see value in using VO₂ peak as a final outcome. Confounding any findings is that these patients might also be taking other prescription medications that are interfering with exercise’s efficacy, such as statins and beta-blockers.

We understand, said lead author Mikel Izquierdo, professor in the Department of Health Sciences, Public University of Navarra in Pamplona, Spain. “Please pass on my appreciation to your two experts, whose skepticism is exactly the right instinct.”

So why write this article, besides documenting the-raising-awareness point?

Because these researchers are taking the long view. They are stressing that people with insulin sensitivity diseases — who can be, at least in the US, prescribed metformin off-label — are on this medication for a long time; they are ultimately concerned about its effect on cardiovascular health, not necessarily on A1c reductions; and they are stressing that those with type 2 diabetes are getting older, and older.

The authors of the Physiology meta-analysis said: “With recent investigations implicating metformin as a longevity medication, given that it may be linked with increased lactate and perceived exertion, clinicians should also consider the impacts of co-prescription of metformin and exercise in aging adults.”

The takeaway here, Izquierdo said, is not to “stop metformin,” but to “not assume the combination [metformin and exercise] is automatically potentiating, and don’t be surprised if fitness and blood pressure improve less than expected.”

And one other takeaway: exercise isn’t a maybe-thing, it is a must-thing for those with insulin resistance disease and should be viewed as a prescribed therapy.

Three Studies and Two Skeptics

Approved in 1994 to treat type 2 diabetes, metformin reduces levels of glucose by: increasing glycogenesis, thereby reducing production of hepatic glucose; reducing glucose absorption in the intestines; and decreasing gluconeogenesis and glycogenolysis — both of which are crucial in supplying energy to contracting skeletal muscle during exercise.

“Metformin and exercise both act on AMP [adenosine monophosphate]-activated protein kinase and on redox/reactive-oxygen-species signaling, and these pathways overlap and may compete,” said Izquierdo. A separate study “showed that metformin inhibited mitochondrial adaptations to aerobic training in older adults; the MASTERS trial showed that it blunted muscle hypertrophy to resistance training.”

Izquierdo’s team found nine studies to data-mine for their chosen outcomes, which besides VO₂ peak and blood pressure data included rates on glycemic markers and lipids. The studies compared exercise plus metformin with the same exercise regimen plus placebo or minus metformin. Compared with exercise alone, metformin was linked with slighter VO₂ peak improvements (median difference, -1.19); blood pressure reductions were 3.76, systolic, and 1.98, diastolic. No important differences were found in the other outcome variables.

The findings, he said, tell a “coherent biological story — a shared upstream constraint on the hemodynamic and mitochondrial/redox stimulus [including reduced nitric-oxide-mediated vasodilation] limiting both VO₂ and blood-pressure adaptations, while fasting glucose and HbA1c are dominated by other factors.”

And including other insulin resistant diseases was clinically appropriate, he said, as they share underlying pathophysiologic mechanisms.

Sheri R. Colberg, PhD, professor emerita of exercise science, Old Dominion University, Norfolk, Virginia, said the findings showed minimal potential impact and aren’t “critical to worry about.” “With [so such a small cohort], it is easier to find significant differences that may not be that clinically relevant,” she said. “Also, VO₂ peak is not equivalent to aerobic endurance and overall fitness levels.” She also argued that metformin and exercise act through different mechanisms.

Kevin O Hwang, MD, an internist with UT Health Houston in Houston, said the trials — and only two looked at type 2 diabetes — included interventions with supervised exercise, which is not common in primary care. Also, while the pooled blood pressure effects stood up to sensitivity analyses, the latter wasn’t “fully described,” and “did not address whether baseline blood pressure modified the effect.”

“Considering the challenge of adhering to exercise for the long-term, the addition of metformin may have different effects in patients with type 2 diabetes seen in primary care,” Hwang said.

Malin, overall, liked Izquierdo’s study. “Low levels of VO₂ max have consistently been shown to relate to all-cause mortality and cardiovascular disease risk. Increasing VO₂ max thus is helpful as it combats chronic disease and helps improve overall quality of life.”

As for advice for primary care providers who care to look at metformin with a more cautious view, Izquierdo advised:

• Adopt an exercise-first/exercise-intensified mindset
• Monitor those signals his study showed are affected, namely fitness and blood pressure. If the patient is training adequately but the measures don’t prove it, suspect the drug-exercise interaction
• If fitness or blood pressure reduction is the key target, consider prescribing vigorous aerobic work or interval training, and higher-intensity resistance plus power training
• Look at VIVIFRAIL — www.vivifrail.com — a free assessment and prescription tools, training materials and exercise passports

The ultimate message for patients, Izquierdo said, is this: “Exercise will improve almost everything about your health and how you live, whatever your glucose does.”

No reported disclosures.