A researcher in the Department of Molecular and Integrative Physiology at the University of Kansas School of Medicine has launched a new study to investigate some surprising ways that statins, which are some of the most prescribed medications in the world, can adversely impact a person's health over time.

In the United States, where cardiovascular disease is the leading cause of death, slightly more than half of American adults, more than 40 million people, take a statin to lower their cholesterol and ward off heart attack and stroke, according to the Centers for Disease Control and Prevention.

John Thyfault, Ph.D., who is also a research scientist at the Kansas City VA Medical Center, is collaborating with Darrell Neufer, Ph.D., director of the East Carolina Diabetes and Obesity Institute and professor in the Department of Physiology at Brody School of Medicine at East Carolina University, to conduct a clinical trial to determine how atorvastatin, the most prescribed statin in the United States, can impede skeletal muscle function and, ironically, lessen the benefits of the simplest, most effective way to improve cardiovascular health: aerobic exercise. The study is supported by a $3 million grant from the National Institutes of Health.

Statins were designed to fight cardiovascular disease by blocking the liver's production of low-density lipoprotein, also known as "bad" cholesterol, that at high levels forms blockages that stop the flow of blood to the heart and brain. In 2013, the American Heart Association and the American College of Cardiology jointly recommended that statins be prescribed not only when a patient has survived a cardiovascular event or has high levels of bad cholesterol, but also for prevention of cardiovascular disease when a patient has other metabolic risk factors, such as obesity and high blood pressure. This change in guidelines encouraged providers to prescribe statins for primary prevention (before disease even occurs) to patients with even a moderate risk of a heart attack.

"That's a big question: should statins be used for primary prevention or not?" said Thyfault.

Thyfault and Neufer both stress that the purpose of the study is not to discount the life-saving benefit that statins offer people with, or at high risk for, cardiovascular disease.

"Millions of people take and benefit from them," said Thyfault. "Statins are important. "But we don't know enough yet about the risk-benefit ratio for taking them. That's why we're doing this study."

A Catch-22

Before joining forces, Thyfault and Neufer each conducted research separately on the effect of statins on a critical biological component of metabolic health: skeletal muscle mitochondria. Mitochondria are tiny energy factories in the cell that consume oxygen and use it to convert food into energy. The more high-functioning mitochondria that skeletal muscles have, the more they can consume oxygen. Muscle mitochondria plays a key role in aerobic fitness, which is the capacity for the body to use oxygen during exercise and a critical indicator of a person's cardiovascular health.

Research in animals had shown that some statins reduce the number of mitochondria in muscles and their ability to use oxygen. Neufer's research team in North Carolina wanted to see if the same thing were true in humans. They put study participants on a high dose of a daily statin and took skeletal muscle biopsies before and throughout the eight-week study period. The result? By the end of the study, the capacity of the mitochondria to consume oxygen was cut in half.

"We'd never seen anything like that in a human," said Neufer. "It was kind of shocking."

Meanwhile, Thyfault had led a 2013 study looking at how taking statins impact the benefits of doing regular aerobic exercise. Aerobic exercise improves aerobic fitness, the body's ability to consume and utilize oxygen, and skeletal muscle is a key component. Aerobic fitness has been shown to be a significant predictor of a person's cardiovascular health and their risk for early death. Regular aerobic exercise should lead to higher aerobic fitness and better skeletal muscle mitochondrial function, important exercise adaptations that improve health.

In this study, a group of overweight, sedentary participants were put on a 12-week exercise program, either jogging or walking on a treadmill for 5 days each week. Meanwhile, half the participants took a daily statin, while the other half did not. At the end of 12 weeks, the statin-free participants increased their aerobic fitness and their skeletal muscle mitochondrial content by at least 10 percent. Meanwhile, those on the statin had no increase in their aerobic fitness — and the number of mitochondria in their muscles actually declined.

Thyfault and Neufer knew the drop in mitochondrial function demonstrated in both studies was meaningful as well as concerning. For one thing, it could explain statins' already-known potential side effects: mild muscle pain and weakness and an increased risk for type 2 diabetes.

But it also presented an interesting catch-22: People on statins are routinely advised to get regular aerobic exercise to further minimize their chance of having a cardiovascular problem. At what point does the benefit of a statin cease to outweigh its potential to curtail the cardiovascular gains made by exercising?

Cost-benefit analysis

Instead of looking at the impact of just one dosage of statins, Thyfault and Neufer's ongoing new study will measure the effects of both low (20 milligrams) and high (80 milligrams) dosages of atorvastatin at multiple points in time over the course of a year. In doctor's offices all across the country, patients are routinely prescribed the high dose because previous large trials had shown that dose lowered mortality in patients who had already had a heart attack or stroke.

"But the truth is, 20 milligrams also lowers cholesterol significantly, and many people might not need that 80 milligram dose," said Thyfault.

At different timepoints during the study year, skeletal muscle biopsies will be taken and put into a machine that measures the capacity of mitochondria to "respire," or use oxygen. Mitochondrial content in muscle will also be measured. Participants will also undergo blood tests, as well as assessments of skeletal muscle function, strength, and performance as well as aerobic capacity. These measures will show whether the statin causes a progressive decline in muscle mitochondrial function and aerobic fitness, and how the decline is determined by the dose of the statin and how long it was taken.

In the second part of the study, the researchers will also examine how low or high statin therapy affects the ability of the participants to improve aerobic fitness following a 12-week exercise intervention. The participants will exercise — either on a bike, treadmill or elliptical machine — five times per week. At the beginning and end of the trial, the researchers will measure aerobic fitness and other indicators of skeletal muscle mitochondrial function. Participants will breathe into a machine that measures how much oxygen they consume while they are exercising. The more oxygen they take in, the better their aerobic capacity.

By comparing these measurements as well as other factors such as heart rate after exercise, the researchers can determine if the statin lessens the aerobic fitness benefits of exercise, and if so, how that impairment is determined by the duration and dose of the statin.

They expect the high dose of the statin, and longer durations of taking it, to lead to decreased mitochondrial function. Their hope is that the 20 milligram dose will not have a negative effect on skeletal muscle mitochondrial function or interfere with a person's ability improve their aerobic fitness. Ultimately Thyfault and Neufer want their research to help both physicians and patients understand the cost-benefit ratio of prescribing and taking a statin.

"If we're right, that means some patients could potentially take the low dose of a statin and exercise, and get all the benefits of both without the negative effects of the statin," said Thyfault. "That seems like a better way to go."

And as Neufer points out, the study has other implications as well. It could, for example, indicate how different doses of a statin affect the natural muscle loss that occurs with aging. People lose muscle mass gradually after age 30, and reason for that is believed to be that muscles lose mitochondrial function over time. "One of our concerns is that statins could accelerate that process," he said. "This study is a starting point to understand that."