The researchers emphasize that weight loss associated with GLP-1 drugs has many clear health benefits for people with obesity, type 2 diabetes and heart failure, including improving blood-sugar control, short-term cardiorenal benefits and improvements in survival outcomes. But doctors may need to consider recommending exercise programs or develop other approaches, such as nutrition supplements or complementary medications, to help GLP-1 patients get the full cardiorespiratory benefits of substantial weight loss over the long-run, the researchers say.

"Some patients literally told me that they felt that they were losing muscle or muscle was slipping away from them while they were on these medications," said researcher Zhenqi Liu, MD, Professor of Medicine and James M. Moss Professor of Diabetes at the University of Virginia School of Medicine and former chief of UVA Health's Division of Endocrinology and Metabolism. "This is a serious concern. Muscle, especially axial muscle, is essential for posture, physical function and overall well-being. Losing lean body mass can increase the risk of cardiovascular disease, all-cause mortality and diminished quality of life. We need to make sure that patients prescribed these medications aren't already at risk for malnutrition or low muscle mass."

About GLP-1 Drugs

While GLP-1 drugs help people lose fat, this comes with loss of fat-free mass, of which muscle makes up 40% to 50%. In fact, fat-free mass lost accounts for 25-40% of the total pounds lost, while age-related declines in fat-free mass are only 8% per decade.

Liu and his collaborators, graduate student Nathan R. Weeldreyer and Siddhartha S. Angadi, PhD, Associate Professor of Kinesiology at UVA's School of Education and Human Development, wanted to better understand the potential long-term consequences of this muscle loss, so they reviewed available data on the drugs' effects on cardiorespiratory fitness, or CRF.

CRF (or VO₂max) is a measure of how well the body can use oxygen during exercise. It is a handy way for doctors to assess how well the heart, lungs, muscle and blood vessels work together, and it is used to predict all-cause and cardiovascular mortality (risk of death).

Patients with obesity often have low CRF. In some cases, this is because the person lacks muscle mass; in others, a person may have enough muscle, but the quality of that muscle is compromised by fat that has penetrated it.

"Cardiorespiratory fitness is a potent predictor of all-cause and cardiovascular mortality risk across a range of populations, including obesity, diabetes and heart failure," said Angadi, a cardiovascular exercise physiologist with UVA's Department of Kinesiology. "In a recent study by our group that examined mortality outcomes from almost 400,000 individuals across the world, we found that CRF was far superior to overweight or obesity status for predicting the risk of death. In fact, once CRF was factored in, body weight failed to predict the risk of mortality. This is why it's so important to understand the effects of this new class of drugs on it."

In their review of the available medical literature, the researchers found that GLP-1 drugs improve certain measures of heart function, yet those improvements don't translate into significant improvements in VO₂max.

Some small studies, they note, have suggested that exercise can help improve VO₂max for patients taking GLP-1 drugs, but these had poor controls and larger, well-designed studies are needed to bear that out.

Ensuring Healthy Weight Loss

The researchers ultimately conclude that GLP-1 drugs "significantly reduce body weight and adiposity, along with a substantial FFM [fat-free mass] loss, but with no clear evidence of CRF enhancement." They remain concerned that this could take a toll on patients' metabolic health, healthspan/frailty and overall longevity. They are urging additional research to better understand the effects of the drugs and ensure patients get the best possible outcomes.

They note, however, that there are promising signs that we may be able to develop medications to help, such as a monoclonal antibody already in the pipeline that may be able to offset lean-muscle loss.

"This is an area of active research, and we are hopeful that better solutions are coming soon," Liu said. "But for now it is important that patients prescribed GLP-1 drugs have conversations with their healthcare providers about strategies to preserve muscle mass. The American Diabetes Association recommends screening for malnutrition and low muscle mass risk before starting these medications and promoting adequate protein intake and regular exercise throughout treatment."

"Finally," Angadi added, "exercise training during GLP1 therapy remains to be assessed in its ability to preserve or improve VO₂max during GLP1 therapy."

Findings Published

The researchers have published their findings in JCEM, the Journal of Clinical Endocrinology & Metabolism. The work was supported by the National Institutes of Health, grants R01DK124344 and R01DK125330.

In an invited editorial published in the current issue of Trends in Cardiovascular Medicine, researchers from Florida Atlantic University's Schmidt College of Medicine urge practicing cardiologists to achieve lower LDL cholesterol levels beginning with the highest doses of the most potent statins, namely rosuvastatin and atorvastatin. The authors emphasize that high-potency statins should be the primary pharmacologic in the treatment of cardiovascular disease as adjuncts to therapeutic lifestyle changes.

The researchers emphasize that therapeutic lifestyle changes will be effective in the absence and presence of adjunctive therapies in treating and preventing cardiovascular diseases. Lifestyle changes of proven benefit include avoidance or cessation of cigarette smoking, achieving and maintaining healthy body weight and blood pressure, regular physical activity, and restricting alcohol consumption.

Despite the proven effectiveness of therapeutic lifestyle changes, approximately 40% of adults in the United States have metabolic syndrome, a constellation of risk factors including obesity, hypertension, dyslipidemia, and insulin resistance. These individuals have a cardiovascular risk equivalent to those with prior heart attacks or strokes, yet many are underdiagnosed and undertreated.

The authors also underscore that only about 21% of Americans meet the minimum daily requirement for physical activity, and that meaningful increases in physical activity are possible at any age, including among older adults.

Based on the robust totality of randomized trial data and their meta-analyses, the authors conclude that statins - particularly rosuvastatin and atorvastatin - have the strongest and most consistent body of evidence supporting their prescription in treatment and prevention in both men and women including older adults.

Because most patients tend to stay on their initially prescribed statin dose, the authors recommend that cardiologists consider starting therapy with the highest dose of these agents and titrating down if necessary. They also highlight that the benefits of statins and aspirin are at least additive and potentially synergistic. Most secondary prevention patients should be prescribed aspirin. In primary prevention, however, individual clinical judgments are necessary, and aspirin should be considered after statins - and if the residual risk of occlusion exceeds that of major bleeding, predominantly gastrointestinal.

"Practicing cardiologists may wish to consider that all adjunctive drug therapies to therapeutic lifestyle changes should be added only after achieving maximal doses of statins. Further, statins have the largest and most persuasive body of evidence of any pharmacological adjunctive therapy in treatment and prevention of cardiovascular disease," said Charles H. Hennekens, M.D, FACC, senior and corresponding author and the first Sir Richard Doll Professor of Medicine and Preventive Medicine, and interim chair, Department of Population Health, Schmidt College of Medicine.

The researchers offer cautious views of adjunctive therapies such as ezetimibe and evolocumab, which tend to be used more widely than optimal. For example, in the IMPROVE-IT trial, the addition of ezetimibe to simvastatin showed only a minor benefit, while the FOURIER trial demonstrated evolocumab's efficacy in secondary prevention only in patients with familial hypercholesterolemia already on maximal statin doses. While FOURIER was a completed trial of secondary prevention, ILLUMINATE is an ongoing trial in high-risk primary prevention patients with familial hypercholesterolemia.

"These findings suggest that such therapies may be more appropriately reserved for select high-risk patients who have not achieved LDL goals with statins alone," said Hennekens.

The authors also discuss the role of omega-3 fatty acids, noting that earlier trials were positive but later tended to show no net benefit. The authors opine that this may have been due to widespread statin use. They note that in REDUCE-IT, a large-scale randomized trial, icosapent ethyl was the only omega-3 fatty acid to demonstrate significant added benefits when added to evidence-based doses of high potency statins. Patients assigned at random to icosapent ethyl, a purified form of eicosapentanoic acid, experienced a significant 25% reduction in major cardiovascular events, with a number needed to treat of just 21.

Hennekens also reflected on the enduring relevance of Benjamin Franklin's 1736 observation that "an ounce of prevention is worth a pound of cure."

First author of the editorial is John Dunn, a third-year medical student in the Schmidt College of Medicine.