Despite strong recommendations that patients treated with GLP-1s get regular exercise to offset losses in lean muscle mass, patients in fact often show declines in physical activity, with sedentary behavior rates well above those of non-GLP-1 treated populations, new studies reported.

“We know that the weight loss from GLP-1s occurs independently of physical activity, but while people are losing weight, they are not spontaneously moving more along the way,” said Sajana Maharjan, MD, of Hospital Sisters Health System, St. John’s Hospital, Springfield, Illinois, and lead author of one of the recent studies documenting the trend.

While recommendations for regular physical activity may be standard with any weight-loss intervention, concerns of the loss of lean muscle mass specifically with GLP-1s (though subject to some debate) intensify that advice with the therapies.

With evidence lacking on how well those recommendations are being followed, Maharjan and colleagues conducted a retrospective pre-post cohort study of 753 patients with obesity and treated with GLP-1s, who were enrolled in the National Institutes of Health’s nationwide All of Us Research Program between January 2013 and August 2023.

The patients, who had a mean age of 52.7 years and were 78.6% women, all had Fitbit data available from a year prior to and the year after starting a GLP-1.

The results, presented in June at ENDO 2026, the Endocrine Society’s annual meeting, showed significant reductions in daily Fitbit step counts following treatment initiation, from an average of 5047 at baseline to 4487 steps/d, for an average reduction of 560 steps (P < .001).

In addition, their moderate-to-vigorous physical activity, also measured by Fitbit, declined from an average of 27.9 to 22.2 min/d, for a change of 5.7 minutes (P < .001).

Subgroup analyses showed that greater declines in activity were observed in men vs women in terms of measures of steps (-986 vs -445; P = .006) as well as moderate-to-vigorous physical activity ( -15.3 vs -2.9 minutes; P < .001).

Of note, as many as 81% of patients in the study reported having musculoskeletal pain, consistent with a population with obesity, and those patients also showed significantly greater reductions in average steps per day vs those without musculoskeletal pain (-679 vs -22 steps/d; P = .002).

However, no significant differences in activity were observed based on factors including age, morbid obesity, stroke history, or heart failure status.

“This is the first long-term evidence to answer the question of how active people [on GLP-1s] actually were rather than relying on what they reported, and the results that we found were generally surprising,” Maharjan said in an Endocrine Society interview.

“It seems intuitive that losing weight would make exercise easier and more and more appealing,” she added. “But rather than physical activity going up, actually it went down.”

Important limitations included the inability to assess exercise habits in relation to the amount of weight loss, or whether exercise patterns improved or worsened over the course of treatment.

Among key theories for the declines in exercise include responses to weight loss, side effects, and/or the effects of lean muscle loss, Maharjan told Medscape Medical News.

“Several theories are plausible and may compound one another,” she said.

“The first is energy availability — these drugs sharply reduce appetite and calorie intake, and with less fuel coming in, the body may conserve energy by cutting spontaneous, nonexercise movement,” she explained.

“Second, side effects, including nausea, reduced intake, and early-treatment fatigue can make people less inclined to move.”

And “third, muscle loss — a substantial share of the weight lost on these medications comes from lean tissue, and less muscle can reduce capacity and drive for activity, potentially creating a feedback loop,” Maharjan added.

Another factor could simply be a perception that weight can successfully be lost with just a weekly injection, even without exercise.

“There may be a behavioral element where some people feel the medication is handling their weight and perceive less need to exercise, though that may be the most speculative explanation,” Maharjan said.

Importantly, the results were observed regardless of the degree of excess weight, pointing to other factors, she added.

“If declining activity were primarily mechanical or driven by the biomechanical burden of carrying excess weight, you would expect the pattern to differ by [obesity] severity, and it did not (P = .126),” Maharjan said.

Exercise Levels on GLP-1s Fall Short of Recommendations

A separate study also involving the All of Us Research Program but looking at data at single time points, further details that exercise levels among those treated with GLP-1s very often fall below recommended standards.

That study, published in Diabetes, Obesity and CardioMetabolic CARE, included 298 participants who were enrolled in the All of Us Research Program between 2018 and 2022, were treated with GLP-1s, and who also had valid fitness tracking data.

Their mean age was 52.6 years and 72% were women; 64% had type 2 diabetes, 80% had obesity, and 8% had atherosclerotic coronary artery disease.

Overall, patients showed a daily total average physical activity time of 204 minutes, including 24 minutes of moderate-to-vigorous activity, however, more than half, 57.7%, were found to have not met the minimum of at least 150 min/wk of moderate-to-vigorous activity recommended in clinical guidelines for obesity and diabetes.

The patients had a mean step count per day of 5944 steps (a bit higher than the average of 4487 of those after treatment initiation observed in Maharjan’s study) and the study also offered insights on sedentary behavior, with patients showing a relatively high mean sedentary time of 947 min/d.

Sedentary Time Substantially Higher Than General Population

Representing nearly 16 h/d, the mean sedentary time compares with the much lower 11.1 hours of average sedentary time observed in the broader population of All of Us participants with fitness tracker data (including those with or without diabetes or obesity), and of 9.7 hours reported in the US population, the authors noted.

First author Kacey Chae, MD, of the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, said the sedentary behavior findings were surprising, however, she cautioned that “our sample was relatively small and included only people who were taking GLP-1 medications and had wearable fitness-tracker data available.”

“I think the findings raise an important question about sedentary behavior in this population, but they need to be confirmed in larger and more representative cohorts,” she told Medscape Medical News.

The study further showed that injectable semaglutide was associated with a significantly greater amount of mean total physical activity compared with treatment with other types of GLP-1s, with a mean difference 22.3 min/d.

Factors associated with lower physical activity included age 65 years or older, female sex, lower annual household income, and type 2 diabetes status.

While the study does not show a causative role, Chae noted that “we found that many people taking GLP-1 medications are not achieving recommended levels of physical activity, highlighting an important opportunity to better support healthy movement while on treatment.”

Dose Reductions?

The general lower exercise and higher sedentary behaviors are consistent with anecdotal reports of diminished motivation and anhedonia-like symptoms associated with GLP-1 treatment that have received a fair amount of attention, and one case series, adds to the discussion, suggesting a role of higher doses, and hence the possible solution of a simple dose adjustment.

In the study, three patients on high doses of tirzepatide (15 mg/wk) reported “reduced motivation, emotional ‘flatness,’ or loss of interest in exercise and previously enjoyable activities despite successful weight loss,” the authors reported.

With the symptoms described as emerging after prolonged treatment at or near maximal dosing, and improving for one patient after temporary discontinuation, the doses for all three were reduced to 10 mg/wk or lower.

Following the change, two of the patients experienced a marked improvement and motivation and enjoyment of daily activities, and the third patient improved after also receiving adjunctive bupropion therapy.

The cases suggest that anhedonia-like symptoms represent a “potentially underrecognized neurobehavioral effect of GLP-1 treatment, that may occur in a subset of patients receiving high-dose tirzepatide,” the authors suggested.

Therefore, “clinicians should consider monitoring for changes in motivation and reward perception during treatment, particularly at higher doses,” they recommend.

“Dose reduction, with or without adjunctive dopaminergic therapy such as bupropion, may alleviate symptoms while preserving therapeutic benefits.”

Strategies for Addressing the GLP-1 Exercise ‘Conundrum’

The authors of an editorial published in JAMA addressed the overall “conundrum” clinicians face in encouraging patients on GLP-1s to exercise, describe key compelling benefits of exercising with GLP-1 treatment — which likely could resonate with patients.

These include, in addition to the obvious benefit of preventing lean mass loss, tackling the all-too-common plateaus in weight loss that can occur by 50-72 weeks of GLP-1 treatment; preventing weight regain, and promoting fat oxidation to boost the burning of fat, even at rest, wrote first author Daniel E. Lieberman, PhD, of the Department of Human Evolutionary Biology, at Harvard University, Cambridge, Massachusetts, and colleagues.

They underscore a key randomized trial of 195 participants showing that after 1 year, those who exercised four times a week lost an average of 4.1 kg; those who took liraglutide (3.0 mg/d) lost 6.8 kg, yet those who combined exercise with liraglutide lost the most — an average of 9.5 kg, while also “improving their A1c levels, insulin sensitivity, bone health, and cardiorespiratory fitness,” the authors noted.

Key strategies that clinicians can take to help get patients exercising include recommending the integration of exercise into a daily routine and identifying types of exercise they find enjoyable, Lieberman told Medscape Medical News.

“Physicians and others need to take the time to find out what barriers people have to exercise — for instance time, access to facilities, disabilities, etc., and then devising strategies with the patient to overcome those barriers,” he said. “This takes time and resources.”

Some of the best strategies simply involve “helping each individual figure out how to make exercise both necessary and rewarding, [and] for many people that means making it social,” Lieberman added.

“Who thinks of walking with a friend or going dancing as exercise?” he said.

Chae echoed the importance of clinicians’ proactive involvement in helping patients get the exercise that is so essential with GLP-1 treatment.

“From a clinical perspective, I think the most important approach is not to view GLP-1 therapy as a stand-alone treatment,” she said.

“Patients benefit most when medication is paired with lifestyle support, including physical activity counseling, ideally in a multidisciplinary care setting.”

Maharjan, Lieberman, and Chae had no disclosures to report.