Stopping and restarting certain GLP-1s to lose weight may make the drug less effective

Inconsistent use of some GLP-1 weight-loss medications, like Ozempic and Wegovy, may significantly lessen their effectiveness, according to a new preclinical study from researchers at the Perelman School of Medicine at the University of Pennsylvania. The study, published in the Journal of Clinical Investigation Insight, showed that each time overweight mice stopped and restarted GLP-1s, they dropped less and less weight compared their original weight-loss.

“The effectiveness of these medications may depend heavily on consistency,” said Thomas H. Leung, MD, PhD, the Herman Beerman, MD, II Professor in Dermatology at Penn. “Taking GLP-1s may be one of those decisions that people need to discuss and make with their doctor, knowing that taking the drug requires a long-term commitment, and it may not be the best fit for people who struggle with taking medication daily or weekly.”

Study conducted amidst a spike in weight loss medication market

GLP-1s have surged in popularity with approximately 1 in 8 adults in the United States saying they have used them for weight loss. However, adherence remains a challenge; over half of people discontinue GLP-1 therapy within 24 months, and many later restart therapy.

“Since stopping and starting is so common, my colleagues and I thought it was worth investigating whether or not the GLP-1s work as well each time,” said Leung.

Leung and his colleagues studied two groups of overweight mice over a four-month period. One group was given the GLP-1 semaglutide consistently for the entire four-month study period. The second group followed a “stop-and-start” cycle (two weeks on, two weeks off the drug) for three cycles before switching to consistent use for the final two months.

While both groups saw similar weight loss in the first two weeks, the stop-and-start group rapidly regained weight during every “off” period. Crucially, when they restarted the drug, they were unable to return to their previous lowest weight. Even after 62 days of consistent use at the end of the study, the intermittent group remained 20 percent heavier than the consistent group.

The idea that having to take a drug consistently for its best effects is nothing new. Drugs like minoxidil, for example, that help regrow hair also show diminished returns when used inconsistently. GLP-1s may fall into the same category.

Unpacking the science behind the findings

The reason for the decrease in GLP-1 effective from stopping and starting may lie in body composition, according to the researchers. Weight loss from GLP-1s typically consists of 40 percent muscle and 60 percent fat. However, when a patient stops the drug and regains weight, they almost exclusively regain fat. By the time a patient restarts the medication, their muscle-to-fat ratio has shifted. Using MRI to track body composition, the researchers found that the body appears to reach a “muscle floor,” said Leung.

“The body seems to receive a biological signal that it cannot afford to lose more muscle mass,” he said explained. “Once that muscle percentage hits a certain low point, the body may resist further weight loss to protect itself.”

While the results needs to be confirmed through more research, especially research in people, the findings highlight a vital need for clinicians to help their patients preserve muscle mass through exercise or nutrition while the patients are on GLP-1s. Future research will also need to investigate whether these same “diminishing returns” apply to drugs like tirzepatide (brand name Zepbound) which target both GLP-1 and additional receptors to help people lose weight.