The treatment of obesity has been revolutionized by new drugs such as semaglutide and tirzepatide. In clinical trials, these medications led to substantial weight loss — as much as an average of 21% of participants’ body weight1 — and semaglutide has also been shown to cut the risk of severe cardiovascular problems, which specialists celebrated as a groundbreaking result. But as demand for the drugs increases, there’s a growing interest in investigating their potential side effects. Researchers have been looking into the gastrointestinal problems and loss of muscle mass connected with the medications and shared some findings earlier this month.
The latest generation of anti-obesity drugs mimic a hormone called glucagon-like peptide 1 (GLP-1), which is associated with appetite regulation. Semaglutide was approved by the US Food and Drug Administration in 2017, under the name Ozempic, to treat type 2 diabetes, and later, in 2021, as Wegovy, for the treatment of obesity. Tirzepatide, marketed as Mounjaro, was approved in 2022 to treat diabetes, but is also prescribed off-label for weight loss.
A research letter published last week in JAMA2 looked at a sample of people with obesity in a large health-insurance database. The authors found that the incidence of pancreatitis — inflammation of the pancreas — was 4.6 times higher in people taking semaglutide than in people taking a weight-loss medication that does not mimic GLP-1. The study also found that semaglutide and liraglutide, another GLP-1 medication, were associated with an increased incidence of gastroparesis, a disorder that slows or stops the movement of food from the stomach to the intestine.
Clinical trials had already shown an association between GLP-1 drugs and gastrointestinal side effects, including nausea, constipation and rare cases of pancreatitis3. “What’s new is that, for all of them, we actually gave an incidence number,” says Mahyar Etminan, an epidemiologist at the University of British Columbia in Vancouver, Canada, and an author of the JAMA research.
Jaime Almandoz, an endocrinologist at the University of Texas Southwestern Medical Center in Dallas, says that because clinical trials tend to exclude people who are at a higher risk of developing certain conditions, epidemiological studies can provide better insight into complications that might arise in the real world.
But the study has an important limitation, says Daniel Drucker, an endocrinologist at the University of Toronto in Canada. It relies on diagnoses recorded on health-care claims, which might not always be accurate. “A doctor can write down pancreatitis and there it is on the health-care claim. There’s no additional scrutiny as to whether or not that’s correct,” he says.
Marilyn Tan, an endocrinologist at Stanford University in California, says that she routinely counsels patients with diabetes about the potential for gastrointestinal side effects from GLP-1 medications. She notes, however, that as more providers who are not specialists in diabetes or obesity prescribe these medications, “it’s unclear if all patients are being fully informed about the potential risks”.
Meanwhile, muscle-mass loss seems to be a concern for pharmaceutical companies developing anti-obesity drugs. Eli Lilly, the maker of tirzepatide, recently acquired Versanis, a company developing a medication called bimagrumab, which is being tested in combination with semaglutide for its potential ability to preserve muscle mass during weight loss.
“I think it is possible we will begin to see an occasional person with what we describe as sarcopenic obesity,” Drucker says, referring to a combination of obesity and low skeletal muscle mass that results in muscle weakness. “How many of those people will there be? We don’t know. This is something we’ll need to monitor carefully.”
Data presented last week at the European Association for the Study of Diabetes annual meeting in Hamburg, Germany, offered some reassurance. Researchers, including some from Eli Lilly, used magnetic resonance imaging to evaluate changes in body composition seen in people taking tirzepatide and concluded that some of the muscle volume lost was actually intramuscular fat. The loss of lean muscle mass, the authors concluded, wasn’t greater than expected given the weight loss.
Calculating the risks
Specialists say that both gastrointestinal adverse events and muscle-mass loss can be prevented or managed with adequate dietary modifications, physical activity and other drugs. “It’s about educating patients with regards to the risks of these medications and educating providers who are going to be prescribing these drugs,” says Almandoz.
But researchers say there’s still a lot to learn about the effects of these drugs in the real world, beyond the controlled conditions of clinical trials. Drucker notes that GLP-1 drugs have mainly been studied in people with type 2 diabetes or obesity. For those who fall outside those groups — for example, people who want to lose weight for solely aesthetic reasons — there’s no clear understanding of the risks and benefits. “There’s a big data gap for those people. That’s where we don’t have a clear idea of whether the side-effect profile would be the same.”
But, for most people with obesity, the benefits far exceed the risks, Almandoz notes. “It can be problematic when there is kind of a push to highlight negative impacts of these medications and almost bury this overwhelming sea of data that’s coming out with regards to the benefits of these medicines,” he says.
Jastreboff, A. M. et al. N. Engl. J. Med. 387, 205–216 (2022).
Sodhi, M., Rezaeianzadeh, R., Kezouh, A. & Etminan, M. JAMA https://doi.org/10.1001/jama.2023.19574 (2023).
Wilding, J. P. H. et al. N. Engl. J. Med. 384, 989–1002 (2021).