1/24/24 Recent case reports have raised the possibility that semaglutide could be tied to a higher risk of suicidal ideation. Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist. But a retrospective study that included about 241 000 patients with overweight or obesity as well as about 1.6 million patients with type 2 diabetes did not confirm that link.
Instead, researchers found the opposite. People taking semaglutide had a lower risk of both first-time and recurrent suicidal ideation compared with those taking non–GLP-1 receptor agonists to manage obesity, such as phentermine, as well as those used to manage type 2 diabetes, such as metformin.
Because it was retrospective, the current study could not establish a causal link between semaglutide and the lower risk of suicidal ideation, the researchers—including Nora Volkow, MD, the director of the US National Institute on Drug Abuse at the National Institutes of Health—wrote in Nature Medicine. They also noted the need for additional controlled trials to better understand the relationship.
Article Information
Published Online: January 24, 2024. doi:10.1001/jama.2023.27968
Emily Harris
JAMA. 2024;331(6):466. doi:10.1001/jama.2023.27968
11/15/23 Additional Information:
As Semaglutide’s Popularity Soars, Rare but Serious Adverse Effects Are Emerging
In June of 2021, the US Food and Drug Administration (FDA) approved the drug semaglutide for chronic weight management under the brand name Wegovy, ushering in a new era of obesity treatment. Since then, demand for Wegovy and the type 2 diabetes therapy Ozempic—which contains the same drug and has commonly been prescribed off-label for weight loss—have outpaced production, causing ongoing shortages of these injections. And on November 8 of this year, the FDA approved tirzepatide injections for weight management under the brand name Zepbound. The much-anticipated new antiobesity drug, which has been sold as Mounjaro for diabetes since last year, includes 2 active ingredients, one of them in the same drug class as semaglutide.
Amid this fervor, rare but serious adverse effects have recently emerged for this class of hormone-mimicking medications, called glucagon-like peptide 1, or GLP-1, receptor agonists, which in different forms have been on the market for diabetes treatment for almost 2 decades.
This June, the American Society of Anesthesiologists issued new guidance to stop taking GLP-1 agonists before elective surgery because of safety concerns about vomiting while under anesthesia. More recently, in October, a Research Letter in JAMA reported dangerous stomach complications in some patients with obesity using GLP-1 agonists.
“When treating millions of people with medications like semaglutide, even relatively rare side effects will occur in a large number of people,” said Susan Yanovski, MD, senior scientific advisor for clinical obesity research and codirector of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases.
Although the incidence is low, people should know about serious adverse effects, Yanovski said in an interview with JAMA. But she emphasized that for many people with obesity, particularly those with more severe obesity who have related complications, the benefits of these medications are quite likely to outweigh the risks.
Novo Nordisk’s semaglutide, the agent in Wegovy and Ozempic, has been found highly effective for many patients looking to manage their weight. In clinical trials, people who received it alongside a standard diet and exercise intervention shed an average of about 15% of their body weight while also seeing improvements in cardiovascular and glycemic health and physical functioning. Semaglutide is one of several GLP-1 agonists, including liraglutide (marketed as Victoza for diabetes and Saxenda for weight loss) and dulaglutide (marketed as Trulicity for diabetes), that work by curbing appetite and delaying stomach emptying.
These medications simulate gut hormones, and most of their adverse effects are gastrointestinal, including nausea, vomiting, constipation, and diarrhea. But besides these common issues, the rarer and more serious complications are gaining attention.
Serious Stomach Problems
The recent analysis in JAMA focused on serious stomach disorders and GLP-1 agonists.
Researchers in Canada compared safety outcomes for GLP-1 agonists and bupropion-naltrexone, an older class of weight-loss medication. The retrospective analysis included 4144 people with obesity who were prescribed liraglutide, 613 prescribed semaglutide, and 654 prescribed the older treatment. People with a diabetes code in their health record were excluded from the study.
The GLP-1 group had a 9 times greater risk of pancreatitis, a 4 times greater risk of bowel obstruction, and a more than 3 times greater risk of gastroparesis, which causes stomach paralysis. The absolute risks in the GLP-1 group, however, were all about 1% or less per year of GLP-1 use. And semaglutide and liraglutide were not associated with biliary disease, which affects the gallbladder and bile production.
Acute pancreatitis and acute gallbladder disease are known adverse effects of GLP-1 agonists and are listed on the labels for all formulations of semaglutide and liraglutide. But study author Mahyar Etminan, PharmD, an epidemiologist at the University of British Columbia in Vancouver, said in an interview that gastroparesis and bowel obstruction are “a bit more unheard of.”
“Gastroparesis is very new,” he said, adding that the findings support what he’s heard from case reports and posts on social media of people using semaglutide for weight loss.
Yanovski, who was not involved in the study, said the findings “reinforce that these are potent medications, and all medications have side effects.” However, she noted that while the relative risk was significantly elevated for some gastrointestinal adverse effects, the absolute risk was still low.
The study’s limitations included a lack of information on baseline body mass index, the amount of weight lost, and whether GLP-1 agonists were actually being used for weight loss, Yanovski wrote in an email. The authors also noted the latter limitation in their Research Letter.
Anesthesia Complications
Stomachs—and the unexpected expulsion of their contents—also caught the attention of anesthesiologists earlier this year.
Pulmonary aspiration is a rare but potentially fatal complication of anesthesia. To reduce the risk of inhaling the stomach’s contents into the lungs, physicians recommend patients avoid solid foods for 6 hours and clear liquids for 2 hours before scheduled surgeries like colonoscopies or knee replacements.
Reports of people using GLP-1 agonists who regurgitated or aspirated food during anesthesia surfaced this spring in scientific journals. Some of the reports were striking due to the volume of stomach contents the patients regurgitated despite having fasted.
In June, the American Society of Anesthesiologists warned physicians about these concerns in a statement that also provided updated guidance to not use daily GLP-1 agonists on the day of elective surgery and to stop weekly formulations, like Wegovy and Ozempic, 7 days before surgery.
Two factors—delayed stomach emptying and reduced mobility in the gastrointestinal tract, called ileus—could explain why people using GLP-1 agonists experience problems, said Girish P. Joshi, MD, an anesthesiologist at the University of Texas Southwestern Medical Center in Dallas who helped developed the new guidance. This September, the FDA updated Ozempic’s label to warn about reports of ileus; Saxenda’s label added the warning earlier this year.
In an interview, Joshi said he hasn’t been surprised to learn of GLP-1 agonists’ rarer adverse effects as more people worldwide use them for both diabetes and obesity.
He wrote in a recent statement in Anesthesia & Analgesia that high-quality studies “are urgently needed to investigate the safety” of these drugs as they relate to anesthesia.
Timing matters too, he said. During the first 3 to 5 months of using a GLP-1 agonist, people may experience a heightened delay in stomach emptying, which could increase the likelihood of food remaining in their stomachs on the day of surgery despite fasting.
A Self-Harm Signal
This July, case reports of depression and suicidality prompted the European Medicines Agency to review about 150 instances of possible self-injury and suicidal thoughts among people using liraglutide or semaglutide. The review will also include other GLP-1 receptor agonists and is expected to conclude this November, an agency spokesperson confirmed to JAMA.
Yanovski said it’s not known if the medications caused these incidents, but that suicidal thoughts and behavior have been reported with other classes of antiobesity medications.
The Wegovy, Saxenda, and Zepbound drug labels include a warning to monitor for depression or suicidal thoughts, but other GLP-1 agonists do not carry the warning.
People with a history of depression or suicidal behavior or ideation were excluded from clinical trials of Wegovy and Saxenda. According to Saxenda’s label, 9 of 3384 people, or 0.3%, who received the drug in clinical trials reported suicidal ideation vs 2 of 1941 participants, or 0.1%, who received a placebo.
“It’s certainly a good idea for clinicians to use these drugs with caution in people who have a history of suicidality or are currently suicidal and to monitor patients for it,” Yanovski said.
What About Long-Term Risks?
GLP-1 agonists like semaglutide are meant to be long-term and potentially lifelong weight-management medications. Yet there’s still not much known about adverse effects that may play out over time, especially among people taking the drugs for obesity, Etminan said.
Medullary thyroid cancer is a potential risk based on studies in rodents, but because cancer is a latent disease it will take many years to gather data on people. A personal or family history of medullary thyroid cancer is a contraindication for dulaglutide, liraglutide, and semaglutide, as well as for the newly approved tirzepatide. The latter is a GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, which means it mimics 2 gut hormones instead of just 1.
“We’re starting people on medications for potentially long periods of time. We’re going to learn new things about these medications,” Kasia Lipska, MD, an associate professor of medicine in endocrinology at the Yale School of Medicine, said in an interview. But she added that she suspects these newly recognized adverse effects will be uncommon.
Etminan is now turning his attention from the stomach to the eyes. He’s planning to study GLP-1 agonists’ potential ocular adverse effects among people with obesity. Some studies have suggested that people with type 2 diabetes who use semaglutide may have an increased risk of retinopathy, he explained, but he and his colleagues didn’t find this association in a 2018 study.
Takeaway for Clinicians
Both Lipska and Yanovski said the drugs’ common gastrointestinal effects are typically mild to moderate and usually lessen over time. To help the body acclimate, patients are advised to start Wegovy at a 0.25-mg weekly dose and escalate to a maximum weekly dose of 2.4 mg. Dosing for Rybelsus, a once-daily oral formulation of semaglutide approved for type 2 diabetes, also ramps up over time.
“Starting low and going slow is important to minimize side effects,” Yanovski said, adding that it takes several months to titrate to the full dose of Wegovy. Some people need to increase their dose even more slowly.
Tolerating these medicines is important but only if there’s benefit. Roughly 15% of people will lose 5% or less of their body weight. “These drugs don’t work for everybody,” Yanovski said.
With the Zepbound approval, more hormone-based options are filling the pipeline. In a pivotal trial, the drug helped people lose an average of 23.6 kg (52 lb), or 22.5%, of their body weight. It’s expected to be available in the US by the end of 2023, according to drugmaker Eli Lilly.
Further out is Lilly’s investigational drug retatrutide, which targets 3 hormone receptors—GLP-1 and GIP, plus glucagon. Participants who received retatrutide in a phase 2 trial lost nearly a quarter of their body weight in less than a year.
For both tirzepatide and retatrutide, gastrointestinal adverse effects were common and associated with increasing doses.
“We don’t yet know about the more rare side effects. It’s too early to tell—there were very few of these events in the individual trials,” Lipska wrote in an email.
As the landscape of these drugs expands, physicians will need more guidance. Clinical guidelines for antiobesity medications exist, but many were written before the widespread use of potent GLP-1 agonists, Yanovski noted.
“Professional societies are very involved right now in developing new guidance for how to use these drugs safely and effectively in clinical practice,” she said.
Anesthesiologists like Joshi, for instance, are working toward developing new recommendations. Patients might be asked to stop taking GLP-1 agonists earlier than a day or week before surgery or may need to receive an ultrasound to check their stomach contents before being administered anesthesia. In the meantime, Joshi said primary care physicians and endocrinologists should advise patients undergoing procedures to tell the anesthesiologist if they use a GLP-1 agonist.
Decision aids similar to those developed for discussion of diabetes therapies could help clinicians and patients engage in shared decision-making about the best options for weight loss, including semaglutide, Lipska said.
Yanovski agreed: “Patients who are considering these drugs should have a relationship with their clinician, who is not only assessing whether these medications are right for them but sharing decision-making about the potential risks and benefits and following patients closely so they can identify quickly if there are serious adverse events.”
Beware Unsafe Formulations
Trouble accessing glucagon-like peptide 1 (GLP-1) agonists has led some patients to turn to compounded versions, which may not always be safe or effective.
Medicare doesn’t cover antiobesity medications, Medicaid coverage varies by state, and commercial insurance coverage also varies. And less than half of the estimated 110 million adults in the US with obesity have coverage for Wegovy under commercial health insurance or Medicaid, according to an investor presentation by Novo Nordisk, which manufactures semaglutide. That leaves some people paying out-of-pocket for Wegovy and Saxenda, whose list prices are both roughly $16 000 a year. Lilly has announced that Zepbound’s list price will be about $12 700 a year.
As it stands today, even people who can afford semaglutide or who have insurance coverage for it often can’t access it. Increased demand for Wegovy, especially at the lower doses, and Ozempic has caused shortages, according to the FDA’s website.
The supply-and-demand issues aren’t going away soon. A Novo Nordisk spokesperson told JAMA in an email: “We anticipate ongoing supply disruption, and some patients will continue having difficulty filling Wegovy prescriptions.”
Despite semaglutide’s high cost and limited availability, Yanovski cautions against buying compounded versions on the internet. The FDA has warned about reports of adverse events associated with compounded semaglutide and says patients and health care professionals should know that some products may not contain the same active ingredient as the FDA-approved product. In October, the agency sent warning letters for unlawful sale of unapproved and misbranded drugs to companies selling semaglutide and tirzepatide online
Article Information
Published Online: November 15, 2023. doi:10.1001/jama.2023.16620
Kate Ruder, MSJ
JAMA. 2023;330(22):2140-2142. doi:10.1001/jama.2023.16620