Greater access to obesity drugs puts spotlight on safety
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GLP-1 receptor agonists come with known adverse events — some common and some rare — but recent reports by the public of alopecia and suicidal ideation have the FDA investigating.
Healio | Endocrine Today talked with prescribers about the likely origin and burden of these reports. The experts Healio | Endocrine Today spoke with reiterated that, with appropriate counseling, the medications remain safe for use among people with type 2 diabetes and obesity.
Photo by Susan R Symonds for Mainframe Photographics Inc. Printed with permission..
Adverse events with GLP-1s have been the focus of news reports several times over the past year. An FDA quarterly report released Jan. 2 stated that the agency was investigating possible safety signals involving alopecia and suicidal ideation with the use of GLP-1 receptor agonists, including liraglutide (Saxenda, Novo Nordisk) and semaglutide (Ozempic/Wegovy, Novo Nordisk) and the GIP/GLP-1 dual agonist tirzepatide (Mounjaro/Zepbound, Eli Lilly). The FDA stated that the investigation was initiated based on reports to the FDA Adverse Event Reporting System (FAERS).
The news of adverse events raised some concern among the public, but some providers, such as Caroline M. Apovian, MD, co-director of the Center for Weight Management and Wellness in the division of endocrinology, diabetes and hypertension at Brigham and Women’s Hospital and a Healio | Endocrine Today Editorial Board Member, said she believes that the benefits that GLP-1s offer outweigh the risk for adverse events.
“We have patients who have serious problems: prediabetes, diabetes, hypertension, heart disease, congestive heart failure,” Apovian told Healio | Endocrine Today. “They can’t get on a heart transplant list because their BMI is too large. We have patients who have respiratory problems. These reports are being blown out of proportion for the public that may not have the disease of obesity.”
Apovian said the reports of alopecia and suicidal ideation should not be a surprise for endocrinologists, as the events may be connected to losing a large amount of body weight.
Richard E. Pratley, MD, a Healio | Endocrine Today Co-editor and the Samuel E. Crockett chair in diabetes research and medical director of AdventHealth Diabetes Institute, said there have not been any safety signals in trials indicating that GLP-1s increase risks for alopecia and suicidal ideation. He noted that the FDA’s investigation was prompted by reports from the FAERS, which is uncontrolled and may contain reports of adverse events that have a cause separate from GLP-1 therapy.
“[FAERS] is not a great system for assessing clinical risk,” Pratley told Healio | Endocrine Today.
One question some providers have is whether people receiving the medications and experiencing adverse events are using the authentic drug from the pharmaceutical company or a counterfeit product, according to Susan Cornell, PharmD, CDCES, FAPhA, FADCES, associate director of experiential education and professor in the department of pharmacy practice at Midwestern University College of Pharmacy in Downers Grove, Illinois, and a Healio | Endocrine Today Editorial Board Member. Cornell said increased demand from people who want to use a GLP-1 agent to lose weight has led not only to drug shortages, but also to an influx of counterfeit medications that could be potentially unsafe.
“Do we know, with everything that’s out there, what product they were taking?” Cornell said in an interview. “Unfortunately, your average patient doesn’t know any better, meaning they believe the product they have is the brand name made by the manufacturer, but it may be a product made by an unregulated compounding facility and not the pharmaceutical company. [They’ll say,] ‘I’m taking Ozempic’ or ‘I’m taking semaglutide.’ They think all semaglutide is Ozempic, which is not true. I see this discussion a lot on social media; it’s on Facebook, it’s on Instagram, it’s on TikTok. People don’t know or understand the differences, they just want weight loss. They’ll take whatever you’re giving them.”
Sangeeta Kashyap, MD, assistant chief of clinical affairs in the division of endocrinology, diabetes and metabolism at NewYork-Presbyterian/Weill Cornell Medical Center and a Healio | Endocrine Today Co-editor, said the recent reports emphasize the importance of continuing to study adverse events associated with GLP-1 medications, especially as access and indications for the drugs expand.
“The adverse event profile needs to be looked at from a real-world setting, because clinical trials are skewed. Those patients are carefully selected,” Kashyap told Healio | Endocrine Today. “But in a real-world setting, it’s important to look at all of these different adverse events in clinical practice. More data needs to be generated.”
Linking weight loss and suicidal ideation, alopecia
Alopecia and suicidal ideation are adverse events that can potentially occur for anyone with obesity who loses a large percentage of their body weight, according to Apovian and Kashyap. Studies that examined adults receiving bariatric and metabolic surgery found the procedures are also associated with increased risks for alopecia and suicidal ideation. A study published in Annals of Surgery in 2023 examined suicidal ideation rates among veterans who had gastric bypass or sleeve gastrectomy performed from 2000 to 2016 compared with veterans with obesity who did not have surgery. Those who underwent surgery had a 21% higher risk for suicidal ideation than nonsurgical controls.
“I’ve seen people’s depression worsen after bariatric surgery because they use food as a way to console and comfort themselves,” Kashyap said. “It’s the same thing with these drugs, they get rid of their appetite and craving so that satisfaction isn’t there. I can see their depression getting worse.”
Bariatric surgery has also been linked to alopecia. A systematic review and meta-analysis published in Obesity Surgery in 2021 estimated that about 57% of people who undergo bariatric surgery have hair loss, with alopecia more common for younger adults and women. Apovian said alopecia is common among adults who lose a lot of weight, and GLP-1s are likely not the cause of some of the reports the FDA is investigating.
Data released in January assuaged some concerns about GLP-1 medications increasing suicidal ideation risk. A study published in Nature Medicine found adults with obesity or type 2 diabetes who received semaglutide have a lower risk for suicidal ideation than people taking non-GLP-1 medications. One week after the study was published, the FDA announced that preliminary results revealed no association between GLP-1 receptor agonists and suicidal ideation.
Despite the FDA’s preliminary findings, Irl B. Hirsch, MD, professor of medicine at the University of Washington School of Medicine in Seattle, said it is important for researchers to continue monitoring and conducting studies on potential adverse events, especially those involving mental health because GLP-1 receptor agonists affect the brain as well as the gut.
“We need to see how common it is,” Hirsch told Healio | Endocrine Today. “We need to see how many people on a GLP-1 will get suicidal ideation.”
Gastroparesis, pancreatitis rare
In August, news reports and legal action questioned whether GLP-1s were associated with an increased risk for gastroparesis. However, risk for gastroparesis is low for most adults, Apovian said. A study published in JAMA in October found gastroparesis occurred in 1% of adults receiving semaglutide. Apovian said the percentage found in that study is similar to what she has observed in her own practice.
“This is rare,” Apovian said of the gastroparesis risk. “It is overblown in the media and called permanent paralytic ileus, which is a disservice. It’s a disservice to the disease of obesity and all of the patients who need these agents.”
The risk for pancreatitis, another adverse event that has garnered public attention, is also rare, according to Pratley. In the SELECT trial, which was published in The New England Journal of Medicine in November, adults with preexisting heart disease and overweight or obesity were randomly assigned to once-weekly semaglutide or placebo. In the trial, the incidence rate of acute pancreatitis was similar among adults receiving semaglutide and the placebo group. Another study published in JAMA Network Open in January found adults with type 2 diabetes receiving GLP-1 receptor agonists had a similar risk for pancreatic cancer as those receiving basal insulin.
One adverse event that Kashyap said deserves more attention is malnourishment. GLP-1 medications may suppress a person’s appetite so much that it leads to them not eating enough. Kashyap said it is important for providers to monitor nutrient intake regularly for people receiving the medications. She also said more studies are needed to examine the potential for malnourishment with GLP-1 use.
“I’ve seen more severe weight loss and malnourishment with tirzepatide,” Kashyap said. “I’ve had patients say they have to force themselves to eat because they have absolutely no desire to eat. It can very quickly lead to malnutrition.”
The FDA has added some safety warnings to the Ozempic label in the past year. In September, the FDA directed a label change to include a potential increased risk for ileus based on post-marketing adverse reaction reports. The label was also updated to warn patients to avoid using Ozempic with an insulin secretagogue or insulin due to a potential increased risk for hypoglycemia.
Use of counterfeit medications
Cornell said she suspects some of the news surrounding adverse events may be tied to a rise in counterfeit GLP-1 medication use. The FDA issued a warning in December that counterfeit semaglutide products were circulating in the U.S. drug supply chain and that five adverse events linked to counterfeit semaglutide had been reported. In January, Eli Lilly followed with its own warning about compounded tirzepatide, stating some compounded versions of the drug contained high amounts of impurities and may lead to serious health risks.
“We’re starting to see hospitalizations,” Cornell said. “There’s been this ileus warning put on for Ozempic. My question is, how do we know the patient truly got the brand semaglutide vs. an imitation product? The counterfeit drugs are causing problems for the big manufacturers.”
Communication necessary
Hirsch said the media attention on adverse events has begun to outweigh its reports on the potential benefits of GLP-1 receptor agonists, which are only growing. In the SELECT study, adults assigned semaglutide had a 20% reduction in cardiovascular risk compared with placebo. Additionally, in October, Novo Nordisk announced that it ended a clinical trial that will assess the effect of semaglutide on kidney function for adults with type 2 diabetes and chronic kidney disease after certain prespecified criteria were met in an interim analysis. Results from the trial are expected to be presented this year.
“We’ve known these drugs have these CV benefits to the point that, in the [American Diabetes Association] Standards of Care, it has said for the last few years that if you have somebody at high risk or known coronary artery disease, stroke or peripheral vascular disease claudication, that you should use these drugs independent of HbA1c,” Hirsch said. “These drugs have been proven and the evidence is clear that, independent of glucose lowering, these drugs are CV drugs.”
Apovian agreed and said although adverse events are trumpeted in the media, she has not heard many concerns from her patients. She said she believes that many of the concerns are coming from people without type 2 diabetes or obesity who are still using the agents off-label to lose weight. In Lilly’s open letter from January, the company stated that “Mounjaro and Zepbound are indicated for the treatment of serious diseases; they are not approved for — and should not be used for — cosmetic weight loss.”
“These are serious diseases,” Apovian said. “[GLP-1s] are not for those patients who just want to lose a few pounds. Patients who are coming in with BMIs that are 25 kg/m2 or 26 kg/m2, that’s the patient who should be eating healthy, exercising and lifting weights to protect their muscle mass.”
Kashyap, Pratley and Hirsch said providers must take the time to communicate the risks for adverse events with patients when prescribing a GLP-1 medication. Kashyap makes sure to include all of the safety information for any medication in the patient portal in addition to discussing potential risks in person. She said most patients will come to an appointment having already read the safety information and will ask more specific questions at that time.
Kashyap also emphasized the importance of individualizing care for each person, saying that a GLP-1 medication may not be best treatment for everyone.
“You have to try and take that information and personalize it to the patient,” Kashyap said. “For example, if the patient has a history of eating disorders, are you going to [prescribe] these drugs or are you going to try something else?”
Pratley said he focuses on the most common adverse events associated with the drug class, which are mild gastrointestinal events such as nausea and vomiting. Pratley said those adverse events can serve as an indication that the medication is working.
“What we talk about is the benefits in the short term that will keep people on the medications,” Pratley said.
Hirsch similarly said providers must discuss medications in detail with patients before prescribing. He said focusing on the known benefits of GLP-1 receptor agonists as well as the potential risks can give a patient a clear picture of what to expect.
“The problem with these discussions is they take time,” Hirsch said. “It’s important to me, though, that they understand [the benefits and risks]. I will take the time, even if it puts me behind in clinic, because each patient deserves to have the individualized discussion.”
- References:
- Dankner R, et al. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2023.50408.
- Drug Safety-related Labeling Changes (SrLC). Available at: https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=2183. Published Sept. 22, 2023. Accessed Feb. 9, 2024.
- FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-use-counterfeit-ozempic-semaglutide-found-us-drug-supply-chain. Published Dec. 21, 2023. Accessed Feb. 9, 2024.
- Hung A, et al. Ann Surg. 2023;doi:10.1097/SLA.0000000000005825.
- Lincoff AM, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2307563.
- Open letter regarding the use of Mounjaro (tirzepatide) and Zepbound (tirzepatide). Available at: https://investor.lilly.com/news-releases/news-release-details/open-letter-regarding-use-mounjaror-tirzepatide-and-zepboundtm. Published Jan. 4, 2024. Accessed Feb. 9, 2024
- Wang W, et al. Nat Med. 2024;doi:10.1038/s41591-023-02672-2.
- Zhang W, et al. Obes Surg. 2021;doi:10.1007/s11695-021-05311-2.
- For more information:
- Caroline M. Apovian, MD, can be reached at capovian@mgb.org. X (Twitter): @MarsApovian.
- Susan Cornell, PharmD, CDCES, FAPhA, FADCES, can be reached at scorne@midwestern.edu.
- Irl B. Hirsch, MD, can be reached at ihirsch@uw.edu.
- Sangeeta Kashyap, MD, can be reached at srk4008@med.cornell.edu.
- Richard E. Pratley, MD, can be reached at Richard.Pratley.MD@AdventHealth.com; X (Twitter): @RpratleyMD
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