Evaluating and managing semaglutide risk

Semaglutide belongs to a class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists. It mimics the GLP-1 hormone that is released in the gastrointestinal tract in response to eating. GLP-1 prompts the body to produce more insulin, which reduces blood glucose and in conjunction with diet and exercise treats Type 2 diabetes.¹

Semaglutide is also used to lower the risk of heart attack, stroke or death in patients with Type 2 diabetes. Semaglutides are only available by a prescription. In 2017, the FDA approved some semaglutides for the control of Type 2 diabetes. In 2018, researchers noted the weight loss properties of the drug as a side effect.²

The FDA Adverse Event Reporting System has received over 10,000 reports about semaglutide variants.³ In September 2023, FDA added a warning to Ozempic® for intestinal blockage and obstruction and ileus.³ Serious side effects of GLP-1 agonists include pancreatitis, gastroparesis/stomach paralysis, bowel obstruction and gallstone attacks/bile duct blockage. Labels have been updated to add intestinal blockage (ileus) as an adverse reaction.

Gastroparesis is not on the label yet because these cases are believed to be rare and may not be direct results of the drugs themselves. FDA is also investigating cases of hair loss, aspiration (when food or other objects get into the airways) and suicidal ideation. GLP-1 drugs for weight loss typically involve higher dosages than the same drug taken to manage diabetes which may lead to additional adverse events as the drugs are more widely used for weight loss.

In February 2024, lawsuits were combined into a multijurisdictional litigation with the main allegation being the manufacturer concealed these side effects. Other GLP-1 agonists similar to Ozempic® (Mounjaro®, Rybelsus®, Saxenda® and Wegovy®) have the potential to be named in lawsuits. To date, no lawsuits have been filed against the makers of Rybelsus® or Wegovy®, but patients who used these drugs and were diagnosed with gallbladder disease may file in the future.

There is data suggestive of a link between semaglutide and suicidal ideation. This warning is required for all chronic weight loss medication in the United States. Studies found a link between use of semaglutide drugs with an increased risk of gallbladder disease. Research has also indicated there is no association between semaglutides and any type of cancer.^4-5

Studies have not been performed on the relationship of age to the effects of Ozempic® and Wegovy® in the pediatric or geriatric population. There are no adequate studies determining infant risk when using this medication during breastfeeding.

Wegovy® is approved to help adults and children aged 12 years and older with obesity. Some of the other semaglutide drugs are not. Many of these drugs are being prescribed for weight loss for patients who are not obese or with weight- related medical problems.

Some of these drugs are being prescribed for off label use which includes 1) drugs approved for diabetes used for weight loss (for example, Ozempic®) or 2) drugs approved for weight loss in obese patients or patients with weight-related medical conditions prescribed to patients who do not meet these criteria.

The risk for the use of these drugs off-label may outweigh the benefits. Physicians have been involved in legal claims when prescribing or promoting medication for off-label use.⁶ If the off-label use is the cause of injury, a patient may bring a case of medical malpractice for lack of informed consent and negligence. To date, no appellate court has ruled that physicians must disclose off-label status as part of informed consent.⁶

FDA does not require informed consent for off-label use, only experimental use. Providing patients with information about off-label use may offer some protection from liability. Whether off-label informed consents may be beneficial and protective for physicians is something they should consider with input from their legal counsel.

Negligence may be claimed if prescribing physician deviated from the standard of acceptable practice when prescribing off-label. Because the active ingredient has been approved for weight loss for one of these drugs, the physician can refer to the approval along with peer-reviewed, published evidence focusing on a drug’s off-label use.

Both Ozempic® and Wegovy® are on FDA’s Drug Shortages list due to the demand which has resulted in pharmacies that meet FDA requirements making a compounded version of that drug. Compounded drugs have not been reviewed by FDA for safety, effectiveness or quality. FDA has received reports that compounders may be using salt forms of semaglutide which are different active ingredients than is used the approved drugs.

Demand for less expensive GLP-1s has also led to an increase of counterfeit, fraudulent or unapproved products on the market. FDA alert highlighted incidents of patients overdosing from compounding formulations and is in fact the most prevalent issues for compounded versions of these drugs.⁷

Managing/evaluating semaglutide risk

• Potential problems/side effects may be realized as this class of medication is still in its infancy and long-term negative effects may not have been fully realized.
• Consider adding a “parent/guardian” signature after discussion.
• Consider prescribers having a checklist of topics to address with the patient so all risks can be explained.
• Consider a special informed consent form to ensure the patient is aware of all the potential risks and acknowledges that this is being use off-label.
• Consider the age groups the medications are being prescribed to.
• Medications should only be obtained from reputable and FDA-approved sources.
• Inherent safety mechanisms with commercially produced, FDA-approved auto-injector devices are bypassed using compounded medications and that self-dosing errors may lead to patient harm.
• All medications being taking needs to be disclosed to the physician.
• Other weight loss medications should not be taken without advising physician.
• Refer to the product literature for safety issues.

References:
¹ https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss
² A - Blundell J, Finlayson G, Axelsen M, et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab.2017;19:1242– 1251. https://doi.org/10.1111/dom.12932
³ https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/july-september-2023-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
⁴ https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type
⁵ https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/july-september-2023-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
⁶ The Law and Practice of Off-Label Prescribing and Physician Promotion Journal of the American Academy of Psychiatry and the Law Online November 2020, JAAPL.200049-20. https://jaapl.org/content/early/2020/11/24/JAAPL.200049-20
⁷ https://medlineplus.gov/druginfo/meds/a618008.html U.S. Food and Drug Administration (2024 July 26). FDA Alerts Health Care Providers, Compounders and Patients of Dosing Errors Associated With Compounded Injectable Semaglutide Product