Study: Unexpected Safety Signals Identified for Semaglutide in Diabetes, Obesity

Glucagon-like peptide-1 (GLP-1) agonist receptors are getting constant recognition, but there are concerns around adverse events (AEs) from these medications. In January 2024, the FDA issued a statement about reports of suicidal thoughts or actions for patients treated with GLP-1 medications. However, the agency’s preliminary evaluation did not show evidence that the medications contributed to suicidal thoughts or actions.¹

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At the American Diabetes Association's 84th Scientific Sessions, presenter John-Michael Gamble, PhD, from the University of Waterloo, discussed the potential link between suicide risk and GLP-1 medications. In the studies mentioned, there was evidence to show that GLP-1s actually decreased the risk of suicide attempts and lowered the risk for incident and recurrent suicidal ideation.²

The FDA Adverse Event Reporting System (FAERS) identified other potential safety signals for these medications in 2023, including alopecia, aspiration, and suicidal ideation. The FDA is evaluating the need for regulatory action regarding all 3 signals. The content was also updated in June 2024. The presenters at the Scientific Sessions also included the potential of AEs affecting the pancreas and gallbladder, colorectal cancer, aspiration, thyroid cancer, and increased risk of pregnancy.^2,3

In a study published in the Journal of Diabetes Investigations, investigators identified 10 unexpected adverse signals for semaglutide (Ozempic, Wegovy; Novo Nordisk), which include signals related to pancreatic cancer, intestinal obstruction, cholecystitis, and polycystic ovary. Authors of the study emphasize the need for more pharmacovigilance post-marketing of GLP-1 medications. They analyzed data from FAERS from the first quarter of 2018 through the second quarter of 2023 using scientific algorithms for more accurate insight into potential safety signals and potential risks.⁴

Investigators used real data for AEs associated with semaglutide, including datasets for demographic and administrative information, drug-related details, reports on adverse drug reactions, patient outcomes, sources of the reports, drug therapy duration, and indications for use and diagnosis. There were 14,512 AEs related to semaglutide, excluding 625 events where there was unknown or missing gender, with approximately 59.72% of events with female individuals and 35.97% with male individuals. Excluding 7413 reports for unknown or missing age, the median age was 50 years, with only 0.12% for individuals less than 20 years old. There were a total of 21 system organ classes observed, with gastrointestinal disorders being the most common. Metabolic and nutritional disorders, nervous system disorders, general disorders and administration site conditions, endocrine system diseases, and hepatobiliary system diseases were all included. For Preferred Terms, the top 6 included poor weight loss, injection site extravasation, eructation, medullary thyroid carcinoma, diabetic retinopathy, and pancreatitis, according to the investigators.⁴

As for AEs that were not mentioned on the package insert, investigators also observed signals for starvation ketoacidosis, chronic cholecystitis, obstructive pancreatitis, allodynia, pancreatic enlargement, breath odor, pancreatic chronic, and polycystic ovaries.⁴

Furthermore, there were differences in AEs for indications, with the most common for type 2 diabetes being nausea, vomiting, and diarrhea, and the most common for obesity being overdosing, nausea, and product use for unapproved indications. Investigators called for more post-marketing surveillance to understand the potential risk of semaglutide.⁴

References

1. FDA. Update on FDA’s ongoing evaluation of reports of suicidal thoughts or actions in patients taking a certain type of medicines approved for type 2 diabetes and obesity. Updated January 30, 2024. Accessed July 9, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type

2. Gallagher A. Experts Discuss Serious Adverse Events for GLP-1 Medications. Pharmacy Times. June 23, 2024. Accessed July 9, 2024. https://www.pharmacytimes.com/view/experts-discuss-serious-adverse-events-for-glp-1-medications

3. FDA. July - September 2023 | Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS). June 21, 2024. Accessed July 9, 2024. 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. Du Y, Zhang M, Wang Z, et al. A real-world disproportionality analysis of semaglutide: Post-marketing pharmacovigilance data. J Diabetes Investig. Published online June 29, 2024. doi:10.1111/jdi.14229