Semaglutide, Liraglutide Use for Weight Loss Associated with Gastrointestinal Event Risk

Mahyar Etminan, PharmD, MSc

Credit: The University of British Columbia

Glucagon-like peptide-1 (GLP-1) receptor agonists used for weight loss were associated with an increased risk for gastrointestinal adverse events, compared with the use of bupropion-naltrexone, according to a new report.¹

In the analysis, the diabetes drug class, including semaglutide and liraglutide, used for weight management in approximately 5000 individuals, increased the risk of pancreatitis, gastroparesis, and bowel obstruction, but not biliary disease.

These results follow recent safety-related labeling changes for semaglutide from the US Food and Drug Administration (FDA) warning of the potential for an increased risk of ileus. An additional label update indicated those using semaglutide in combination with an insulin secretagogue or insulin may experience an increased risk of hypoglycemia.²

“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes,” wrote the investigative team, led by Mahyar Etminan, PharmD, MSc of The Eye Care Center, University of British Columbia.¹

Evidence has suggested patients with diabetes experience increased risks of gastrointestinal adverse events, even at baseline. However, the accompanying risk in patients taking these agents for other indications may differ from diabetes care. Etminan noted recent randomized trials on the efficacy of GLP-1s were unable to detect these events, given their small sample size and short follow-up time.³

In this analysis, investigators examined gastrointestinal adverse events during weight loss treatment in a clinical setting. A random sample of 16 million patients from the 2006 - 2020 PharMatrics Plus database was collected for the study.¹ The cohort included new users of semaglutide (n = 613) or liraglutide (n = 4144) and the active comparator bupropion-naltrexone (n = 654).

Given semaglutide was marketed for weight loss in 2021, after the study period, the investigative team noted only those users with an obesity code in the 90 days prior or up to 30 days after cohort entry were included in the analysis. Those with diabetes or an antidiabetic drug code were excluded from the analysis. Participants were followed from the first prescription of a study agent to the first mutually exclusive incidence of a gastrointestinal adverse event (biliary disease, pancreatitis, bowel obstruction, or gastroparesis).

Analyses were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in ≤30 days, and geographic location – each was identified as a common cause variable or risk factor. Overall, incidence rates were increased among GLP-1 agonist users for all 4 gastrointestinal outcomes, compared with bupropion-naltrexone users.

Data showed the use of GLP-1 agonists compared with bupropion-naltrexone was associated with an increased risk of pancreatitis (adjusted HR, 9.09; 95% CI, 1.25 - 66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02 - 17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15 - 11.90). Analyses did not show an increased risk of biliary disease (HR, 1.50; 95% CI, 0.89 - 2.53).

In their conclusion, the investigative team noted the exclusion of hyperlipidemia from the analysis did not change the analysis’s findings, while the inclusion of GLP-1 agonists regardless of history of obesity did not change the significance of the results.

“Inclusion of GLP-1 agonists regardless of history of obesity reduced hazard ratios and narrowed confidence intervals, but did not change the significance of the results,” investigators wrote.

References

1. Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. Published online October 05, 2023. doi:10.1001/jama.2023.19574
2. Campbell P. FDA adds new warning for ileus to semaglutide (ozempic) label. HCP Live. September 28, 2023. Accessed October 6, 2023. https://www.hcplive.com/view/fda-adds-new-warning-for-ileus-to-semaglutide-label.
3. Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022;327(2):138–150. doi:10.1001/jama.2021.23619