“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,” according to University of British Columbia–led researchers.
Published as a research letter in the Journal of the American Medical Association, the study noted that GLP-1s for weight loss are medications approved for the treatment of diabetes that recently have also been used off-label for weight loss. “Studies have found increased risks of gastrointestinal adverse events (biliary disease, pancreatitis, bowel obstruction and gastroparesis) in patients with diabetes,” the researchers advised. “Because such patients have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ.”
The study team pointed out that randomized trials examining the efficacy of GLP-1 agonists for weight loss were not designed to capture those events because of small sample sizes and short follow-ups. In response, it set out to examine GI adverse events associated with GLP-1 agonists used for weight loss in a clinical setting.
A random sample of 16 million patients (2006-2020) was pulled from the PharMetrics Plus database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the United States through ICD-9 or ICD-10 codes. The cohort study included new users of semaglutide or liraglutide, two of the most prescribed GLP-1 agonists, and compared them to bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists.
Ultimately, the cohort included 4,144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users.
“Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code,” the authors advised. “Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent).” Follow-up continued until June 2020.
The results indicated that incidence rates for the four outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users. “For example, incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrexone and 4.6, 7.9, and 1.0, respectively, for pancreatitis,” the researchers explained. “Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (adjusted HR [hazard ratio], 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) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]).”
The authors noted that the exclusion of hyperlipidemia from the analysis did not change the results. They added, “Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results. E-value HRs did not suggest potential confounding by BMI.”
The study pointed out that its results are limited because—although all GLP-1 agonist users had a record for obesity without diabetes—whether GLP-1 agonists were all used for weight loss is uncertain.
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