Major GI Events Rare but Real in Weight-Loss Patients on GLP-1 Drugs

When used as a weight-loss tool, the glucagon-like peptide-1 (GLP-1) receptor agonists semaglutide (Ozempic) and liraglutide (Saxenda), both sold by Novo Nordisk, raise the odds that patients will develop gastrointestinal problems—including serious side effects—according to new data published Thursday in JAMA.

The increases in pancreatitis, bowel obstruction, and gastroparesis mirror those previously observed in the setting of diabetes, the authors say, but it was important to look specifically at the weight-loss population. “Because [patients with diabetes] have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ,” write Mohit Sodhi, MSc (University of British Columbia, Vancouver, Canada), and colleagues. Additionally, the RCTs testing these drugs for weight loss weren’t designed to capture these GI events.

Mahyar Etminan, PharmD, MSc (University of British Columbia), senior author of the research letter, told TCTMD in an email that it’s important to keep the risk in perspective.

Gastrointestinal adverse event rates with the GLP-1 drugs in their study hovered at around 1% to 2%, he said. “The concern is that since millions of people are taking them this can still translate to a lot of people.” Additionally, healthy individuals using the medications for weight loss, rather than treating diabetes, might be less willing to take them due to the potential harm.

Etminan suggested that patients with preexisting GI conditions, in particular, might want to discuss these possible side effects with their physicians.

Demand has surged for GLP-1 receptor agonists, which first emerged as a treatment for diabetes but can also produce dramatic weight loss. Following the recent release of top-line results for semaglutide from the SELECT trial that showed a reduction in CV events for patients who are overweight or obese, the popularity of GLP-1 receptor agonists stands to grow even further. SELECT will be presented in full at the upcoming American Heart Association 2023 Scientific Sessions in November.

But the medications are not without controversy. Recent headlines have addressed reports of suicidal ideation with semaglutide and liraglutide, while a range of more-minor gastrointestinal side effects like nausea, vomiting, abdominal pain, constipation, and diarrhea are noted in the labelling. Many of these same adverse events have been reported for other diet drugs, including bupropion-naltrexone (Contrave; Currax Pharmaceuticals).

For their analysis, the researchers delved into PharMetrics Plus, a health claims database that captures 93% of all US outpatient prescriptions and physician diagnoses, to check for more-serious symptoms reported for patients taking GLP-1 receptor agonists.

Their analysis included 4,144 new users of liraglutide and 613 new users of semaglutide, as well as 654 individuals taking bupropion-naltrexone for obesity.

Compared with those on bupropion-naltrexone, use of the GLP-1 drugs was linked to higher risks of pancreatitis, bowel obstruction, and gastroparesis. However, unlike what’s been seen in the diabetes setting, there was no difference in the risk of biliary disease.

GI Adverse Events With GLP-1 Receptor Agonists vs Bupropion-Naltrexone

The associations were confirmed by a sensitivity analysis excluding hyperlipidemia. Broadening the cohort to include patients with an obesity code in their medical records reduced the hazard ratios and narrowed the confidence intervals without erasing statistical significance.

However, as noted by Etminan, the actual incidence of these events was low. Per 1,000 person-years, the incidence of pancreatitis was 4.6 with semaglutide, 7.9 with liraglutide, and 1.0 with bupropion-naltrexone. Figures for gastroparesis were 9.1, 7.3, and 3.1, respectively. There were no cases of bowel obstruction with semaglutide, but the adverse event occurred at an incidence of 8.1 per 1,000 person-years with liraglutide and 1.7 per 1,000 person-years with bupropion-naltrexone.

“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,” the study authors urge.

Going forward, Etminan said he’d like to assess these associations in an even larger population and tease out the effects of the individual GLP-1 agents.