A family of diabetes drugs that includes Ozempic is associated with an increased risk of gastrointestinal issues, according to international research published in JAMA, under the auspices of the American Medical Association.
The team from Canada, led by Dr Mohit Sodhi, used information from a health database to compare potential side effects of glucagon-like peptide 1 agonists liraglutide and semaglutide (Ozempic) with the obesity medication bupropion-naltrexone (Contrave).
Significantly the study highlighted that semaglutide and liraglutide were associated with increased risks of pancreatitis, gastroparesis, and bowel obstruction.
“Glucagon-like peptide 1 (GLP-1) agonists are medications approved for treatment of diabetes that recently have also been used off label for weight loss. As well as lowering blood glucose, they also have other favourable effects such as reducing blood pressure and providing protection for the heart and kidneys, but studies have found increased risks of gastrointestinal adverse events in patients with diabetes,” Dr Sodhi said.
“Because such patients have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ. Randomized trials examining efficacy of GLP-1 agonists for weight loss were not designed to capture these events due to small sample sizes and short follow-up.”
A random sample of 16 million patients captured between 2006-2020 by the PharMetrics Plus database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the international classification of diseases (ICD-9 and ICD-10), before being screened down to include 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,” Dr Sodhi explained.
“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.”
Two sensitivity analyses were undertaken, one excluding hyperlipidaemia (because more semaglutide users had hyperlipidaemia) and another including patients without diabetes regardless of having an obesity code.
The team found that incidence rates for the four outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users: the incidence of biliary disease (per 1000 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.
Use of GLP-1 agonists compared with bupropion-naltrexone was associated with 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) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]).
The exclusion of hyperlipidaemia from the analysis did not change the results.
Dr Ian Musgrave, a Senior Lecturer in the Faculty of Medicine, from the School of Medicine Sciences, at the University of Adelaide explained that glucagon like Peptide-1 agonists (GLP-1 agonists) such as Ozempic mimic hormones that link the absorption of nutrients from the gastrointestinal tract with pancreatic hormone secretion and help regulate insulin release after eating.
“As well, they have multiple effects such as increased satiety, decreased appetite and decreased gastric motility that results in weight loss, and as a result, off label prescription of these drugs for weight loss has increased to the point that in the UK there is a shortage of GLP-1 agonists fortype-2 diabetes that is expected to last until 2024,” he said.
“While GLP-1 agonists are generally well tolerated, there is a low incidence of serious side effects.”
“However, those already on anti-obesity treatment should not stop their medication, especially if they have no symptoms or side-effects, however, should speak to their doctor if they have any concerns,” added Dr Georgia Rigas, a VMO-Obesity Doctor & Senior Bariatric Medical Practitioner at St George Private Hospital, Kogarah and the founder & past chair of the RACGP Obesity Management Network.
Dr Rigas warned that doctors should ‘interpret this research letter with caution.’
“Patients considering starting anti-obesity treatment should have an in-depth assessment and subsequent discussion with a doctor experienced in managing people living with overweight/obesity so that any recommendations are tailored to the patient’s individual health profile,” she said.
“Nothing we do/take or decide to not do/take is without risk – the key is patients need to be informed of what the medical evidence tells us, have it put it into context, with a goal to assist them in making an informed decision. Furthermore, empowering patients with a list of ‘what to lookout for’ and what to do about it if they develop symptoms during and out of office hours.
“As the incidence of these complications is low, we can still prescribe as is clinically indicated, however as with all prescribed and over the counter preparations, we still need to remain vigilant.”
Adjunct Professor of Nutrition, Dr Peter Clifton from the University of SA noted that the paper was ‘a timely reminder that there are potentially rare side effects with this class of drugs.”
“Despite the very wide use of these drugs, the number of patients examined and the number of events are low and the confidence intervals very wide,” he said.
“Weekly semaglutide may cause fewer problems than daily liraglutide, but the duration of use is shorter, and this research should prompt further examination of adverse event reporting in Australia.”