Diabetes drugs now popular for their serendipitous by-product – weight loss – have also been linked to increased risk of gastrointestinal side effects, including inflammation in the pancreas and obstructions of the digestive system, in people without diabetes.
Scientists say the drugs, which help people with diabetes to lose about 15% of their body weight, belong to a class called GLP-1 agonists and include semaglutide, the main ingredient in Ozempic, Wegovy and Rybelsus; tirzepatide, which is found in Mounjaro; and liraglutide, used in Victoza and Saxenda.
In September, the US Food and Drug Administration (FDA) asked manufacturers of the semaglutide drugs to include a warning in the medication label about the possible risk of intestinal blockage, after receiving around 8 500 reports of the condition from both diabetic and non-diabetic users.
Scientists wanted to know how common the side effects and risks are in people who don’t have diabetes, and who are increasingly taking the drugs to lose weight, and came to some worrying conclusions.
TIME reports that in a research letter published in JAMA, scientists at the University of British Columbia provide additional data on the magnitude of those risks for people taking the drugs purely for weight loss.
They report that among 4 700 people without diabetes taking some form of GLP-1 and 650 people taking an older, different combination of weight loss drugs, those taking GLP-1s had a nine times greater risk of pancreatitis and four times higher risk of both obstructed bowels and gastroparesis, which is a slower emptying of the stomach into the intestines.
“We wanted to examine these risks taking diabetes out of the equation,” said Mohit Sodhi, a fourth-year medical student at University of British Columbia and first author of the study, “since so many people are taking these (medications) specifically for weight loss and don’t have diabetes.”
While the researchers only studied semaglutide and liraglutide, they say the adverse effects in the GI system may occur with all drugs in the GLP-1 class, including tirzepatide, which the FDA has approved for treating diabetes but is still reviewing for weight loss.
The absolute risk of these side effects remains small, but given how many people are starting to take the medications not to treat diabetes but purely to lose a a few kilograms, these side effects could become significant.
“Say that a million people are taking GLP-1s,” said Sodhi. “If you look at the incidence of gastroparesis in our study, it was about 1%. If you take 1% of 1m, that’s 10 000 people who are potentially experiencing that adverse event. Blow that up to millions more patients taking these drugs, and the numbers can get extremely high.”
For people with diabetes, who are more vulnerable to other health complications related to uncontrolled blood sugar, such as circulation issues and kidney and eye abnormalities, the benefits in controlling those conditions may outweigh the gastrointestinal risks.
But for those without diabetes, those risks may outweigh the benefits of shedding a few kilos.
Although there are some studies showing other positive health outcomes associated with the weight loss drugs for people without diabetes, including reduction in heart disease risk, more research is needed to confirm those findings.
Additional studies are also needed to better understand why GLP-1 drugs have such adverse effects on the stomach and intestines.
Some early work in people with and without diabetes suggests that the medications slow the normal motion of the stomach and intestines, possibly even stunning the nervous system into inaction.
“We’re hoping that our paper will spur additional research to see if people can replicate our findings and hopefully give people more informed consent when using these medications,” said Sodhi.
Study details
Risk of gastrointestinal adverse events associated with glucagon-like Peptide-1 receptor agonists for weight loss
Mohit Sodhi, Ramin Rezaeianzadeh, Abbas Kezouh, et al.
Published in JAMA Network on 5 October 2023
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. Studies have found increased risks of gastrointestinal adverse events (biliar disease, pancreatitis, bowel obstruction, and gastroparesis) in patients with diabetes. Because such patients have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ. Randomised 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. We examined gastrointestinal adverse events associated with GLP-1 agonists used for weight loss in a clinical setting.
Methods
We used a random sample of 16 million patients (2006-2020) from 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, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists. 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.
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). They were followed up to the end of the study period (June 2020) or censored during a switch. Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors. Two sensitivity analyses were undertaken, one excluding hyperlipidemia (because more semaglutide users had hyperlipidemia) and another including patients without diabetes regardless of having an obesity code. Due to absence of data on body mass index (BMI), the E-value was used to examine how strong unmeasured confounding would need to be to negate observed results, with E-value HRs of at least 2 indicating BMI is unlikely to change study results. Statistical significance was defined as 2-sided 95% CI that did not cross 1.
Results
Our cohort included 4144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Incidence rates for the 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users. For example, incidence of biliary disease (per 1000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrex one 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]). Exclusion of hyperlipidemia from the analysis did not change the results. 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.
Discussion
This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.
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. Limitations include that 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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