Glucagon-like peptide 1 (GLP-1) agonists are medications approved for the treatment of diabetes that have recently also been used off-label for weight loss. Studies have found increased risks of gastrointestinal adverse events (bile disease, pancreatitis, intestinal obstruction, and gastroparesis) in patients with diabetes. Because these patients are at increased baseline risk for gastrointestinal adverse events, the risk in patients taking these medications for other indications may differ.
Randomized trials examining the effectiveness of GLP-1 agonists for weight loss were not designed to capture these events due to small sample size 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 (IQVIA) database, a large health claims database that captures 93% of all outpatient prescriptions and medical diagnoses in the US. .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 , two major 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 that all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the previous 90 days or up to 30 days after cohort entry, excluding those with diabetes. or antidiabetic drug code.
Patients were observed from the first prescription of a study drug until the first mutually exclusive incidence (defined as the first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including pancreatitis due to gallstones), intestinal obstruction or gastroparesis (defined as the use of a code or a promoting agent).
They were followed until the end of the study period (June 2020) or censored during a change. Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol consumption, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors. . Two sensitivity analyzes were performed, one that excluded hyperlipidemia (because more semaglutide users had hyperlipidemia) and another that included patients without diabetes regardless of having an obesity code.
Due to the absence of data on body mass index (BMI), the E value was used to examine how strong unmeasured confounders would have to be to negate the observed results; E-value HR values of at least 2 indicate that BMI is unlikely to change the study results. Statistical significance was defined as a two-sided 95% CI not crossing 1. Analyzes were performed using SAS version 9.4. Ethical approval was obtained from the University of British Columbia Clinical Research Ethics Board with a waiver of informed consent.
Results
Our cohort included 4144 liraglutide users, 613 semaglutide users and 654 bupropion-naltrexone users . Incidence rates for all 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users. For example, the 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 .
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]), intestinal 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]).
Excluding hyperlipidemia from the analysis did not change the results. Inclusion of GLP-1 agonists, regardless of obesity history, reduced HRs and reduced CIs, but did not change the significance of the results. E-HR values did not suggest potential confounding by BMI.
Discussion This study found that the use of GLP-1 agonists for weight loss compared with the use of bupropion-naltrexone was associated with an increased risk of pancreatitis, gastroparesis, and intestinal obstruction, but not with biliary disease . Given the wide use of these medications, these adverse events, although rare, should be considered by patients who are considering using the medications for weight loss because the risk-benefit calculation for this group may differ from that for those using them for weight loss. diabetes. Limitations include that although all GLP-1 agonist users had a history of obesity without diabetes, it is not known if all GLP-1 agonists were used for weight loss. |
Comments
First epidemiological study links popular weight-loss drugs to stomach paralysis and other serious gastrointestinal conditions
They are being hailed as an effective way to lose weight, but diabetes medications like semaglutide may carry a higher risk of serious gastrointestinal problems.
This is according to new research from the University of British Columbia that shows that drugs known as GLP-1 agonists are associated with an increased risk of serious medical conditions, such as stomach paralysis, pancreatitis, and problems such as intestinal blockages.
While previous studies have highlighted some of these risks in patients with diabetes, this is the first large population-based study to examine adverse gastrointestinal events in non-diabetic patients using medications specifically for weight loss. The findings were published in JAMA .
"Given the wide use of these medications, these adverse events, although rare, should be considered by patients considering using them for weight loss," said first author Mohit Sodhi, a graduate of UBC’s experimental medicine program and fourth-year medical student at UBC. “The risk calculation will vary depending on whether a patient is using these medications for diabetes, obesity, or just general weight loss. “People who are otherwise healthy may be less willing to accept these potentially serious adverse events.”
GLP-1 agonists were originally developed to manage type 2 diabetes, but their popularity has skyrocketed over the past decade as an off-label weight loss tool, reaching approximately 40 million prescriptions in the US in 2022.
It was not until 2021 that some forms of medications were approved as a treatment for obesity. However, randomized clinical trials examining the effectiveness of weight loss medications were not designed to capture rare gastrointestinal events due to their small sample sizes and short follow-up periods.
"There have been anecdotal reports of some patients using these medications to lose weight and then experiencing repeated episodes of nausea and vomiting secondary to a condition known as gastroparesis ," said lead author Dr. Mahyar Etminan, an epidemiologist and associate professor at the Department of Ophthalmology and Visual Sciences, UBC Faculty of Medicine. "But until now, there has been no data from large epidemiological studies."
To help fill this knowledge gap, UBC researchers examined the health insurance claims records of approximately 16 million American patients and looked at people who were prescribed semaglutide or liraglutide , two major GLP-1 agonists. , between 2006 and 2020. They included patients with a recent history of obesity and excluded those with diabetes or who had been prescribed another antidiabetic medication.
Researchers analyzed records to see how many patients developed one of four gastrointestinal conditions and compared that rate to patients using another weight-loss drug, bupropion-naltrexone.
Compared with bupropion-naltrexone, GLP-1 agonists were associated with:
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Researchers say that although the events are rare, as millions of people around the world use these drugs, they could still cause hundreds of thousands of people to experience these conditions.
“These medications are becoming more accessible and it is worrying that in some cases people may simply go online and order these types of medications when they do not have a full understanding of what could happen. This goes directly against the mantra of informed consent,” Sodhi said.
In the meantime, researchers hope that regulatory agencies and drug manufacturers will consider updating the warning labels on their products, which currently do not include the risk of gastroparesis.
"This is critical information that patients should know so they can seek timely medical care and avoid serious consequences," Sodhi said.
