Do GLP-1 agonists increase the risk of gallstones and pancreatitis?
GLP-1 agonists measurably increase the risk of gallstones, but the risk of pancreatitis does not appear to be elevated in the larger studies. If you already have gallstones or have had pancreatitis before, discuss this explicitly with your doctor.
Gallstones occur more frequently in people who use GLP-1 agonists. Several large studies consistently show this pattern: a 30% higher chance of gallstones compared with other agents, 15% more gallbladder disease compared with SGLT2 inhibitors, and after two to three years of use up to 44% more gallstones in people with type 2 diabetes. Semaglutide and dulaglutide appear to cause more gallstone formation than liraglutide and exenatide. In absolute terms, this amounts to fewer than one extra case per 1,000 treatment-years, but after three years of use the risk of gallbladder inflammation and gallbladder removal also rises measurably.
For pancreatitis (inflammation of the pancreas), the picture is different. An analysis of more than one hundred randomised trials found no significantly elevated risk. A large Danish study involving more than 12,000 pancreatitis patients likewise found no elevated risk, and a study of more than 1.2 million patients comparing GLP-1 agonists with SGLT2 inhibitors also found no difference. An early American study did find an elevated risk at the time, but that was an observational study in which confounding factors such as obesity, gallstones and alcohol use likely distorted the results.
A striking finding: in people who developed pancreatitis despite using GLP-1 agonists, the course of that pancreatitis was less severe. The chance of a complicated course was more than twice as low in the GLP-1 group, and death from pancreatitis was also less common. This has not yet been explained and requires confirmation.
Not everyone carries the same level of risk. In people who used GLP-1 agonists for obesity, a history of gallstones or a prior episode of pancreatitis was found to substantially increase the risk of pancreatitis (approximately three-fold and five-fold, respectively). Cardiovascular disease and smoking also increased the risk. If you have these risk factors, it is advisable to discuss this with your doctor before starting GLP-1 therapy. Tirzepatide, a combination agent that also acts on another hormone, showed a nearly two-fold elevated risk of gallbladder disease compared with placebo, but not compared with other GLP-1 agonists.
The gallstone evidence rests on several large studies, including analyses of one hundred-plus randomised trials and studies involving more than one million patients, which makes the finding credible. The pancreatitis evidence is remarkably consistently negative across the larger and better-designed studies; the early positive signal from 2013 stands in contrast to several later, larger studies that find no effect. The finding that pancreatitis follows a less severe course with GLP-1 use is preliminary and comes from a single retrospective study. The risk-factor analysis in patients with obesity is based on a relatively small group and requires confirmation.