GLP-1 analogues tied to higher risk of gallbladder disease, not pancreatitis

Reuters Health Information: GLP-1 analogues tied to higher risk of gallbladder disease, not pancreatitis

GLP-1 analogues tied to higher risk of gallbladder disease, not pancreatitis

Last Updated: 2016-08-02

By Will Boggs MD

NEW YORK (Reuters Health) - Taking glucagon-like peptide 1 (GLP-1) analogues is associated with an increased risk of bile duct and gallbladder disease, but not pancreatitis, in people with type 2 diabetes, according to two new studies.

"Using real-world data, our studies suggest that incretin-based drugs do not appear to increase the risk of acute pancreatitis, although a small risk cannot be excluded," Dr. Laurent Azoulay from McGill University in Montréal, Québec, Canada, told Reuters Health by email.

"With respect to GLP-1 analogues, their use may increase the risk of bile duct and gallbladder events and therefore physicians should be aware of this possibility and exercise vigilance when prescribing these drugs," he said.

Incretin-based drugs - dipeptidyl-peptidase-4 (DPP-4) inhibitors and GLP-1 analogues - are relatively new antidiabetic therapies recommended as second- or third-line treatments for type 2 diabetes.

In some studies, liraglutide (a GLP-1 analogue) has been associated with an increase in gallbladder-related events, and incretin-based drugs in general have been linked with an increased risk of acute pancreatitis. But this research has significant limitations.

To investigate the putative link to gallbladder and bile duct diseases in people with type 2 diabetes, Dr. Azoulay and colleagues analyzed data from two U.K. databases.

Among more than 71,000 new users of antidiabetic drugs who were followed for an average 3.2 years, current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease, the team reports in JAMA Internal Medicine, online August 1.

In contrast, current use of GLP-1 analogues was associated with a significant 79% increase in the risk of bile duct and gallbladder disease (6.1 cases per 1,000 person-years versus 3.3 per 1,000 person-years for other combinations of oral antidiabetic drugs).

The increased risk appeared to be limited to the first 180 days of treatment, although later duration categories were based on fewer events.

Current use of GLP-1 analogues was also tied to a significant increase in the risk of undergoing cholecystectomy (adjusted hazard ratio, 2.08), whereas current use of DPP-4 inhibitors was not.

In another study, also online August 1 in JAMA Internal Medicine, Dr. Azoulay's team tapped into databases from Canada, the United States, and the United Kingdom. Their analysis included more than 1.5 million patients with type 2 diabetes, 5,165 of whom were hospitalized for acute pancreatitis (for a crude incidence of 1.49 cases per 1,000 person-years).

Here, current use of incretin-based drugs was not associated with an increased risk of hospitalization for acute pancreatitis, compared with current use of two or more oral antidiabetic drugs. Results were similar in a subgroup analysis by category.

"DPP-4 inhibitors and GLP-1 analogues are effective at lowering glycemic levels, and certainly, both have a place as second- to third-line agents in the treatment of type 2 diabetes," Dr. Azoulay concluded.

"While our findings single out GLP-1 analogues with respect to their effects on increasing the risk of bile duct and gallbladder disease, this needs to be balanced with their known benefits, such as lowering body weight and decreasing the risk of cardiovascular and cerebrovascular events (as shown in the recently published LEADER trial)," he said.

"In patients with uncontrolled type 2 diabetes and obesity, the addition of GLP-1 mimetics to metformin and, if necessary, to insulin, is a logical choice given current evidence if there is no history of pancreatic or biliary disease or thyroid cancer," writes Dr. Peter C. Butler from David Geffen School of Medicine at UCLA in Los Angeles, California, in a related editorial.

"The possible increased risk of pancreatitis with the GLP-1 class of drugs, based on consistent findings in sufficiently powered RCTs, seems reassuringly low," he said. "However, the unresolved concern is whether the relatively low risk of pancreatitis and the more frequently observed increase in lipase levels herald a subclinical proinflammatory effect that in the longer term could increase the risk for pancreatic cancer."

"With the increasing adoption of electronic health records, postmarketing surveillance for unexpected adverse outcomes might reasonably be established for all new drug classes, and will hopefully be more robust than diagnoses now largely dependent on insurance claims," Dr. Butler concluded.

Dr. Mark Smits from VU University Medical Center in Amsterdam, who also recently reported a possible relationship between GLP-1 analogues and gallbladder disease, told Reuters Health by email, "In general, the effects of GLP-1 receptor agonists are more pronounced compared with DPP-4 inhibitors, given that GLP-1 receptor agonists mimic pharmacological GLP-1 levels, while DPP-4 inhibitors raise GLP-1 levels to slightly higher than physiological levels."

"One very important question is whether all GLP-1 receptor agonists increase the risk of gallbladder events, or only liraglutide," he said. "At this point, we only have data regarding liraglutide. In the ELIXA-trial, lixisenatide did not appear to increase gallbladder events (yet gallbladder events were clustered with 'hepatic' events into 'hepatobiliary events'). It might be interesting to perform a new analysis on the ELIXA-data. Moreover, the data of other large cardiovascular safety trials should shine some additional light on this issue."

"Also, what would be very interesting is a follow-up analysis, where GLP-1 receptor agonists are divided into short- and long-acting categories," said Dr. Smits, who was not involved in the new studies. "We know that - after prolonged intervention - there are several differences between short- and long-acting GLP-1 receptor agonists, which may lead to different effects on gallbladder events."

Dr. Smits concluded, "I think that we need more studies to understand what is going on: why do GLP-1 receptor agonists increase the risk of gallbladder disease? Are there high-risk patient groups? Is this only with liraglutide or also with other agents? Is there a difference between short- and long-acting agents? If we know the answer to these questions, we could individualize the therapy options. In the meanwhile, I guess that it might be safest not to prescribe GLP-1 receptor agonists to patients with known (asymptomatic) gallstones or biliary sludge, although there is no evidence to back up this suggestion."

SOURCE:, and

JAMA Intern Med 2016.

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