Patients taking liraglutide (Victoza, Novo Nordisk) were at increased risk for gallbladder and biliary tract-related events in the LEADER trial but the mechanisms are unclear, a post-hoc analysis has found.
Data from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial were published online August 9 in Diabetes Care by Michael A. Nauck, MD, Diabetes-Center Bochum-Hattingen, St Josef-Hospital, Ruhr-University Bochum, Germany, and colleagues.
“Although LEADER was not specifically designed to assess acute gallbladder or biliary disease, the trial showed an increased risk of gallbladder- or biliary tract–related events with liraglutide versus placebo, which appeared to be consistent across four categories of these events. Further studies should investigate the relevant mechanisms,” Nauck and colleagues write.
Type 2 diabetes itself raises the risk for biliary disease approximately twofold, with the mechanism possibly linked to insulin resistance and obesity. Previous evidence has been mixed regarding a link between the glucagon-like peptide 1 (GLP-1) receptor agonist drug class and biliary diseases. The risk is mentioned in the prescribing label for liraglutide but not all GLP-1 receptor agonists.
An increase in gallbladder-related adverse events was reported in the clinical development program for the 3.0-mg dose of liraglutide for weight loss (Saxenda, Novo Nordisk) versus placebo but not in the clinical development program for the 1.8-mg glucose-lowering dose (Victoza).
Asked to comment, Scott J. Pilla, MD, assistant professor of medicine, Division of General Internal Medicine, Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News, “I think this is a well-done study. Their analysis is appropriate, and their findings are accurately presented…Clinicians should understand that the risk of serious gallbladder-related illness is likely increased by treatment with GLP-1 receptor agonists.”
However, Pilla added, “While these adverse events are serious, they are relatively uncommon, and shouldn’t be a reason not to use GLP-1 receptor agonists because all diabetes medications can have serious side effects.”
Drilling Down in LEADER: Biliary Complications Common Across Categories
Primary results from LEADER, in which 9340 patients with type 2 diabetes and high cardiovascular risk were randomized to liraglutide or placebo for a median 3.8 years, demonstrated a significantly decreased risk for major adverse cardiovascular events with liraglutide.
The proportion of patients with acute gallstone disease was higher with liraglutide than placebo (3.1% vs 1.9%; P < 0.001), driven primarily by the rates of cholelithiasis (1.5% vs 1.1%) and acute cholecystitis (0.8% vs 0.4%).
This post-hoc analysis is the first to explore the subtypes of gallstone disease observed and their implications. Overall, 275 events were reported in 235 patients, with seven events subsequently excluded for non-relevance.
Gallbladder or biliary tract-related events were higher with liraglutide versus placebo (141 vs 88 patients; hazard ratio, 1.60; P < 0.001). Baseline characteristics were similar between those experiencing events in the two groups.
Among patients with events, those taking liraglutide were more likely than those in the placebo group to have uncomplicated gallbladder stones (16 vs 5 patients), complicated gallbladder stones (52 vs 40), cholecystitis (51 vs 33), and biliary obstruction (25 vs 16).
Cholecystectomy was more common in the liraglutide-treated patients (1.74% vs 1.11%, respectively; hazard ratio, 1.56; P = .013). However, among those with gallbladder- or biliary tract–related events during the trial, the proportions undergoing cholecystectomy were similar (57% vs 59%, respectively).
Nauck and colleagues note that this finding “should be interpreted with caution, as patients who experienced gallbladder- or biliary tract–related events in the liraglutide or placebo groups may not have been comparable across these treatment groups.”
And, they add, “cholecystectomy was more common in patients treated with liraglutide versus placebo overall, probably because more gallbladder- and biliary tract–related events occurred in liraglutide-treated individuals.”
Patients who experienced a gallbladder- or biliary tract-related event lost more weight during the trial (25.3 kg with liraglutide vs 23.3 kg with placebo) than those who didn’t have such events (23.0 kg and 20.6 kg, respectively). Weight loss of 1 kg in the trial was associated with an approximately 4% increased risk for a gallbladder- or biliary tract–related event.
In addition to weight loss, another potential mechanism might be an inhibitory effect on gallbladder motility, which can lead to sludge and gallstone formation and has been described as a contributing factor to the development of gallstones with other medications such as the somatostatin analog octreotide, the researchers point out.
Moreover, they write, “in other studies of populations with diabetes, the reported prevalence of gallstones, at 18%, was much higher than reported here for LEADER.”
“While these findings are convincing, other studies of GLP-1 receptor agonists haven’t looked closely at this, so more research is needed to truly understand how high the risk is,” Pilla said.
In the meantime, he advised, “It will be important to counsel patients about this potential risk, and consider choosing a different diabetes medication in patients who have a high risk of gallbladder disease, or in whom developing this complication could be more serious such as people who are frail or have multiple serious health conditions. That being said, it’s difficult to determine who may be at high risk of gallbladder disease, so there’s not a lot that can be done preventively.”
The study was sponsored by Novo Nordisk. Nauck has reported receiving fees for serving on advisory boards from AstraZeneca, Berlin-Chemie, Eli Lilly, Fractyl, Hanmi, MSD, Novo Nordisk, and Intarcia Therapeutics/Servier; lecture fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Medscape, MSD, and Novo Nordisk; travel support from Berlin-Chemie, Eli Lilly, MSD, Novo Nordisk, and Intarcia Therapeutics/Servier; and grant support (to his institution) from AstraZeneca, Eli Lilly, GlaxoSmithKline, Intarcia Therapeutics/Servier, MSD, Novartis, and Novo Nordisk. Pilla has reported no relevant financial relationships.
Diabetes Care. Published online August 9, 2019. Abstract