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Increased Risk of Pancreatitis with Liraglutide?

There have been many conclusions drawn about the relationship between liraglutide and pancreatitis…

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In 2007, the U.S. Food and Drug Administration issued an update to the exenatide twice daily label to include a warning for acute pancreatitis based on six acute pancreatitis cases in patients receiving the drug during clinical trials. Similar observations have been made with liraglutide. Since its initial approval in 2009, mixed conclusions have been drawn in publications related to liraglutide and pancreatitis.

Researchers pooled all the pancreatitis cases from intermediate and long term (phase 2 and 3), Novo Nordisk-sponsored, randomized clinical trials with liraglutide complete by April 19, 2014. A Cochran-Mantel-Haenszel test was performed to estimate the relative risk of acute pancreatitis in the pooled liraglutide group versus the two different active comparator groups (total active comparator group glimepiride, rosiglitazone, insulin glargine, sitagliptin, and exenatide; active comparator group: glimepiride, rosiglitazone, and insulin glargine only).

A total of 9,016 patients were included in the study. Acute pancreatitis was present in eight patients receiving liraglutide (0.13% of liraglutide-treated patients), with six of the patients receiving 1.8 mg of liraglutide and two patients receiving 1.2 mg of liraglutide. There was only one case of pancreatitis within the comparator group, with a patient receiving glimepiride (0.05% of all active comparator-treated patients). There were no cases reported with any of the other comparator drugs. The reporting rate for acute pancreatitis was 1.6 cases/1,000 patient-years exposure (PYE) for liraglutide vs. 0.7 cases/1,000 PYE for total active comparators and 0.9 cases/1,000 PYE for comparators excluding sitagliptin and exenatide. The relative risk with liraglutide versus total active comparators was 2.1 (95%) and 1.7 (95% CI) versus the active comparator group excluding sitagliptin and exenatide.

Chronic pancreatitis was recorded in four patients receiving liraglutide (0.06% of liraglutide-treated patients), with three receiving liraglutide 1.8 mg and one receiving 0.6 mg of liraglutide. There were no cases of chronic pancreatitis in patients receiving comparator drugs.

In conclusion, the incidence of reported acute pancreatitis was numerically greater with liraglutide than with comparators (1.6 cases/1,000 PYE in the liraglutide group, 0.7 cases/1,000 PYE in the total active comparator group, and 0.9 cases/1,000 PYE in the active comparator group excluding sitagliptin and exenatide). Previous studies in type 2 diabetes patients reported an incidence of acute pancreatitis of 0.5-5.6 events/1,000 PYE. A trend toward an increase in the relative risk of acute pancreatitis was seen in the liraglutide group versus the active comparator groups (2.1[95% CI 0.3, 16.0], P = 0.4478 vs. all active comparators; 1.7 [0.2, 13.2], P = 0.6241 vs. active comparators excluding sitagliptin and exenatide), although this trend was based on very few cases. The CIs for the relative risk were wide, showing an imprecise estimate of risk and low power to detect a difference in the incidence of acute pancreatitis between groups. Therefore, the results of these analyses should be considered as preliminary and inconclusive.

Practice Pearls:

  • Liraglutide has been shown to cause more cases of chronic pancreatitis opposed to other drugs.
  • Clinicians should pay special attention to patients prescribed liraglutide and perform the necessary lab work to be proactive in preventing acute and chronic pancreatic events.

Jensen TM, Saha K, Steinberg W. Is There a Link Between Liraglutide and Pancreatitis? A Post Hoc Review of Pooled and Patient-Level Data From Completed Liraglutide Type 2 Diabetes Clinical Trials. Diabetes Care. June 2015. 38(6)1058-66.