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Liraglutide and Acute Pancreatitis in Patients With Type 2 Diabetes

Study focuses on elevation of amylase and lipase levels as predictors of pancreatitis.

This study was done to evaluate serum amylase and lipase levels, and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5-5.0 years.  A total of 9,340 patients with type 2 diabetes were randomized to either liraglutide or placebo (median observation time 3.84 years). Fasting serum lipase and amylase were monitored. Acute pancreatitis was adjudicated in a blinded manner.

The results showed that, compared with the placebo group, liraglutide-treated patients had increases in serum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 6 months and then remained stable. During the study, 18 liraglutide-treated and 23 placebo patients had acute pancreatitis confirmed by adjudication. Most acute pancreatitis cases occurred ≥12 months after randomization. Liraglutide-treated patients with prior history of pancreatitis (n = 147) were not more likely to develop acute pancreatitis than similar patients in the placebo group (n = 120). Elevations of amylase and lipase levels did not predict future risk of acute pancreatitis (positive predictive value <1.0%) in patients treated with liraglutide.

The current studies are very important contributors to our understanding of the relationship between GLP-1 receptor agonists and the risk of acute pancreatitis. This study describes a large cohort of patients treated with liraglutide vs placebo, demonstrating that although amylase and/or lipase levels elevate in patients treated with liraglutide in a dose-dependent manner, the risk of acute pancreatitis is not elevated.

These are important and very practical results for several reasons. For one, they exonerate liraglutide as a cause of acute pancreatitis and make the very important point that serial measurement of amylase and/or lipase while taking this medication is unwarranted. Second, because of the very robust findings demonstrating a lack of causation of this particular GLP-1 receptor agonist, the findings suggest that perhaps these results can be applied to the entire class of GLP-I agonists. In fact, you might expect that as more cohort studies are performed specifically investigating the association between GLP-1 agonists and acute pancreatitis, similar results will be reported for other agents in this class. And finally, these findings support the epidemiological data that acute pancreatitis in this population is rare and when it does occur, it is most likely caused by biliary disease.

Subsequently, analyses of pooled data from shorter phase III clinical trials of GLP-1 receptor agonists have noted an association with 38 cases of acute pancreatitis among 17,775 patient-years of observation (PYO) (event rate 2.1/1,000 PYO) compared with 9 cases after 5,863 PYO (event rate 1.5/1,000 PYO). For DPP-4 inhibitors, though meta-analysis of shorter regulatory trials failed to show an association with pancreatitis, meta-analysis of the longer cardiovascular outcomes trials does suggest a small increased risk. Due to the previous results and the lack of long-term data, pancreatitis continues to be of interest in studies of GLP-1 receptor agonists, particularly in studies where long-term safety data can be collected. Furthermore, serial amylase and lipase measurements have been suggested to predict the development of acute pancreatitis.

So in conclusion, in a population with type 2 diabetes at high cardiovascular risk, there were numerically fewer events of acute pancreatitis among liraglutide-treated patients (regardless of previous history of pancreatitis) compared with the placebo group. Liraglutide was associated with increases in serum lipase and amylase, which were not predictive of an event of subsequent acute pancreatitis.

Practice Pearls:

  • Acute pancreatitis occurred in 0.4% and 0.5% of the liraglutide and placebo groups.
  • The incidence of acute pancreatitis in patients with type 2 diabetes was lower among patients treated with liraglutide than among those randomized to placebo.
  • Regardless of a previous history of pancreatitis, whereas serum levels of amylase and lipase were increased for type 2 patients treated with liraglutide, incidence of acute pancreatitis in patients with type 2 diabetes was lower.

Diabetes Care; 2017 May 05; EPub Ahead of Print; WM Steinberg, JB Buse, MLM Ghorbani, et al.