A systematic review of acute pancreatitis as an adverse event of type 2 diabetes drugs: from hard facts to a balanced position

Giorda CB, Nada E, Tartaglino B, Marafetti L, Gnavi R. A systematic review of acute pancreatitis as an adverse event of type 2 diabetes drugs: from hard facts to a balanced position. Diabetes Obes Metab. 2014;16:1041-1047.

The incidence of acute pancreatitis is higher among people with type 2 diabetes. Prior to the availabilty of incretins for type 2 diabetes treatment, a retrospective cohort study estimated the risk of acute pancreatitis as 2.8 times higher in people with type 2 diabetes than in those without diabetes. The risk increases to 5 times higher in people under age 45. 

This review examines the current evidence for an association between type 2 diabetes therapies and an increased risk of pancreatitis to aid healthcare practitioners weight the risk versus benefits of diabetes medications. Several case reports suggest a possible association between metformin and acute pancreatits in patients with renal insufficiency. However, there is no report of acute pancreatitis at appropriate doses in patients with normal renal function. 

Sulfonylureas have been implicated in causing acute pancreatitis:
  • A 4-year cohort study of 85,525 subjects found a significantly higher risk in sulfonylurea users (entire class; odds ratio 2.58, 1.34–4.96)
  • A population-based case-control study of 1.4 million subjects in Sweden found that use of glyburide had a crude odds ratio of 3.2 [95% confidence interal, 1.5–5.9]
No association was found for SGLT2 inhibitors, glinides, alpha-glucosidase inhibitors, or pramlintide. Thiazolidinediones may decrease the severity of acute pancreatitis.

Claims for an increased relative risk for acute pancreatitis of up to 30-fold with the use of incretin-based therapies has raised concerns about their safety in the treatment of type 2 diabetes. Reports of hemorrhagic or necrotizing pancreatitis in patients taking exenatide in 2008, and acute pancreatitis in patients taking sitagliptin form 2006 through 2009 prompted a revision of the package inserts for these agents.

A 2011 study of the FDA’s database of adverse events associated with sitagliptin and exentatide demonstrated a six-fold increase in the odds ratio for reported pancreatitis as compared with other therapies. However, this study was based on self-reported, non-standarized events and the results may have been influenced by the FDA warnings.
In the drug development program and clinical trials of both DPP-4 inhibitors and GLP-1 receptor agonists, the incidence of pancreatitis was never higher than that see in placebo cohorts. Seven of eight pharmacoepidemilogic observational studies were based on claims from US insurance databases (See slide). Despite the case reports, a clear-cut pharmacoepidemiologic relationship between incretin-based therapies and a higher risk of pancreatic damage has never been demonstrated. 

Two large randomized controlled trials on cardiovascual safety also did not show evidence of an increase in pancreatitis with use of DPP-4 inhibitors
  • In SAVOR TIMI, the incidence of pancreatitis with saxagliptin was 0.3% versus 0.2% for placebo
  • In EXAMINE, the incidence of pancreatitis with alogliptin was 0.4% versus 0.3% for placebo group
If a link between use of incretin-base therapies and acute pancreatitis does exist, it is not as strong as previously suggested. Because the studies only evaluated severe pancreatitis, an association with mild pancreatitis leading to progressive organ damage cannot be ruled out.

All slides available for download in the Slide Library. 

Related content: 

For more on pancreatitis & type 2 diabetes, click here 


Any pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. 

November 2014 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

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