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Diabetes drugs that work via the glucagon-like peptide-1 (GLP-1) pathway may raise the risk of acute pancreatitis, researchers found.

In a case-control study, patients who had used either sitagliptin (Januvia) or exenatide (Byetta) were about twice as likely to be hospitalized with acute pancreatitis as diabetic patients who didn't take them, Sonal Singh, MD, MPH, of Johns Hopkins, and colleagues reported in JAMA Internal Medicine.

"Our results support findings from mechanistic studies and spontaneous reports submitted to the FDA that such an association may be causal," they wrote.

Concerns have already been raised that GLP-1-based therapies may increase the risk of acute pancreatitis, and were most prominently brought to the forefront in an analysis of FDA adverse event data by Peter Butler, MD, of the University of California Los Angeles, published in Gastroenterology.

Singh and colleagues looked at data on diabetic patients from seven Blue Cross Blue Shield (BCBS) plans. They found 1,269 cases in which patients were hospitalized with acute pancreatitis, and matched them with an equal number of diabetic controls.

Cases were more likely to have hypertriglyceridemia, alcohol use, gall stones, tobacco abuse, obesity, biliary and pancreatic cancer, cystic fibrosis, and any neoplasm.

After adjusting for the available confounders and metformin use, Singh and colleagues found that the use of incretin therapies was associated with a higher risk of acute pancreatitis for patients who had used the drugs:

• Within past 30 days (adjusted odds ratio [aOR] 2.24, 95% CI 1.36 to 3.69, P=0.01)
• Within past 2 years (aOR 2.01, 95% CI 1.37 to 3.18, P=0.01)
• Ever (aOR 2.07, 95% CI 1.36 to 3.13, P=0.01)

The findings remained significant in sensitivity analyses:

• Past 30 days: (aOR 2.01, 95% CI 1.19 to 3.38, P=0.01)
• Past 2 years: (aOR 1.95, 95% CI 1.21 to 3.14, P=0.01)
• Any use: (aOR 2.02, 95% CI 1.31 to 3.01, P=0.01)

The study was limited by the potential for residual confounders and in its generalizability in that it can't be applied to older patients over 65.

Still, the researchers called for further studies to clarify the risk of pancreatitis, to determine whether any particular subgroups are especially vulnerable, and to assess any effects on pancreatic cancer risk.

In an accompanying editorial, Butler -- the lead author of the Gastroenterology paper -- and Belinda Gier, PhD, also of the University of California Los Angeles, wrote that the "time has come to move forward and address the wider implications of this finding," given that pancreatitis is a major risk factor for pancreatic cancer.

They noted that incretins are "heavily promoted and prescribed as having purported advantages that outweigh the risks. Singh and colleagues provide a timely reminder that despite large numbers of underpowered studies claiming the contrary from marketing companies, little is yet known about long-term adverse effects of the GLP-1 class of drugs on the exocrine pancreas."

"Unfortunate recent history documents unacceptable delays by regulatory authorities to act on serious adverse effects detected in postmarketing surveillance of drugs for [type 2 diabetes]," they wrote. "We hope history will not repeat itself with the GLP-1 based drugs, because in this case, three times would not be a charm."