Incretin-Based Diabetes Drugs Linked to Bile Duct, Gallbladder Disease

Two population-based studies conducted by McGill University in Canada have found no association between incretin-based drugs for type-2 diabetes (T2D) and the development of acute pancreatitis, but these medications were shown to increase the risk of bile duct and gallbladder disease. The findings were published in JAMA Internal Medicine.

“The totality of the evidence accumulated to date suggests that incretin-based drugs are effective and generally safe,” said lead investigator Dr. Laurent Azoulay. “Nonetheless, it’s important that clinicians and patients alike be well informed about possible adverse effects. As a result of the gallbladder finding, it would be prudent for doctors to warn their patients to seek treatment if they experience symptoms, such as pain in their right side.”

Incretin-based drugs are popular treatments for patients with T2D because of their efficacy without causing hypoglycemia (a problem with other classes of diabetes medications), and for having beneficial effects on body weight. While these medications have been prescribed to millions of patients during the decade that they have been on the market, their safety profile has been controversial.

There are two types of incretin-based drugs: one blocks the dipeptidyl peptidase-4 (DPP-4) enzyme and is taken orally; the other is a glucagon-like peptide-1 (GLP-1) analogue and is an injectable. Neither type was found to be associated with acute pancreatitis in patients with T2D.

“Early signal-detection studies suggested that an association might exist. The suspicion was credible because these drugs act directly on the pancreas, and there was a concern that they could be responsible for inflammation,” Azoulay explained. “However, ours was the largest study ever to address the question––involving a cohort of more than 1.5 million patients––and there is no evidence to support that either type of incretin-based drug causes acute pancreatitis.”

The bile duct and gallbladder study was the first population-based investigation to look at the possibility of an association with incretin-based drugs. In this case, GLP-1 analogues were found to be associated with a 79% increased risk. In other words, nearly three more patients per 1,000 exhibited symptoms compared with those not taking an incretin-based medication. Gallstones were the most common adverse effect of treatment. At their most severe, they can lead to surgical removal of the gallbladder.

“Clinical trials are the gold standard to assess whether medications are effective, but because of their relatively small sample sizes and short durations of follow-up, they are not designed to assess the risk of uncommon but clinically important adverse events,” Azoulay said. “This is where well-designed studies conducted in the real-world setting can provide critical information on the safety of medications.”

Sources: McGill University (link is external); August 1, 2016; and JAMA Internal Medicine (link is external); August 1, 2016.

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