Is there a link between incretin-based diabetes drugs and pancreatitis? In 2008, the FDA issued a warning, based on its review of 30 postmarketing reports of acute pancreatitis in patients taking exenatide. In 2013, the FDA updated its warning about safety risks to include a preliminary caution about a potential increase in the risk of precancerous cellular changes, although it had not yet reached any conclusions.
Because there are still concerns about safety, but evidence to support a causal relationship is weak, an international team of researchers reviewed randomized and nonrandomized studies in hopes of producing a more rigorous assessment of the risk of pancreatitis. They analyzed data from 60 studies: 55 randomized controlled trials (all industry funded), ranging from 12 to 234 weeks, and involving 33,350 patients; and 5 observational studies with 320,289 patients.
Of the randomized trials, 27 explicitly stated that no events of pancreatitis occurred during the study. Eight studies mentioned pancreatic enzymes, but none reported usable data. Overall, 37 events of pancreatitis occurred in 33,227 patients who used ≥ 1 drug. The risk did not differ by the type of incretin (GLP-1 agonists vs DPP-4 inhibitors).
Four of the 5 observational studies—3 retrospective cohort studies and 1 case-control study—found no evidence to suggest a greater risk of pancreatitis. The fifth, a case-control study of 1,269 patients, reported a greater risk of admission for acute pancreatitis for patients using sitagliptin or exenatide.
However, the risk of pancreatitis was low, the researchers conclude. In randomized trials, similar numbers of patients developed pancreatitis (0.11% in both those taking incretins and in control patients). In cohort studies, the risk of acute pancreatitis was somewhat higher (0.47%), potentially because of a higher incidence of risk factors, such as gallstones and longer follow-up, the researchers say.
These results should be interpreted cautiously, the researchers say. For one, many of the randomized trials had small sample sizes and relatively short follow-up. Moreover, the trials (mostly phase III studies) often recruited patients who had fewer comorbidities than had patients in real-world clinical practice. And finally, because pancreatitis is rare in general, the confidence intervals around relative effects are wide, the researchers say, leaving the possibility of an undetected increase in risk. They note that the trials may have failed to identify patients with subclinical, minimally symptomatic pancreatitis—the increases in pancreatic enzymes may have been signals of something they weren’t able to fully investigate for lack of complete data.
By contrast, the observational studies had larger samples but were limited, in part, because they often used the ICD-9 coding system, which meant diagnosis criteria varied.
On a further note of caution, the researchers cite the FDA adverse drug event system, which has documented 2,327 spontaneously reported cases of pancreatitis in patients taking exenatide, 888 cases in those taking liraglutide, 718 cases in those taking sitagliptin, and 125 in those taking saxagliptin. The number of cases of pancreatitis seemed larger, the researchers say, in patients taking incretins than in those taking other antidiabetic drugs.
In addition to the lack of definitive evidence to support an increased risk of pancreatitis, the researchers note that incretins are not superior to less expensive and already widely used antidiabetic drugs, such as metformin. The benefits of incretins might be outweighed by the uncertainties.
Source
Li L, Shen J, Bala MM, et al. BMJ. 2014;348:g2366.
doi: 10.1136/bmj.g2366.