PracticeUpdate Diabetes March 2019

EDITOR’S PICKS 12

Incretin-Based Drugs and Risk of Cholangiocarcinoma Among Patients With Type 2 Diabetes British Medical Journal Take-home message • The GLP-1 incretin hormone has been shown to have proliferative and anti-apoptotic effects on cholangiocytes, which raises the possibility that the incretin-based DPP-4 inhibitors and GLP-1 receptor agonists could increase the risk of cholangiocarci- noma. The authors of this population-based cohort study sought to determine whether DPP-4 inhibitors and GLP-1 receptor agonists were associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes. Study partic- ipants were 154,162 adults newly treated with antidiabetic drugs from March 2007 to March 2017 and followed until March 2018. During 614,274 person-years of follow-up, 105 incident cholangiocarcinoma events were observed. Use of DPP-4 inhibitors was associated with a near doubling of the risk of cholangiocarcinoma. A similar association was observed with GLP-1 receptor agonists but was not statistically significant. • Incretin-based drugs may be associated with an increased risk of cholangiocarci- noma in people with type 2 diabetes. Michael Allen MD

COMMENT By Michael Nauck MD

I ncretin-based glucose-lowering medications now are widely used. DPP-4 inhibitors are – broadly speaking – safe (includ- ing cardiovascular safety) and almost free from a class-specific profile of clinical adverse events. GLP-1 receptor agonists have the potential to prevent cardiovascular events and premature death. Both classes had been incremented to be associated with acute pancreatitis, but current analyses of large-scale car- diovascular trials attest of their safety in this respect. Now, the current publication reports a signal regarding chol- angiocarcinoma to be associated with a new prescription of DPP-4 inhibitors (significant) and GLP-1 receptor agonists (trend). The overall number of events is small (0.02 % per year), and the difference in DPP-4 inhibitor- and GLP-1 receptor agonist treated patients increased the risk by 0.01% and 0.004% per year. This results in numbers needed to harm of 10,000 and 25,000, respectively. Thus, the results of the present manuscript, even if confirmed, would not impact much on the estimated benefit–risk relationship estimated for either class. Are the results plausible? It may appear difficult to comprehend that a median duration of new use of DPP-4 inhibitors or GLP-1 receptor agonists of less than 2 years will result in clinical cholangiocarcinoma. Recent data, however, confirm an interaction of GLP-1 receptor stimulation with the biliary system: gallbladder disease and bil- iary obstruction was more prevalent with liraglutide treatment in the LEADER trial, 1 and GLP-1 receptor stimulation (the mechanism

common to DPP-4 inhibitors and GLP-1 receptor agonists) results in changes in gallbladder, and perhaps, biliary tract motility. 2 A mechanism has been suggested recently. 3 Based on the small numbers of events, the relatively short duration of follow-up, and lack of details regarding clinical presentation and conse- quences, the current signals need to be viewed as preliminary. They do, however, open our eyes to watch out for this and other rare adverse events that can only be detected with large cohorts followed for prolonged periods of time. References 1. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375(4):311-322. 2. Keller J, Trautmann ME, Haber H, et al. Effect of exenatide on cholecystokinin- induced gallbladder emptying in fasting healthy subjects. Regul Pept 2012;179(1-3):77-83. 3. Rehfeld JF, Knop FK, Asmar A, Madsbad S, Holst JJ, Asmar M. Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs. Scand J Gastroenterol 2018 Nov 19:1-4. doi: 10.1080/00365521.2018.1530297. [Epub ahead of print]

Dr. Nauck is Head of Clinical Research at Diabetes Center Bochum-Hattingen, St. Josef Hospital, Ruhr-University Bochum in Bochum, Germany.

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