Clinics and Research in Hepatology and Gastroenterology (2015) 39, e37—e38

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LETTER TO THE EDITOR Pancreatitis in incretin-based therapies To the Editor We report four cases of pancreatitis associated with exposure to the DPP-4 inhibitors sitagliptin (patient 1) and vidagliptin (patient 2) and the GLP-1 agonist liraglutide (patients 3 and 4). Table 1 summarizes demographic and clinical characteristics. Patients 1, 2 and 4 progressed to chronic pancreatitis even though the offending medications were immediately withdrawn on admission; patient 3 had an acute self-limiting pancreatitis with no relapse over a long-term follow-up after liraglutide was interrupted. Pancreatitis was an early or late event in our series. Patient 3 had pancreatitis less than one month since the start of liraglutide whereas the other three patients had pancreatitis between three and five months after treatment was initiated. This suggests that

Table 1

the duration of exposure to incretin-based therapies could not predict by itself the risk of pancreatitis. A past history of gallstones and cholecystectomy was reported by patient 1 while gallstones and sludge were disclosed in patients 3 and 4. None of them had clinical or imaging evidence of cholecystitis nor dilated intra- and extra-hepatic biliary ducts, which rules out the passage of stones or sludge as the cause of pancreatitis. We did not perform re-challenge tests, i.e. the gold-standard for the diagnosis of drug-induced pancreatitis, for both ethical and safety reasons. However, the lack of any personal or family history of acute or chronic pancreatic disorders, the careful exclusion of other causes of pancreatitis such as alcohol use, toxic habits, hypertriglyceridemia, hypercalcemia, renal failure, autoimmunity, and viral infections, and scoring on the Naranjo scale [1] indicate in all patients a causal relationship between pancreatitis and exposure to incretin-based therapies. Three patients were taking other drugs with a known although weak potential to induce pancreatitis (metformin

Demographic and clinical characteristics of patients. Age/sex

Clinical course


Other drugs



Patient 1



Sitagliptin 100 mg

Metformin, bisoprolol

Hypertension, cholecystectomy

Patient 2



Vidagliptin 100 mg

Hypertension, ischemic heart disease, stroke

Patient 3



Liraglutide 1.2 mg

Amiodarone, losartan, furosemide,repaglinide, carvedilol, atorvastatin, warfarin, Metformin, gliclazide

Patient 4



Liraglutide 1.6 mg

Metformin, glibenclamide, omeprazole, ramipril

Gallbladder stone, reflux acid disease, Barrett’s esophagus, hypertension, paroxysmal supra ventricular tachycardia, bladder cancer

Asymptomatic at 3 months, with mildly elevated pancreatic enzymes Asymptomatic at 2 months, with mildly elevated pancreatic enzymes No relapse at one year Asymptomatic at three months, mildly elevated blood lipase, normal amylase 2210-7401/© 2014 Elsevier Masson SAS. All rights reserved.

Biliary sludge

e38 in patients 1, 3 and 4, amiodarone, losartan and furosemide in patient 2, and ramipril in patient 4) [2], however the longterm use and no recent change in dosage argue against the involvement of these drugs in the pathogenesis of pancreatitis in our cases. Analyses of data from experimental studies and clinical trials provide no compelling evidence of an increased risk of pancreatitis among patients treated with GLP-1 agonists and DPP-4 inhibitors [3] in contrast with observational postmarketing surveys that indicate a small risk of pancreatitis associated with incretin-based therapies [4—6]. However, findings of observational studies are often confounded by methodological shortcomings, limited statistical power, and the presence of other co-morbidities and risk factors for pancreatitis. One important point is that both the U.S. Food and Drug Administration and the European Medicines Agency continue to consider pancreatitis a potential risk associated with these drugs [7]. We do not know if incretin-based therapies may exert an enhancing effect on or share common pathways mechanistically linked with the pathogenesis of pancreatitis. It is also unclear if the slowed gastric and gallbladder emptying could be implicated in the pathogenesis of pancreatitis at least in cases associated with GLP-1 agonists such as liraglutide [8,9]. Accumulation of toxic metabolites, hypersensitivity or idiosyncratic reactions are a very unlikely mechanism. The magnitude of the beneficial effect of incretin-based therapies on achieving a better metabolic control with very low rates of hypoglycemia and no weight gain is probably much greater than the risk of acute or chronic pancreatitis. However, clinicians should be aware of this potential adverse effect and adopt a prudent approach in subjects with one or more risk factors for pancreatitis. We advise against prescribing incretin-based therapies to patients with gallstones or sludge or other underlying biliary and pancreatic disorders. The long-term outcome of patients progressing to chronic pancreatitis is unknown.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

Letter to the editor

References [1] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30, 239-45.1. [2] Nitsche C, Maertin S, Scheiber J, et al. Drug-induced pancreatitis. Curr Gastroenterol Rep 2012;14:131—8. [3] Giorda CB, Nada E, Tartaglino B, et al. 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—7. [4] Singh S, Chang HY, Richards TM, et al. Glucagon-like peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case — control study. JAMA Intern Med 2013;173: 534—9. [5] Dore DD, Hussein M, Hoffman C, et al. A pooled analysis of exenatide use and risk of acute pancreatitis. Curr Med Res Opin 2013;29:1577—86. [6] Faillie JL, Babai S, Crépin S, et al. Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database. Acta Diabetol 2014;51:491—7. [7] Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs. FDA and EMA assessment. N Engl J Med 2014;370:794—7. [8] Marathe CS, Rayner CK, Jones KL, et al. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes Care 2013;36:1396—400. [9] Keller J, Trautmann ME, Haber H, et al. Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects. Regul Pept 2012;179:77—83.

Giuseppe Famularo a,∗ Lelio Morviducci b Laura Gasbarrone a a Department of Internal Medicine, San Camillo Hospital, Rome, Italy b Diabetology Unit, San Camillo Hospital, Rome, Italy ∗ Corresponding author. Department of Internal Medicine, San Camillo Hospital, Circonvallazione Gianicolense, 00152 Rome, Italy. Tel.: +0039 6 58704283; fax: +0039 6 58704609. E-mail address: [email protected] (G. Famularo) Available online 5 January 2015

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