Comment on Andersen et al, Pancreatitis–Diabetes–Pancreatic Cancer : Summary of an NIDDK-NCI Workshop

Abstract

To the Editor We have read the summary of the National Cancer Institute/National Institutes of Diabetes and Digestive and Kidney Diseases–sponsored workshop on Pancreatitis, Diabetes, and Pancreatic Cancer held in June 2013, written by Andersen et al,1 with considerable interest. Novo Nordisk was as industry representative invited by the organizers to present the current evidence around pancreatic cancer and type 3c diabetes in the liraglutide development program. We commend the organizers for having organized a conference of high scientific merit and for thoroughly summarizing the proceedings in this article. There are a few statements in the section concerning the Novo Nordisk data that should be clarified. The publication states that the incidence rate of acute pancreatitis in type 2 diabetes is 0.55 to 1.37 cases per 1000 patient-years. As quoted in our presentation, based on work by several authors,2–5 the incidence rate can be estimated to be 0.5 to 5.6 cases per 1000 patient-years, that is, up to 3 times higher than in a population of individuals without diabetes. These estimates place the incidence rate of acute pancreatitis observed in the clinical development program of liraglutide in type 2 diabetes within the range seen in the background type 2 diabetes population.6 Based on available data, Novo Nordisk can neither confirm nor exclude a causal relationship for liraglutide and pancreatitis because of the low number of adjudicated events reported in our trials. The labeling for Victoza (Novo Nordisk A/S, Bagsvaerd, Denmark) includes a warning for pancreatitis and describes the symptoms of this condition to assist clinicians in their decision making. Importantly, based on the totality of information available to Novo Nordisk, there is no evidence that liraglutide increases the risk of pancreas cancer in humans or induces dysplasia or precancerous lesions in animal models. Using a new monoclonal antibody for immunohistochemistry, we detected the GLP-1 receptor (GLP-1R) in the non–human primate pancreas. The GLP-1R was predominantly localized in beta cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R, in agreement with results using in situ ligand binding in samples from pancreatic ductal adenocarcinomas.7 To generate more definite evidence to assess the association between liraglutide administration and pancreatic disease, Novo Nordisk is conducting a large-scale, double-blind cardiovascular outcome study (LEADER; NCT01179048) that will prospectively evaluate the overall safety of liraglutide. The trial has enrolled 9340 patients with type 2 diabetes. Adjudication of all adverse reactions related to pancreatitis and any neoplasm is an integral part of the protocol.8 While Novo Nordisk also is pursuing prospectively designed pharmacovigilance studies,9 randomized, controlled, large, long-duration trials with independent adjudication provide the most objective way to evaluate infrequent adverse effects, as also mentioned by Drucker recently.10 The LEADER study will be reported in 2016. Alan Charles Moses, MD Global Chief Medical Office, Research & Development, Novo Nordisk A/S, Bagsværd Denmark Lotte Bjerre Knudsen, BSc Diabetes Research Unit, Research & Development, Novo Nordisk A/S, Måløv Denmark Claus Bo Svendsen, MD, PhD Global Medical Affairs GLP-1 Diabetes, Novo Nordisk A/S, Denmark [e-mail]