Representatives of the companies Bristol-Myers Squibb, Novo Nordisk, Sanofi, Merck, Novartis, Boehringer Ingelheim and Takeda were contacted with the request to provide the event numbers of acute pancreatitis with the respective drug and non-incretin comparators as well as the corresponding number of patient-years of exposure (PYOs) for the approved GLP-1 receptor agonists exenatide twice daily, exenatide weekly, liraglutide and lixisenatide, as well as the DPP-4 inhibitors sitagliptin, saxagliptin, vildagliptin, alogliptin and linagliptin. These data had already been published for vildagliptin and were therefore derived from the original manuscript. Takeda did not wish to disclose these data, because they intended to publish data on the risk of pancreatitis with alogliptin separately. All other companies responded to our request and provided the data. However, no information on patient characteristics or laboratory variables, particularly amylase and lipase concentrations, could be obtained for further analyses. Because the results of the underlying studies were not always available as published manuscripts, it was also not possible to derive more details on these variables from the published literature.
Because pancreatitis was not further specified in the cases of saxagliptin and vildagliptin, no distinction could be made between acute and chronic pancreatitis in this analysis. In the other cases, only events of acute pancreatitis were analysed. All reported adverse events categorised as acute pancreatitis were included, irrespective of whether or not adjudication had been performed. All other incretin-based medications were excluded from the comparator group. Only in the case of liraglutide did the comparator medications include sitagliptin and exenatide. However, no cases of pancreatitis had occurred with these comparator treatments.
All the data were primarily derived from the phase III clinical trial programmes. Because prospective endpoint studies comprising large patient populations had just been published for saxagliptin (The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus [SAVOR]–Thrombolysis in Myocardial Infarction [TIMI] 53 trial [SAVOR-TIMI 53]; NCT01107886) and alogliptin (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care [EXAMINE]; NCT00968708), the respective incidence numbers of acute pancreatitis that were reported from these trials were also included in a broader analysis [7, 8]. In the case of alogliptin, the exact exposure time was not reported in the manuscript. Therefore, exposure was estimated by multiplying the patient number by the median duration of exposure. With saxagliptin, only events adjudicated as definite and possible pancreatitis were available from the final SAVOR-TIMI 53 manuscript.
Data were pooled for the GLP-1 receptor agonists and DPP-4 inhibitors in comparison with the respective control groups (including placebo and non-incretin drugs) and expressed as exposure-adjusted incidence rates.
Events of reported pancreatitis and exposure (patient years) to either incretin-based drugs (GLP-1 receptor agonists or DPP-4 inhibitors) or non-incretin-based comparator drugs/placebo were compared using contingency table analysis, calculating the ORs, 95% CIs and p values for the comparison, using GraphPad Prism version 5.02 for Windows (GraphPad Software, San Diego, CA, USA; www.graphpad.com). This was done for each compound and for events within each drug class (either GLP-1 receptor agonists or DPP-4 inhibitors). In addition, a meta-analysis was performed comparing pancreatitis events and exposure (patient-years) using Comprehensive Meta-Analysis version 2.2.064 (Englewood, NJ, USA), calculating the rate ratios and their 95% CIs, and the p value or difference.