Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis

Abstract

Recent case reports of acute pancreatitis in patients with type 2 diabetes (T2DM) treated with incretin-based therapies have triggered interest regarding the possibility of a mechanism-based association between pancreatitis and glucagon-like peptide-1 mimetics or dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review was to describe the controlled preclinical and clinical trial data regarding the incidence of pancreatitis with sitagliptin, the first DPP-4 inhibitor approved for use in patients with T2DM. Tissue samples from multiple animal species treated with sitagliptin for up to 2 years at plasma exposures substantially in excess of human exposure were evaluated to determine whether any potential gross or histomorphological changes suggestive of pancreatitis occurred. Sections were prepared by routine methods, stained with haematoxylin and eosin and examined microscopically. A pooled analysis of 19 controlled clinical trials, comprising 10,246 patients with T2DM treated for up to 2 years, was performed using patient-level data from each study for the evaluation of clinical and laboratory adverse events. Adverse events were encoded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 system. Incidences of adverse events were adjusted for patient exposure. Tissue samples from preclinical studies in multiple animal species did not reveal any evidence of treatment-related pancreatitis. The pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patient-years vs. 0.10 events per 100 patient-years, respectively). Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin.

Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes

“…In this pooled analysis, in which 82% of patients had cardiovascular risk factors in addition to diabetes and CVD, there was no difference between groups in the evaluation of cardiovascular complications overall, but a trend for a lower incidence of major ischemic events in the sitagliptin-treated group than in the non-exposed group, as already mentioned [63]. Finally, the same pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patientyears vs 0.10 events per 100 patient-years, respectively) [70]. Nevertheless, post-marketing careful check of the incidence of pancreatitis with incretin-based therapies, including sitagliptin, is still recommended.…”

Incidence of Pancreatitis and Pancreatic Cancer in a Randomized Controlled Multicenter Trial (SAVOR-TIMI 53) of the Dipeptidyl Peptidase-4 Inhibitor Saxagliptin

“…These concerns include possible triggers for acute pancreatitis and initiation or acceleration of histological changes, suggesting silent or clinical chronic pancreatitis with preneoplastic lesions and potentially pancreatic cancer (2,3). Although some reports have supported the linkage of type 2 diabetes treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors or GLP-1 receptor agonists and increased risk of pancreatitis (4,5), others have not supported this association (6)(7)(8)(9).…”

Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys

“…In a human autopsy series, use of incretin-based therapies was associated with an increase in whole pancreas cell proliferation and presence of PanIN (Butler et al 2013a); however, a variety of methodological issues, such as differences between the studied groups with respect to age, gender, disease duration, and treatments, limit the ability to interpret this study (Drucker 2013;Kahn 2013;BonnerWeir, In't Veld, and Weir 2014). In contrast to studies suggesting a relationship between incretin therapy and proliferation of the exocrine pancreas, toxicology studies using liraglutide (Nyborg et al 2012;Gotfredsen et al 2014), exenatide (Tatarkiewicz et al 2010), lixisenatide (European Public Assessment Report, Lyxumia [EPAR] 2012), albiglutide (Mirabile, Kambara, and Maier 2013), semaglutide (Gotfredsen et al 2014), and sitagliptin (Engel et al 2010) did not detect proliferative lesions in the pancreas due to treatment nor were pancreatic tumors increased in rodent carcinogenicity studies. These studies included evaluation of pancreatic histology in mice, rats, dogs, and monkeys in toxicology studies that utilized relatively high doses of these agents.…”