Assessment of pancreas safety in the development program of once-weekly GLP-1 receptor agonist dulaglutide

OBJECTIVE: To assess the risk of acute pancreatitis during treatment with glucagon-like peptide 1 receptor agonist dulaglutide, placebo, and active comparators across phase 2/3 dulaglutide trials. RESEARCH DESIGN AND METHODS: A total of 6,005 patients with type 2 diabetes participated (dulaglutide group N = 4,006 [dose range 0.1-3.0 mg]; active comparator group [metformin, sitagliptin, exenatide twice daily, insulin glargine]N= 1,541; placebo groupN= 703; 245 placebotreated patients subsequently received dulaglutide or sitagliptin and were also included in these groups) for up to 104 weeks. The following events were adjudicated: investigator-reported pancreatitis, adverse events (AEs) of severe or serious abdominal pain of unknown etiology, and confirmed asymptomatic increases in pancreatic enzymes ≥3× the upper limit of normal range. RESULTS: Overall, 203 events from 151 patients underwent adjudication (dulaglutide group n = 108; comparator group including placebo n = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide n = 3, placebo n = 1, sitagliptin n = 3). Exposure-adjusted incidence rates were as follows: dulaglutide group 0.85 patients/1,000 patient-years, placebo group 3.52 patients/1,000 patient-years, sitagliptin group 4.71 patients/1,000 patient-years. No events of pancreatitis were confirmed by adjudication in patients treated with exenatide twice daily, metformin, or glargine. Increases in median values of lipase and pancreatic amylase within the normal range were observed with all treatments except glargine. These changes were not associated with AEs. CONCLUSIONS: The exposure-adjusted incidence rate of acute pancreatitis in dulaglutide-treated patients was similar to the rates with placebo, with few reported cases during the entire program.