Assessment of Pancreas Safety in the Development Program of Once-Weekly GLP-1 Receptor Agonist Dulaglutide

• Published in: Diabetes care Vol. 40; no. 5; pp. 647 - 654
• Main Authors: Nauck, Michael A., Frossard, Jean-Louis, Barkin, Jamie S., Anglin, Greg, Hensley, Ingrid E., Harper, Kristine D., Milicevic, Zvonko
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.05.2017
• Subjects: Acute Disease; Adjudication; Amylases; Antidiabetics; Clinical trials; Comparators; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Enzymes; Etiology; Exposure; Female; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptides - adverse effects; Glucagon-Like Peptides - analogs & derivatives; Glucagon-Like Peptides - therapeutic use; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Immunoglobulin Fc Fragments - adverse effects; Immunoglobulin Fc Fragments - therapeutic use; Incidence; Insulin; Insulin Glargine - adverse effects; Insulin Glargine - therapeutic use; Lipase; Male; Medical treatment; Metformin; Metformin - adverse effects; Metformin - therapeutic use; Middle Aged; Pain; Pancreas; Pancreatitis; Pancreatitis - chemically induced; Patients; Peptides; Peptides - adverse effects; Peptides - therapeutic use; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - therapeutic use; Research design; Risk assessment; Sitagliptin Phosphate - adverse effects; Sitagliptin Phosphate - therapeutic use; Venoms - adverse effects; Venoms - therapeutic use
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc16-0984

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. A total of 6,005 patients with type 2 diabetes participated (dulaglutide group = 4,006 [dose range 0.1-3.0 mg]; active comparator group [metformin, sitagliptin, exenatide twice daily, insulin glargine] = 1,541; placebo group = 703; 245 placebo-treated 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. Overall, 203 events from 151 patients underwent adjudication (dulaglutide group = 108; comparator group including placebo = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide = 3, placebo = 1, sitagliptin = 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. 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.