Occurrence of spontaneous pancreatic lesions in normal and diabetic rats: a potential confounding factor in the nonclinical assessment of GLP-1-based therapies.
Glucagon-like peptide 1-based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk of pancreatitis and pancreatic cancer with incretins based in part on findings from a small number of rodents. However, extensive toxicology assessments in a substantial number of animals dosed up to 2 years at high multiples of human exposure do not support these concerns. We hypothesized that the lesions being attributed to incretins are commonly observed background findings and endeavored to characterize the incidence of spontaneous pancreatic lesions in three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats, and rats expressing human islet amyloid polypeptide [HIP]; n = 36/group) on a normal or high-fat diet over 4 months. Pancreatic findings in all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations in large pancreatic ducts similar to those described in the literature, with an incidence of exocrine atrophy/inflammation seen in S-D (42-72%), HIP (39%), and ZDF (6%) rats. These data indicate that the pancreatic findings attributed to incretins are common background findings, observed without drug treatment and independent of diet or glycemic status, suggesting a need to exercise caution when interpreting the relevance of some recent reports regarding human safety.
Drug Safety Evaluation, Bristol-Myers Squibb, New Brunswick, NJ.
Kristina D
KD
Chadwick
Anthony M
AM
Fletcher
M Cecilia
MC
Parrula
Susan
S
Bonner-Weir
Raja S
RS
Mangipudy
Evan
E
Janovitz
Michael J
MJ
Graziano
Denis
D
Roy
Timothy P
TP
Reilly
D000818:Animals; D003920:Diabetes Mellitus / Q000503:physiopathology; D059305:Diet, High-Fat; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000627:therapeutic use*; D054795:Incretins / Q000009:adverse effects; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D010182:Pancreatic Diseases / Q000209:etiology*; D010195:Pancreatitis / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015430:Weight Gain
D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D052216:Glucagon-Like Peptide 1