The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates
Open accessAbstract
Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks’ duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks’ dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.
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Preclinical studies with semaglutide found no adverse signals in pancreatic tissue.
“Preclinical studies with semaglutide also found no adverse signals in pancreatic tissue (76).”
From Safety of Semaglutide (2021) · cites this paper as [76]
The majority of animal studies did not find any effect of GLP-1RAs on pancreatic physiology, even with doses up to 240 times the normal human dose.
“However, the majority of animal studies did not find any effect of GLP-1RAs on pancreatic physiology, even with doses up to 240 the normal human dose (73–76).”
From Safety of Semaglutide (2021) · cites this paper as [76]
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References 47 · Cited by 60
- Authors
- Gotfredsen, C. F., Mølck, A.-M., Thorup, I., Nyborg, N. C. B., Salanti, Z., Knudsen, L. B., & Larsen, M. O.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- Corresponding author
- Knudsen, Lotte Bjerre
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-06-14
- Volume
- 63
- Issue
- 7
- Pages
- 2486-2497
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2163387116
- Cited by
- 60
- References
- 47
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 10 · 2014: 8
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- liraglutide, semaglutide, GLP-1 receptor agonists, pancreatic histopathology, pancreas weight, sitagliptin, exenatide, non-human primates, Macaca fascicularis, drug safety
- MeSH terms
- Liraglutide, Semaglutide, Animals, Body Weight, Drug Evaluation, Preclinical, Glucagon-Like Peptides, Female, Humans, Hypoglycemic Agents, Macaca fascicularis, Male, Organ Size, Pancreas, Primates, Glucagon-Like Peptide 1
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