The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

Gotfredsen, Carsten F.; Mølck, Anne‐Marie; Thorup, Inger; Nyborg, Niels C. Berg; Salanti, Zaki; Knudsen, Lotte Bjerre; Larsen, Marianne O.

doi:10.2337/db13-1087

Cited by 52 publications

(61 citation statements)

References 48 publications

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“…Other long-term animal studies did not find a harmful effect of incretin-mimetic drugs on pancreatic tissue [164,165]. Furthermore, analyses from adverse reporting systems are useful, but are difficult to control for confounding factors that increase the risk of pancreatitis and cancer, such as obesity, alcohol consumption, smoking, and the use of other drugs.…”

Section: Cancermentioning

confidence: 99%

Adverse Effects of GLP-1 Receptor Agonists

2014

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■ AbstractGlucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.

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Section: Cancermentioning

confidence: 99%

Adverse Effects of GLP-1 Receptor Agonists

2014

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“…Despite lack of evidence for GLP-1R expression in acinar cells of the rodent pancreas, several preclinical studies have demonstrated that GLP-1R agonists increase the mass of the pancreas, predominantly in mice (7,8) and in a subset of male nonhuman primates (9). Nevertheless, the increase in pancreatic weight following treatment with GLP-1R agonists has not been associated with histological abnormalities in the pancreas (3,9,10), and mechanistic explanations for changes in pancreatic mass have not been forthcoming.…”

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confidence: 99%

“…Nevertheless, the increase in pancreatic weight following treatment with GLP-1R agonists has not been associated with histological abnormalities in the pancreas (3,9,10), and mechanistic explanations for changes in pancreatic mass have not been forthcoming. We show here that exendin-4 (Ex-4) and liraglutide increase pancreatic weight via induction of protein synthesis, without changes in acinar cell proliferation or DNA content.…”

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confidence: 99%

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

et al. 2014

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Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R–dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R–dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

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“…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.…”

Section: Discussionmentioning

confidence: 95%

“…One study of liraglutide administered to NHP at supraphysiological doses for 87 weeks did not report any pancreatic structural changes (Nyborg et al 2012). An additional report described a 52-week NHP study of liraglutide and 13-and 52-week NHP studies of semaglutide (a structurally different GLP-1 receptor agonist) and did not report any histopathologic alterations of the exocrine pancreas (Gotfredsen et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect that dulaglutide, an approved GLP-1 receptor agonist, has on the exocrine pancreas. Dulaglutide 8.15 mg/kg (approximately 500 times the maximum recommended human dose based on plasma exposure) was administered twice weekly for 12 months to cynomolgus monkeys. Serum amylase and lipase activities were measured and 6 sections of each pancreas were examined microscopically. Ductal epithelial cell proliferation was estimated using Ki67 labeling. Dulaglutide administration did not alter serum amylase or lipase activities measured at the end of treatment compared to control values. An extensive histologic evaluation of the pancreas revealed no changes in the acinar or endocrine portions and no evidence of pancreatitis, necrosis, or pancreatic intraepithelial neoplasia. An increase in goblet cells noted in 4 of the 19 treated monkeys was considered an effect of dulaglutide but was not associated with dilation, blockage, or accumulation of mucin in the pancreatic duct. There was no difference in cell proliferation in ductal epithelium between control and dulaglutide-treated monkeys. These data reveal that chronic dosing of nondiabetic primates with dulaglutide does not induce inflammatory or preneoplastic changes in exocrine pancreas.

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The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

Cited by 52 publications

References 48 publications

Adverse Effects of GLP-1 Receptor Agonists

Adverse Effects of GLP-1 Receptor Agonists

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

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

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