Effects of Dulaglutide on Thyroid C Cells and Serum Calcitonin in Male Monkeys

Vahle, John L.; Byrd, Richard A.; Blackbourne, Jamie L.; Martin, Jennifer A.; Sorden, Steven D.; Ryan, Thomas E.; Pienkowski, Thomaş P.; Wijsman, John A.; Smith, Holly W.; Rosol, Thomas J.

doi:10.1210/en.2014-1717

Cited by 13 publications

(10 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dulaglutide was assessed in nonhuman primates in a companion study (17) to the 52-week rat study reported here and no effects on thyroid C cells were detected based on quantitative assessment of C-cell mass, provocative testing for serum calcitonin, and systematic histological examination. Likewise, studies in dogs with lixisenatide have not shown effects on thyroid C cells.…”

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents

et al. 2015

Self Cite

View full text Add to dashboard Cite

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.

show abstract

Section: Discussionmentioning

confidence: 95%

“…The end points evaluated included basal and CaCl 2 -stimulated plasma calcitonin concentrations, thyroid weight parameters, histopathology, and morphometric evaluations of the thyroid. This 52-week rat study was conducted in parallel with another 52-week study in nonhuman primates that included extensive evaluation of thyroid C cells (17).…”

mentioning

confidence: 99%

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast to the results in rodents, in vivo animal studies with cynomologus monkeys did not show any liraglutideinduced calcitonin release or any effect on relative C-cell fraction in the thyroid gland after 87 weeks at doses up to 60-fold higher than the highest dose recommended in humans [169]. Another study in monkeys also showed that dulaglutide at doses amounting to the 500-fold maximum human plasma exposure for 52 weeks were not associated with increases in serum calcitonin or alterations in thyroid weight, histology, C-cell proliferation, or absolute/relative C-cell volume [171].…”

Section: Cancermentioning

confidence: 97%

Adverse Effects of GLP-1 Receptor Agonists

2014

View full text Add to dashboard Cite

■ 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.

show abstract

“…Regulatory concerns surrounding the risk of thyroid C-cell hyperplasia and medullary thyroid carcinoma (MTC) were based entirely on data from mice and rats, which express the canonical GLP-1R on thyroid C cells, linked to stimulation of calcitonin secretion and C-cell proliferation (66,67). In contrast, it is difficult to detect GLP-1R expression within primate thyroid C cells (67), and sustained GLP-1R agonism does not induce C-cell hyperplasia in monkeys (67,68). Indeed, associated reports of GLP-1R expression within the normal and neoplastic human thyroid (69) reflected the use of nonspecific, incompletely validated GLP-1R antisera not suitable for detection of the GLP-1R (32,51).…”

Section: Adverse Events Associated With Glp-1r Agonistsmentioning

confidence: 99%

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Drucker

2018

Diabetes

View full text Add to dashboard Cite

Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. We discuss the controversies, unanswered questions, and established use of GLP-1R agonists from a mechanistic and clinical perspective. We highlight methods for detection and cellular sites of GLP-1R expression, key uncertainties, recent insights, and experimental caveats surrounding the use of GLP-1R agonists for the treatment of diabetes and the reduction of diabetes-related complications.

show abstract

Effects of Dulaglutide on Thyroid C Cells and Serum Calcitonin in Male Monkeys

Cited by 13 publications

References 26 publications

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents

Adverse Effects of GLP-1 Receptor Agonists

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Contact Info

Product

Resources

About