Cargando…
Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus
INTRODUCTION: Dapagliflozin is a selective inhibitor of the sodium–glucose co-transporter 2 (SGLT2) that increases urinary glucose excretion to reduce hyperglycemia in the treatment of type 2 diabetes mellitus. A robust carcinogenicity risk assessment was undertaken to assess the chronic safety of d...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Healthcare
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065287/ https://www.ncbi.nlm.nih.gov/pubmed/24474422 http://dx.doi.org/10.1007/s13300-014-0053-3 |
_version_ | 1782322055071399936 |
---|---|
author | Reilly, Timothy P. Graziano, Michael J. Janovitz, Evan B. Dorr, Thomas E. Fairchild, Craig Lee, Francis Chen, Jian Wong, Tai Whaley, Jean M. Tirmenstein, Mark |
author_facet | Reilly, Timothy P. Graziano, Michael J. Janovitz, Evan B. Dorr, Thomas E. Fairchild, Craig Lee, Francis Chen, Jian Wong, Tai Whaley, Jean M. Tirmenstein, Mark |
author_sort | Reilly, Timothy P. |
collection | PubMed |
description | INTRODUCTION: Dapagliflozin is a selective inhibitor of the sodium–glucose co-transporter 2 (SGLT2) that increases urinary glucose excretion to reduce hyperglycemia in the treatment of type 2 diabetes mellitus. A robust carcinogenicity risk assessment was undertaken to assess the chronic safety of dapagliflozin and SGLT2 inhibition. METHODS: Genotoxicity potential of dapagliflozin and its metabolites was assessed in silico, in vitro, and in vivo. Dapagliflozin was administered daily by oral gavage to mice, rats, and dogs to evaluate carcinogenicity risks, including the potential for tumor promotion. SGLT2(−/−) mice were observed to evaluate the effects of chronic glucosuria. The effects of dapagliflozin and increased glucose levels on a panel of human bladder transitional cell carcinoma (TCC) cell lines were also evaluated in vitro and in an in vivo xenograft model. RESULTS: Dapagliflozin and its metabolites were not genotoxic. In CD-1 mice and Sprague–Dawley rats treated for up to 2 years at ≥100× human clinical exposures, dapagliflozin showed no differences versus controls for tumor incidence, time to onset for background tumors, or urinary bladder proliferative/preneoplastic lesions. No tumors or preneoplastic lesions were observed in dogs over 1 year at >3,000× the clinical exposure of dapagliflozin or in SGLT2(−/−) mice observed over 15 months. Transcription profiling in Zucker diabetic fatty rats showed that 5-week dapagliflozin treatment did not induce tumor promoter-associated or cell proliferation genes. Increasing concentrations of glucose, dapagliflozin, or its primary metabolite, dapagliflozin 3-O-glucuronide, did not affect in vitro TCC proliferation rates and dapagliflozin did not enhance tumor growth in nude mice heterotopically implanted with human bladder TCC cell lines. CONCLUSION: A multitude of assessments of tumorigenicity risk consistently showed no effects, suggesting that selective SGLT2 inhibition and, specifically, dapagliflozin are predicted to not be associated with increased cancer risk. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13300-014-0053-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4065287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer Healthcare |
record_format | MEDLINE/PubMed |
spelling | pubmed-40652872014-06-25 Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus Reilly, Timothy P. Graziano, Michael J. Janovitz, Evan B. Dorr, Thomas E. Fairchild, Craig Lee, Francis Chen, Jian Wong, Tai Whaley, Jean M. Tirmenstein, Mark Diabetes Ther Original Research INTRODUCTION: Dapagliflozin is a selective inhibitor of the sodium–glucose co-transporter 2 (SGLT2) that increases urinary glucose excretion to reduce hyperglycemia in the treatment of type 2 diabetes mellitus. A robust carcinogenicity risk assessment was undertaken to assess the chronic safety of dapagliflozin and SGLT2 inhibition. METHODS: Genotoxicity potential of dapagliflozin and its metabolites was assessed in silico, in vitro, and in vivo. Dapagliflozin was administered daily by oral gavage to mice, rats, and dogs to evaluate carcinogenicity risks, including the potential for tumor promotion. SGLT2(−/−) mice were observed to evaluate the effects of chronic glucosuria. The effects of dapagliflozin and increased glucose levels on a panel of human bladder transitional cell carcinoma (TCC) cell lines were also evaluated in vitro and in an in vivo xenograft model. RESULTS: Dapagliflozin and its metabolites were not genotoxic. In CD-1 mice and Sprague–Dawley rats treated for up to 2 years at ≥100× human clinical exposures, dapagliflozin showed no differences versus controls for tumor incidence, time to onset for background tumors, or urinary bladder proliferative/preneoplastic lesions. No tumors or preneoplastic lesions were observed in dogs over 1 year at >3,000× the clinical exposure of dapagliflozin or in SGLT2(−/−) mice observed over 15 months. Transcription profiling in Zucker diabetic fatty rats showed that 5-week dapagliflozin treatment did not induce tumor promoter-associated or cell proliferation genes. Increasing concentrations of glucose, dapagliflozin, or its primary metabolite, dapagliflozin 3-O-glucuronide, did not affect in vitro TCC proliferation rates and dapagliflozin did not enhance tumor growth in nude mice heterotopically implanted with human bladder TCC cell lines. CONCLUSION: A multitude of assessments of tumorigenicity risk consistently showed no effects, suggesting that selective SGLT2 inhibition and, specifically, dapagliflozin are predicted to not be associated with increased cancer risk. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13300-014-0053-3) contains supplementary material, which is available to authorized users. Springer Healthcare 2014-01-29 2014-06 /pmc/articles/PMC4065287/ /pubmed/24474422 http://dx.doi.org/10.1007/s13300-014-0053-3 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Research Reilly, Timothy P. Graziano, Michael J. Janovitz, Evan B. Dorr, Thomas E. Fairchild, Craig Lee, Francis Chen, Jian Wong, Tai Whaley, Jean M. Tirmenstein, Mark Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus |
title | Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus |
title_full | Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus |
title_fullStr | Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus |
title_full_unstemmed | Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus |
title_short | Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium–Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus |
title_sort | carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium–glucose co-transporter 2, in the treatment of type 2 diabetes mellitus |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065287/ https://www.ncbi.nlm.nih.gov/pubmed/24474422 http://dx.doi.org/10.1007/s13300-014-0053-3 |
work_keys_str_mv | AT reillytimothyp carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT grazianomichaelj carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT janovitzevanb carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT dorrthomase carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT fairchildcraig carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT leefrancis carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT chenjian carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT wongtai carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT whaleyjeanm carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus AT tirmensteinmark carcinogenicityriskassessmentsupportsthechronicsafetyofdapagliflozinaninhibitorofsodiumglucosecotransporter2inthetreatmentoftype2diabetesmellitus |