A study in a rat initiation-promotion bladder tumour model demonstrated no promoter/progressor potential of dapagliflozin

Billger, Martin; Kirk, Jason; Chang, Jane; Bédard, Agathe; Attalla, Bassem; Hailé, Solomon; Söderberg, Magnus

doi:10.1016/j.yrtph.2019.01.031

Cited by 8 publications

(10 citation statements)

References 11 publications

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“…However, the DECLARE–TIMI 58 study, which included more than 17 000 patients, reported a lower incidence rate of bladder cancer with dapagliflozin treatment compared with placebo (n = 26 and n = 45, respectively; HR, 0.57; 95% CI, 0.35‐0.93; P = .02) . Furthermore, in a well‐established validated animal model of bladder cancer, dapagliflozin, which was administered at seven times the clinical exposure at the maximum therapeutic dose, did not promote or progress bladder cancer …”

Section: Safety Considerationsmentioning

confidence: 99%

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Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Chilton

2019

Diabetes Obesity Metabolism

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Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT‐2i therapy. The observed improvements in CV and renal outcomes with SGLT‐2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add‐on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT‐2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti‐inflammatory and renal effects.

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Section: Safety Considerationsmentioning

confidence: 99%

“…5 Furthermore, in a well-established validated animal model of bladder cancer, dapagliflozin, which was administered at seven times the clinical exposure at the maximum therapeutic dose, did not promote or progress bladder cancer. 118…”

Section: Microvascular Effectsmentioning

confidence: 99%

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Chilton

2019

Diabetes Obesity Metabolism

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“…К разряду в определенном смысле позитивных можно отнести и недавние наблюдения in vivo, в которых другой ингибитор SGLT2 дапаглифлозин назначался крысам на 8-34-й неделях после того, как эти животные в течение предыдущих 6 нед получали канцероген из группы нитрозаминов; выяснилось, что под влиянием дапаглифлозина не отмечается инициации/промоции опухолевого роста в мочевом пузыре, что ослабляет, как полагают авторы исследования [17], некоторые опасения, приписывавшиеся этому классу антидиабетических препаратов ранее.…”

Section: экспериментальные исследования онкологической направленностиunclassified

Is cancer incidence modified by SGLT2 inhibitors?

Berstein¹

2019

Diabetes mellitus

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ОнкОлОгическая забОлеваемОсть пО данным клинических испытаний ингибитОрОв SGLT2Проведение исходных клинических испытаний ингибиторов натрий-глюкозных котранспортеров оказалось сверхполезным не только для диабетологии как таковой, но и дало очень много в отношении того, чего мОдифицируется ли ОнкОлОгическая забОлеваемОсть пОд влиянием ингибитОрОв SGLT2?Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова, Санкт-Петербург Одним из ярких достижений диабетологии во втором десятилетии XXI в., несомненно, является внедрение в клиническую практику ингибиторов натрий-глюкозных котранспортеров (SGLT2) в качестве нового класса сахароснижающих препаратов при сахарном диабете 2 типа (СД2). Наряду с глюкозурией, индуцируемой этими средствами и рассматриваемой в качестве основного варианта достижения антидиабетического эффекта, прием ингибиторов SGLT2 сопровождается и некоторыми иными последствиями, часть из которых -в частности, в области онкологии -пока (в противоположность другим) исследованы недостаточно. В результате анализа доступных публикаций настоящее сообщение позволяет прийти к заключению о том, что онкологическая заболеваемость у больных СД2, лечившихся ингибиторами SGLT2, существенно не меняясь, может характеризоваться определенной органоспецифичностью, а с другой, стороны, препараты этого класса могут оказаться полезными и при различных вариантах противоопухолевой терапии, что нуждается в дальнейшем изучении.One of the most important achievements of diabetology in the second decade of the 21st century is undoubtedly the introduction into clinical practice of sodium-glucose cotransporter inhibitors (SGLT2) as a new class of glucose-lowering treatments for type 2 diabetes. Along with the glucosuria induced by these agents and regarded in this case as the main pathway for achieving an 'antidiabetic recovery' , the intake of SGLT2 inhibitors is accompanied by some other consequences, several of which, in particular, in the field of oncology, have not been extensively studied. As a result of the analysis of the available publications, this report allows us to conclude that cancer morbidity in patients with T2DM treated with SGLT2 inhibitors, although not changing significantly, may be characterized by a certain organ-specificity, and, on the other hand, preparations of this class -as can be supposed -may be useful in various variants of antitumor therapy, which needs further study.

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“…Contrary to other SGLT2is such as canagliflozin (CANA) and dapagliflozin (DAPA), EMPA is associated with UC significantly as demonstrated by both meta‐analysis and experimental studies . CANA may even protect against certain (gastrointestinal, GI) cancers, yet it had been implicated in other tumours that may be secondary to glucose malabsorption .…”

Section: Introductionmentioning

confidence: 99%

“…22 Contrary to other SGLT2is such as canagliflozin (CANA) and dapagliflozin (DAPA), EMPA is associated with UC significantly as demonstrated by both meta-analysis and experimental studies. 10,23,24 CANA may even protect against certain (gastrointestinal, GI) cancers, 10 yet it had been implicated in other tumours that may be secondary to glucose malabsorption. 25 Interestingly, SGLT expression has been demonstrated in many carcinomas, and specifically, SGLT2 was detected in pancreatic, prostatic tumours 26 and in glioblastoma suggesting SGLT2is as a novel antitumour therapy.…”

Section: Introductionmentioning

confidence: 99%

Dysplastic urothelial changes accompany empagliflozin administration in urinary bladder of experimental diabetes

Abdel-Hamid

Firgany

2019

Int J Experimental Path

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Summary Empagliflozin (EMPA) is a promising novel antidiabetic drug; however, doubts have been raised regarding its use and the increased risk of urinary bladder carcinoma. In this study, we evaluated urothelium expression of cytokeratins (CKs) and Ki‐67 proliferative activity in the urinary bladder of diabetic (DM + EMPA) and non‐diabetic rats after EMPA administration. By routine histology, dysplastic changes were detected in the urothelium of diabetic as well as non‐diabetic animals after EMPA administration. Moreover, the expression of CK‐7 and CK‐8 was significantly decreased (P < .05) while that of CK‐20 as well as Ki‐67 was significantly increased (P < .05) in EMPA per se and DM + EMPA urothelium groups compared to that of control and diabetics. The dysplastic changes together with the increased proliferative activity in urothelium after EMPA administration provide a cellular evidence that supports the former clinical concerns.

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A study in a rat initiation-promotion bladder tumour model demonstrated no promoter/progressor potential of dapagliflozin

Cited by 8 publications

References 11 publications

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Is cancer incidence modified by SGLT2 inhibitors?

Dysplastic urothelial changes accompany empagliflozin administration in urinary bladder of experimental diabetes

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