Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study

Jonghe, Sandra De; Johnson, Mark D.; Mamidi, Rao N. V. S.; Vinken, Petra; Feyen, Bianca; Lammens, G; Proctor, Jim

doi:10.1016/j.cbi.2017.09.008

Cited by 6 publications

(6 citation statements)

References 10 publications

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“…A previous study [80,81] indicated that canagliflozin increased the risk of developing renal tubule tumors, pheochromocytomas and testicular Leydig cell tumors in rats. The mechanism may be related to the inhibition of intestinal carbohydrate absorption, the increase in calcium excretion in renal tubules and the synthesis of luteinizing hormone induced by canagliflozin.…”

Section: Safety Evaluation Of Sglt2imentioning

confidence: 99%

SGLT2i: beyond the glucose-lowering effect

Yuan

Chen

et al. 2020

Cardiovasc Diabetol

144

115

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Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a new type of glucose-lowering drug that can reduce blood glucose by inhibiting its reabsorption in proximal tubules and by promoting urinary glucose excretion. SGLT2i are widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). In recent studies, SGLT2i were found to not only reduce blood glucose but also protect the heart and kidney, which can significantly reduce cardiovascular events, delay the progression of renal failure, greatly improve the quality of life of patients, and reduce medical expenses for families and society. As adverse cardiac and renal events are the most common and serious complications of T2DM, it is very important to understand the cardio- and renoprotective mechanisms of SGLT2i. This article reviews the historical development, pharmacological mechanism, heart and kidney protection and safety of SGLT2i. The information presented provides a theoretical basis for the clinical prevention and treatment of diabetes and its complications and for the development of new glucose-lowering drugs.

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Section: Safety Evaluation Of Sglt2imentioning

confidence: 99%

SGLT2i: beyond the glucose-lowering effect

Yuan

Chen

et al. 2020

Cardiovasc Diabetol

144

115

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“…showed increased incidence of pheochromocytomas and renal tubular tumors, while testicular Leydig cell tumors were observed also with doses 10 and 30 mg/kg [138]. However, further study revealed that these tumors were secondary to malabsorption of glucose, and were not due to a direct effect of canagliflozin [139]. Moreover, the highest dose of canagliflozin was over 20-fold higher than it is used in clinical practice.…”

Section: Sodium-glucose Cotransporter-2 Inhibitorsmentioning

confidence: 92%

Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

Dąbrowski

2021

IJMS

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In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions—with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.

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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 . Interestingly, SGLT expression has been demonstrated in many carcinomas, and specifically, SGLT2 was detected in pancreatic, prostatic tumours and in glioblastoma suggesting SGLT2is as a novel antitumour therapy .…”

Section: Introductionmentioning

confidence: 99%

“…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. 27,28 Therefore, further studies should be performed to clarify the exact risk benefit of SGLT2 inhibition.…”

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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Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study

Cited by 6 publications

References 10 publications

SGLT2i: beyond the glucose-lowering effect

SGLT2i: beyond the glucose-lowering effect

Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

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

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