Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for New Anti-Diabetic Agent

Nomura, Sumihiro

doi:10.2174/156802610790980567

Cited by 20 publications

(14 citation statements)

References 39 publications

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“…The 50 % inhibitory concentration (IC 50 ) values ranged from 2.2 to 4.4 nM for SGLT2 while they were 684-910 nM for SGLT1 [7,8], thus giving selectivity ratios of 160-410 for SGLT2 compared with SGLT1. The corresponding selectivity ratio was approximately 1200 for dapagliflozin [9] and approximately 2600 for empagliflozin [10].…”

Section: In Vitro Pharmacologymentioning

confidence: 99%

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Devineni

Polidori

2015

Clin Pharmacokinet

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The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RTG throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RTG is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen.

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Section: In Vitro Pharmacologymentioning

confidence: 99%

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Devineni

Polidori

2015

Clin Pharmacokinet

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“…SGLT2 is located in the S1 segment and accounts for 90% of the glucose reabsorption from the kidneys [44][45][46][47]. Na + absorption across the cell membrane creates an energy gradient that in turn allows the absorption of glucose.…”

Section: Discussionmentioning

confidence: 99%

Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice

Baaij

Millar

Gault

et al. 2019

Nephron

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Background: Inhibition of the Na⁺/glucose co-transporter 2 is a new therapeutic strategy for diabetes. It is unclear how proximal loss of Na⁺ (and glucose) affects the subsequent Na⁺ transporters in the proximal tubule (PT), thick ascending limb of loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD). Methods: Mice on a high fat diet were administered 3 doses streptozotocin 6 days prior to oral dapagliflozin administration or vehicle for 18 days. A control group of lean mice were also included. Body weight and glucose were recorded at regular intervals during treatment. Renal Na⁺ transporters expression in nephron segments were analyzed by RT-qPCR and Western blot. Results: Dapagliflozin treatment resulted in a significant reduction in body weight and blood glucose compared to vehicle-treated controls. mRNA results showed that Na⁺-hydrogen antiporter 3 (NHE3), Na⁺/phosphate cotransporter (NaPi-2a) and epithelial Na⁺ channel expression was increased, Ncx1, ENaCβ and ENaCγ expression declined (p all < 0.05), respectively, in dapagliflozin-treated mice when compared with saline vehicle mice. Na-K-2Cl cotransporters and Na-Cl cotransporter mRNA expression was not affected by dapagliflozin treatment. Na⁺/K⁺-ATPase (Atp1b1) expression was also increased significantly by dapagliflozin treatment, but it did not affect Atp1a1 and glucose transporter 2 expression. Western blot analysis showed that NaPi-2a, NHE3 and ATP1b1 expression was upregulated in dapagliflozin-treated diabetic mice when compared with saline vehicle mice (p < 0.05). Conclusion: Our findings suggest that dapagliflozin treatment augments compensatory changes in the renal PT in diabetic mice.

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“…Specifi cally, SGLT2 is known to reabsorb nearly all fi ltered glucose load at its location in the early proximal tubule, independent of insulin [23,34] . Inhibition of this cotransporter results in increased urinary glucose excretion and may prove to be an important addition to glucose management in diabetic patients [34][35][36].…”

Section: Type 2 Diabetes and Kidney Diseasementioning

confidence: 99%

Natural History and Diagnosis of Diabetic Kidney Disease

Karl

Sharma

2012

Diabetes and Kidney Disease

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Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for New Anti-Diabetic Agent

Cited by 20 publications

References 39 publications

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice

Natural History and Diagnosis of Diabetic Kidney Disease

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