Tubular Injury Causing Protracted Glycosuria Following Withdrawal of a Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor: A Possible Role in the Development of Protracted Hypoglycemia and Ketoacidosis

ObjectiveTo investigate the change of chronic diabetic macular oedema (DMO) in vitrectomised eyes when the administration of sodium–glucose cotransporter 2 (SGLT2) inhibitors is initiated as a systemic medical treatment.Methods and analysisThis study involved 10 eyes of five patients with chronic DMO lasting more than 6 months who had previously undergone vitrectomy and whose systemic medical treatments were newly changed to SGLT2 inhibitors. In this study, chronic DMO was defined as persistent diffuse macular oedema despite ophthalmic treatment in patients with diabetes. Patients who received antivascular endothelial growth factor therapy or steroids administration, or change of eye-drop medication from at 3 months before and after the initiation of SGLT2 inhibitors, were excluded. In this study, visual acuity (VA) and central retinal thickness (CRT, μm) prior to and at 3, 6 and 12 months after the initiation of SGLT2 inhibitors were retrospectively compared. The Wilcoxon signed-rank test was used for statistical analysis.ResultsIn the 10 treated eyes, from at baseline to at 3, 6 and 12 months after the initiation of SGLT2 inhibitor, median VA (logMAR) improved from 0.35 to 0.15 (p=0.038), 0.2 (p=0.157) and 0.2 (p=0.096), respectively, and median CRT significantly reduced from 500.5 µm to 410 µm (p<0.01), 378 µm (p<0.01) and 339 µm (p<0.01), respectively.ConclusionAlthough this study involved only five patients, our findings indicate that SGLT2 inhibitors might have structural efficacy for chronic DMO in vitrectomised eyes.

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Enhanced Expression and Function of Renal SGLT2 (Sodium-Glucose Cotransporter 2) in Heart Failure: Role of Renal Nerves

Circulation Heart Failure ◽

10.1161/circheartfailure.121.008365 ◽

2021 ◽

Author(s):

Kenichi Katsurada ◽

Shyam S. Nandi ◽

Neeru M. Sharma ◽

Kaushik P. Patel

Keyword(s):

Heart Failure ◽

Clinical Studies ◽

Sglt2 Inhibitor ◽

Renal Nerves ◽

Coronary Artery Ligation ◽

Functional Responses ◽

Sodium Glucose Cotransporter ◽

And Function ◽

Renal Sympathetic

Background: Recent clinical studies demonstrate that SGLT2 (sodium-glucose cotransporter 2) inhibitors ameliorate heart failure (HF). The present study was conducted to assess the expression and function of renal SGLT2 and the influence of enhanced renal sympathetic tone in HF. Methods: Four weeks after coronary artery ligation surgery to induce HF, surgical bilateral renal denervation (RDN) was performed in rats. Four groups of rats (Sham-operated control [Sham], Sham+RDN, HF and HF+RDN; n=6/group) were used. Immunohistochemistry and Western blot analysis were performed to evaluate the renal SGLT2 expression. One week after RDN (5 weeks after induction of HF), intravenous injection of SGLT2 inhibitor dapagliflozin were performed to assess renal excretory responses. In vitro, human embryonic kidney cells were used to investigate the fractionation of SGLT2 after norepinephrine treatment. Results: In rats with HF, (1) SGLT2 expression in the proximal tubule of the kidney was increased; (2) the response of increases in urine flow, sodium excretion, and glucose excretion to dapagliflozin were greater; and (3) RDN attenuated renal SGLT2 expression and normalized renal functional responses to dapagliflozin. In vitro, norepinephrine promoted translocation of SGLT2 to the cell membrane. Conclusions: These results indicate that the enhanced tonic renal sympathetic nerve activation in HF increases the expression and functional activity of renal SGLT2. Potentiated trafficking of SGLT2 to cell surface in renal proximal tubules mediated by norepinephrine may contribute to this functional activation of SGLT2 in HF. These findings provide critical insight into the underlying mechanisms for the beneficial effects of SGLT2 inhibitors on HF reported in the clinical studies.

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Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice

Therapeutic Advances in Chronic Disease ◽

10.1177/2040622320974833 ◽

2020 ◽

Vol 11 ◽

pp. 204062232097483

Author(s):

Qing-Qing Zhang ◽

Guo-Qing Li ◽

Yi Zhong ◽

Jie Wang ◽

An-Ning Wang ◽

...

Keyword(s):

Myocardial Dysfunction ◽

Sglt2 Inhibitor ◽

Heart Tissue ◽

Left Ventricular ◽

Tissue Samples ◽

Beneficial Effects ◽

Reduced Body ◽

Sodium Glucose Cotransporter ◽

And Function ◽

Visceral Adipose

Background: Chronic exposure to excess glucocorticoids is frequently associated with a specific cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has beneficial effects as it aids in the reduction of heart failure and cardiovascular mortality in hospitalized patients. The aim of this study was to investigate the effects of empagliflozin on chronic hypercortisolism-induced myocardial fibrosis and myocardial dysfunction in mice. Methods: Male C57BL/6J mice (6 weeks old) were randomized to control, corticosterone (CORT), and empagliflozin + CORT groups. After 4 weeks of administration, heart structure and function were evaluated by echocardiography, and peripheral blood and tissue samples were collected. Expressions of Ccl2, Itgax, Mrc1, and Adgre1 mRNA in heart tissue were evaluated by RT-PCR, and signal transducer and activator of transcription 3 (STAT3) and Toll-like receptor 4 (TLR4) protein expression were analyzed by Western blotting. Results: Empagliflozin effectively reduced body weight, liver triglyceride, visceral adipose volume, and uric acid in CORT-treated mice. Left ventricular hypertrophy and cardiac dysfunction were improved significantly, phosphorylated STAT3 and TLR4 were alleviated, and macrophage infiltration in the myocardium was inhibited after administration of empagliflozin in CORT-treated mice. Conclusion: Empagliflozin has beneficial effects on specific cardiomyopathy associated with CORT, and the results provide new evidence that empagliflozin might be a potential drug for the prevention of this disease.

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Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-020-0516-9 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Akinobu Nakamura ◽

Hideaki Miyoshi ◽

Hiraku Kameda ◽

Kumiko Yamashita ◽

Yoshio Kurihara

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Creatinine Ratio ◽

Sodium Glucose Cotransporter ◽

Clinical Records

Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria. Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018

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How should we monitor the cardiovascular benefit of sodium–glucose cotransporter 2 inhibition?

Cardiovascular Diabetology ◽

10.1186/s12933-020-01191-5 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Atsushi Tanaka ◽

Koichi Node

Keyword(s):

Sglt2 Inhibitor ◽

Cardiovascular Outcomes ◽

Sglt2 Inhibitors ◽

Inhibitor Therapy ◽

Cardiovascular Outcome ◽

Cardiovascular Outcome Trials ◽

Amino Terminal ◽

Sodium Glucose Cotransporter ◽

Diabetes Status ◽

Cardiovascular Benefit

AbstractSodium–glucose cotransporter 2 (SGLT2) inhibitors are increasingly prescribed for the treatment of patients with type 2 diabetes to reduce the risk of cardiovascular events, including heart failure (HF). The mechanisms by which SGLT2 inhibitors reduce such risk are likely to be independent of diabetes status and improvement of glycemic control. In this commentary, based on recent mediation analyses of cardiovascular outcome trials with SGLT2 inhibitors, we discuss the prognostic role of a well-known HF-related biomarker, amino-terminal pro-B-type natriuretic peptide (NT-proBNP), in patients receiving SGLT2 inhibitors. Interestingly, the NT-proBNP concentration had a relatively small impact on the SGLT2 inhibitor-associated benefit on HF events, suggesting a limited value in measuring NT-proBNP concentrations to monitor effects on cardiovascular outcomes after initiation of SGLT2 inhibitor therapy. Instead, clinical factors, such as body weight and volume status, were prognostic for cardiovascular outcomes. As shown in some biomarker studies, short-term SGLT2 inhibitor treatment significantly improved volume and HF-related health status, despite the absence of a significant change in NT-proBNP concentration. Given the early and continuous risk reduction in HF events seen in the cardiovascular outcome trials with SGLT2 inhibitors, changes in these fundamental clinical parameters after initiation of SGLT2 inhibitor therapy, independent of NT-proBNP, could be more prognostic and could represent key determinants to identify responders or non-responders to SGLT2 inhibitors for cardiovascular outcomes. Thus, this commentary highlights the clinical importance of establishing how clinicians should monitor patients initiating SGLT2 inhibitor therapy to predict the expected cardiovascular benefit. Further detailed investigations and discussion to better understand this ‘‘black box’’ are urgently warranted.

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Severe candidal balanoposthitis on concurrent treatment with secukinumab and the antidiabetic agent empagliflozin (sodium‐glucose cotransporter 2 inhibitor – SGLT2‐inhibitor)

JDDG Journal der Deutschen Dermatologischen Gesellschaft ◽

10.1111/ddg.13807 ◽

2019 ◽

Vol 17 (4) ◽

pp. 456-458

Author(s):

I. Moldenhauer ◽

R.U. Pliquett ◽

B. Kreft ◽

C. Sunderkötter

Keyword(s):

Sglt2 Inhibitor ◽

Antidiabetic Agent ◽

Concurrent Treatment ◽

Sodium Glucose Cotransporter

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P6267Novel direct effects of SGLT2 inhibitor, Canagliflozin, on myocardial redox state in humans

European Heart Journal ◽

10.1093/eurheartj/ehz746.0866 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H Kondo ◽

I Akoumianakis ◽

N Akawi ◽

M Cristina ◽

L Herdman ◽

...

Keyword(s):

Redox State ◽

Ex Vivo ◽

Sglt2 Inhibitor ◽

Underlying Mechanism ◽

Sglt2 Inhibitors ◽

Nadph Oxidases ◽

Glucose Levels ◽

Compound C ◽

Sodium Glucose Cotransporter

Abstract Background Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that control plasma glucose levels by inhibiting reabsorption of glucose in kidney. Recent clinical trials have suggested a class effect of SGLT2 inhibitors in preventing hospitalization due to heart failure. However, the underlying mechanism has not been fully elucidated. Purpose We investigated the direct effect of the SGLT2 inhibitor, Canagliflozin (Cana), on myocardial redox state in humans. Methods The study included 48 patients undergoing cardiac surgery. Fresh myocardial tissues were incubated ex vivo with or without Cana and then used for superoxide quantification and Western immunoblotting. NADPH-oxidases activity was evaluated with NADPH 100μM stimulation, while nitric oxide synthase (NOS) coupling was assessed by using N(ω)-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). A human cardiomyocyte (HCM) cell line was also used for in vitro validation of the effects of Cana on myocardium. Results Ex vivo incubation of myocardium with Cana significantly reduced baseline (A) and NADPH-oxidase-derived O2·− (B) and improved NOS coupling reflected by positive L-NAME delta O2·− values (C). Regulation of NADPH-oxidases activity by Cana was found to result from reduced GTP-activation (D) and consequent membrane translocation (E) of Rac1, a key subunit of NADPH-oxidases. Cana also reduced tetrahydrobiopterin (BH4) oxidation, increasing its bioavailability (F), which is a key mechanism to improve NOS coupling. Incubation with Cana enhanced phosphorylation of AMPK, and the downstream signalling, ACC (not shown). Additional Compound C, which is inhibitor of AMPK, significantly reversed these effects of Cana (A, B, C, D, E, F). These findings were replicated in HCM (not shown). In line with these, Cana increased the ADP/ATP ratio of cytoplasm in HCM, which could provide an upstream mechanism for AMPK activation. Conclusions We demonstrate for the first time in humans, that Cana suppresses myocardial NADPH-oxidases activity and improves NOS coupling through an AMPK-mediated pathway. This could be an underlying mechanism for the cardioprotective effects of SGLT2 inhibitors.

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Renal outcomes with sodium glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, in obese insulin-resistant model

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2018.03.017 ◽

2018 ◽

Vol 1864 (6) ◽

pp. 2021-2033 ◽

Cited By ~ 8

Author(s):

Krit Jaikumkao ◽

Anchalee Pongchaidecha ◽

Nuttawud Chueakula ◽

Laongdao Thongnak ◽

Keerati Wanchai ◽

...

Keyword(s):

Sglt2 Inhibitor ◽

Renal Outcomes ◽

Insulin Resistant ◽

Sodium Glucose Cotransporter

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Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice

Journal of the American Society of Nephrology ◽

10.1681/asn.2018070703 ◽

2019 ◽

Vol 30 (5) ◽

pp. 782-794 ◽

Cited By ~ 6

Author(s):

Kenichi Ishizawa ◽

Qin Wang ◽

Jinping Li ◽

Ning Xu ◽

Yoshikazu Nemoto ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cultured Cells ◽

Sglt2 Inhibitor ◽

Distal Convoluted Tubule ◽

Protective Effects ◽

Human Embryonic Kidney Cells ◽

Sodium Glucose Cotransporter ◽

Tubule Cells ◽

Nacl Cotransporter

BackgroundMechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption via NaCl cotransporter (NCC).MethodsWe used the db/db diabetes mouse model to explore KLHL3′s role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells.ResultsWe observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3S433-P). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3S433-P and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3S433-P levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC’s causal role in KLHL3S433-P and NCC induction.ConclusionsDysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.

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