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

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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Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report

BMC Pharmacology and Toxicology ◽

10.1186/s40360-019-0381-z ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Miho Nakamura ◽

Junya Nakade ◽

Tadashi Toyama ◽

Masaki Okajima ◽

Takumi Taniguchi

Keyword(s):

Renal Function ◽

Blood Glucose ◽

Blood Glucose Level ◽

Glucose Level ◽

Sglt2 Inhibitor ◽

Severe Hypoglycemia ◽

Olmesartan Medoxomil ◽

Sglt2 Inhibitors ◽

Glucose Levels ◽

Sodium Glucose Cotransporter

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors inhibit SGLT2, which is expressed in the proximal renal tubule, and thus reduce blood glucose levels by enabling the urinary excretion of excess glucose. SGLT2 inhibitors have been reported to suppress the complications of diabetes and reduce overall mortality. However, little is known about the types of symptoms that may occur in response to an overdose of an SGLT2 inhibitor. Here, we describe a case of intoxication caused by an overdose of an SGLT2 inhibitor. Case presentation An otherwise physically healthy adult woman ingested an overdose of ipragliflozin, an SGLT2 inhibitor, and a polypill of olmesartan medoxomil, and azelnidipine in a suicide attempt. Although her blood ipragliflozin concentration was very high (9516.3 ng/mL) upon hospital arrival, her initial blood glucose level was normal, and she did not exhibit symptoms such as hypoglycemia or polyuria. Moderate renal dysfunction associated with an estimated glomerular filtration rate of 42.3 mL/min/1.73 m2 was observed. Thirty-six hours after ingestion, her blood ipragliflozin concentration decreased to a level equivalent to that observed after a therapeutic dose and her renal function improved almost simultaneously. After improvement in her renal function, the osmotic diuretic effect of the drug progressed. Her blood glucose level declined slightly but was in the normal range due to glucose administration. During the clinical course, fatal hypoglycemia was not observed. Conclusions Our case showed that an overdose of an SGLT2 inhibitor caused toxic effects on renal function, but severe hypoglycemia was not observed. Additional cases of intoxication from SGLT2 inhibitors alone would be helpful to clarify the mechanism of intoxication.

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SGLT2 inhibitors: a narrative review of efficacy and safety

Journal of Osteopathic Medicine ◽

10.1515/jom-2020-0153 ◽

2021 ◽

Vol 121 (2) ◽

pp. 229-239

Author(s):

Donald S. Nelinson ◽

Jose M. Sosa ◽

Robert J. Chilton

Keyword(s):

Adverse Events ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Narrative Review ◽

Atherosclerotic Cardiovascular Disease ◽

Comorbid Conditions ◽

Postprandial Plasma Glucose ◽

Renal Outcomes ◽

Glucose Levels ◽

Wide Range

Abstract Type 2 diabetes mellitus (T2DM) is a cardio-renal-metabolic condition that is frequently associated with multiple comorbidities, including atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD). The sodium-glucose co-transporter-2 (SGLT2) inhibitors, which lower glycated hemoglobin, fasting and postprandial plasma glucose levels, body weight, and blood pressure, as well as reduce the risk of a range of cardiovascular and renal outcomes without increasing hypoglycaemic risk, have heralded a paradigm shift in the management of T2DM. These drugs are compatible with most other glucose-lowering agents and can be used in patients with a wide range of comorbid conditions, including ASCVD, HF, and CKD, and in those with estimated glomerular filtration rates as low as 30 mL/min/1.73 m2. However, there are misunderstandings surrounding the clinical implications of SGLT2 inhibitors’ mechanism of action and concerns about the key adverse events with which this class of drugs has been associated. This narrative review summarizes the data that support the efficacy of SGLT2 inhibitors in reducing the risks of cardiovascular and renal outcomes in patients with T2DM and comorbid conditions and clarifies information relating to SGLT2 inhibitor-related adverse events.

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The Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors for the treatment of chronic diabetic macular oedema in vitrectomised eyes: a retrospective study

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2017-000130 ◽

2018 ◽

Vol 3 (1) ◽

pp. e000130 ◽

Cited By ~ 4

Author(s):

Hiroki Mieno ◽

Kazuhito Yoneda ◽

Masahiro Yamazaki ◽

Ryosuke Sakai ◽

Chie Sotozono ◽

...

Keyword(s):

Macular Oedema ◽

Sglt2 Inhibitor ◽

Diabetic Macular Oedema ◽

Sglt2 Inhibitors ◽

Rank Test ◽

Sodium Glucose Cotransporter ◽

Signed Rank ◽

Before And After ◽

Patients With Diabetes ◽

Signed Rank Test

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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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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miR-23a-3p is a Key Regulator of IL-17C-Induced Tumor Angiogenesis in Colorectal Cancer

Cells ◽

10.3390/cells9061363 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1363 ◽

Cited By ~ 2

Author(s):

Yunna Lee ◽

Su Jin Kim ◽

Jieun Choo ◽

Gwangbeom Heo ◽

Jin-Wook Yoo ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Tumor Angiogenesis ◽

Ex Vivo ◽

Underlying Mechanism ◽

Vegf Receptor ◽

Invasion And Migration ◽

Novel Target ◽

And Migration

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy.

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Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00203.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. E27-E36 ◽

Cited By ~ 16

Author(s):

Servane Le Plénier ◽

Arthur Goron ◽

Athanassia Sotiropoulos ◽

Eliane Archambault ◽

Chantal Guihenneuc ◽

...

Keyword(s):

Protein Synthesis ◽

Ex Vivo ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Fold Increase ◽

Underlying Mechanism ◽

Muscle Homeostasis

Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated ( P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass control.

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Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

International Journal of Molecular Sciences ◽

10.3390/ijms22189852 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9852

Author(s):

Alex Ali Sayour ◽

Mihály Ruppert ◽

Attila Oláh ◽

Kálmán Benke ◽

Bálint András Barta ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Large Scale ◽

Sglt2 Inhibitor ◽

Basic Research ◽

Additional Benefit ◽

Sglt2 Inhibitors ◽

Preclinical Studies ◽

Sodium Glucose Cotransporter

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

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Multicentre prospective observational study of sodium-glucose cotransporter-2 inhibitor-associated postoperative ketoacidosis: the SAPKA study protocol

BMJ Open ◽

10.1136/bmjopen-2021-049592 ◽

2021 ◽

Vol 11 (11) ◽

pp. e049592

Author(s):

Hiroyuki Seki ◽

Norifumi Kuratani ◽

Toshiya Shiga ◽

Yudai Iwasaki ◽

Kanae Karita ◽

...

Keyword(s):

Observational Study ◽

General Anaesthesia ◽

Study Protocol ◽

Prospective Observational Study ◽

Surgical Stress ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Sodium Glucose Cotransporter ◽

Urinary Glucose ◽

Tract Infections

IntroductionSodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antihyperglycaemic agents that promote urinary glucose excretion in the renal proximal tubule and have cardio-protective and renal-protective properties. However, there are several safety concerns related to increased risks of hypoglycaemic, urinary tract infections and ketoacidosis. Ketoacidosis is a potentially fatal complication that often presents as euglycaemic ketoacidosis during SGLT2 inhibitor treatment. Furthermore, invasive treatment and related surgical stress may increase the risk of ketogenesis. Therefore, this study aims to clarify the incidence of SGLT2 inhibitor-associated postoperative ketoacidosis (SAPKA) among patients who are receiving SGLT2 inhibitors and undergoing surgery under general anaesthesia.Methods and analysisThis multicentre, prospective, observational study will recruit 750 adult Japanese patients with diabetes who are receiving SGLT2 inhibitors and undergoing surgery under general anaesthesia. Urine samples will be collected on postoperative days 0, 1, 2 and 3. Blood gas analysis will be performed when urine ketone positivity is detected. The incidence of postoperative ketoacidosis will be identified based on urine ketone positivity and a blood pH of ≤7.3. The study will also collect data to identify risk factors for SAPKA.Ethics and disseminationThe study protocol has been approved by the ethics committee of Kyorin University (approval number: 785, 26 October 2020) and local ethical approval will be required at each participating centre. Study findings will be submitted to peer-reviewed journals and abstracts will be submitted to relevant national and international meetings.Trial registration numberUMIN000042795

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