Focusing on Sodium Glucose Cotransporter-2 and the Sympathetic Nervous System: Potential Impact in Diabetic Retinopathy

The prevalence of diabetes is at pandemic levels in today’s society. Microvascular complications in organs including the eye are commonly observed in human diabetic subjects. Diabetic retinopathy (DR) is a prominent microvascular complication observed in many diabetics and is particularly debilitating as it may result in impaired or complete vision loss. In addition, DR is extremely costly for the patient and financially impacts the economy as a range of drug-related therapies and laser treatment may be essential. Prevention of microvascular complications is the major treatment goal of current therapeutic approaches; however, these therapies appear insufficient. Presently, sodium glucose cotransporter-2 (SGLT2) inhibitors may offer a novel therapy beyond simple glucose lowering. Excitingly, the EMPA-REG clinical trial, which focuses on the clinically used SGLT2 inhibitor empagliflozin, has been extremely fruitful and has highlighted beneficial cardiovascular and renal outcomes. The effects of SGLT2 inhibitors on DR are currently a topic of much research as outlined in the current review, but future studies are urgently needed to fully gain mechanistic insights. Here, we summarize current evidence and identify gaps that need to be addressed.

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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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How and why SGLT2 inhibitors should be explored as potential treatment option in diabetic retinopathy: clinical concept and methodology

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018819891886 ◽

2019 ◽

Vol 10 ◽

pp. 204201881989188 ◽

Cited By ~ 2

Author(s):

Marcus May ◽

Theodor Framke ◽

Bernd Junker ◽

Carsten Framme ◽

Amelie Pielen* ◽

...

Keyword(s):

Treatment Option ◽

Microvascular Complications ◽

Treatment Options ◽

Sglt2 Inhibitors ◽

Diabetic Microangiopathy ◽

Potential Treatment ◽

Treatment And Prevention ◽

Clinical Complications ◽

Sodium Glucose Cotransporter ◽

Increased Risk

Patients suffering from type 2 diabetes are at an increased risk of developing classical microvascular complications such as retinopathy, neuropathy, and nephropathy, which represent a significant health burden. Tight control of blood glucose, blood pressure, and serum cholesterol reduce the risk of microvascular complications but effective pharmacologically targeted treatment options for the treatment and prevention of diabetic microangiopathy are still lacking. Pharmacological inhibition of sodium glucose cotransporter 2 (SGLT2) might have the potential to directly protect against microvascular complications and could represent a potential treatment option. Randomized controlled clinical proof of concept trials are needed to investigate a potential central role of SGLT2 inhibitors in the prevention of diabetic microangiopathy and its classical clinical complications of retinopathy, neuropathy, and nephropathy.

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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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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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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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New SGLT2 inhibitor ertugliflozin: safe and effective in the management of type 2 diabetes

Medical Council ◽

10.21518/2079-701x-2020-7-32-41 ◽

2020 ◽

pp. 32-41

Author(s):

V. V. Salukho ◽

T. A. Ilyinskay

Keyword(s):

Type 2 Diabetes ◽

Body Mass ◽

Clinical Studies ◽

Sglt2 Inhibitor ◽

Evidence Base ◽

Sglt2 Inhibitors ◽

Adverse Outcomes ◽

Positive Effects ◽

Sodium Glucose Cotransporter

Type 2 diabetes mellitus (T2DM) is closely associated with the risk of developing cardiovascular complications. A new approach to treatment of T2DM, based on the inhibition of the sodium-glucose cotransporter type 2 (SGLT2) ensures reliable insulin-independent glycemic control with quick overcome of glucotoxicity, reduction of insulin resistance, and positive effects on body mass, blood pressure and other rates. Besides, pronounces clinical efficacy of SGLT2 inhibitor is marked by its use safety and minimized frequency of adverse events. Along with this, the results of carried-out, randomized clinical studies of cardiovascular safety of different SGLT2 inhibitors showed, that apart from bearing on the risk factors, the inhibition of sodium-glucose cotransporter type 2 leads to cardioand renoprotective effects. In addition, their influence on cardiovascular and renal outcomes is the stronger the more different the pre-existing status of cardiovascular diseases of the patient is, the condition of his renal function and the severity of albuminuria. This article summarizes the main results of carried-out randomized clinical studies of SGLT2 inhibitors, which demonstrate their cardiovascular advantages and compile encouraging results of multicentered studies VERTIS, examining different aspects of the use of the ertugliflazine SGLT2 inhibitor in patients with type 2 diabetes. There is data provided demonstrating a powerful glucoselowering, body-mass lowering and hypotensive impacts of ertugliflazine comparable to the same performance of the best representatives of the class. This article describes an evidence base of the use of the drug in monotherapy and its ability to be combined with other oral hypoglycemic agentsand highlightes a high level of safety of the use of ertugliflazine correspondinding to minimized frequency of adverse outcomes of SGLT2 inhibition and so the potential of SGLT2 inhibitors as a new promising class for the treatment of patients with type 2 diabetes and established cardiovascular disease is revealed.

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Novel imaging biomarkers in diabetic retinopathy and diabetic macular edema

Therapeutic Advances in Ophthalmology ◽

10.1177/2515841420950513 ◽

2020 ◽

Vol 12 ◽

pp. 251584142095051 ◽

Cited By ~ 2

Author(s):

Ashish Markan ◽

Aniruddha Agarwal ◽

Atul Arora ◽

Krinjeela Bazgain ◽

Vipin Rana ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Macular Edema ◽

Diabetic Macular Edema ◽

Vision Loss ◽

Imaging Modality ◽

Microvascular Complications ◽

Response To Treatment ◽

Fundus Photography ◽

Imaging Biomarkers ◽

Potential Contribution

Diabetic retinopathy is one of the major microvascular complications of diabetes mellitus. The most common causes of vision loss in diabetic retinopathy are diabetic macular edema and proliferative diabetic retinopathy. Recent developments in ocular imaging have played a significant role in early diagnosis and management of these complications. Color fundus photography is an imaging modality, which is helpful for screening patients with diabetic eye disease and monitoring its progression as well as response to treatment. Fundus fluorescein angiography (FFA) is a dye-based invasive test to detect subtle neovascularization, look for areas of capillary non-perfusion, diagnose macular ischemia, and differentiate between focal and diffuse capillary bed leak in cases of macular edema. Recent advances in retinal imaging like the introduction of spectral-domain and swept source-based optical coherence tomography (OCT), fundus autofluorescence (FAF), OCT angiography, and ultrawide field imaging and FFA have helped clinicians in the detection of certain biomarkers that can identify disease at an early stage and predict response to treatment in diabetic macular edema. This article will summarize the role of different imaging biomarkers in characterizing diabetic retinopathy and their potential contribution in its management.

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Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

International Journal of Molecular Sciences ◽

10.3390/ijms22147684 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7684

Author(s):

Anastasios Lymperopoulos ◽

Jordana I. Borges ◽

Natalie Cora ◽

Anastasiya Sizova

Keyword(s):

Blood Glucose ◽

Adrenal Medulla ◽

Blood Glucose Control ◽

Sglt2 Inhibitor ◽

Cardiovascular Effects ◽

Sglt2 Inhibitors ◽

Current Evidence ◽

Western World ◽

Reduced Ejection Fraction ◽

Therapeutic Modalities

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

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