Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies

Ghosh, Raktim; Bandyopadhyay, Dhrubajyoti; Hajra, Adrija; Biswas, Monodeep; Gupta, Anjan

doi:10.1016/j.ijcard.2016.02.134

Cited by 49 publications

(32 citation statements)

References 55 publications

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“…3 The long-term cardiovascular safety of DAPA is currently being evaluated in an international multicenter trial, DECLARE-TIMI 58. 6 Identification of non-fluid-mediated weight loss, reductions in systolic blood pressure together with reductions in high-sensitivity C-reactive protein (hsCRP) and modest improvements in serum lipid ratio profiles in DAPAtreated patients 7 suggest potential cardiovascular benefits Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis of this agent via either direct SGLT-2 inhibition or novelmolecular mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis

Gaspari

Spizzo

Liu

et al. 2017

Diabetes and Vascular Disease Research

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Background: Sodium glucose transporter type 2 inhibitors may reduce cardiovascular events in type 2 diabetes. Our study aimed to determine the effect of the sodium glucose transporter type 2 inhibitor dapagliflozin on endothelial cell activation, vasoreactivity and atherogenesis using in vitro and in vivo models and identify associated molecular mechanisms. Methods:In vitro studies utilised human vascular endothelial cells stimulated with tumour necrosis factor α or hyperglycaemic conditions. In vivo studies were performed in C57Bl/6J mice to evaluate direct vasorelaxation responses evoked by acute dapagliflozin administration and acute vaso-protective effects of dapagliflozin on hyperglycaemia-induced endothelial dysfunction. Adult and aged Apolipoprotein E-deficient mice maintained on a high-fat diet were used to investigate endothelial-dependent vascular reactivity and atherogenesis. Dapagliflozin treatment (1.0 mg/kg/day) was administered for 4 weeks. Results:In vitro studies demonstrated dapagliflozin-mediated attenuation of tumour necrosis factor α-and hyperglycaemiainduced increases in intercellular adhesion molecule-1, vascular cell adhesion molecule-1, plasminogen activator inhibitor type 1 and NFκB expression. Acute dapagliflozin administration dose-dependently induced endothelium-independent vasorelaxation. Chronic dapagliflozin treatment improved endothelial function and significantly reduced in vivo vascular adhesion molecule and phospho-IκB expression together with macrophage vessel wall infiltration. Conclusion: These observations identify a potential role for dapagliflozin in the attenuation of atherogenesis and identify anti-inflammatory molecular mechanisms associated with these effects.

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Section: Introductionmentioning

confidence: 99%

Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis

Gaspari

Spizzo

Liu

et al. 2017

Diabetes and Vascular Disease Research

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“…However, the underlying mechanism for the benefit of empagliflozin in cardiovascular risk reduction remains to be determined. Interestingly, SGLT2 inhibitors including empagliflozin exert non-glycemic effect in type 2 diabetic patients [11, 21, 24–26] or animal models [16, 17, 19, 39], such as reduction in blood pressure, decrease in body weight, or natriuresis. Therefore, SGLT2 inhibition is proposed to provide cardiovascular protection partially independently of blood glucose control.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome

Kurihara

Koibuchi

Hasegawa

et al. 2016

Cardiovasc Diabetol

123

103

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BackgroundThe potential benefit of SGLT2 inhibitors in metabolic syndrome is with prediabetic stage unclear. This work was undertaken to investigate the non-glycemic effect of empagliflozin on metabolic syndrome rats with prediabetes.MethodsSHR/NDmcr-cp(+/+) rats (SHRcp), a model of metabolic syndrome with prediabetes, were given empagliflozin for 10 weeks to examine the effects on urinary sodium and water balance, visceral and subcutaneous adipocyte, and cardiac injury. Further, the effect of empagliflozin on blood pressure and autonomic nervous system was continuously investigated by using radiotelemetry system.ResultsEmpagliflozin significantly reduced urinary sodium and water balance of SHRcp only within 1 week of the treatment, but later than 1 week did not alter them throughout the treatment. Empagliflozin significantly reduced body weight of SHRcp, which was mainly attributed to the significant reduction of subcutaneous fat mass. Empagliflozin significantly reduced the size of visceral adipocytes and increased the number of smaller size of adipocytes, which was associated with the attenuation of oxidative stress. Empagliflozin ameliorated cardiac hypertrophy and fibrosis of SHRcp, in association with the attenuation of cardiac oxidative stress and inflammation. However, empagliflozin did not significantly change blood pressure, heart rate, sympathetic activity, or baroreceptor function, as evidenced by radiotelemetry analysis.ConclusionsOur present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect. Thus, SGLT2 inhibition seems to be a promising therapeutic strategy for prediabetic metabolic syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0473-7) contains supplementary material, which is available to authorized users.

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“…These compounds have a distinct mechanism of action in the renal proximal tubule, by blocking the reabsorption of glucose. Besides promoting glucosuria, they can exert pleiotropic effects, which could reduce several CV risk factors and potentially CV complications [24,25]. Among these pleiotropic effects, a reduction in arterial BP has been consistently reported with all SGLT2 inhibitors [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Scheen

2016

Diabetes Research and Clinical Practice

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Please cite this article as: A.J. Scheen, Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME, Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres. 2016.09.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummaryEmpagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown a remarkable reduction in cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) and antecedents of cardiovascular disease in the EMPA-REG OUTCOME trial. This effect has been attributed to a hemodynamic rather than a metabolic effect, partly due to the osmotic/diuretic effect of empagliflozin and to the reduction in arterial blood pressure. The present review will : 1) summarize the results of specific studies having tested the blood pressure lowering effects of SGLT2 inhibitors; 2) describe the results of meta-analyses of trials having evaluated the effects on mortality and cardiovascular outcomes of lowering blood pressure in patients with T2D, with a special focus on baseline and target blood pressures; 3) compare the cardiovascular outcome results in EMPA-REG OUTCOME versus other major trials with antihypertensive agents in patients with T2D; and 4) evaluate post-hoc analyses from EMPA-REG OUTCOME, especially subgroups of patients of special interest regarding the blood pressure lowering hypothesis. Although BP reduction associated to empagliflozin therapy may partly contribute to the benefits reported in EMPA-REG OUTCOME, other mechanisms most probably play a greater role in the overall CV protection and reduction in mortality observed in this trial.

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Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies

Cited by 49 publications

References 55 publications

Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis

Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis

Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

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