Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study

Shigiyama, Fumika; Kumashiro, Naoki; Miyagi, Masahiko; Ikehara, Kayoko; Kanda, Eiichiro; Uchino, Hiroshi; Hirose, Takahisa

doi:10.1186/s12933-017-0564-0

Cited by 183 publications

(144 citation statements)

References 43 publications

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“…Given the results of large-scale cardiovascular safety studies with the SGLT-2 inhibitor empagliflozin suggest potential cardiovascular benefits 2 together with recent observations of improvements in vascular endothelial function in early-stage type 2 diabetic patients treated with DAPA, 19 our pre-clinical observations identifying DAPAmediated effects on vascular reactivity and endothelial cell activation may portend potential cardiovascular benefits from DAPA treatment. The results of cardiovascular safety studies in the setting of type 2 diabetic patients treated with DAPA 6 will further elucidate the cardiovascular effects of this agent in the clinical arena.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Empagliflozin has been shown to improve endothelial dysfunction in preclinical studies in diabetic rat models, but human data are scarce. A recent 16‐week study demonstrated that dapagliflozin add‐on therapy to metformin improved endothelial function, as evaluated by flow‐mediated dilation, in patients with inadequately controlled early‐stage type 2 diabetes mellitus . Although there are no comparative data from studies that have investigated the effects of SGLT‐2 inhibitors in women with PCOS, the results of our 12‐week intervention contrast those of a longer study which demonstrated that metformin treatment for 6 months improved or even normalized abnormal flow‐mediated dilation on the brachial artery and improved plasma endothelin‐1 levels in women with PCOS .…”

Section: Discussionmentioning

confidence: 56%

“…A recent 16-week study demonstrated that dapagliflozin add-on therapy to metformin improved endothelial function, as evaluated by flow-mediated dilation, in patients with inadequately controlled early-stage type 2 diabetes mellitus. 36 Although there are no comparative data from studies that have investigated the effects of SGLT-2 inhibitors in women with PCOS, the results of our 12-week intervention contrast those of a longer study which demonstrated that metformin treatment for 6 months improved or even normalized abnormal flow-mediated dilation on the brachial artery and improved plasma endothelin-1 levels in women with PCOS. 37 The discrepancies in these results may be at least partially explained by differences in study duration and the use of different endothelial function measures.…”

Section: Discussionmentioning

confidence: 64%

Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study

Javed

Papageorgiou

Deshmukh

et al. 2019

Clinical Endocrinology

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Summary Background Empagliflozin is a sodium‐glucose‐cotransporter‐2 inhibitor that improves cardiovascular risk and promotes weight loss in patients with type‐2 diabetes. Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular risk; therefore, empagliflozin may be of benefit for these women. The aim of this study was to compare the effects of empagliflozin vs metformin on anthropometric and body composition, hormonal and metabolic parameters in women with PCOS. Materials and methods A randomized open‐label study was conducted in women with PCOS who were randomized to either empagliflozin 25 mg (n = 19) or metformin 1500 mg (n = 20) daily for 12 weeks. The main outcomes assessed were changes in anthropometric and body composition, hormonal and metabolic parameters. Results Univariate analysis showed significant differences in weight (empagliflozin: −1.4 ± 3.2% vs metformin: 1.2 ± 2.3%; P = 0.006), body mass index (empagliflozin: −1.4 ± 3.2% vs metformin: 1.1 ± 2.2%; P = 0.006), waist circumference (empagliflozin: −1.6 ± 2.8% vs metformin: 0.2 ± 2.1%; P = 0.029) and hip circumference (empagliflozin: −2.0 ± 3.0% vs metformin: 1.1 ± 1.9%; P = 0.001), basal metabolic rate (empagliflozin: −1.8 ± 2.9% vs metformin: 0.1 ± 1.9%, P = 0.024) and fat mass (empagliflozin: −0.7 ± 4.9% vs metformin, 3.2 ± 5.0%; P = 0.023) between the empagliflozin and the metformin groups. These differences were confirmed in linear regression analysis after adjustment for relevant covariates. There were no significant changes in hormonal or metabolic parameters between both groups. Conclusion There was a significant improvement in anthropometric parameters and body composition, in overweight and obese women with PCOS after 12 weeks of treatment with empagliflozin compared to metformin, although no changes were seen in hormonal or metabolic parameters.

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“…In a pooled analysis of five Phase III trials (duration up to 24 weeks) in patients with T2DM (N = 3300; 823 patients with hypertension), treatment with empagliflozin improved the markers of arterial stiffness (pulse pressure and arterial stiffness index) and vascular resistance (mean arterial pressure) . The DEFENCE study was a 16‐week, prospective, randomized, open‐label, parallel‐group study designed to evaluate the effect of dapagliflozin on endothelial function, assessed by flow‐mediated dilation (FMD), in Japanese patients with T2DM treated with metformin . In patients with HbA1c ≥ 7%, treatment with dapagliflozin improved FMD with a mean (SD) change from baseline of 1.05% (2.59; P = 0.041).…”

Section: Role Of Sglt‐2 Inhibitors In Patients With T2dm and Multiplementioning

confidence: 99%

“…The exact mechanism of BP lowering by SGLT‐2 inhibitors is probably related to the osmotic diuretic and mild natriuretic effects . In addition, empagliflozin and dapagliflozin have been shown to reduce arterial stiffness and to improve vascular endothelial function, respectively, which may contribute to BP lowering …”

Section: Role Of Sglt‐2 Inhibitors In Patients With T2dm and Multiplementioning

confidence: 99%

Use of sodium‐glucose co‐transporter‐2 inhibitors in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors: An Asian perspective and expert recommendations

Deerochanawong

Chan

Matawaran

et al. 2019

Diabetes Obesity Metabolism

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Diabetes mellitus in Asia accounts for more than half of the global prevalence. There is a high prevalence of cardiovascular disease (CVD) in the region among people with type 2 diabetes mellitus (T2DM) and it is often associated with multiple risk factors including hypertension, renal disease and obesity. The early onset of T2DM and the eventual long disease duration portends an increasing proportion of the population to premature CVD. In addition to lowering blood glucose, sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors exert favourable effects on multiple risk factors (including blood pressure, body weight and renal function) and provide an opportunity to reduce the risk of CVD in patients with T2DM. In this article, we consolidated the existing literature on SGLT‐2 inhibitor use in Asian patients with T2DM and established contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, published data from clinical trials in the Asian population (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin), CVD outcomes trials (EMPAREG‐OUTCOME, CANVAS and DECLARE‐TIMI 58) and real‐world evidence studies (CVD‐REAL, EASEL, CVD‐REAL 2 and OBSERVE‐4D). A series of clinical recommendations on the use of SGLT‐2 inhibitors in Asian patients with T2DM was deliberated among experts with multiple rounds of review and voting. Based on the available evidence, we conclude that SGLT‐2 inhibitors represent an evidence‐based therapeutic option for the primary prevention of heart failure hospitalization and secondary prevention of CVD in patients with T2DM, and should be considered early on in the treatment algorithm for patients with multiple risk factors, or those with established CVD.

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Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study

Cited by 183 publications

References 43 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

Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study

Use of sodium‐glucose co‐transporter‐2 inhibitors in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors: An Asian perspective and expert recommendations

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