The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels

Li, Hongliang; Shin, Seungjae; Seo, Mi Seon; An, Jin Ryeol; Choi, Il‐Whan; Jung, Won‐Kyo; Firth, Amy L.; Lee, Daesung; Yim, Mi‐Jin; Choi, Grace; Lee, Jeong Min; Na, Sung Hun; Park, Won Sun

doi:10.1016/j.lfs.2018.01.032

Cited by 77 publications

(48 citation statements)

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“…These data are consistent with results from studies that used ipragliflozin [ 28 ], empagliflozin [ 29 – 31 ], and canagliflozin [ 32 , 33 ] in diabetic mice. Likewise, the findings from ex vivo studies indicated that various SGLT-2 inhibitors could induce direct vasorelaxation [ 26 , 34 – 36 ]. This beneficial effect on endothelial cell function points to several potential mechanisms of vasodilation, including modulation of adhesion molecules, attenuation of inflammation, activation of eNOS phosphorylation, potassium/calcium channel mediation independent of the endothelium;,decreased cardiac macrophage infiltration, and reduced oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Effect of Sodium-Glucose Cotransporter-2 Inhibitors on Endothelial Function: A Systematic Review of Preclinical Studies

et al. 2020

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Introduction: While the beneficial effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes are recognized, their direct effects on endothelial function remain unclear. We, therefore, undertook a systematic review to evaluate the current literature in this area. Methods: Electronic databases (PubMed, EMBASE, and Medline) were systematically searched using PRISMA guidelines for studies involving the in vitro, in vivo, or ex vivo administration of SGLT-2 inhibitors to animals, vascular tissue, or vascular endothelial cells. Results: Of 144 retrieved publications, 24 experimental studies met the inclusion criteria. Reporting of possible sources of bias were poor, making the overall risk of bias difficult to assess. Within the 24 studies, the SGLT-2 inhibitors canagliflozin, ipragliflozin, empagliflozin, dapagliflozin, tofogliflozin, and luseogliflozin were assessed as interventions. Animal model studies (n = 17) demonstrated that all SGLT-2 inhibitors prevented endothelial dysfunction and enhanced endothelium-dependent vasorelaxation in diabetic and non-diabetic models. In vitro studies (n = 9) using human endothelial cells indicated a direct anti-inflammatory effect of dapagliflozin (1-100 nM) and canagliflozin, (10 lM), while empagliflozin (1 and 10 lM) improved viability of hyperglycemic cells. Potential mechanisms of action of the SGLT-2 inhibitors include a reduction in oxidative stress, modulation of adhesion molecules and reductions in pro-inflammatory cytokines. Conclusions: Preclinical studies indicate that SGLT-2 inhibitors attenuate vascular dysfunction in preclinical models via a combination of mechanisms that appear to act independently of glucose-lowering benefits.

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Section: Discussionmentioning

confidence: 99%

Effect of Sodium-Glucose Cotransporter-2 Inhibitors on Endothelial Function: A Systematic Review of Preclinical Studies

et al. 2020

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“…Other possible mechanisms for the pleiotropic effects of SGLT2i on cardiovascular benefit involving the reduction of serum uric acid levels [41], haemoconcentration [42], improving endothelial function and aortic stiffness [43, 44] and may induce vasodilatation through activation of protein kinase G and the voltage-dependent K + channel [45].…”

Section: Discussionmentioning

confidence: 99%

Effects of the SGLT2 inhibitor dapagliflozin on cardiac function evaluated by impedance cardiography in patients with type 2 diabetes. Secondary analysis of a randomized placebo-controlled trial

Bonora

Kreutzenberg

Avogaro

et al. 2019

Cardiovasc Diabetol

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Background and aims Cardiovascular outcome trials have documented a strong benefit of sodium glucose cotransporter-2 inhibitors (SGLT2i) on the risk of hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D) with or without established cardiovascular disease or prior history of HF. The mechanisms, however, are not entirely clear. We aimed to evaluate whether treatment with SGLT2i affected cardiac function using impedance cardiography (ICG) in a randomized placebo-controlled trial. Materials and methods Thirty-three patients with T2D were randomized to receive blind dapagliflozin 10 mg or matching placebo for 12-week on top of their ongoing glucose lowering medication regimen. Cardiac function was evaluated by resting ICG at baseline and at the end of the 12-week treatment period. ICG is a non-invasive technology based on the continuous measurement of thoracic electrical conductivity to process a cardiodynamic parameters related to fluid content, blood flow, cardiac function, and circulatory function. We also evaluated changes in glycaemic control, blood pressure, and body weight. Results Thirty-one patients completed the study, 1 was excluded because ICG data was missing. Patients included in the final analysis were on average 63.4-year-old, with a known diabetes duration of 14.1 years and a baseline HbA1c of 8.2% (66 mmol/mol). 63.3% of patients had established cardiovascular disease (symptomatic or asymptomatic) and 36.7% had microangiopathy, but none had a prior history of HF. After 12 weeks, patients randomized to dapagliflozin, as compared to those randomized to placebo, showed improvements in HbA1c (− 1.2%; 13 mmol/mol), systolic blood pressure (− 3.7 mmHg), and body weight (− 3.3 kg). Based on ICG, in both groups, we detected no significant change in parameters of blood flow (stroke volume, cardiac output, cardiac index), systolic function (ejection fraction, acceleration and velocity indexes, systolic time ratio), circulatory function (systemic vascular resistance index), and fluid status (thoracic fluid content) after treatment. Conclusion This is the first study exploring cardiac effects of SGLT2i using ICG in T2D. We observed no change in cardiac function parameters estimated by ICG in T2D patients who received dapagliflozin versus placebo for 12 weeks. Trial registration ClinicalTrial.gov NCT02327039. Registered 30 December 2014

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“…Aortic vasodilation is induced by dapagliflozin in a dose-dependent manner. This may occur via activation of Kv channels and protein kinase G. This finding was independent of other K þ channels, Ca 2þ channels, intracellular Ca 2þ and the endothelium (95). In 16 patients with T2DM, dapagliflozin also decreased systolic blood pressure and induced an increase in 24-h diuresis (96); furthermore, brachial artery flow-mediated dilation was significantly increased and pulse-wave velocity was reduced.…”

Section: Improvements In Ventricular Afterload With Sglt-2 Inhibitionmentioning

confidence: 79%

Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus

Sharma

Verma

2020

Canadian Journal of Diabetes

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Some glucagon-like-peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated efficacy in reducing the risk of cardiovascular outcomes. There are extensive overlapping and distinct mechanisms of action for each class of drugs. GLP-1 receptor agonists mechanisms of action appear to reduce atherothrombotic outcomes, whereas SGLT-2 inhibitors mechanisms of action preferentially target heart failure outcomes.

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The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels

Cited by 77 publications

References 27 publications

Effect of Sodium-Glucose Cotransporter-2 Inhibitors on Endothelial Function: A Systematic Review of Preclinical Studies

Effect of Sodium-Glucose Cotransporter-2 Inhibitors on Endothelial Function: A Systematic Review of Preclinical Studies

Effects of the SGLT2 inhibitor dapagliflozin on cardiac function evaluated by impedance cardiography in patients with type 2 diabetes. Secondary analysis of a randomized placebo-controlled trial

Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus

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