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

Abstract

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.

Safety and Efficacy of SGLT2 Inhibitors: A Multiple-Treatment Meta-Analysis of Clinical Decision Indicators

“…Several mechanism(s), most of them proven in both human and animal models, have been proposed as responsible for the benefits on cardiovascular risk of SGLT2 inhibition [ 2 ], including diuresis/natriuresis that lead to blood pressure reduction, enhanced cardiac energy metabolism, reduction of inflammation reduction, inhibition of the sympathetic nervous system, prevention of ischemia/reperfusion injury, decreasing epicardial fat mass, decreasing oxidative stress and improvements on vascular function, among others [ 2 , 9 , 10 ] ( Figure 1 ).…”

Prescribing sodium-glucose co-transporter-2 inhibitors for type 2 diabetes in primary care: influence of renal function and heart failure diagnosis

“…However, this might be a temporal effect as the benefits within the heart failure group have only recently been incorporated into international (EASD/ADA) guidelines and have yet to be included as part of the treatment algorithm in the UK based NICE guidelines for type 2 diabetes, which focus principally on improving glycaemic control [ 11 , 15 ]. There is accumulating data on the benefits of SGLT-2is on cardiac function, vascular endothelial function, and cardio-metabolic risk factors [ 38 – 43 ], which may further enhance utilisation of these drugs in real-world clinical practice.…”

Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

“…Several cell-signaling pathways are involved in its pleiotropic action and lead to cardiovascular benefits. First, activation of the PI3K/AKT pathway decreases ROS generation and increases the phosphorylation of AKT/eNOS, which reduces inflammation and increases NO production [ 103 ]. Li et al reported that phlorizin suppressed the expression of SGLT-1 and SGLT-2, activated the PI3K/AKT/eNOS signaling pathway, and increased the output of NO in palmitic acid–incubated human vascular endothelial cells [ 104 ].…”