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

Alshnbari, Afnan S.; Millar, Sophie A.; O�Sullivan, Saoirse E.; Idris, Iskandar

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 µM), while empagliflozin (1 and 10 µM) 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.

• Journal Article Type: Article
• Acceptance Date: Jun 8, 2020
• Online Publication Date: Jul 27, 2020
• Publication Date: 2020-09
• Deposit Date: Aug 13, 2020
• Publicly Available Date: Aug 13, 2020
• Journal: Diabetes Therapy
• Print ISSN: 1869-6953
• Electronic ISSN: 1869-6961
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Pages: 1947–1963
• DOI: https://doi.org/10.1007/s13300-020-00885-z
• Keywords: Internal Medicine; Endocrinology, Diabetes and Metabolism
• Public URL: https://nottingham-repository.worktribe.com/output/4829489
• Publisher URL: https://link.springer.com/article/10.1007/s13300-020-00885-z