Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.

Keywords: SGLT2 inhibitors; atherosclerosis; cardiovascular complications; diabetes; therapy.

Figure 1

Potential molecular targets of SGLT2i in atherosclerosis. Although the existing evidence is not sufficient to directly prove the anti-atherosclerotic mechanism of action of SGLT2i, some preclinical and clinical studies have revealed some potential mechanisms. SGLT2i may inhibit the progression of atherosclerosis by impacting the levels of related inflammatory factors in the serum, inhibiting endothelial dysfunction, VSMC proliferation and migration, macrophage inflammation, foam cell formation, platelet activation, and oxidative stress and improve autophagy impairment. Abbreviations: ABCA1: ATP-binding cassette transporter A1; ACAT1: acetyl-coenzyme A acetyltransferase 1; AGEs: advanced glycation end-products; AMPK: AMP-activated protein kinase; BHB: β-hydroxybutyrate; HbA1c: glycosylated hemoglobin; eNOS; endothelial nitric oxide synthases; HO-1: hemeoxygenase-1; ICAM-1: intercellular cell adhesion molecule-1; IL-1β: interleukin-1β; IL-6: interleukin-6; Lox-1; lectin-like oxidized low-density lipoprotein receptor-1; M1: M1 macrophages; M2: M2 macrophages; MCP-1: monocyte chemoattractant protein-1; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor-κB; NLRP3: nucleotide-binding domain-like receptor protein 3; NO: nitric oxide; PAI-1: plasminogen activator inhibitor-1; ROS: reactive oxygen species; SIRT1: sirtuin-1; STAT3: signal transducer and activator of transcription 3; TLR4: toll-like receptors; TNF-α: tumor necrosis factor-α; VCAM-1: vascular cell adhesion molecule-1.

Figure 2

Potential cardiovascular actions of SGLT2i. SGLT2i have pleiotropic cardiovascular protective effects, such as: reduce weight, blood pressure, blood glucose, insulin resistance and glucotoxicity in patients, increases hemoconcentration, and inhibits oxidative stress and inflammation. The most direct effect of SGLT2i is inhibition of the reabsorption of glucose and a diuretic and natriuretic effect. In addition, SGLT2i also exerts other effects such as regulating ion channels, activating autophagy, inhibiting iron overload, attenuating activation of the NLRP3 inflammasome, and inhibiting the signaling of advanced glycation end products. The synergistic effects of these benefits may provide a therapeutic basis for the cardioprotective effects of SGLT2i.