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.

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

“…An evidence-based clinical decision when prescribing an SGLT2i in patients with T2DM to patients at high risk of atherosclerotic CVD should consider both cardiorenal benefits and safety issues [ 41 ]. In this sense, the first conclusion of the analysis of Figure 5 is that ertugliflozin is a less beneficial drug than the other three SGLT2i.…”

Metformin, Macrophage Dysfunction and Atherosclerosis

“…SGLT2i, including empagliflozin, dapagliflozin and canagliflozin, have been shown recently to reduce the hospitalization rate of patients with heart failure and decrease the mortality rate from cardiovascular diseases (207)(208)(209)(210). Inhibiting the inflammatory actions of macrophages is one of the important mechanisms through which SGLT2is exert CVD protection.…”

Endothelial Dysfunction and Cardiovascular Disease: History and Analysis of the Clinical Utility of the Relationship

“…The functional and therapeutic difference in these two designations are exemplified by the actions of newer anti-diabetes drugs—these drugs including sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists have beneficial effects in large clinical trials where cardiovascular events and deaths are reduced by treatment with the index agents. It has however been very difficult to show consistent favorable actions on endothelial function assessed as enhanced vasodilation [ 25 , 26 ]. This suggests that the favorable cardiovascular effects arise from anti-inflammatory actions on the endothelium; these anti-inflammatory actions are more disparate and difficult to characterize than measures of vasodilatory capacity.…”