The Role of SGLT2 Inhibitors in Atherosclerosis: A Narrative Mini-Review

Abstract

Objective: Sodium glucose cotransporter 2 inhibitors (SGLT2-is) are antidiabetic drugs that improve glycemic control by limiting urinary glucose reuptake in the proximal tubule. SGLT2-is might suppress atherosclerotic processes and ameliorate the prognosis of patients with diabetes mellitus diagnosed with or at high risk of atherosclerotic cardiovascular disease (ASCVD). In this mini review, we examine the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical atherosclerosis to ASCVD.Data Sources—PubMed and Google Scholar were searched for publications related to SGLT2-is and atherosclerosis. All types of articles were considered, including clinical trials, animal studies, in vitro observations, and reviews and meta-analyses. Data were examined according to their impact and clinical relevance.Synopsis of Content—We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2-is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds. Additionally, we propose future directions that can improve our understanding of SGLT2-is and atherosclerosis.

Comparison of cardiovascular and renal outcomes between dapagliflozin and empagliflozin in patients with type 2 diabetes without prior cardiovascular or renal disease

“…The benefits of SGLT2i observed in clinical trials can be explained by multiple mechanisms, beyond the glucose lowering effect: improvement in ventricular loading condition by natriuresis and osmotic diuresis, improvement in cardiac metabolism, reduced myocardial necrosis and fibrosis, and restoration of tubuloglomerular feedback [ 10 , 11 ]. In addition, the pleiotropic effects of SGLT2i include benefits on endothelial function by attenuating oxidative stress and inflammation, and reductions in plaque size and vulnerability, as shown in preclinical and clinical studies [ 14 , 34 ].…”

Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials

“…A meta-analysis, including 40 trials and ~60,000 participants, found a 14% reduction in the incidence of MI in SGLT2i users compared to controls ( 78 ). Nevertheless, no reduction was found in the occurrence of angina pectoris ( 79 ).…”

Comparison of cardiovascular and renal outcomes between dapagliflozin and empagliflozin in patients with type 2 diabetes

“…Therefore, our study supports a SGLT2i class effect and, simultaneously, suggests that the benefits of SGLT2i use for ASCVD prevention are independent of the management of glucose and lipid profile. In particular, it has been suggested that SGLT2i can prevent endothelial dysfunction by reducing oxidative stress and sympathetic activation, reduce inflammatory cytokines, and reduce the plaque size while stabilizing their vulnerability (28).…”