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Introduction
Atherosclerotic cardiovascular disease (CVD), which is accelerated in patients with prolonged diabetes, impairs quality of life and is a major cause of mortality [1, 2]. Several studies have shown that abnormal glycemic metabolism plays an important role in the pathogenesis of atherosclerosis and that poor glycemic control accelerates the risk for CVD in subjects with type 2 diabetes mellitus (T2DM) [3]. However, recent studies have cast doubt on the benefits of enforcing strict glycemic control on CVD in patients with established atherosclerosis or longstanding T2DM [4, 5–6] due to attenuation of the beneficial effects of the former by an increased incidence of hypoglycemic episodes [7, 8]
T2DM is often closely related with insulin resistance and accompanied by other cardiovascular (CV) risk factors, such as obesity, hypertension, and dyslipidemia. Thus, early and comprehensive medical intervention to address these risk factors has been shown to be an effective strategy to prevent the development of diabetic CVD [9, 10]. Taking into account the multifaceted pathogenesis of CVD in diabetes, it would be an advantage to have a specific intervention which could attenuate CV risk in a multi-dimensional fashion beyond glycemic control alone.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of anti-diabetic agents that lower blood glucose concentrations by enhancing urinary glucose excretion [11]. Although they lack direct action on insulin secretion from β-cells, it is expected that their glucose-lowering effect will reduce glucotoxicity and improve β-cell function and insulin sensitivity in subjects with T2DM [12, 13, 14–15]. Since the mode of action of SGLT2 inhibitors is independent of insulin secretion, these agents are associated with a low risk of hypoglycemia, which is linked to an increased of CV events [7, 8, 16]. They have also been demonstrated to ameliorate a variety of CV risk factors and potential pathways: these agents, as monotherapy or in combination with other glucose-lowering drugs, reduce visceral adipose tissue, body weight, blood pressure, and circulating uric acid levels as well as improve serum lipid profiles [17]. These findings indicate a strong rationale for expecting that these compounds will protect against CV events.
Indeed, the EMPA-REG OUTCOME trial, a clinical trial designed to clarify the effects of the SGLT2 inhibitor empagliflozin on clinical CV outcomes in patients with T2DM and established CV...