Mechanism of Action of Sglt2-inhibitors

T2DM individuals manifest a 2-3 times greater risk of CV events compared to non-diabetics, and CV mortality is responsible for ~70% of total mortality. In T2DM patients without MI, risk of CV death is similar to individuals without diabetes with prior MI.1 Although hyperglycemia is a strong risk factor for microvascular complications, it is a weak risk factor for CV disease (CVD), and interventional studies focused on reducing plasma glucose in T2DM have only a minor effect to reduce CV risk.2-5 Furthermore, it takes many years to observe the CV benefit associated with improved glycemic control.6,7 Most T2DM individuals manifest insulin resistance (metabolic syndrome), which is associated with multiple metabolic abnormalities, i.e., obesity, dyslipidemia, and hypertension, all of which are CV risk factors. The molecular mechanisms responsible for insulin resistance directly contribute to the pathogenesis of atherosclerosis, independent of the associated metabolic abnormalities.8 Thus, obese individuals without diabetes with the insulin resistance syndrome manifest a similarly increased risk for CVD compared with T2DM patients, supporting the concept that hyperglycemia is not a major determinant for the development of CVD in T2DM. Consequently, lowering blood pressure and improving lipid profile have a greater effect to reduce CVD risk than lowering plasma glucose concentration in T2DM.9 Therefore, it is not surprising that antidiabetes agents, e.g. sulfonylureas,10 insulin,11 and DPP4-inhibitors (12-14), that lower plasma glucose without affecting other metabolic abnormalities associated with the insulin resistance syndrome have little beneficial effect to lower CVD risk in T2DM, especially when these agents are started late in the natural history of T2DM and atherosclerosis. Conversely, pioglitazone, which improves insulin sensitivity and multiple components of insulin resistance syndrome, i.e., blood pressure and lipids, exerts a favorable effect on CVD risk in T2DM individuals, independent of its glucose-lowering action.15 In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), pioglitazone lowered the main secondary end point (CV death, nonfatal MI, and stroke) by 16% (P = 0.025).15 While SGLT2-inhibitors can exert a beneficial effect on CV risk by having favorable effects on weight and blood pressure, and also other favorable hemodynamic effects.16