Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects

Abstract

Diabetes is a global epidemic and a leading cause of death with more than 422 million patients worldwide out of whom around 392 million alone suffer from type 2 diabetes (T2D). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel and effective drugs in managing glycemia of T2D patients. These inhibitors gained recent clinical and basic research attention due to their clinically observed cardiovascular protective effects. Although interest in the study of various SGLT isoforms and the effect of their inhibition on cardiovascular function extends over the past 20 years, an explanation of the effects observed clinically based on available experimental data is not forthcoming. The remarkable reduction in cardiovascular (CV) mortality (38%), major CV events (14%), hospitalization for heart failure (35%), and death from any cause (32%) observed over a period of 2.6 years in patients with T2D and high CV risk in the EMPA-REG OUTCOME trial involving the SGLT2 inhibitor empagliflozin (Empa) have raised the possibility that potential novel, more specific mechanisms of SGLT2 inhibition synergize with the known modest systemic improvements, such as glycemic, body weight, diuresis, and blood pressure control. Multiple studies investigated the direct impact of SGLT2i on the cardiovascular system with limited findings and the pathophysiological role of SGLTs in the heart. The direct impact of SGLT2i on cardiac homeostasis remains controversial, especially that SGLT1 isoform is the only form expressed in the capillaries and myocardium of human and rodent hearts. The direct impact of SGLT2i on the cardiovascular system along with potential lines of future research is summarized in this review.

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

“…The observed reduction in CV and renal outcomes with SGLT‐2is (Figure ) among patients with T2D and a high risk of CVD or established CVD that has been reported in CVOTs indicates that these benefits may be a class effect . Further, the SGLT‐2is have been shown to significantly reduce the risk of HF and hospitalization for HF and to provide renal protection in patients with and without preexisting atherosclerotic CVD .…”

“…Impact of SGLT‐2i–mediated systemic and direct myocardial effects on cardiac homeostasis . Reprinted by permission from Kaplan A, Abidi E, El‐Yazbi A, Eid A, Booz GW, Zouein FA.…”

“…The observed reduction in CV and renal outcomes with SGLT-2is ( Figure 5) among patients with T2D and a high risk of CVD or established CVD that has been reported in CVOTs indicates that these benefits may be a class effect. 119 Further, the SGLT-2is have been shown to significantly reduce the risk of HF and hospitalization for HF and to provide renal protection in patients with and without preexisting atherosclerotic CVD. 40 Of note, the significant reduction in the risk of hospitalization for HF with dapagliflozin in the DECLARE-TIMI 58 trial was observed in a study population that included a majority of patients (59%) with multiple risk factors but without atherosclerotic CVD, 5 whereas most patients in the EMPA-REG OUTCOME trial (>99%) 3 and the CANVAS trial (66%) 4 had established CVD ( Table 1).…”

“…Treatment guidelines for T2D usually recommend metformin as first-F I G U R E 5 Impact of SGLT-2i-mediated systemic and direct myocardial effects on cardiac homeostasis. 119 Reprinted by permission from Kaplan A, Abidi E, El-Yazbi A, Eid A, Booz GW, Zouein FA. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects.…”

Sodium–glucose cotransporter 2 inhibitors and inflammation in chronic kidney disease: Possible molecular pathways

“…SGLT2 inhibitors represent a new antidiabetic drug category that reduce renal tubular absorption of glucose, thus enhancing glycosuria and resulting in blood glucose lowering and improved glycemic control (Vallon, 2015). Apart from glucose reduction, SGLT2 inhibitors may beneficially affect several cardiometabolic risk factors, such as body weight, blood pressure, uric acid, fat distribution, arterial stiffness, and vascular resistance, as well as cardiac metabolism, function, and hemodynamics (Athyros, Katsiki, & Karagiannis, 2016;Kaplan et al, 2018;Katsiki, Athyros, & Mikhailidis, 2017;Katsiki, Mikhailidis, & Theodorakis, 2017;Katsiki, Purrello, Tsioufis, & Mikhailidis, 2017;Mamakou et al, 2017;Tikkanen, Chilton, & Johansen, 2016;Upadhyay et al, 2018;).…”