Amelioration of endothelial dysfunction by sodium glucose co‐transporter 2 inhibitors: pieces of the puzzle explaining their cardiovascular protection

Abstract

Sodium glucose co-transporter 2 inhibitors (SGLT-2is) improve cardiovascular outcomes in both diabetic and non-diabetic patients. Preclinical studies suggest that SGLT-2is directly affect endothelial function in a glucose-independent manner. The effects of SGLT-2is include decreased oxidative stress and inflammatory reactions in endothelial cells. Furthermore, SGLT2is restore endothelium-related vasodilation and regulate angiogenesis. The favourable cardiovascular effects of SGLT-2is could be mediated via a number of pathways: (1) inhibition of the overactive sodium-hydrogen exchanger; (2) decreased expression of nicotinamide adenine dinucleotide phosphate oxidases; (3) alleviation of mitochondrial injury; (4) suppression of inflammationrelated signalling pathways (e.g., by affecting NF-κB); (5) modulation of glycolysis; and (6) recovery of impaired NO bioavailability. This review focuses on the most recent progress and existing gaps in preclinical investigations concerning the direct effects of SGLT-2is on endothelial dysfunction and the mechanisms underlying such effects.

Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction

“…Therefore, besides inducing a low-grade ketonemia, empagliflozin might be associated with broader, additional pleiotropic effects independent of BOHB. It has been suggested that SGLT2 inhibition may lead to a greater benefit by augmenting endothelial function and vasodilatation, 3,12,26 improvements in nutrient deprivation signaling/autophagy 27 or tapping the native response of tissues to ischemia (hypoxia-inducible factor). 28…”

“…Therefore, besides inducing a low-grade ketonemia, empagliflozin might be associated with broader, additional pleiotropic effects independent of BOHB. It has been suggested that SGLT2 inhibition may lead to a greater benefit by augmenting endothelial function and vasodilatation, 3,12,26 improvements in nutrient deprivation signaling/autophagy 27 or tapping the native response of tissues to ischemia (hypoxia-inducible factor). 28 One-week duration of treatment before MI was selected based on previous experimental studies with rodents showing the critical importance of timing and duration of treatment when it applies to cardioprotection.…”

Perspective of SGLT2i in the treatment of abdominal aortic aneurysms

“…The efficacy of SGLT2i in improving cardiovascular complications was found to be independent of the hypoglycemic effect. 22 The pharmacological mechanisms by which SGLT2i exert cardioprotective effects include improving hemodynamics through blood pressure/volume reduction and inhibiting PVAT remodeling 23 ; inhibiting glucose oxidation, increasing fat oxidation, and raising plasma ketone body levels to improve cardiac energy efficiency 24 ; improving endothelial function and vascular stiffness by anti-inflammatory and antioxidant effects 25 , 26 ; and inhibiting myocardial Na + /H + exchange (NHE), reducing intracellular Na + and Ca 2+ concentrations in cardiomyocytes, and enhancing resistance to oxidative stress. 27 Owing to its prominent and significant cardiovascular protective effect, guidelines in many countries recommend its use in nondiabetic patients with heart failure.…”

Vericiguate: a new treatment for chronic heart failure

“…Существует несколько возможностей косвенного фармакологического влияния на эти процессы с помощью препаратов, которые уже успешно применяются для лечения СН (ингибиторы АПФ и блокаторы ангиотензиновых рецепторов, валсартан/сакубитрил и ингибиторы SGLT2) [58][59][60][61][62], а также атеросклероза (статины) [63]. Что касается заместительной терапии в форме применения нитратов и донаторов NO, то их положительное влияние на гемодинамику, ремоделирование, а в некоторых группах пациентов (у афроамериканцев с тяжелой СН) -на выживаемость [58,64] обычно с течением времени нивелируется в результате возникновения побочных эффектов (чаще артериальной гипотензии), толерантности и оксидативного стресса.…”