Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the first antidiabetic compounds that effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetics. Being explicitly designed to inhibit SGLT2 in the kidney, SGLT2i have lately been investigated for their off-target cardiac actions. Here, we review the direct effects of SGLT2i Empagliflozin (Empa), Dapagliflozin (Dapa), and Canagliflozin (Cana) on various cardiac cell types and cardiac function, and how these may contribute to the cardiovascular benefits observed in large clinical trials. SGLT2i impaired the Na+/H+ exchanger 1 (NHE-1), reduced cytosolic [Ca2+] and [Na+] and increased mitochondrial [Ca2+] in healthy cardiomyocytes. Empa, one of the best studied SGLT2i, maintained cell viability and ATP content following hypoxia/reoxygenation in cardiomyocytes and endothelial cells. SGLT2i recovered vasoreactivity of hyperglycemic and TNF-α-stimulated aortic rings and of hyperglycemic endothelial cells. Anti-inflammatory actions of Cana in IL-1β-treated HUVEC and of Dapa in LPS-treated cardiofibroblast were mediated by AMPK activation. In isolated mouse hearts, Empa and Cana, but not Dapa, induced vasodilation. In ischemia-reperfusion studies of the isolated heart, Empa delayed contracture development during ischemia and increased mitochondrial respiration post-ischemia. Direct cardiac effects of SGLT2i target well-known drivers of diabetes and heart failure (elevated cardiac cytosolic [Ca2+] and [Na+], activated NHE-1, elevated inflammation, impaired vasorelaxation, and reduced AMPK activity). These cardiac effects may contribute to the large beneficial clinical effects of these antidiabetic drugs.
Highlights
Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the first antidiabetic compounds that effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetics
We review the direct effects of SGLT2i Empagliflozin (Empa), Dapagliflozin (Dapa), and Canagliflozin (Cana) on various cardiac cell types and cardiac function, and how these may contribute to the cardiovascular benefits observed in large clinical trials
SGLT2 is located in the first part of the proximal tubule, where it enables ∼90% of glucose reabsorption from the urine; the other 10% reabsorption is through sodium glucose cotransporter 1 (SGLT1), which is located in the distal part of the proximal tubule
Summary
This review provides an overview of the direct effects of SGLT2i in the heart and in the most prominent cell types present in the heart, including cardiomyocytes, endothelial cells, vascular SMC and cardiofibroblasts. In isolated hearts SGLT2i improved vasodilation, delayed ischemic contracture and increased post-ischemic STAT3 phosphorylation These preclinical cell/organ studies clearly show that there are direct cardiac effects of SGLT2i, offering several off-target, cardioprotective mechanisms that may contribute to the beneficial effects observed in the clinical trials. Preclinical studies have shown that pharmacological interventions targeting sarcolemmal sodium ion transporters proved effective in ameliorating heart failure (Kusumoto et al, 2001; Engelhardt, 2002; Baartscheer et al, 2003b, 2005, 2008; Baartscheer and Van Borren, 2008) These promising preclinical studies in the setting of HF on the use of NHE-1 inhibition never translated into clinical testing for HF, because of negative results obtained with the use of these inhibitors in the setting of acute cardiac ischemia. Since SGLT2i have demonstrated direct anti-inflammatory actions in vascular cells, targeting this new paradigm may potentially and at least partly explain the positive results observed in the clinical trials and may identify novel therapeutic implications for SGLT2i
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