Sodium-glucose cotransporter 2 inhibitors alter cardiac glucose transporter expression in patients with heart failure

Abstract Background Inhibitors of sodium-glucose cotransporter 2 (SGLT2) were initially developed to manage type-2 diabetes by decreasing renal reabsorption of glucose. Surprisingly, clinical trials showed an additional benefit in terms of reduced risk of hospitalisation and cardiovascular mortality in heart patients with reduced or preserved ejection fraction, regardless of their diabetes status [1, 2]. Purpose While SGLT2 inhibitors improve overall heart health through various factors, including volume regulation and metabolic changes, their impact on cardiac glucose supply remains largely unknown. In this study, the effect of SGLT2 inhibitors on the expression of key glucose transporters in left ventricular tissue of patients with cardiomyopathies was investigated. Methods Left ventricular tissue samples were gathered from patients with dilated or ischaemic cardiomyopathy who underwent implantation of continuous-flow left ventricular assist devices. Gene expression of glucose transporters (SGLT1, SGLT2, GLUT1 and GLUT4) and transcription factors (SP1 and SP3) was analysed via qPCR and protein levels were further examined by western blot analysis. In addition, the distribution of glucose transporters in cardiac tissue was examined in histological preparations using immunofluorescence staining. Results Tissue samples from 65 patients diagnosed with either dilated (n=41) or ischaemic (n=24) cardiomyopathy were analysed, of which 18 were treated with SGLT2 inhibitors (Dapagliflozin or Empagliflozin). Of this cohort, 9 patients were female (mean age: 54.4±13.2 years) and 56 male (mean age: 55.7±13.7 years). Our results show no differences in the expression levels of SGLT1, GLUT1 and GLUT4 between dilated and ischaemic cardiomyopathy. Notably however, expression of SGLT1, GLUT1 and GLUT4 in ventricular heart tissue was reduced by more than 50% in patients treated with SGLT2 inhibitors compared to untreated patients. Furthermore, expression of the GLUT1 transcription factor SP3 was also significantly reduced by inhibition of SGLT2, whereas SP1 expression was not altered. Finally, we were unable to detect the presence of SGLT2 in ventricular tissue, supporting data that emphasise the absence of SGLT2 in cardiac tissue. Conclusion These findings suggest that SGLT2 inhibitors modulate the expression of SGLT1, GLUT1 and GLUT4 in left ventricular heart tissue of patients with cardiomyopathies and may alter cellular glucose supply. Further studies are needed to determine the clinical relevance of these changes for heart failure management.