CARDIAC EFFECTS OF COMBINED SGLT 1/2 INHIBITION FOLLOWING EXPERIMENTAL MYOCARDIAL INFARCTION IN THE RAT

Abstract

Dual SGLT1/2 inhibition offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from that gut as well and to stimulate glucagon-like peptide 1 (GLP-1) secretion. However, beyond the kidney and gut, SGLT1 is expressed in other organs including the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, this study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the diseased heart. Hyperglycaemic Fischer F344 rats were randomized to receive either vehicle, the dual SGLT1/2 inhibitor, T-1095, or the selective SGLT2 inhibitor, dapagliflozin. Animals were then further randomized to undergo sham surgery or ligation of the left anterior descending (LAD) coronary artery. Cardiac function was assessed prior to termination 4 weeks later that was followed by assessment of cardiac structure and expression of glucose transporters GLUT1, GLUT4 and SGLT1. Dapagliflozin and T-1095 induced glucosuria to a similar extent in both the control and myocardial infarction settings with similar effects on glycaemia. Neither dapagliflozin nor T-1095 had any demonstrable effect on cardiac function or structure in the control setting. Following myocardial infarction, however, significant (p < 0.05) differences were noted. When compared with vehicle or dapagliflozin-treated animals, rats that received T-1095 displayed worse cardiac function as evidenced by (i) lower EF, (ii) reduced dP/dt max, (iii) impaired isovolumic relaxation in diastole (dP/dt min), (iv) prolongation of Tau, and (v) increase in the end-diastolic pressure volume relationship (EDPVR). While vehicle and dapagliflozin-treated rats underwent hypertrophic changes following myocardial infarction this did not occur in animals that had received T-1095. Following myocardial infarction, lung weight was higher in T-1095 treated rats than in those animals that had received either vehicle of dapagliflozin. Notably, expression of GLUT 1 and GLUT4 were reduced in the hearts of all animals that had sustained myocardial infarction while that of SGLT1 was unchanged. T-1095 prevented the hypertrophic response following experimental myocardial infarction in the rat with adverse consequences on both systolic and diastolic function. The reduction in GLUT expression post-MI suggests that the heart may be more reliant on SGLT1-mediated glucose transport in the disease setting. These findings suggest the need for caution with dual SGLT1/2 inhibition in patients with diabetes at high cardiovascular risk.