Sex-Specific Improvements in Myocardial Function and Angiogenesis with SGLT-2 Inhibitor Canagliflozin in a Swine Model of Metabolic Syndrome

There is a significant body of literature to suggest that coronary artery disease (CAD) is a highly sex-specific disease. The study of sex-specific therapeutics and sex-specific responses to treatment for CAD remains underreported in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are of growing interest in the treatment of ischemic heart disease and heart failure; however, the sex-specific response to SGLT2 inhibitors is unknown. We studied an SGLT2 inhibitor, canagliflozin, in a swine model of metabolic syndrome (MS) and chronic myocardial ischemia with emphasis on the sex-specific outcomes. Yorkshire swine (<i>n</i> = 21) were obtained at 6 weeks of age and fed a high-fat diet to induce MS. Left thoracotomy was performed on all swine at 11 weeks of age for the placement of an ameroid constrictor to model chronic myocardial ischemia. Swine recovered for two weeks, then were assigned to either the drug group, CAN 300 mg daily group (M = 5, F = 5), or the control group (CON, M = 5, F = 6). Both groups received 5 weeks of therapy. After completion of therapy, swine underwent functional assessment and terminal harvest. The male animals treated with CAN (CAN-M) had significant increases in stroke volume and cardiac output (<i>p</i> = 0.047, <i>p</i> < 0.001) compared to control males (CON-M), which were not seen in females treated with CAN (CAN-F) compared to control females (CON-F). Effective arterial elastance was decreased in CAN-M compared to CON-M. The CAN-F group had a significant increase in ischemic myocardial capillary density compared to CON-F (<i>p</i> = 0.04). There was no difference in capillary density between the CAN-M and CON-M groups. CAN treatment resulted in sex-specific changes in angiogenesis and myocardial function. The CAN-M group had significant improvements in cardiac function based on afterload reduction, stroke volume, and increased cardiac output not seen in the CAN-F group. The CAN-F group had increased ischemic myocardial capillary density. These findings provide a foundation for further investigation of the sex-specific effects of SGLT-2 inhibitors in humans.