Linagliptin exerts a sex-specific effect on cardiac function, collateralization, and metabolism in a swine model of cardiometabolic disease.

Abstract

There are striking sex disparities among cardiometabolic disorders; however, the understanding of its underlying disease pathology remains uncertain, creating insufficient preventative and therapeutic approaches. Our study investigates the sex-specific response to the dipeptidyl peptidase-4 inhibitor, linagliptin in a clinically meaningful model of metabolic syndrome and chronic myocardial ischemia. Yorkshire swine were fed a high-fat diet for 5 weeks to induce metabolic syndrome and subsequently underwent placement of an ameroid constrictor to the left circumflex coronary artery, inducing chronic myocardial ischemia. Swine received no drug (n = 8; 4 females, 4 males) or 2.5 mg linagliptin daily (n = 8; 3 males, 5 females). Five weeks later, the swine underwent hemodynamic measurements, microsphere injections to determine perfusion, and terminal harvest for left ventricular sectioning and molecular and proteomic analysis. Linagliptin-treated female swine demonstrated improved cardiac function compared with treated males and controls, including cardiac output, stroke work, and left ventricular end-diastolic volume (all P < .05). There was an increase in arteriolar and capillary density in treated female swine compared with control (P = .002, P = .031, respectively), with associated sex-specific changes in angiogenic proteins. Treated male swine had reduced glycogen stores by periodic acid-Schiff staining compared with control (P = .017). In contrast, female-treated swine had a nonsignificant reduction in glycogen stores and an upregulation of proteins associated with overall mitochondrial function and glycolysis. Linagliptin treatment resulted in a preferential improvement in left ventricular function, angiogenesis, and "metabolic flexibility" in female swine compared with male swine and controls in the setting of metabolic syndrome and coronary artery disease.