Empagliflozin, alone or in combination with liraglutide, limits cell death in vitro: role of oxidative stress and nitric oxide

Abstract

Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide are characterized as having cardiovascular benefits in patients with type 2 diabetes (T2D). Little is known regarding the underlying mechanisms nor the potential interactions between cardiovascular benefits of these two drugs when combined. We sought to investigate: (1) whether combination of empagliflozin and liraglutide has additive effect against diabetes-induced cytotoxicity, and (2) potential mechanisms involved in cardioprotective effect of empagliflozin and liraglutide in diabetes. Capacity of empagliflozin and liraglutide alone and in combination to reduce cardiac injury in diabetes was evaluated. HL-1 cells, a cardiac muscle cell line, were exposed to hyperglycemia/hyperinsulinemia and treated with/without empagliflozin, liraglutide or empagliflozin + liraglutide for 24h. At the end of treatments, cytotoxicity, oxidative stress, nitric oxide (NO) production, nitric oxide synthase (NOS) activity and phospho-eNOS (Thr495) expression were determined. We found that empagliflozin treatment alone and combined treatment decreased in vitro HL-1 cell death caused by hyperglycemia. Liraglutide treatment alone improved NOS activity followed by increased NO production, while empagliflozin had little effect. Furthermore, the effects of empagliflozin + liraglutide to decrease diabetes-induced cytotoxicity and oxidative stress were synergistic. While empagliflozin alone attenuated diabetes-induced cytotoxicity, combined treatment of liraglutide can synergistically ameliorates cell death and oxidative stress. This effect is potentially due to improved NOS activity and increased NO production induced by liraglutide.