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

BACKGROUND: 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. METHODS: 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 24 h. At the end of treatments, cytotoxicity, oxidative stress, nitric oxide (NO) production, nitric oxide synthase (NOS) activity and phospho-eNOS (Thr) expression were determined. RESULTS: 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. CONCLUSION: 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.