Inhibition of Human Endothelial Cell Function by Metformin and Canagliflozin

Metformin is the drug of first choice in treating hyperglycemia in patients with type 2 diabetes mellitus. Its primary action is to inhibit hepatic glucose production and increase the sensitivity of peripheral tissues to insulin. Recently, sodium-glucose cotransporter 2 inhibitors such as canagliflozin, which reduce blood glucose levels by blocking glucose reabsorption in the kidney, have also been approved for use in type 2 diabetes mellitus either alone or in combination with other drugs, including metformin. Intriguingly, both metformin and canagliflozin have been shown to improve cardiovascular outcomes in patients with type 2 diabetes mellitus. While reductions in body weight, adiposity, blood pressure, and arterial stiffness have been suggested to contribute to the cardiovascular benefit of these drugs, their effects on vascular cell function have not been fully considered. In the present study, we tested the hypothesis that metformin and canagliflozin directly effect human endothelial cell function. Treatment of human umbilical vein endothelial cells with metformin or canagliflozin inhibited their proliferation in a concentration-dependent manner. The anti-proliferative action of both drugs was associated with a significant reduction in DNA synthesis and the arrest of endothelial cells in the G0/G1 phase of the cell cycle. While pharmacologically relevant concentrations of canagliflozin (10μM) blocked endothelial cell proliferation, much higher supra-pharmacological concentrations of metformin were needed to repress endothelial cell growth. In addition, both drugs inhibited the migration of endothelial cells and the differentiation of endothelial cells into tubes in a concentration-dependent fashion. Furthermore, incubation of endothelial cells with a clinically attainable concentration of metformin (10μM) potentiated the ability of canagliflozin to block endothelial cell proliferation, but not endothelial cell migration or differentiation. In conclusion, metformin and canagliflozin inhibits human endothelial cell proliferation, migration, and tube formation. Moreover, metformin potentiates the anti-proliferative action of canagliflozin, demonstrating a novel and clinically relevant interaction between these two anti-diabetic agents on endothelial cell function. The ability of these drugs to modify endothelial cell function either individually, or in combination, may contribute to their cardiovascular actions in patients with type 2 diabetes mellitus. Support or Funding Information American Diabetes Association Grant #1-17-IBS-290. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.