Empagliflozin in the treatment of type 2 diabetes: evidence to date

Abstract

In the last decade, researchers have gained a greater understanding of the pathophysiologic mechanisms of type 2 diabetes as a chronic and progressive disease. One of the more recent treatment targets is the kidney. The kidneys become maladaptive in diabetes by increasing the reabsorption of glucose above the normal physiologic renal threshold. This discovery has led to the development of the sodium/glucose cotransporter 2 inhibitors (SGLT2). These agents readjust the renal threshold for glucose reabsorption to a lower level and decrease glucose reabsorption, while increasing urinary glucose when the glucose is above the renal threshold and subsequently lowering plasma glucose. The mechanism of action of the SGLT2 inhibitors is insulin independent, which makes them a novel treatment of diabetes. At the time of preparation of this manuscript, there were three SGLT2 inhibitors available in the US. This manuscript focuses on empagliflozin, the newest SGLT2 inhibitor, the trials in its development, and the clinical data available to date. Further, the authors propose future applications of empagliflozin, including in the treatment of type 1 diabetes, and its potential role in renoprotection.

Keywords: SGLT-2 inhibitors; empagliflozin; glucosuria; kidneys; type 1 diabetes; type 2 diabetes.

Figure 1

Physiology of glucose reabsorption in the proximal convoluted tubule. Note: Reproduced from Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12(2):78–89, copyright ©2015 by (SAGE Publications). Reprinted by Permission of SAGE Publications, Ltd. Abbreviations: GLUT, glucose transporter; PT, proximal tubule; KCNE1, potassium voltage-gated channel Isk-related family member 1; KCNQ1, potassium voltage-gated channel KQT-like subfamily member 1; SGLT, sodium-dependent glucose transporter.

Figure 2

Downstream renal effects of SGLT1 and SGLT2 inhibition. Note: Reproduced from Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res 2015;12(2):78–89, copyright ©2015 by (SAGE Publications). Reprinted by Permission of SAGE Publications, Ltd. Abbreviations: GLUT, glucose transporter; SGLT, sodium glucose transporter; PT, proximal tubule; LOH, loop of Henle; DT, distal tubule; CD, collecting duct; NHE3, sodium hydrogen exchanger-3; EGP, endogenous glucose production; SNGFR, single nephron glomerular filtration rate; TGF, tubuloglomerular feedback.

Figure 3

Chemical structure of empagliflozin (Jardiance^®).