Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

Abstract

In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the United States. By inhibiting glucose reabsorption in the proximal tubule, these agents promote glycosuria, thereby reducing blood glucose concentrations and often resulting in modest weight loss. Recent work in humans and rodents has demonstrated that the clinical utility of these agents may not be limited to diabetes management: SGLT2 inhibitors have also shown therapeutic promise in improving outcomes in heart failure, atrial fibrillation, and, in preclinical studies, certain cancers. Unfortunately, these benefits are not without risk: SGLT2 inhibitors predispose to euglycemic ketoacidosis in those with type 2 diabetes and, largely for this reason, are not approved to treat type 1 diabetes. The mechanism for each of the beneficial and harmful effects of SGLT2 inhibitors-with the exception of their effect to lower plasma glucose concentrations-is an area of active investigation. In this review, we discuss the mechanisms by which these drugs cause euglycemic ketoacidosis and hyperglucagonemia and stimulate hepatic gluconeogenesis as well as their beneficial effects in cardiovascular disease and cancer. In so doing, we aim to highlight the crucial role for selecting patients for SGLT2 inhibitor therapy and highlight several crucial questions that remain unanswered.

Keywords: SGLT2 inhibitor; cancer; counterregulation; dehydration; diabetes; diabetic ketoacidosis; euglycemic-ketoacidosis; glucagon; gluconeogenesis; glucose; heart failure; insulinopenia; ketogenesis; lipolysis; type 1 diabetes; type 2 diabetes.

Figure 1.

The location of SGLT1 and SGLT2 transporters in the nephron and the mechanism by which SGLT2 inhibitors promote renal glucose wasting.

Figure 2.

Two-hit hypothesis for the effect of SGLT2 inhibitors to promote euglycemic ketoacidosis via both predisposing to volume depletion and lowering plasma insulin concentrations.

Figure 3.

Proposed mechanisms by which SGLT2 inhibitors may reduce heart failure and improve cardiovascular outcomes.

Figure 4.

Beneficial effects of SGLT2 inhibitors that have been observed in clinical and preclinical studies. Mechanistic trials to explain how these improvements may occur and how they may be interrelated are ongoing.