Hormonal, Metabolic and Hemodynamic Adaptations to Glycosuria in Type 2 Diabetes Patients Treated with Sodium-Glucose Co-Transporter Inhibitors

Background & Introduction: The advent of the sodium-glucose cotransporter-2 inhibitors [SGLT-2i] provides an additional tool to combat diabetes and complications. The use of SGLT-2i leads to effective and durable glycemic control with important reductions in body weight/fat and blood pressure. These agents may delay beta-cell deterioration and improve tissue insulin sensitivity, which might slow the progression of the disease.

Methods & Results: In response to glycosuria, a compensatory rise in endogenous glucose production, sustained by a decrease in plasma insulin with an increase in glucagon has been described. Other possible mediators have been implicated and preliminary findings suggest that a sympathoadrenal discharge and/or rapid elevation in circulating substrates (i.e., fatty acids) or some yet unidentified humoral factors may have a role in a renal-hepatic inter-organ relationship. A possible contribution of enhanced renal gluconeogenesis to glucose entry into the systemic circulation has not yet been ruled out. Additionally, tissue glucose utilization decreases, whereas adipose tissue lipolysis is stimulated and, there is a switch to lipid oxidation with the formation of ketone bodies; the risk for keto-acidosis may limit the use of SGLT-2i. These metabolic adaptations are part of a counter-regulatory response to avoid hypoglycemia and, as a result, limit the SGLT-2i therapeutic efficacy. Recent trials revealed important cardiovascular [CV] beneficial effects of SGLT-2i drugs when used in T2DM patients with CV disease. Although the underlying mechanisms are not fully understood, there appears to be "class effect". Changes in hemodynamics and electrolyte/body fluid distribution are likely involved, but there is no evidence for anti-atherosclerotic effects.

Conclusion: It is anticipated that, by providing durable diabetes control and reducing CV morbidity and mortality, the SGLT-2i class of drugs is destined to become a priority choice in diabetes management.