Metabolic and hemodynamic effects of sodium‐dependent glucose cotransporter 2 inhibitors on cardio‐renal protection in the treatment of patients with type 2 diabetes mellitus

Abstract

The specific sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β‐cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole‐body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio‐renal protection through metabolic and hemodynamic effects, with long‐term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole‐body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio‐renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes.

Impact of obesity on annual medical expenditures and diabetes care in Japanese patients with type 2 diabetes mellitus

“…Finally, the present study was carried out before 2014, when SGLT2 inhibitors became commercially available in Japan. SGLT2 inhibitors reportedly have numerous beneficial medical effects on diabetes care, such as reduced hyperglycemia, hypertension and bodyweight. In addition, the growing use of SGLT2 inhibitors might influence medical expenditures and the number of prescribed medications in obese patients with type 2 diabetes.…”

Sodium–glucose cotransporter 2 inhibitor‐associated diabetic ketoacidosis in patients with type 1 diabetes: Metabolic imbalance as an underlying mechanism

“…Sodium–glucose cotransporter 2 (SGLT2) inhibitors, the newest class of oral antidiabetes drugs for type 2 diabetes, ameliorate hyperglycemia primarily by preventing the reabsorption of urinary glucose in the kidneys. Within less than 5 years, abundant evidence for favorable characteristics of SGLT2 inhibitors has accumulated.…”

“…Within less than 5 years, abundant evidence for favorable characteristics of SGLT2 inhibitors has accumulated. Of note, large‐scale clinical trials have shown that these drugs prevent cardiovascular events, at least in cohorts at high risk for such events, and that they slow the decline in renal function. Whereas metabolic and humoral changes induced secondarily by SGLT2 inhibition likely contribute to the beneficial effects of these drugs, the full picture regarding such changes remains unclear.…”

“…Treatment with SGLT2 inhibitors is often associated with an increase in the blood concentration of ketone bodies. Given that these drugs lower blood glucose levels through a mechanism independent of insulin, their amelioration of hyperglycemia leads to the suppression of insulin secretion from pancreatic β‐cells.…”

Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure

“…SGLT2i may induce relative glucose deficiency, and then may trigger increased lipolysis and fatty acid oxidation which increase hepatic ketone body production [7]. SGLT2 is expressed in pancreatic α cells, and SGLT2i promote glucagon secretion [8].…”