Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. In patients with type 2 diabetes mellitus, SGLT2 inhibitors have been found to consistently reduce measures of hyperglycemia, including hemoglobin A1c, fasting plasma glucose, and postprandial glucose, throughout the continuum of disease. By inducing the renal excretion of glucose and its associated calories, SGLT2 inhibitors reduce weight and have the potential to be disease modifying by addressing the caloric excess that is believed to be one of the root causes of type 2 diabetes mellitus. Additional benefits, including the possibility for combination with insulin-dependent antihyperglycemic drugs, a low potential for hypoglycemia, and the ability to reduce blood pressure, were anticipated from the novel mechanism of action and have been demonstrated in clinical studies. Mechanism-related risks include an increased incidence of urinary tract and genital infections and the possibility of over-diuresis in volume-sensitive patients. Taken together, the results of Phase III clinical studies generally point to a positive benefit-risk ratio across the continuum of diabetes patients. To date, data on dapagliflozin, a selective SGLT2 inhibitor in development, demonstrate that the kidney is an efficacious and safe target for therapy, and that SGLT2 inhibition may have benefits for patients with type 2 diabetes mellitus beyond glycemic control.

Responses of renal hemodynamics and tubular functions to acute sodium–glucose cotransporter 2 inhibitor administration in non-diabetic anesthetized rats

“…These studies have indicated that SGLT2 inhibitor-induced reduction in GFR is associated with an increase in the activity of tubuloglomerular feedback (TGF) mechanism. However, SGLT2 inhibitor did not have a significant effect on GFR in the early diabetic condition 18 . In agreement with the results in non-diabetic mice 9 and rats 19 , our data also showed that acute infusion of luseogliflozin did not have any immediate significant effects on renal hemodynamics in non-diabetic SD rats.…”

Changes in HbA1c, body weight, and systolic blood pressure in type 2 diabetes patients initiating dapagliflozin therapy: a primary care database study

“…The results from the present real-world study demonstrate that similar reductions in BW (−2.5 kg at 6 months) can be achieved in primary care patients. This weight loss has been attributed to the ~200–300 cal of glucose excreted per day as a result of treatment with dapagliflozin 23. Although the impact of this amount of weight loss on mortality and cardiovascular events is debatable, even small weight decreases in T2D have been shown to improve treatment satisfaction and quality of life 24,25…”

Synthesis of empagliflozin, a novel and selective sodium‐glucose co‐transporter‐2 inhibitor, labeled with carbon‐14 and carbon‐13

“…The molecule itself was known since 1835 and is a naturally occurring compound isolated from the bark of pear, apple, cherry, and other fruit trees . This compound was superseded by better and more selective synthetic analogs like canagliflozin,, dapagliflozin, and empagliflozin (Figure ).…”