Building Competency in Diabetes Education THE ESSENTIALS

TREATMENT MODALITIES: PHARMACOLOGICAL THERAPIES | 6-36

Sodium Glucose Co-transporter 2 (SGLT2) Inhibitors The kidney normally filters approximately 180 g of glucose each day and reabsorbs 99% of filtered glucose back into circulation; thereby contributing to overall glycemic levels. Sodium- glucose transport proteins in the proximal renal tubule facilitate glucose reabsorption in the kidney (SGLT2: 90% of the glucose reabsorption and SGLT1: 10% of glucose reabsorption). Studies have shown the expression of SGLT2 is enhanced in type 2 diabetes, (i.e. there is upregulation of SGLT2 receptors), resulting in increased renal glucose reabsorption (i.e. more receptors can reabsorb more spilled glucose from the urine), a higher renal threshold for glucosuria (i.e. as more glucose can be reabsorbed from the urine, the body works to preserve hyperglycemia and glucose does not spill into the urine until higher blood glucose levels) , leading to elevated blood glucose levels (76,77) . SGLT2 inhibitors block the reabsorption of glucose in the kidney, thereby decreasing glucose reabsorption, and promoting glycosuria. The result is a decrease in blood glucose levels, weight reduction(2-3 kg) due to the loss of calories (approximately 200-300 calories/day) and blood pressure reduction due to increased sodium excretion (77). The effect of SGLT2 inhibitors is: • independent of insulin; therefore this agent can be used at any stage of declining beta cell function • blood glucose-dependent; there is a minimal risk of hypoglycemia as, when blood glucose is high, the proximal tubules are exposed to more glucose, more glucose is available for reabsorption via SGLT receptors; whereas when blood glucose is “normal”, the SGLT receptors in the proximal tubule can only reabsorb what passes into the proximal tubule (i.e.less glucose passes into the proximal tubule, and less glucose is reabsorbed). Exception: hypoglycemia is possible when SGLT2 inhibitors are used in combination with other agents are associated with hypoglycemia (e.g. secretagogues, insulin). The CVD-Real Study included 309,056 participants from six countries newly initiated on SGLT2 inhibitors or other glucose lowering therapies. The study compared rates of hospitalization for heart failure (HHF) and death. Only 13% of subjects had established cardiovascular disease (78). The study concluded SGLT2 inhibitors were associated with a (p<0.001): • 39% decrease incidence of HHF • 51% lower rate of death • 46% lower rate of combined HHF or all-cause death SGLT2 inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA) in people with type 1 and type 2 diabetes (79). A meta-analysis of 10 randomized control trials, involving over 13,000 subjects, reported the rate of DKA with SGLT2 inhibitor use was <0.1% (80). The number of reported cases were higher in people with type 1 diabetes (off-label use) and, in many cases, these individuals presented with euglycemic ketoacidosis with BG levels only