Diabetes mellitus (DM) is a metabolic disorder affecting about 5% to 13% of the population in the US.1 Since 1552, the earliest record of a person with DM, many treatment advances have been made.2Sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the newest antidiabetic pharmaceuticals on the market. The SGLT2 inhibitor drugs include canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin; however, only canagliflozin, dapagliflozin, and empagliflozin have been approved by the US Food and Drug Administration (FDA). These pharmaceuticals promote glycosuria via the kidneys and enhance sugar excretion from the body. Along with lifestyle changes and self-care measures, such as healthful eating and increased physical activity, SGLT2 inhibitor pharmaceuticals provide antidiabetic efficacy by facilitating normoglycemia and minimizing vascular pathology.
Although SGLT2 inhibitor pharmaceuticals are newly introduced into the market, their discovery dates to 1835.3 Phlorizin, a nonselective SGLT inhibitor, was first isolated by French chemists from the bark of an apple tree.4 Phlorizin inhibits SGLT1 mostly in small intestinal cells, and SGLT2 similarly affects the kidney.4 Renal SGLT2 is the primary therapeutic target. Canagliflozin was the first pharmaceutical SGLT2 inhibitor approved by the FDA in 2013. Dapagliflozin’s FDA approval followed in 2013 and empagliflozin in 2014.5
Mechanism Of Action
In healthy individuals, tubular glucose is absorbed, resulting in no urinary glucose excretion. Sodium-glucose cotransporters 1 and 2 contribute to the renal absorption of glucose. A SGLT2 is responsible for 90% of the glucose reuptake in the segment 1 of the proximal tubule, while SGLT 1 is accountable for the remaining 10%.3 Unlike other antidiabetic medications, which act by increasing insulin secretion or improving insulin sensitivity for the receptors, SGLT2 inhibitor drugs prevent the reuptake of glucose into the bloodstream. This selective action spares the inhibition of SGLT1 present in other tissues, avoiding gastrointestinal effects.6
Benefits
The SGLT2 inhibitor action is focused on renal excretion of glucose and is independent of insulin action.
Hemoglobin A1c Levels
Canagliflozin, dapagliflozin, and empagliflozin reduce hemoglobin A1c (HbA1c) levels.5 Inagaki and colleagues found significant reductions in HbA1c and weight gain with > 100 mg canagliflozin compared with that of placebo when used for 12 weeks.7 In a study where 2.5-mg, 5-mg, and 10-mg dapagliflozin was compared with placebo, the mean HbA1c change from the baseline was -0.23% with placebo; -0.58% at 2.5 mg; -0.77% at 5 mg; and -0.89% at 10 mg.8 Empagliflozin was more effective in reducing HbA1c levels than was sitagliptin.9 When patients were treated with 10-mg empagliflozin, 25-mg empagliflozin, and sitagliptin, HbA1c levels dropped -1.44%, -1.43%, and -1.04%, respectively.9
Cholesterol
Sodium-glucose cotransporter 2 inhibitors have the beneficial effect of reducing vascular disease risk factors.10,11 A study by Hayashi and colleagues found that dapagliflozin decreases harmful atherogenic small, low-density lipoprotein-cholesterol (LDL-C), increases less atherogenic large, buoyant LDL-C, and increases high-density, lipoprotein-2 cholesterol (HDL-2C).10 Empagliflozin, however, can cause a small dose-dependent increase in HDL-C and LDL-C.11 Although there is an increase in serum LDL-C concentrations, empagliflozin can induce a decrease in intestinal absorption of cholesterol, thus promoting fecal excretion of LDL-C and macrophage-derived cholesterol.11