A Review of the Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitors: A Focus on Diabetic Ketoacidosis.

Abstract

Diabetes is a complex, chronic medical condition affecting 29.1 million people in the United States (9.3% of the population) and is projected to affect one in three Americans by 2050 if the current trend continues (1). Diabetes management can be challenging, often requiring multiple therapeutic agents as the disease progresses. Current guidelines recommend metformin as first-line pharmacological therapy for the treatment of type 2 diabetes. Multiple second-line options are available for patients whose A1C goal is not achieved with monotherapy, and selection should be based on patient- and drug-specific factors. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, the newest U.S. Food and Drug Administration (FDA)–approved oral antidiabetic agents, are among these options for patients with type 2 diabetes. Canagliflozin, dapagliflozin, and empagliflozin are the currently available SGLT2 inhibitors in the United States (2,3). Sodium–glucose cotransporter 1 (SGLT1) is predominantly located in the small intestine, but is also expressed in the kidneys, trachea, heart, and colon (4,5). In the kidneys, SGLT1 is primarily located in the S3 segment of the proximal convoluted tubule (PCT) (4). SGLT2 is expressed in the kidneys and primarily located in the S1 and S2 segments of the PCT (4,5). In normoglycemic adults, about 180 g of glucose (Figure 1) is filtered per day in the glomerulus, and most is reabsorbed (4,6). In people with diabetes, reabsorption of glucose is increased compared to people without diabetes (7,8). SGLT1 and SGLT2 are located in the apical membrane and facilitate the transport of glucose with sodium from the renal tubular lumen into the cells (Figure 2) (4). FIGURE 1. Structures of glucose, phlorizin, canagliflozin, dapagliflozin, and empagliflozin. FIGURE 2. Cotransport of glucose and sodium by SGLT1 and SGLT2 in the PCT. Phlorizin (Figure 1), an O -glucose derivative/ O -glycoside, was discovered in …