Sodium-glucose co-transporter 2 inhibitors for the treatment of type 2 diabetes mellitus
- Anthony DeSantis, MD
Anthony DeSantis, MD
- Clinical Professor of Medicine
- University of Washington Medical School
Current treatments for type 2 diabetes have centered on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose by increasing urinary glucose excretion.
This topic will review the mechanism of action and therapeutic utility of SGLT2 inhibitors for the treatment of type 2 diabetes mellitus. A general discussion of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes is presented separately. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
MECHANISM OF ACTION
The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. The ability to lower blood glucose and glycated hemoglobin (A1C) levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. Moreover, although the currently developed SGLT2 inhibitors almost completely block proximal tubular glucose reabsorption, the measured inhibition is less than 50 percent based on urine glucose excretion.
The glucose-lowering effect is independent of insulin (beta cell function and insulin sensitivity). Thus, they do not usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia. SGLT2 inhibitors decrease blood pressure and weight .
SGLT2 inhibitors are relatively weak glucose-lowering agents, with mean reductions in A1C compared with placebo ranging between 0.4 to 1.1 percent depending on baseline level of hyperglycemia. They have been studied as monotherapy and in combination with metformin, sulfonylureas, pioglitazone, sitagliptin, and insulin [1-5]. Dapagliflozin, canagliflozin, and empagliflozin are available in Europe and the United States [6-8], and other SGLT2 inhibitors are in development.
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- MECHANISM OF ACTION
- GLYCEMIC EFFICACY
- CARDIOVASCULAR EFFECTS
- MICROVASCULAR OUTCOMES
- WEIGHT LOSS
- PRACTICAL MANAGEMENT ISSUES
- Contraindications and precautions
- Choice of therapy
- Pretreatment evaluation
- ADVERSE EFFECTS
- Genitourinary tract
- Acute kidney injury
- Bone fracture
- Diabetic ketoacidosis
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS