Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes

Abstract

BackgroundThe kidney plays an important role in glucose metabolism, and has been considered a target for therapeutic intervention. The sodium-glucose cotransporter type 2 (SGLT2) mediates most of the glucose reabsorption from the proximal renal tubule. Inhibition of SGLT2 leads to glucosuria and provides a unique mechanism to lower elevated blood glucose levels in diabetes. The purpose of this review is to explore the physiology of SGLT2 and discuss several SGLT2 inhibitors which have clinical data in patients with type 2 diabetes.MethodsWe performed a PubMed search using the terms “SGLT2” and “SGLT2 inhibitor” through April 10, 2012. Published articles, press releases, and abstracts presented at national and international meetings were considered.ResultsSGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes. They are generally well tolerated. However, due to side effects, such as repeated urinary tract and genital infections, increased hematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important. Results of ongoing clinical studies of the effect of SGLT2 inhibitors on diabetic complications and cardiovascular safety are crucial to determine the risk-benefit ratio. A recent decision by the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products, including insulin, and as a monotherapy for metformin-intolerant patients. Clinical research also remains to be carried out on the long-term effects of glucosuria and other potential effects of SGLT2 inhibitors, especially in view of the observed increase in the incidence of bladder and breast cancer. SGLT2 inhibitors represent a promising approach for the treatment of diabetes, and could potentially be an addition to existing therapies.

State of the art paper Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns

“…These drugs exert their main activity in the proximal tubule by inhibiting glucose reabsorption, resulting in increased glucose excretion through the kidney; they have also been associated with significant weight loss [ 225 ]. Dapagliflozin has been approved by the European Medicines Agency (EMA) and canagliflozin by the US Food and Drug Administration (FDA) for the treatment of patients with T2D [ 226 ]. Intestinal bypass procedures, mainly Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch, have resulted not only in significant weight reduction but also in the remission of T2D within days or weeks after the procedure; they can also reduce any possible future renal and cardiovascular complications as well as cardiovascular mortality [ 227 – 230 ].…”

Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association

“…In clinical trials, a higher dose of liraglutide is being investigated as a long-term treatment for obesity ( 87 ). The sodium–glucose cotransporter-2 inhibitors block the sodium–glucose cotransporter in the renal tubule and can produce modest weight loss, although long-term safety data are not yet available ( 88 ). If all other things are equal, the health care provider may wish to use antidiabetes drugs that produce weight loss.…”

Sodium Glucose Cotransporter-2 Inhibition in Heart Failure

“…In the kidney, SGLT2 inhibition-mediated proximal tubular natriuresis increases sodium delivery to the macula densa, which activates tubuloglomerular feedback, afferent vasoconstriction and reduces glomerular pressure, as reviewed elsewhere 41, 49, 50 . These intrarenal hemodynamic effects may account for the 30-40% reduction in albuminuria observed with SGLT2 inhibitor agents including empagliflozin, dapagliflozin and canagliflozin 25 .…”