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A large number of patients with type 2 diabetes do not maintain optimal plasma glucose levels, even with the use of current treatment options. There is, therefore, a need for development of novel treatment strategies. A new class of diabetes medication is making its way onto the market; these medications act in a completely different way than current treatments for type 2 diabetes. They act independently of insulin, inhibiting the activity of Sodium Glucose Transporter-2 (SGLT2), and have thus been termed SGLT2 Inhibitors. Available data suggests that SGLT2 inhibitors are generally safe and well tolerated and are currently the subject of extensive clinical research.

The kidneys are a key contributor in controlling glucose levels in the blood. Once blood is filtered by the kidneys, glucose is reabsorbed back into the plasma, thus maintaining blood-glucose levels. SGLT2 is a low-affinity, high capacity glucose transporter protein found in the kidneys, and is responsible for 90% of glucose reabsorption. SGLT2 inhibitors block this reabsorption of glucose by SGLT2 in the kidneys, thereby increasing the amount of glucose excreted in the urine. Ultimately, this results in an overall reduction in blood-glucose levels.

This mode of blocking SGLT2 activity is an attractive new strategy as, unlike current treatment options, SGLT2 inhibitors are completely independent of insulin secretion, suggesting that these drugs impose a low risk of hypoglycemia.  Moreover, because of their unique mechanism of action, they may also prove useful in combination with current therapies for type 2 diabetes.

There are several SGLT2 inhibitors currently in clinical trials, including: Empagliflozin, Ipragliflozin, Dapagliflozin, and Canagliflozin. The first in-class SGLT2 inhibitor, and currently the only one approved by the Federal Drug Administration (USA) for treatment of type 2 diabetes, is Canagliflozin.

Recently published in The Lancet, Professor Cefalu and colleagues conducted a safety and efficacy study of Canagliflozin. They reported a greater reduction in plasma glucose compared to the anti-diabetic drug, Glimepiride. They report that Canagliflozin is well tolerated in patients with type 2 diabetes who are receiving Metformin, with the most common side effects being vaginal yeast infections and urinary tract infections. However, approval of Canagliflozin by the FDA required five further studies assessing long-term cardiovascular safety, enhanced pharmacovigilance studies, and pediatric studies. These studies are currently underway in centers across the USA and around the world.

Inhibiting renal glucose reabsorption and increasing urinary glucose excretion is a novel strategy for treating type 2 diabetes. Moreover, because SGLT2 inhibitors act independently of insulin, they are potentially still effective in patients with advanced diabetes, whose beta cell function is low. SGLT2 Inhibitors are showing great promise in clinical trials, and future studies will continue to elucidate the potential this class of drugs has in treating patients with type 2 diabetes.

 

William T Cefalu, Lawrence A Leiter, Kun-Ho Yoon, Pablo Arias, Leo Niskanen, John Xie, Dainius A Balis,William Canovatchel, Gary Meininger. “Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial” The Lancet 382(9896): 941-950, Sept 2013.

Michaela Diamant, Linde M Morsink. “SGLT2 inhibitors for diabetes: turning symptoms into therapy” The Lancet, 382(9896): 917-918, Sept 2013.

ClinicalTrials.gov “A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R)” Available from: http://clinicaltrials.gov/ct2/show/NCT01989754?term=NCT+01989754&rank=1 Last Accessed: Dec 10, 2013.

ClinicalTrials.gov “A Study to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of Canagliflozin in Older Children and Adolescents With Type 2 Diabetes Mellitus” Available from: http://clinicaltrials.gov/ct2/show/NCT02000700?term=NCT02000700&rank=1 Last Accessed: Dec 16, 2013.

ClinicalTrials.gov “A Study to Evaluate the Effectiveness, Safety, and Tolerability of Canagliflozin in Combination With Metformin in the Treatment of Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control With Diet and Exercise” Available from: http://clinicaltrials.gov/ct2/show/NCT01809327?term=NCT01809327&rank=1 Last Accessed: Dec 16, 2013.

ClinicalTrials.gov “A Study to Compare the Pharmacodynamics of Canagliflozin and Dapagliflozin in Healthy Volunteers” Available from: http://clinicaltrials.gov/ct2/show/NCT01877889?term=NCT01877889&rank=1 Last Accessed: Dec 16, 2013.

ClinicalTrials.gov “Evaluation of Blood Pressure Reduction, Safety, and Tolerability of Canagliflozin in Patients With Hypertension and Type 2 Diabetes Mellitus on Stable Doses of Anti-hyperglycemic and Anti-hypertensive Agents” Available from: http://clinicaltrials.gov/ct2/show/NCT01939496?term=NCT01939496&rank=1 Last Accessed: Dec 16, 2013.

 

 

Written by Deborah Tallarigo, PhD

 

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