SGLT2 Inhibitors: A New Class of Medications for Type 2 Diabetes Mellitus

Traditionally, primary care clinicians initially treat diabetes (T2DM) through diet, lifestyle changes such as smoking cessation and exercise, and having the patient monitor blood sugar levels. If blood glucose continues to be elevated, medications are prescribed for insulin regulation and/or to increase sensitization of target organs to insulin. Despite these efforts, many diabetic patients do not obtain adequate control of T2DM.  But now, physicians and diabetic patients may have an alternative, a new class of medication, SGLT2 (sodium-glucose cotransporter 2) inhibitors to consider. [1] These include dapagliflozin, canagliflozin, remogliflozin, sergliflozin, ipragliflozin, and tofogliflozin.[2]

Canagliflozin was FDA approved in March, 2013.[3] Its safety and efficacy were evaluated in 9 clinical trials involving over 10,000 subjects with T2DM. The FDA is requiring 5 post-marketing studies to monitor potential long-term adverse events.[4]

Dapagliflozin has been studied in Phase 3 clinical trials [5, 6, 7] and was approved by the European Commission in November, 2012 for the treatment of T2DM in the European Union.[8] Results from clinical trials also suggest that SGLT2 inhibitors may assist diabetic patients control their weight which in turn promotes insulin responsiveness.[9]

SGLT2 is found in the S1 segment of the proximal tubule and is responsible for 90% of reabsorbed glucose by the kidney in individuals without T2DM. In T2DM, due to sustained elevated serum glucose levels, there is an increased capacity for renal glucose reabsorption. When the cotransporter is inhibited, both sodium and glucose are excreted in higher amounts than the kidney would normally allow thus reducing the glucose burden. Studies have shown, in addition to promoting glucose excretion and decreasing A1C, this medication appears to lower blood pressure in subjects with T2DM, perhaps by decreasing the amount of sodium that is excreted in the urine.[10]

Because SGLT2 inhibitors do not directly affect glucose metabolism, these drugs may be complementary to present interventions for glucose regulation.[11] In clinical trials, dapagliflozin was associated with a low occurrence of adverse events in subjects with T2DM.[12] The major adverse event was urinary tract infections, which the researchers suggested may be due to the increased glucose in the urine providing an environment conducive to bacterial growth in the bladder. Long-term consequences of dapagliflozin and other SGLT2 inhibitors in development have yet to be defined.

However, one study found that magnesium and phosphate levels in the blood increased in patients given dapagliflozin. The increase in phosphate possibly occurred due to the increase concentration of sodium being excreted that was reabsorbed with phosphate at a different transporter inside the kidney. An unknown mechanism appears to be involved in the increased serum level of magnesium.[13] Concentrations of these essential electrolytes need to be medically monitored.

Will you likely prescribe canagliflozin for your patients with Type 2 diabetes? Yes  No

 

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  2. Sha S, Devineni D, Ghosh A et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increased urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669–72.
  3. Janssen Pharmaceuticals press release, March 29, 2013. U.S. FDA approves INVOKANA™ (Canagliflozin) for the treatment of adults with type 2 diabetes. Available at: http://www.janssenpharmaceuticalsinc.com/assets/INVOKANA_FDA_Approval_Press_Release.pdf
  4. FDA News Release. FDA approves Invokana to treat type 2 diabetes. First in a new class of diabetes drugs. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm
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  8. AstraZeneca press release November 2012. FORXIGA™ (dapagliflozin) now approved in European Union for treatment of type 2 diabetes. http://www.astrazeneca.com/Media/Press-releases/Article/20121114–forxiga-eu-approval-type-2-diabetes#.UZzSc8_exR8.email
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