Sodium-glucose cotransporter-2 (SGLT2) inhibitors in Type-2 Diabetes: Risk of acute kidney injury

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June 16, 2016 – The sodium-glucose cotransporter 2 (SGLT2) is a protein that is encoded by the SLC5A2 gene. SGLT2 is one member of a larger family of sodium-glucose cotransporters which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibitors are called gliflozins and are therapeutically useful in the treatment of type 2 diabetes. They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2); their efficacy is dependent on renal excretion and in preventing  glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent. Gliflozins enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure.

To date in the US, three gliflozins have been approved by the American Food & Drug Administration (FDA), namely dapagliflozin, canagliflozin and empagliflozin. They are on the market available as Canagliflozin (Invokana), Canagliflozin / Metformin (Invokamet), Dapagliflozin (Farxiga), Dapagliflozin / Metformin (Xigduo XR), Empagliflozin (Jardiance), Empaglifozin / Linagliptin (Glyxambi), and Empagliflozin /Metformin (Synjardi). The medicines containing any one of the three gliflozins may lead to ketoacidosis. Recently, investigation by the FDA and the European Medicines Agency (EMA) on the dangers of bone fractures and amputations of peripheral in connection with the use of canagliflozin-containing medicines have been launched.

Acute Kidney Injury IIHere, in a new Safety Alert, the FDA has strengthened the existing warning about the risk of acute kidney injury for Canagliflozin (Invokana), Canagliflozin / Metformin (Invokamet), Dapagliflozin (Farxiga), Dapagliflozin / Metformin (Xigduo XR).  Based on recent reports, FDA has revised the warnings in the drug labels to include information about acute kidney injury and added recommendations to minimize this risk.

This action is based on the fact that from March 2013, when Canagliflozin (Invokana) was approved, to October 2015, FDA received reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin- or dapagliflozin-containing medicines (see the data summary in the  Drug Safety Communication).  This number includes only reports submitted to FDA, so there are likely additional cases about which we are unaware.

Health care professionals should consider factors that may predispose patients to acute kidney injury prior to starting them on canagliflozin- or dapagliflozin-containg medicines. These include decreased blood volume; chronic kidney insufficiency; congestive heart failure; and taking other medications such as diuretics, blood pressure medicines called angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). They should assess kidney function prior to starting these medicines and monitor periodically thereafter. If acute kidney injury occurs, the drugs should promptly be discontinued and the kidney impairment treated.

Patients should seek medical attention immediately if they experience signs and symptoms of acute kidney injury. This is a serious condition in which the kidneys suddenly stop working, causing dangerous levels of wastes to build up in the body.  Signs and symptoms of acute kidney injury may include decreased urine or swelling in the legs or feet.  Patients should not stop taking their medicine without first talking to their health care professionals.  Doing so can lead to uncontrolled blood sugar levels that can be harmful. Patients should read the Medication Guide they received with the prescription of any one of the canagliflozin- or dapagliflozin-containing medicines. The Medication Guide explains in detail the benefits and risks associated with the medicine.


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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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