New Warnings for SGLT-2 Inhibitors

By Darrell Hulisz, RPh, PharmD
Vanja Raduka, Pha

August 2, 2016

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have been available for treatment of type 2 diabetes mellitus in the United States since early 2013. Drugs in this class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) which work in the kidneys to remove excess glucose via urinary excretion. Last year, the U.S. Food and Drug Administration (FDA) have revised labels of these drugs to include warnings about ketoacidosis, serious urinary tract infections, and bone fracture risk as a result of SGLT-2 inhibitor use.

In June 2016, the FDA replaced the current warnings about the risk of acute kidney injury for canagliflozin and dapagliflozin with more stringent warnings. Since the approval of canagliflozin in 2013 to October of 2015, 101 confirmed cases of acute kidney injury were reported. Some of these cases required prolonged hospital stays or dialysis and some reports occurred in patients under the age of 65. As a result, the FDA now includes information on acute kidney injury and recommendations for prevention on these drug labels.

Prior to starting a patient on either of these SGLT-2 inhibitors, the FDA suggests that health care professionals consider predisposing risk factors for acute kidney injury. Some predisposing conditions include congestive heart failure, hypovolemia, and chronic renal dysfunction. Certain medications that are renally cleared such as diuretics, angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB) and non-steroidal anti-inflammatory drugs (NSAIDs) may also result in acute kidney injury with the use of canagliflozin and dapagliflozin. Regular kidney function monitoring prior to initiating therapy and throughout therapy is recommended. If a patient progresses to acute kidney injury, discontinue the offending agent as soon as possible and treat the renal insult. The FDA advises the health care team to report any adverse reactions that may occur when using these drugs.

Furthermore, as the strengthened warning only pertains to canagliflozin and dapagliflozin, nothing is said about empagliflozin. A recent study (EMPA-REG Outcome trial) investigated the cardiovascular effects and mortality related to type 2 diabetes mellitus with the use of empagliflozin compared to placebo. This randomized, double-blind, placebo-controlled trial's primary outcome was nonfatal stroke or myocardial infarction and death from cardiovascular causes. This primary outcome occurred in 10.5% of patients in the empagliflozin group compared to 12.1% of the placebo group. In addition, a significantly lower portion of the empagliflozin group compared to the placebo group had a risk of death due to cardiovascular causes and death from any cause. Overall, this EMPA-REG study concluded that type 2 diabetics taking empagliflozin may have reduced cardiovascular outcomes compared to placebo although more studies will need to be completed in order to assess the true cardiovascular effects of this drug.

As a result of these recent case reports and strengthened FDA warnings, clearly more information is needed about using SGLT-2 inhibitors in patients with renal impairment. Reporting side effects when they occur is essential for the FDA to properly label these drugs. Lastly, early detection of acute kidney injury and screening patients for predisposing risk factors prior to initiating canagliflozin or dapagliflozin therapy is necessary in all patients who are receiving these medications.