FDA Issues News Warnings for SGLT2 Inhibitors

A safety review by the FDA has led to new warnings to the prescribing information for sodium-glucose co-transporter 2 (SGLT2) inhibitors used to treat type 2 diabetes.
A safety review by the FDA has led to new warnings to the prescribing information for sodium-glucose co-transporter 2 (SGLT2) inhibitors used to treat type 2 diabetes.

A safety review conducted by the Food and Drug Administration (FDA) has led to new warnings added to the prescribing information for sodium-glucose co-transporter 2 (SGLT2) inhibitors used to treat type 2 diabetes. 

SGLT2 inhibitors are a class of drugs that are approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Affected drugs in this class are canagliflozin, dapagliflozin, and empagliflozin.

The new labeling update includes information about the risks of ketoacidosis and serious urinary tract infections—both conditions which can lead to hospitalization. The Warnings and Precautions section also provides prescribing and monitoring recommendations.

In May 2015, the FDA issued a warning about the risk of ketoacidosis with SGLT2 inhibitors and alerting that it would be under continued investigation. A total of 73 cases of ketoacidosis were identified from the FDA Adverse Event Reporting System (FAERS) from March 2013 to May 2015 in patients with type 1 or 2 diabetes that were treated with SGLT2 inhibitors. SGLT2 inhibitors are not FDA-approved to treat patients with type 1 diabetes mellitus.

An additional 19 cases of urosepsis and pyelonephritis were identified from March 2013 to October 2014 that started as urinary tract infections with SGLT2 inhibitors. All patients were hospitalized and some required admission to the intensive care unit or dialysis to treat renal failure.

The FDA is requiring manufacturers to perform a required postmarketing pharmacovigilance study to analyze spontaneous reports of ketoacidosis in patients treated with SGLT2 inhibitors, including specialized follow-up to obtain additional data for up to 5 years. Patients are recommended to discontinue SGLT2 inhibitor use and seek medical attention if they experience any symptoms of ketoacidosis (eg, nausea, vomiting, abdominal pain, tiredness, trouble breathing).

Healthcare professionals are recommended to assess for ketoacidosis and urinary tract infections in patients who present with suggestive symptoms. Before initiating an SGLT2 inhibitor, clinicians should consider factors in the patients' histories that may predispose them to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. Patients treated with an SGLT2 inhibitor who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis, regardless of the presenting blood glucose levels.  

Ketoacidosis associated with SGLT2 inhibitors may be present even if blood glucose levels are less than 250mg/dL. In many of the reported cases, particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized, and treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250mg/dL). In patients treated with an SGLT2 inhibitor, consider monitoring for ketoacidosis and temporarily discontinuing the drug in clinical situations known to predispose to ketoacidosis, such as prolonged fasting due to acute illness or surgery.

With regards to serious urinary tract infections, clinicians should evaluate patients for signs and symptoms and treat promptly if indicated. Details regarding the administered antibiotic agent, course of antibiotic treatment, and evidence of relapse or recurrent infection were not provided in any of the cases.

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