FDA Issues Second Warning About Invokana and Ketoacidosis

On December 4, 2015, the U.S. Food and Drug Administration finally updated a safety announcement, first issued the previous May, about the serious side effects of a recently-approved class of diabetic “wonder drugs.” The medications of that class are known as gliflozins, or “sodium-glucose cotransporter-2 (SGLT-2) inhibitors”, the best known being Invokana. The specific side effect addressed in the warning is a condition known as ketoacidosis, in which the blood becomes dangerously acidic.

Here is the burning question: given that the FDA started receiving reports of ketoacidosis in March of 2013 (less than a month after the drug was approved), why did it take the agency more than a year and a half to publish that specific warning?

When they were first developed, gliflozins were hailed as a new “miracle drug” in the treatment of Type 2 diabetes. Unlike Type 1 diabetes, in which a patient’s pancreas simply does not produce insulin, Type 2 diabetes results when a patient’s cells develop “insulin resistance.” An earlier class of drugs for this condition, known as glitazones, addressed the problem by “waking up” the cell receptors, making them more responsive to insulin. These drugs were associated with an increased risk of bladder cancer, and were banned in several countries outside the U.S. Gliflozins target a specific protein (SGLT2) that reabsorbs excess blood sugar, allowing it to be excreted through the urine.

Several safety concerns about one glifozin drug were raised even before it was approved. Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, pointed out that drugmaker Janssen Pharmaceutica’s request for FDA approval was based only on how well it controlled glucose levels – with no regard to possible safety concerns and the fact that there was “no evidence of any improved clinical outcomes” for patients.

Despite these concerns, the FDA went ahead and granted approval for Invokana, based on “evidence” demonstrating that the benefits to patients outweighed the risk. That approval was given on the contingency that Janssen monitor the drug for adverse events.  Janssen was given four years to complete any post-marketing studies.

Between March 2013 and May 2015, the FDA received 73 reports of adverse events involving ketoacidosis in diabetic patients being treated with SGLT2 inhibitors. In every one of those cases, the patients ended up needing emergency hospital treatment. Furthermore, the FDA acknowledges that there may very well be more cases that have gone unreported. In 19 other reported cases, patients suffered from urocepsis, a dangerously life-threatening blood infection, as well as a kidney infection known as pyelonephritis, an inflammation that can result in kidney failure and is a common risk for diabetics.

Now, the FDA has required the manufactures of SGLT2 inhibitors such as Invokana and Farxiga to add additional warnings on the packaging labels. Patients are now being advised to cease taking such medications and contact their physicians if they experience any symptoms of ketoacidosis or urinary tract infections.


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