FDA Issues Multiple Warnings For Newest Class of Diabetes Drugs

Over the past year, the Food and Drug Administration (FDA) has issued a series of new warnings about serious and, in some cases, potentially fatal events linked to the newest class of diabetes drugs, known as “flozins.” This drug class includes the following FDA-approved products: canagliflozin (INVOKAMET, INVOKANA), dapagliflozin (FARXIGA, XIGDUO XR) and empagliflozin (GLYXAMBI, JARDIANCE, SYNJARDY). Flozins lower blood sugar levels by causing the kidneys to dump glucose into the urine. They are approved only for treatment of Type 2 diabetes.

The recent flurry of FDA warnings reinforces our earlier decision to designate these drugs as Do Not Use, in part because they carry numerous risks — including a significant risk of kidney disease — and offer no advantages over several older, safer diabetes drugs.[1]

Acid buildup

On Dec. 4, 2015, the FDA announced that it had revised the labels for all flozins to include warnings about the risk of ketoacidosis, a serious, sometimes fatal condition caused by the buildup of ketones, a type of acid, in the blood.[2] The agency had issued an initial safety alert about this adverse event in May 2015.[3]

Symptoms of ketoacidosis include difficulty breathing, nausea, vomiting, abdominal pain, confusion and severe fatigue or sleepiness.

The FDA noted that from March 2013 — when the first flozin, canagliflozin, was approved — to May 2015, 73 cases of ketoacidosis in patients treated with flozins had been reported to the agency. All patients required emergency room treatment or hospitalization. Most of the patients had Type 2 diabetes, but 15 had Type 1 diabetes, a condition in which the body no longer makes insulin. The flozins are not FDA- approved for treating Type 1 diabetes.

The FDA’s analysis suggested that flozin-treated patients may be more likely to develop ketoacidosis if they have infections, decreased food intake due to illness or surgery, a reduction in insulin dose, or alcohol abuse.

Serious infections

On Dec. 4, 2015, the FDA also announced that it had revised the labels for all flozins to include warnings about the risk of kidney infections and urosepsis.[4] Urosepsis is a life-threatening complication of urinary tract infections (UTIs), particularly kidney infections, involving the spread of bacteria from the urinary tract to the bloodstream.

The increased levels of glucose in the urine caused by flozins, which is the drugs’ desired effect, promotes bacteria growth in the urine, making patients susceptible to more frequent and more serious UTIs. When the flozins were initially approved, their labels indicated that UTIs were among the most frequent adverse events associated with the drugs.[5],[6],[7] But none of these initial labels warned of serious UTIs, such as kidney infections, or urosepsis.

The new, stronger warning was prompted by an FDA review of adverse event reports submitted to the agency: From March 2013 to October 2014, the FDA received reports of 19 cases of urosepsis associated with flozin use (10 involving canagliflozin and nine dapagliflozin). All patients required hospitalization, but no deaths were reported. Four patients needed treatment in an intensive care unit, and two underwent dialysis for kidney failure. Eight of the patients had documented blood test results showing bacteria in their bloodstreams.

Amputations

On May 18, 2016, the FDA alerted doctors and patients that the agency is investigating a possible association between canagliflozin and an increased risk of leg and foot amputations.[8]

People with diabetes already have a greater risk of foot and leg amputations than those without diabetes. Diabetes patients often develop peripheral vascular disease, which reduces blood flow to the legs and feet. Many also have damaged nerves, which reduces sensation. These factors together make it easier to get foot ulcers and infections that may lead to amputation.[9]

The basis for the FDA’s new warning about canagliflozin was an interim analysis of safety data from an ongoing clinical trial, the Canagliflozin Cardiovascular Assessment Study. The trial involves long-term follow-up of Type 2 diabetes patients who have been randomly assigned to receive canagliflozin or a placebo.

The interim analysis revealed that after an average follow-up period of more than four years, amputations occurred about twice as often in patients treated with canagliflozin as in those receiving placebos. Most of the amputations involved toes. The FDA has not required the addition of any warning about the risk of amputations to the label for canagliflozin.

Kidney damage

Finally, on June 14, 2016, the FDA announced that the agency was strengthening the existing label warnings for canagliflozin and dapagliflozin regarding impaired kidney function. The FDA required the inclusion of new information about the risk of acute kidney failure and steps that should be taken to minimize this risk.[10]

Acute kidney failure is a serious condition in which the kidneys suddenly stop working, causing dangerous levels of wastes to build up in the body. Symptoms of acute kidney injury may include decreased urination, swelling, nausea and vomiting.

When the flozins were initially approved, their labels indicated that decreases in kidney function can occur when using the drugs and that elderly patients and those with existing kidney disease or dehydration are at greater risk.[11],[12],[13] The labeling also recommended periodic monitoring of patients’ kidney function. The decreased kidney function seen with flozins results from excess sugar in the urine, which leads to increased urination and subsequent dehydration.

The FDA’s decision to strengthen these warnings for canagliflozin and dapagliflozin was triggered by an agency review of its adverse event reporting system data. From March 2013 to October 2015, the FDA received reports of 101 cases of acute kidney injury in patients taking canagliflozin or dapagliflozin. In more than 50 percent of the cases reported to the FDA, the kidney injury occurred within a month of starting a flozin. Some patients required hospitalization or dialysis. Eleven patients did not recover, including four who died.

What You Can Do

You should not use any flozin drug. If you are currently taking one of these drugs, talk to your doctor about changing to a safer alternative. For more detailed recommendations about Type 2 diabetes treatments, visit www.WorstPills.org or see the May 2014 issue of Worst Pills, Best Pills News.

References

[1] Risks but no benefits to taking newest drugs for type 2 diabetes. Worst Pills, Best Pills News. /newsletters/view/981. Accessed July 14, 2016.

[2] Food and Drug Administration. FDA drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. December 4, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed July 15, 2016.

[3] Food and Drug Administration. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. May 15, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed July 14, 2016.

[4] Food and Drug Administration. FDA drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. December 4, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed July 16, 2016.

[5] Janssen Pharmaceuticals. Label: canagliflozin (INVOKANA). March 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf. Accessed July 16, 2016.

[6] Bristol-Myers Squibb. Label: dapagliflozin (FARXIGA). January 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf. Accessed July 16, 2016.

[7] Boehringer Ingelheim. Label: empagliflozin (JARDIANCE). August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf. Accessed July 16, 2016.

[8] Food and Drug Administration. FDA drug safety communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. May 18, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm. Accessed July 16, 2016.

[9] American Diabetes Association. Foot complications. http://www.diabetes.org/living-with-diabetes/complications/foot-complications/?referrer=https://www.google.com/. Accessed July 17, 2016.

[10] Food and Drug Administration. FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). June 14, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm. Accessed July 16, 2016.

[11] Janssen Pharmaceuticals. Label: canagliflozin (INVOKANA). March 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf. Accessed July 16, 2016.

[12] Bristol-Myers Squibb. Label: dapagliflozin (FARXIGA). January 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf. Accessed July 16, 2016.

[13] Boehringer Ingelheim. Label: empagliflozin (JARDIANCE). August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf. Accessed July 16, 2016.