FDA Adds Ketoacidosis and Urinary Tract Infection Warnings to SGLT2 Inhibitor Labeling

Commentary by Jack Leahy, MD and Yehuda Handelsman, MD

Elderly Woman Reading Warning Labels on Pill BottlesThe U.S. Food and Drug Administration added warnings about ketoacidosis and serious urinary tract infections to labels of all SGLT2 inhibitors on December 4, 2015. The warnings were made based on reports received through the FDA Adverse Event Reporting System (FAERS) database.

“These warnings are very important because they inform health care providers and patients that there are important side effect issues with these drugs,” said Jack Leahy, MD, Professor of Medicine and Co-Director of the Division of Endocrinology, Diabetes, and Metabolism at the University of Vermont in Colchester, VT. “This information is important not only for prescribers, but also for emergent department staff to be aware that if a patient with diabetes taking SGLT2 inhibitors presents with relatively subtle signs of ketoacidosis (nausea or vomiting, dyspnea, or unexplained abdominal pain or fatigue), they need to be screened by measuring serum electrolytes and urinary ketones in addition to assessing blood glucose levels,” said Dr. Leahy, who also is a member of the Endocrine Society.

Ketoacidosis Warning
The FDA recommends that patients who have any symptoms of ketoacidosis (nausea, vomiting, abdominal pain, unusual tiredness, and trouble breathing) should seek immediate medical attention. The FDA noted that ketoacidosis may occur in patients with blood glucose levels of <250 mg/dL, and that health care professionals should assess for ketoacidosis in patients with suggestive symptoms. In patients who are suspected of having ketoacidosis, SGLT2 inhibitors should be discontinued immediately and treatment for ketoacidosis (insulin, fluids, and carbohydrate replacement) should be initiated promptly.

The FDA also suggested that patients should check their urine for ketones using ketone dipsticks whenever possible. Patients may be at risk for ketoacidosis if they have a history of pancreatic insulin deficiency, caloric restriction, and alcohol abuse.

SGLT2 inhibitors are sometimes used off label for patients with type 1 diabetes, who are already at increased risk for ketoacidosis and should be testing ketone levels regularly, Dr. Leahy noted. “Where this can be complicated, is when patients don’t feel well or have nausea and vomiting, the first thing they will check is their blood sugar level. If the blood sugar level is not so high that they are scared, then they usually won’t check their urine ketone levels.”

“We teach patients with type 1 diabetes that when they have nausea or vomiting, or just don’t feel well, they need to check not only their blood sugar level, but also their urinary ketone levels,” Dr. Leahy explained. “This is particularly true for patients who are receiving an SGLT2 inhibitor off-label.”

“In contrast, virtually no patients with type 2 diabetes are taught how to use urine ketone sticks or have them at home,” Dr. Leahy said. “More and more physicians are realizing that this is a rare but real potential problem with SGLT2 inhibitors, and patients do need to check urine ketone levels at home under the same circumstances.”

Urinary Tract Infection Warning
The FDA recommended that patients be alert and contact a health care professional if they have any signs and symptoms of urinary tract infections (UTIs), such as a burning feeling when urinating, the need to urinate often or right away, pain in the lower stomach area or pelvis, fever, or blood in the urine. Health care professionals should treat UTIs promptly if indicated, according to the FDA.

Basis for the Warnings
Between March 2013 (when the first SGLT2 inhibitor was approved) and May 2015, 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors were reported to the FDA. All patients were hospitalized or treated in an emergency department. While SGLT2 inhibitors are not FDA-approved for use in patients with type 1 diabetes, 15 cases involved patients with this form of diabetes.

Between March 2013 and October 2014, 19 cases of life-threatening urosepsis (blood infection) and pyelonephritis (kidney infections) that began as urinary tract infections in patients taking SGLT2 inhibitors were reported to the FDA. All patients were hospitalized and some required intensive care unit admission (n=4) or dialysis (n=2).

Manufacturers of SGLT2 inhibitors (see Table for brands) are required to conduct post-marketing studies for up to 5 years to assess for these potential adverse effects of treatment.
Table. Brands of SGLT2 Inhibitors

Patients on SGLT2 Inhibitors Should Take Proper Doses of Insulin, Expert Says
“This is a follow-up to a warning the FDA made in May 2015 on the potential risk of ketosis and ketoacidosis when treating patients with SGLT2 inhibitors,” commented Yehuda Handelsman, MD, Medical Director of the Metabolic Institute of America in Tarzana, CA. “In short, this announcement just reinforces that it is important to make sure that people on insulin and SGLT2 inhibitors continued to take proper doses of insulin.”

Dr. Handelsman added that patients exposed to severe stress (eg, surgery, sepsis, extreme physical activity, stroke, myocardial infarction) should consider stopping the SGLT2 inhibitor treatment, under the guidance of their physician. “It is important to note that these recommendations are similar when taking any oral antihyperglycemic agent,” said Dr. Handelsman, who is Immediate Past President of the American College of Endocrinology (ACE).

SGLT2 inhibitors should not be used off-label for the treatment of type 1 diabetes, Dr. Handelsman said. Patients with type 2 diabetes, who are already taking insulin therapy, should have more frequent monitoring for ketoacidosis, he noted.

Dr. Handelsman was surprised to see the warning regarding UTIs and urosepsis, and noted that there seem to be few cases in the FAERS database. “Patients with diabetes mellitus are at a higher risk for these conditions, and we have the impression that with just 19 cases out of millions prescription, the risk may be lower with this class of medications compared to others. In fact, I would like to see a comparative study,” he said.

AACE and ACE Say Risk-Benefit Ratio Favors SLGT2 Inhibitors
A recent panel of experts convened by the American Association of Clinical Endocrinologists (AACE) and ACE concluded that the prevalence of diabetic ketoacidosis is infrequent and the risk-benefit ratio overwhelmingly favors continued use of SGLT2 inhibitors with no changes in current recommendations.

The panel of experts concluded that “For individuals with type 2 diabetes (T2D), it is unclear whether DKA occurs at a higher frequency than it did before the advent of SGLT2 inhibitors.” In addition, the panel concluded that the majority of ketoacidosis cases occur in patients with diabetes who are insulin deficient, such as those with long-standing type-2 diabetes, latent autoimmune diabetes in adults, and type 1 diabetes.


December 8, 2015


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