To maintain the benefits while minimizing risk, consider patient risk factors when prescribing, and monitor for DKA and UTI.
An FDA safety review on sodium-glucose cotransporter-2 (SGLT-2) inhibitors resulted in additional warnings to the label on ketoacidosis, urosepsis, and pyelonephritis.
SGLT-2 are sodium-dependent glucose transport proteins, which can be found in the kidneys. SGLT-2 works on the main site of filtered glucose reabsorption in the kidneys resulting in reduction of glucose reabsorption and increasing urinary excretion of glucose. This in turn lowers the blood glucose levels in the body. Some of SGLT-2 inhibitors include empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana).
In a review of the FDA Adverse Event Reporting System (FAERS) database from March 2013 to May 2015, there were 73 identified cases of ketoacidosis in diabetic patients on SGLT-2 inhibitors. Ketoacidosis occurs when your body does not get enough glucose for its needs and starts burning fat for energy. Ketoacidosis can also occur from a lack of insulin for the body to utilize its glucose. When the body turns to fat for energy, it produces a byproduct known as ketones. As ketones build up in the blood, the blood become more acidic resulting in diabetic ketoacidosis (DKA), which is a serious condition that can lead to diabetic coma or even death.
Patients should watch out for early signs and symptoms of DKA such as thirst, dry mouth, frequent urination, high blood glucose levels, or high levels of ketones in the urine. As DKA progresses, other symptoms will appear such as fatigue, dry or flushed skin, nausea, vomiting, difficulty breathing, fruity odor on breath, or confusion. Ketone levels can be monitored with a simple urine test using a test strip. It is recommended that patients check their ketone levels when their blood glucose is greater than 240 mg/dl. If patients feel any of the above symptoms, their healthcare care provider should be contacted immediately.
In addition to ketoacidosis, the FDA has identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that were reported to FAERS from March 2013 through October 2014. All 19 cases resulted in hospitalization with severe cases resulting in admission to an intensive care unit or dialysis to treat kidney failure.
Patients on SGLT-2 inhibitors have increased risk of developing urinary tract infections, which can lead to pyelonephritis as the infection progresses to the upper urinary system. Ureters are tubes that carry urine from the kidneys to the bladder. Pyelonephritis develops from a UTI when bacteria travels up the ureters to the kidneys. From the kidneys, the infection can further spread to the blood resulting in urosepsis. Some signs and symptoms of an UTI are painful, urgent, or frequent ruining. Once pyelonephritis develops, patients can experience back or flank pain, fever, malaise, nausea and vomiting, and confusion. There are also noticeable changes to the urine such as hematuria or cloudy foul smelling urine. Pyelonephritis can be diagnosed with urinalysis, urine culture, or a blood culture if it has spread to the blood.
As a result of these findings, the FDA has added new warnings to labels of all SGLT-2 inhibitors. The FDA has also mandated that manufacturers of SGLT-2 inhibitors conduct post-marketing study looking at spontaneous post-marketing reports of ketoacidosis in patients on SGLT-2 inhibitors for a period of 5 years.
The FDA recommends that healthcare professionals should assess patients on SGLT-2 inhibitors for ketoacidosis and urinary tract infections. If a patient is suspected as having ketoacidosis, the SGLT-2 inhibitor should be stopped immediately and treatment for ketoacidosis started promptly. Healthcare providers and patients are encouraged to report adverse events or side effects to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
- FDA issues two new Warnings and Precautions to the labels of all SGLT-2 inhibitors for ketoacidosis and risk of serious urinary tract infection.
- Before prescribing an SGLT-2 inhibitor, assess any factors in the patient’s history that may predispose to ketoacidosis.
- Patients on SGLT-2 inhibitors should be assessed for ketoacidosis. If suspected of ketoacidosis, the medication should be discontinued immediately and treatment for ketoacidosis started promptly.
- Patients on SGLT-2 should be assessed for urinary tract infection, which can progress to pyelonephritis or even life-threatening urosepsis. Counseling patients on UTI signs and symptoms, and the need to seek medical care if these occur, is also recommended.
“SGLT-2 Inhibitors: Drug Safety Communication – Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections”. US Food and Drug Administration. 7 December 2015. “DKA (Ketoacidosis) and Ketones.” American Diabetes Association. 7 December 2015