What’s the Problem?
On May 15, 2015, the U.S. Food and Drug Administration (FDA) issued a warning regarding a potential increased risk of diabetic ketoacidosis associated with Invokana and other SGLT2 inhibitor diabetes drugs. The alert followed reports of at least 20 patients who developed the condition between March 2013 and April 2014 after taking SGLT2 inhibitors.
Ketoacidosis Warning Added to Invokana Labeling
As a result of the ketoacidosis reports associated with SGLT2 inhibitors, FDA on December 4, 2015, required that the labeling of these medications be updated with information about this risk. The labels will also include new prescribing and monitoring recommendations for healthcare providers.
What is Diabetic Ketoacidosis?
Diabetic ketoacidosis (also known as DKA, diabetic acidosis, metabolic ketoacidosis or ketosis) is caused by high levels of ketones, which are produced by the body when it is unable to use glucose in the cells. When glucose cannot be transported into the cells, the body must break down fat to use as fuel. Ketones are produced as a byproduct of this process, and cause the blood to become acidic.
Most cases of diabetic ketoacidosis occur slowly. However, when vomiting occurs, the condition can develop in a matter of hours. Early symptoms of DKA include:
- Thirst / dry mouth
- Frequent urination
- High blood glucose (blood sugar) levels
- High levels of ketones in the urine
As ketosis progresses, symptoms may include:
- Constantly feeling tired / fatigue
- Dry or flushed skin
- Nausea, vomiting, or abdominal pain
- Difficulty breathing
- Fruity odor on breath
- A hard time paying attention / confusion
In all ketoacidosis cases associated with SGLT2 inhibitors reported to the FDA, the condition was diagnosed by a healthcare professional, and hospitalization was required for treatment. The median time to onset of symptoms after initiation of treatment was 2 weeks (range, 1–175 days), according to the agency.
In most patients, a high anion-gap metabolic acidosis accompanied by elevated blood or urine ketones was noted. Potential triggering factors included acute illness changes, urosepsis, trauma, reduced caloric / fluid intake, and reduced insulin dose.
The goal of treatment for diabetic ketoacidosis is to correct high blood sugar levels with insulin and replace fluids lost through urination, loss of appetite and vomiting. If you think you may have ketoacidosis, you can test for ketones using urine strips or a glucose meter. If ketones are present, contact your doctor immediately. It is likely that you will have to go to the hospital to receive insulin, fluids and other treatments.
Most patients with ketoacidosis respond favorably to treatment within 24 hours. However, sometimes it takes longer to recover. If DKA is not treated in a timely manner, it can lead to adverse health complications and even death.
Health problems resulting from diabetic ketoacidosis may include:
- Fluid buildup in the brain (cerebral edema)
- Heart stops working (cardiac arrest)
- Kidney failure
Ketone-Related Events Found in Type 1 Diabetics, Study Finds
Ketone-related complications occurred in 5-10% of type 1 diabetics who took 100 mg or 300 mg doses of canagliflozin in addition to insulin, according to a March 2016 study published in Diabetes Care. Researchers looked at data on 351 type 1 diabetes patients who were randomly assigned to take Invokana or a placebo once daily before breakfast. After 18 weeks, 5.1% of patients on the 100 mg dose of canagliflozin and 9.4% of patients on the 300 mg dose had reported suffering a ketone-related complication. Adverse events requiring hospitalization occurred in 4.3% of patients on the 100 mg dose and 6% on the 300 mg dose, according to the study. It should be noted that Invokana is approved for the treatment of type 2 diabetes alone, and prescribing the drug for type 1 diabetes is done so in an “off-label” capacity.
ISMP Report on Invokana
FDA’s warning on Invokana followed a quarterly report by the Institute for Safe Medication Practices (ISMP), which questioned whether risks of the drug outweigh its potential benefits. Invokana was approved in March 2013 despite concerns about side effects associated with it and other SGLT2 inhibitors.
In its first year on the market, Invokana was linked to nearly 500 adverse event reports (more than 92% of drugs monitored by ISMP). These reports included:
- 54 cases of kidney failure / impairment
- 54 cases of dehydration / fluid imbalance
- 52 cases of abnormal weight loss
- 50 cases of urinary tract infections (UTIs)
- 11 cases of kidney stones
- “FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood”. U.S. Food & Drug Administration (FDA). May 15, 2015.
- “QuarterWatch: Monitoring FDA MedWatch Reports”. Institute for Medication Practices (ISMP). May 2015.
- “SGLT2 Inhibitors: Drug Safety Communication – Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections”. U.S. Food & Drug Administration (FDA). December 4, 2015.
- “DKA (Ketoacidosis) & Ketones”. American Diabetes Association. August 21, 2013.
- ”Metabolic Acidosis”. Merck Manual, Professional Version. February 2013.
- “Diabetic Ketoacidosis With Canagliflozin, a Sodium–Glucose Cotransporter 2 Inhibitor, in Patients With Type 1 Diabetes”. Diabetes Care. March 2016.
- “Diabetic ketoacidosis”. U.S. National Library of Medicine. July 24, 2015.