SGLT2 Inhibitors and risk of ketoacidosis

On May 15, 2015, the FDA released a safety warning that SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) may increase the risk of ketoacidosis in diabetic patients. 

A search of the FDA Adverse Event Reporting System (FAERS) database identified 20 cases of ketoacidosis in patients treated with an SGLT2 inhibitor from March 2013 to June 6, 2014. Since June 2014 there have been additional reports of ketoacidosis associated with SGLT2 inhibitors  In a single-arm, open label trial, 40 patients received oral empagliflozin for an 8-week treatment period and there were two reports of ketoacidosis. Although the correlation was not studied, it was stated that the risk of ketosis should be carefully evaluated in future trials. Healthcare professionals and patients should to report side effects involving SGLT2 inhibitors to the FDA MedWatch program.

What are SGLT2 inhibitors and what are they used for?

Here is the list of sodium-glucose cotransporter-2 (SGLT2) inhibitors available in the US:

• Invokana (canagliflozin)
• Invokament (canagliflozin/metformin)
• Farxiga (dapagliflozin)
• Xigduo XR (dapagliflozin/metformin ER)
• Jardiance (empagliflozin)
• Glyxambi (empagliflozin/linagliptin)

SGLT2 inhibitors are a relatively new class of medications used for treating type 2 diabetes. There is insufficient data to recommend their use in type 1 diabetic patients. Unlike sulfonylureas which are more effective during early stages of type 2 diabetes when β-cells are functioning, SGLT2 inhibitors are effective at all stages of type 2 diabetes.

SGLT2 inhibitors block glucose reabsorption in the proximal renal tubule. This increases glucose excretion thus providing insulin-independent blood glucose reduction. In addition, SGLT2 inhibitors cause modest weight loss and reduce blood pressure. SGLT2 inhibitors increase glucose concentrations in the urine thereby increasing the risk of genitourinary infections including urinary tract infections. Due to their localized effect on the kidneys, SGLT2 inhibitors may cause polyuria, volume depletion, hypotension, and associated dizziness.

What is ketoacidosis?

Ketoacidosis is a serious life-threatening condition resulting from excessive levels of ketones in blood. When cells do not have enough glucose for energy the body utilizes fat for energy production. Fat metabolism produces ketones which can be used for energy, however, ketones are acidic. Accumulation of ketones increases the acidity of blood, leading to ketosis or ketoacidosis. This condition presents with elevated urine and serum ketone levels. Diabetic ketoacidosis (DKA) is ketoacidosis in diabetic patients. 

What are risk factors for diabetic ketoacidosis?

Diabetic ketoacidosis occurs during severe hypoglycemia or prolonged fasting. DKA is more common in type 1 diabetic patients and is rare in type 2 diabetic patients. Infection, reduced food and fluid intake, and not taking enough insulin increase the risk of DKA. DKA is associated with elevated blood glucose, however, ketoacidosis associated with SLGT2 inhibitors may not always present with high blood glucose.

What are symptoms of ketoacidosis?

DKA develops slowly with early symptoms of thirst, very dry mouth, frequent urination, high blood glucose, or high urine ketone levels. As the condition progresses patients experience fatigue, dry or flushed skin, fruity odor on breath, difficulty concentrating, confusion, difficulty breathing, abdominal pain, nausea, and vomiting. When vomiting occurs, DKA may progress rapidly.

How to test for ketones

Patients can test for ketones with a ketone urine test strip. Available over-the-counter ketone test strips include Ketostix, Relion Ketone Strips, and Keto-Diastix. Patients should check for urine ketones when blood glucose is >240 mg/dL or when symptoms of ketoacidosis are present. Patients who are ill should check for ketones every 4 to 6 hours. Under normal conditions, ketones are completely metabolized and are not present in urine. Patients who have an abnormal or positive ketone test result should promptly contact their physician for further evaluation. 

How is ketoacidosis treated?

Patients should seek immediate medical attention when experiencing key symptoms of ketoacidosis such as vomiting, abnormal rapid breathing, abdominal pain, nausea, weakness, or confusion. Ketoacidosis requires emergency room visits or hospitalization for treatment. Treatment includes insulin, fluid and electrolyte replacement, correcting blood acidity, and treating infection or other precipitating factors. Healthcare professionals and patients should report adverse events involving SGLT2 inhibitors to the FDA MedWatch program.

Conclusion

The FDA released a safety announcement concerning the potential risk of ketoacidosis with SGLT2 inhibitors due to the temporal association noted in all cases. There are no studies that show a causative relationship between SGLT2 inhibitors and ketoacidosis. Since SGLT2 inhibitors have been prescribed to millions of patients the risk of ketoacidosis from SGLT2 inhibitors is probably rare. Therefore, the association of SGLT2 inhibitors with ketoacidosis should not prevent their use in appropriate patients. Patients receiving SGLT2 inhibitors and their caregivers should learn the symptoms of ketoacidosis and seek immediate medical attention if symptoms of ketoacidosis occur. 

Also Read

Invokana (canagliflozin) Review, Cost, Weight Loss Effect, Side Effects, PI

Jardiance (empagliflozin) Cost, Side effects, Dosing, and Weight Loss

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References

FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood.

Perkins BA et al. SGLT2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial. Diabetes Care 2014; 37: 1480-1483. May 2014. 

Standards of Medical Care in Diabetes – 2015. American Diabetes Association; 38: S1-S94. Jan 2015. Web 19 May 2015.

DKA (Ketoacidosis) & Ketones. American Diabetes Association. 21 Aug 2013. Web 19 May 2015.

Ketone urine test. MedlinePlus. 7 Nov 2013.