SGLT2 Inhibitors and Diabetic Ketoacidosis: What's Behind the FDA Warning

With commentary by Yehuda Handelsman, MD, FACP, FACE, FNLA, an endocrinologist in private practice in Tarzana, CA, Medical Director and Principal Investigator of the Metabolic Institute of America and President of the American College of Endocrinology

People with diabetes who take blood sugar-lowering drugs called SGLT2 inhibitors were recently warned by the U.S. Food and Drug Administration (FDA) that they should watch for signs of a life-threatening condition called diabetic ketoacidosis.

SGLT2 inhibitorsSGLT2 inhibitors work by sending glucose out of the body in a person’s urine and include:

  • canagliflozin (Invokana)
  • dapagliflozin (Farxiga)
  • empagliflozin (Jardiance)

as well as the combination pills:

  • canagliflozin plus metformin (Invokamet)
  • dapagliflozin plus metformin extended-release (Xigduo XR)
  • empagliflozin plus linagliptin (Glyxambi).

“Diabetic ketoacidosis (DKA) can be deadly,” says Amy Hess-Fischl, MS, RD, LDN, BC-ADM, CDE, an advanced practice dietitian at the University of Chicago Kovler Diabetes Center and a member of EndocrineWeb’s advisory board. “DKA is usually more of a concern for people with type 1 diabetes, but this warning is for people with type 2 diabetes who are taking the SGLT2 inhibitors, as well as people with type 1 diabetes who take these medications off label.

DKA — dangerously high acid levels in the bloodstream — happens when your body breaks down fat instead of glucose for energy, releasing acidic compounds called ketones. Early symptoms include thirst, frequent urination and sweet, fruity breath, Hess-Fischl says. You may feel tired and confused, and develop nausea, stomach pain, vomiting and difficulty breathing.  “If you notice symptoms, call your doctor immediately. But if you’re vomiting, can’t catch your breath or are concerned, go to the emergency room,” she says.

Putting the Risk in Perspective

The FDA warning, released on May 15, 2015, is based on 20 reports of people with diabetes treated in emergency rooms or hospitalized between March 2013 and June 2014 for ketoacidosis. All had been taking SGLT2 inhibitors for an average of two weeks. In some of the reports made to the FDA’s Adverse Events Reporting System, ketoacidosis may have been triggered by an illness (such as an infection), a drop in food or water intake or a reduced insulin dose.

 “It’s important to note that the FDA, as yet, is not directly linking these drugs as the cause of ketoacidosis or DKA in these patients. The agency is saying ‘we have these reports and we’re looking into it’ be cautious. However, do not stop them unless advised by your doctor,” says Yehuda Handelsman, MD, FACP, FACE, FNLA, an endocrinologist in private practice in Tarzana, CA, medical director and principal investigator of the Metabolic Institute of America and president of the American College of Endocrinology.  “Dehydration, infection, severe illnesses, not eating, a high-protein and high-fat diet, or taking less insulin can, on their own, cause ketosis. It's not clear yet if the drugs played a role. We need more details about these cases before we rush to judgment."

“It’s important to note that the FDA, as yet, is not directly linking these drugs as the cause of ketoacidosis or DKA in these patients” says Yehuda Handelsman, MD, FACP,  president of the American College of Endocrinology.

SGLT2 inhibitors are effective drugs that help control blood sugar without causing weight gain (they may actually help with weight loss) or low blood sugar (hypoglycemia), he says. “People who take them should be sure to drink plenty of water, be careful with extremely low-carbohydrate diets and if also taking insulin, be cautious about lowering the dose,” Dr. Handelsman adds.

SGLT2 inhibitors work in the proximal tubules of the kidney just beyond nephrons — the tiny filters within the kidneys — where they block the reabsorption of glucose back into the blood system. As a result these drugs reduce blood sugar levels and make the glucose stay in urine. In the process, they can also act as diuretics – both by allowing more fluid out with the extra glucose as well as by also secreting excess sodium into urine. “It is important to maintain a state of hydration given the mechanism of action of these drugs,” says Foiqa Chaudhry, MD, an endocrinology fellow at the University of Florida. “I think it would be reasonable to counsel patients to maintain adequate fluid intake. It is sometimes difficult to identify signs of dehydration.”   

A relatively new class of diabetes drugs, SGLT2 inhibitors received FDA approval in 2013 and 2014 for type 2 diabetes. They are not approved for type 1 diabetes (studies are underway) but diabetes experts contacted by EndocrineWeb say the drugs are frequently prescribed off-label for type 1 diabetes. “I would caution people not to go off-label,” Dr. Handelsman says. “It’s tempting to think you can lower your insulin dose because you’ve got this pill but that may be dangerous. It’s probably smarter to wait for the results of the on-going trials or find a way to join a study.”

At the American Association of Clinical Endocrinologists 24th Annual Scientific and Clinical Conference, May 2015, researchers presented data regarding suspected DKA in two people taking SGLT2 inhibitors. While the case studies were covered in the media, the connection isn’t clear, says Dr. Handelsman. In one, a vaginal infection treated with antibiotics may have triggered the problem. And both patients may have had undiagnosed type 1 diabetes. “It is important to note that DKA develops only when there is a lack of insulin or when insulin does not function,” he says. “I urge all patients to not stop their current medications and to first consult with their physician as necessary.”



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