April 20, 2016
2 min read

AACE/ACE position statement: DKA risk no greater with SGLT2 inhibitors

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The incidence of diabetic ketoacidosis in patients with type 2 diabetes taking an SGLT2 inhibitor is no greater than the low levels occurring in the general diabetes population, according to a joint position statement released by the American Association of Clinical Endocrinologists and the American College of Endocrinology.

The statement published in Endocrine Practice follows a joint meeting between AACE and ACE convened in October, where experts concluded that the risk for DKA when using SGLT2 inhibitors is infrequent and the risk-benefit ratio favors continued use. The FDA released a warning in May 2015 that SGLT2 inhibitors may lead to ketoacidosis.

“There is no definite evidence that these agents are associated with DKA in type 2 diabetes, and some reports have actually described patients with ketosis, or even just ketonuria, which likely are not clinically significant,” Zachary T. Bloomgarden, MD, MACE, an Endocrine Today Editorial Board member and a coauthor of the position statement, said in an interview. “The DKA cases that have been reported generally involve patients with type 1 diabetes, although reports in atypical diabetes (such as that with pancreatic disease) and in patients with longstanding type 2 diabetes who require multiple-dose insulin treatment similar to that used in type 1 diabetes suggests that a necessary mediator of DKA is marked insulin deficiency.”

Zachary Bloomgarden

Zachary T. Bloomgarden

The consensus group reviewed over 80 DKA cases from the literature, including those involving SGLT2 inhibition and cases occurring before SGLT2 inhibitor therapy was available. In patients taking an SGLT2 inhibitor, DKA occurred most often in insulin-deficient individuals, including those with longstanding type 2 diabetes, type 1 diabetes or latent autoimmune diabetes in adults. SGLT2 inhibitors are not FDA approved for patients with type 1 diabetes.

“In the American case series that prompted the FDA safety warning, 7 of 9 patients had [type 1 diabetes],” the researchers wrote.

The statement highlights the importance of metabolically stressful events as additional mediators, including surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting, and other stressful physical and medical conditions.

“Regardless of the type of diabetes, though, when individuals taking SGLT2 inhibitors have abdominal pain, nausea, vomiting, fatigue and/or dyspnea, a diagnosis of DKA should be considered and excluded, recognizing that the blood glucose may be only modestly elevated and even may be normal, rather than the typical severely elevated level seen in typical DKA,” Bloomgarden told Endocrine Today. “Blood ketone measurement is preferred to urine ketone testing for diagnosis, although when blood ketone measurement is not available, urine ketone testing with a measurement of acidosis is certainly reasonable.”

Once diagnosis of DKA is suspected, the SGLT2 inhibitor should be stopped immediately and a DKA protocol initiated, including fluids, insulin and other standard interventions, the researchers wrote.

The statement recommends that SGLT2 inhibitors be stopped at least 24 hours before planned stressful events, such as surgery, or very intensive exercise, such as running a marathon. Patients prescribed SGLT2 inhibitor therapy should also avoid excess alcohol intake and very low carbohydrate diets, both of which are potentially ketogenic, the researchers wrote.

The statement notes that ongoing study involving therapeutic use of SGLT2 inhibitors for type 1 diabetes is reasonable. Investigators designing a future trial for SGLT2 use in type 1 diabetes should consider use of a lower dose, adjustment of insulin doses based on individual response rather than standard reductions, and maintenance of carbohydrate intake, the researchers wrote.

“These agents do have potential benefits which could be useful for certain such patients with type 1 diabetes,” Bloomgarden said. –by Regina Schaffer

Disclosure: Please see the full position statement for the authors’ relevant financial disclosures.