AACE/ACE Panel Supports Continued Use of SGLT2 Inhibitors in Diabetes

The prevalence of diabetic ketoacidosis (DKA) with the use of sodium glucose cotransporter 2 (SGLT2) inhibitors is infrequent, and the risk-benefit ratio supports their continued use in patients with diabetes, an expert panel convened by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) has concluded.

In May 2015, the U.S. Food and Drug Administration (FDA) issued a drug safety communication on the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin due to concerns that they may be associated with ketoacidosis.¹

In light of these reports, AACE/ACE gathered an international group of diabetes experts from October 24-25, 2015, for a public conference in Dallas to examine the clinical and scientific data on the possible association of SGLT2 inhibitors with DKA.

“Our members wanted from us some guidance on what to do. The problem was that we looked at the available published cases by the FDA and others, and it didn’t give us enough information — specific patient data — that we could address, understand, and develop recommendations,” Yehuda Handelsman, MD, FACP, FACE, FNLA, medical director and principal investigator at the Metabolic Institute of America in Tarzana, California, told Endocrinology Advisor.

Dr Handelsman served as program chair for the conference.

Jonathan D. Leffert, MD, FACP, FACE, ECNU, endocrinologist and managing partner at the North Texas Endocrine Center in Dallas, noted that this meeting was important because, “there has been a perceived increase in DKA in those patients who have been on SGLT2 inhibitors.”

The expert panel made several conclusions in a summary statement:²

• It is not clear if DKA occurs more often in patients with type 2 diabetes than prior to the use of SGLT2 inhibitors. Additionally, the panel noted more recently reported cases had poor documentation and may not have all been actual DKA.
• The panel noted that DKA mostly occurs in situations of insulin deficiency such as latent autoimmune diabetes in adults (LADA), type 1 diabetes, and long-standing type 2 diabetes. The panel noted, however, some of the cases presented atypically due to lower-than-anticipated glucose levels.
• Most of the cases occurred in patients undergoing metabolic stress. Further, the panel noted that DKA in type 1 and type 2 diabetes is commonly precipitated by infections, stroke, myocardial infarctions, extensive exercise, and surgery.
• The panel highlighted the fact that urinary ketones and low bicarbonate may be inaccurate measures of DKA and recommends beta hydroxybutyrate and arterial pH for diagnostic confirmation. Likewise, in the setting of SGLT2 inhibitors, normal or modestly elevated glucose does not exclude DKA as a diagnosis.
• With DKA, the panel recommends immediate cessation of the SGLT2 inhibitor and initiation of traditional treatment protocols for DKA.
• To minimize the risk for DKA while using SGLT2 inhibitors, the panel recommends consideration of stopping the medication 24 hours prior to a planned physically stressful event, surgery, or invasive procedure. Likewise, the panel recommends that the SGLT2 inhibitor should be discontinued immediately in the setting of emergency surgery or extreme stress. Avoidance of low carbohydrate or ketogenic diets and excessive alcohol intake should also be considered.

Finally, in the summary statement, the panel calls for continued investigations of the metabolic effects of SGLT2 inhibitors and for initiation of educational activities for physicians on identification and treatment of DKA.

“It is unclear if there is a true increase in DKA or if the criteria used to define DKA is not specific enough to determine if SGLT2 inhibitors are contributing to this situation,” Dr Leffert said.

“A clear-cut diagnosis of DKA cannot always be made based upon the clinical and biochemical parameters because of confounding variables, such as starvation, which can increase ketonuria. The conference called on physicians to use symptoms, signs, and specific biochemical parameters such serum ketones, pH, and blood sugars that may be lower than typically seen in DKA to diagnose cases of DKA associated with SGLT2 inhibitors,” he continued.

“The appearance or inexistence of ketones in the urine by itself is not enough to support or disprove the diagnosis of DKA. Also, normal or modestly elevated blood glucose does not exclude the diagnosis of DKA. Besides, a lot of the reports of people with DKA actually reported of ketogenesis, ketonemia, or even ketonuria, and not really on acidosis,” Dr Handelsman noted.

The full white paper is planned for publication in a future issue of Endocrine Practice.

References

1. 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 and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Updated May 19, 2015. Accessed November 2, 2015.
2. AACE/ACE Scientific and Clinical Review: Association of SGLT2 Inhibitors and DKA. October 24-25, 2015. Conclusion Summary. Accessed November 2, 2015.