SGLT2-Inhibitor Benefit Outweighs Ketoacidosis Risk, Says AACE

Miriam E Tucker

October 28, 2015

Use of sodium-glucose cotransporter-2 inhibitor (SGLT2) drugs should continue in patients with diabetes, in line with current recommendations, conclude the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE), in response to recent concerns from regulators about their safety.

The conclusion came after a 2-day conference in which experts from the United States and Europe reviewed available scientific data related to the possible relationship between SGLT2 inhibitors and diabetic ketoacidosis (DKA).

"The wealth of scientific and clinical data presented at this symposium has been ideal to enhance our understanding of the relationship between SGLT2 inhibitors and DKA," Robert Henry, MD, program chair and chief, section of diabetes, endocrinology and metabolism and the Center for Metabolic Research at the San Diego VA Medical Center, said in an AACE statement.

"I am confident this data will enable AACE to provide recommendations to minimize the occurrence of this complication in patients with diabetes."

The issue initially came to light in May 2015, when the US Food and Drug Administration issued a notice on the basis of 20 cases of DKA associated with SGLT2 inhibitors reported to the agency's adverse-event reporting system. A month later, the European Medicines Agency initiated a review and identified 101 cases worldwide associated with type 2 diabetes.

Since then, there has been widespread debate about the potential risks of using this class of medication, including with regard to the investigational and as-yet off-label use in patients with type 1 diabetes.

It appears that the majority of DKA cases occur in people who are insulin deficient, with type 1 diabetes, latent autoimmune diabetes of adulthood, or longstanding type 2 diabetes. However, a few have cases occurred in people with near-normal blood glucose levels.

After reviewing available data, the panel concluded that "the prevalence of DKA is infrequent and the risk/benefit ratio overwhelmingly favors continued use of SGLT2 inhibitors with no changes in current recommendations."

The group did recommend the following:

  • A diagnosis of DKA should be considered in patients taking an SGLT2 inhibitor who present with symptoms suggestive of DKA such as abdominal pain, nausea, vomiting, fatigue, and dyspnea. Direct measurements of beta-hydroxybutyrate and arterial pH are necessary to confirm the diagnosis, as low bicarbonate and/or the presence of positive urinary ketones may be inaccurate.

  • Because urine ketone measurements can be misleading, blood measurements are preferred for diagnosis of DKA in symptomatic patients.

  • For patients taking SGLT2 inhibitors who develop DKA, the drug should be stopped immediately and traditional DKA treatment protocols initiated.

  • To minimize the risk of DKA associated with SGLT2 inhibitors, consider stopping the drug at least 24 hours prior to elective surgery or anticipated stressful activity such as running a marathon. In cases of emergency surgery or unanticipated extreme stress, the drug should be stopped immediately and appropriate clinical care provided.

  • Routine measurement of blood ketones is not recommended during normal use of SGLT2 inhibitors in patients with type 2 diabetes.

  • Patients taking SGLT2 inhibitors should be advised to avoid excess alcohol intake and very low-carbohydrate/ketogenic diets.

  • Although SGLT2 inhibitors are not approved for use in type 1 diabetes, AACE/ACE encourages continuation of ongoing studies, since initial results have shown a promising impact on glycemic control.

  • Pharmaceutical companies should continue to investigate the mechanisms behind the metabolic effect of SGLT2 inhibitors, and all stakeholders should initiate educational activities regarding the potential for recognizing and treating DKA, including in individuals with normal or near-normal blood glucose levels.

Dr Henry has received grant support from Hitachi, Janssen Research & Development, Eli Lilly, Sanofi, and ViaCyte and is a consultant/advisory board member for Alere, Amgen, AstraZeneca, Boehringer Ingelheim, ClinMet, Eisai, Elcelyx Therapeutics, Gilead, Intarcia Therapeutics, Isis Pharmaceuticals, Janssen Research & Development, Merck, Novo Nordisk, Sanofi, and VIVUS.

AACE/ACE Scientific and Clinical Review. Association of SGLT2 inhibitors and DKA. October 24-25, 2015. Summary

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