American Association Of Clinical Endocrinologists and American College Of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis

Yehuda Handelsman, MD, FACP, FNLA, FACE, Co-Chair; Robert R. Henry, MD, FACE, Co-Chair; Zachary T. Bloomgarden, MD, MACE; Sam Dagogo-Jack, MD, DM, FRCP, FACE; Ralph A. DeFronzo, MD, BMS, MS, BS; Daniel Einhorn, MD, FACP, FACE; Ele Ferrannini, MD; Vivian A. Fonseca, MD, FACE; Alan J. Garber, MD, PhD, FACE; George Grunberger, MD, FACP, FACE; Derek LeRoith, MD, PhD, FACE; Guillermo E. Umpierrez, MD, FACP, FACE; Matthew R. Weir, MD

Disclosures

Endocr Pract. 2016;22(6):753-762. 

In This Article

Executive Summary

Recent reports of diabetic ketoacidosis (DKA) occurring in conjunction with sodium glucose-cotransporter 2 (SGLT-2) inhibitor therapy have raised concerns that these agents may increase the risk of DKA, especially among patients taking exogenous insulin. On May 15, 2015, the U.S. Food and Drug Administration (FDA) issued the following safety communication concerning 20 cases of acidosis in patients taking SGLT-2 inhibitors reported to the FDA Adverse Event Reporting System:[1]

"We are continuing to investigate this safety issue and will determine whether changes are needed in the prescribing information for…SGLT-2 inhibitors…Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing [DKA] signs or symptoms; discontinue SGLT-2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis and monitor sugar levels."

To address these concerns, the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) convened a public conference in which experts from Europe and the United States evaluated relevant cases and clinical data (see Appendix for agenda and participants). A detailed report on the scientific evidence for the association of SGLT-2 inhibitors with DKA follows this statement.

The key points described in this document are as follows:

  1. For individuals with type 2 diabetes (T2D), it is unclear whether DKA occurs at a higher frequency than it did before the advent of SGLT-2 inhibitors. In 2010 in the United States, 142,000 hospitalizations were associated with DKA, 23% of which occurred in patients with T2D.[2] In Denmark, the rate of DKA before the SGLT-2 inhibitor era was 1 to 2 cases per 1,000 patients with diabetes. The incidence of DKA in clinical trials of SGLT-2 inhibitors with T2D was 0.2 to 0.8 cases per 1,000 patient-years.[3,4] However, the low observed incidence in clinical trials may not reflect real-world experience. Seemingly, most of the reported cases have come from clinical practice rather than trials. Patients with type 1 diabetes (T1D) have a higher risk of DKA than those with T2D, and their risk of developing DKA while taking SGLT-2 inhibitors should be further elevated. Up to 9.4% of patients with T1D participating in SGLT-2 inhibitor clinical trials developed ketosis, and up to 6% experienced DKA.[5,6]

  2. However, more data are needed to elucidate this relationship, as many recently reported cases have been poorly documented. Not all cases may have been actual DKA but rather ketosis (buildup of ketones)—which is not necessarily harmful—perhaps resulting from an earlier shift to fat metabolism potentially impacted by a mechanism related to SGLT-2 inhibition.

  3. The majority of cases of SGLT-2 inhibitor–associated DKA have occurred in individuals with diabetes who are insulin deficient, such as those with latent autoimmune diabetes in adults (LADA) and T1D, but cases have also occurred in some patients with long-standing T2D. Generally, these patients presented with classical DKA signs and symptoms. However, some cases had an atypical presentation with a lower-than-expected degree of hyperglycemia. Lower-than-expected hyperglycemia, however, was observed with other agents years before the introduction of SGLT-2 inhibitors.[7,8]

  4. Precipitants of DKA in T1D and T2D include surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting, and other stressful physical and medical conditions; almost all cases of SGLT-2 inhibitor–associated DKA occurred in patients challenged with metabolically stressful events. In both T1D and T2D, diabetes-associated metabolic changes commonly shift substrate metabolism from carbohydrate to fat oxidation, thereby predisposing patients to more readily develop ketonemia and DKA during SGLT-2 inhibitor use.

  5. For patients taking an SGLT-2 inhibitor who present with symptoms suggestive of DKA, such as abdominal pain, nausea, vomiting, fatigue, and dyspnea, a diagnosis of DKA should be considered and appropriate work-up carried out. Although a low bicarbonate and/or the presence of positive urinary ketones may be suggestive of DKA, these measures may be inaccurate. Therefore, AACE/ACE recommends direct measurement of blood ketones (β-hydroxybutyrate) and arterial pH as necessary to confirm the diagnosis. Normal or modestly elevated blood glucose does not exclude the diagnosis of DKA during SGLT-2 inhibitor use.

  6. For management of DKA in patients taking SGLT-2 inhibitors, stop the drug immediately and proceed with traditional DKA treatment protocols. Note that although the drug is discontinued, SGLT-2 inhibitor–mediated increases in urinary glucose loss may persist for several days.

  7. To minimize the risk of DKA associated with SGLT-2 inhibitors, AACE recommends the following:

    • Consider stopping the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity such as running a marathon. As noted above, urinary glucose loss due to SGLT-2 inhibition may persist after the drug is stopped.

    • Avoid stopping insulin or decreasing the dose excessively.

    • For emergency surgery or any extreme stress event, the drug should be stopped immediately, and appropriate clinical care should be provided.

    • Routine measurement of urine ketones is not recommended during use of SGLT-2 inhibitors because this measurement can be misleading. Instead, measurement of blood ketones is preferred for diagnosis of DKA in symptomatic patients.

    • Patients taking SGLT-2 inhibitors should avoid excess alcohol intake and very-low-carbohydrate/ketogenic diets.

  8. SGLT-2 inhibitors are not approved for use in T1D. However, AACE/ACE encourages continuation of ongoing studies because initial study results have shown that SGLT-2 inhibition has a promising impact on glycemic regulation in this population. AACE/ACE suggests that in future T1D trials, lower SGLT-2 inhibitor doses should be considered and insulin dose should not routinely be reduced when SGLT-2 inhibitors are begun. Instead, insulin should be adjusted based on the individual response to the SGLT-2 inhibitor, and carbohydrate intake should be maintained. These recommendations should also be applied if SGLT-2 inhibitors are prescribed off-label to patients with T1D and may be considered for patients with T2D who receive exogenous insulin therapy.

Conclusion

Review of available data on the prevalence of SGLT-2–associated DKA as well as the impact of SGLT-2 inhibitors on human metabolism suggests that DKA occurs infrequently and that the risk-benefit ratio overwhelmingly favors continued use of SGLT-2 inhibitors with no changes in current recommendations. However, DKA diagnosis may be missed or delayed due to atypical presentation involving lower-than-anticipated glucose levels or other misleading laboratory values. This presentation has been seen with SGLT-2 inhibitors but has also been observed for decades before the introduction of these agents.[9] Gaps in understanding call for more studies of the mechanisms behind the metabolic effect of SGLT-2 inhibitors as well as more healthcare professional education focused on the proper diagnosis and treatment of DKA.

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