Elsevier

Endocrine Practice

Volume 22, Issue 6, June 2016, Pages 753-762
Endocrine Practice

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

https://doi.org/10.4158/EP161292.PSGet rights and content

ABSTRACT

Abbreviations:

AACE = American Association of Clinical Endocrinologists

ACE = American College of Endocrinology

DKA = diabetic ketoacidosis

EMA = European Medicines Agency

FDA = U.S. Food and Drug Administration

SGLT-2 = sodium glucosecotransporter 2

T1D = type 1 diabetes

T2D = type 2 diabetes

Section snippets

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

INTRODUCTION

Diabetic ketoacidosis (DKA) is an acute, potentially fatal complication of diabetes that typically occurs when insulin deficiency results in excessive lipolysis and protein breakdown at the tissue level, with increased hepatic beta-oxidation of fatty acids to ketone bodies, leading to ketonemia and metabolic acidosis (8). Sodium glucose-cotransporter 2 (SGLT-2) inhibitors are a class of antihyperglycemic agents that reduce blood glucose levels by blocking glucose re-absorption in the proximal

Does DKA Occur at a Higher Rate with SGLT-2 Inhibitors than with other Antihyperglycemic Medications?

Whether DKA currently occurs at a higher frequency than before the introduction of SGLT-2 inhibitors remains unclear. The Centers for Disease Control and Prevention estimated that the rate of DKA was 7.1 per 1,000 patient-years with diabetes in 2009, and in 2010, DKA accounted for 142,000 hospitalizations in the U.S., 33,000 of which involved patients with type 2 diabetes (T2D) (2,12). In an analysis of 4 large U.S.-based commercial claims databases, the incidence of DKA ranged between 0.32 and

In Whom Has SGLT-2 Inhibitor–Associated DKA Occurred?

The consensus group reviewed over 80 DKA cases from the literature (3,9,11,17., 18., 19., 20.), including those involving SGLT-2 inhibition and cases occurring before these agents were available. Conference participants from clinical practice and industry also presented detailed case reports of SGLT-2 inhibitor–associated DKA. In patients taking SGLT-2 inhibitors, DKA occurred most often in insulin-deficient individuals, including those with longstanding T2D, T1D, or latent autoimmune diabetes

Which Pathophysiologic Factors Contribute to SGLT-2 Inhibitor–Associated DKA?

Ketones such as acetoacetate and β-hydroxybutyrate are acidic alternate fuel molecules produced in the liver through the oxidation of fatty acids when dietary carbohydrates are in short supply. Ketones can be metabolized for energy by cardiac and skeletal muscle, the intestine, kidney, and the brain when sufficient glucose is not readily available, and they are excreted in the urine and through the lungs as acetone. When ketone production exceeds clearance, ketoacidosis may occur (21). DKA

Which Signs and Symptoms are Diagnostic of DKA in Patients Taking an SGLT-2 Inhibitor?

Table 1 lists classic signs and symptoms of DKA, and Table 2 shows recommended diagnostic criteria. Patients with any form of diabetes who have abdominal pain, nausea, vomiting, fatigue, and/or dyspnea should be evaluated for DKA. Because SGLT-2 inhibitors lower the threshold for glucose excretion, normal or modestly elevated blood glucose does not exclude the diagnosis of DKA during SGLT-2 inhibitor use.

Ketonuria and elevated bicarbonate may be suggestive of DKA, but evidence suggests these

How Should DKA Associated with SGLT-2 Inhibitors be Managed?

Once the diagnosis is suspected, the SGLT-2 inhibitor should be stopped immediately and the DKA protocol initiated, including fluids, insulin, and other standard interventions as described elsewhere (8).

How should DKA be Prevented?

Canagliflozin, dapagliflozin, and empagliflozin have similar half-lives, of approximately 13 hours (10). Because of prolonged action on SGLT-2 transporters, these agents should be stopped at least 24 hours before scheduled surgery or other planned activities that might precipitate DKA, such as invasive procedures or extreme physical activity (e.g., running a marathon). For patients with diabetes undergoing emergency surgery or a sudden external severe stress event, the drug should be stopped

Should SGLT-2 Inhibitors be used in Patients with T1D?

SGLT-2 inhibitors are not approved for use in T1D, but clinical trials investigating their efficacy and safety in this population are underway. As yet, few data are available to assess the risk of DKA. In an 18-week, phase 2 canagliflozin study involving 351 patients, ketone-related adverse events (including DKA) occurred among 5.1 and 9.4% of T1D patients receiving canagliflozin 100 and 300 mg, respectively, whereas DKA itself occurred among 4.3 and 6.0% of patients, respectively. No

CONCLUSION

The incidence of DKA in T2D treated with SGLT-2 inhibitors does not appear to exceed the low levels occurring in the general diabetes population. Further study of the mechanisms behind the metabolic effects of SGLT-2 inhibitors is needed to better define the risk of DKA with these agents. Nevertheless, the risk to benefit ratio overwhelmingly favors continued use of SGLT-2 inhibitors in T2D, with no changes in current recommendations. This class has proven benefits in terms of hemoglobin A1C

DISCLOSURE

Dr. Yehuda Handelsman has served as a consultant and/or speaker for Amarin, Amgen, Amylin, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Halozyme, Janssen, Merck, NovoNordisk, Sanofi, and Vivus. He has received research grants from Amgen, Boehringer Ingelheim, GlaxoSmithKline, Gilead, Intarcia, Lexicon, Merck, NovoNordisk, Sanofi, and Takeda.

Dr. Robert R. Henry has served as a consultant for Alere, AstraZeneca, Boehringer Ingelheim, Ionis, Johnson & Johnson/Janssen, and NovoNordisk. He has

ACKNOWLEDGMENT

Amanda M. Justice provided medical writing and editorial support funded by AACE.

REFERENCES (51)

  • Centers for Disease Control and Prevention

    NCHS National Hospital Discharge Survey

    (2010)
  • EronduN. et al.

    Diabetic ketoacidosis and related events in the Canagliflozin Type 2 Diabetes Clinical Program

    Diabetes Care

    (2015)
  • ZinmanB. et al.

    Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

    N Engl J Med

    (2015)
  • HenryR.R. et al.

    Efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes

    Diabetes Care

    (2015)
  • HenryR.R. et al.

    Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study

    Diabetes Care

    (2015)
  • KitabchiA.E. et al.

    Hyperglycemic crises in adult patients with diabetes

    Diabetes Care

    (2009)
  • MunroJ.F. et al.

    Euglycaemic diabetic ketoacidosis

    Br Med J

    (1973)
  • PetersA.L. et al.

    Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotrans-porter 2 inhibition

    Diabetes Care

    (2015)
  • Centers for Disease Control and Prevention

    Diabetes Public Health Resource: crude and age-adjusted hospital discharge rates for diabetic ketoacidosis (DKA) as first-listed diagnosis per 1,000 diabetic population, United States, 1988–2009

    (2016)
  • WangZ.H. et al.

    Ketoacidosis occurs in both type 1 and type 2 diabetes—a population-based study from Northern Sweden

    Diabet Med

    (2008)
  • JulicherS.

    Notification to the PRAC/EMA Secretariat of a referral under article 20 of regulation (EC) 726/2004

    (2015)
  • MillerK.M. et al.

    Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D Exchange clinic registry

    Diabetes Care

    (2015)
  • KargesB. et al.

    Hospital admission for diabetic ketoacidosis or severe hypoglycemia in 31,330 young patients with type 1 diabetes

    Eur J Endocrinol

    (2015)
  • StorgaardH. et al.

    Diabetic ketoacidosis in a patient with type 2 diabetes after initiation of sodium-glucose cotransporter 2 inhibitor treatment

    Basic Clin Pharmacol Toxicol

    (2016)
  • HayamiT. et al.

    Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet

    J Diabetes Investig

    (2015)
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    This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position and consensus statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

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