Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium–Glucose Cotransporter 2 Inhibition

Anne L. Peters; Elizabeth O. Buschur; John B. Buse; Pejman Cohan; Jamie C. Diner; Irl B. Hirsch

Disclosures

Diabetes Care. 2015;38(9):1687-1693. 

In This Article

Abstract and Introduction

Abstract

Objective Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication.

Research Design and Methods Cases identified incidentally are described.

Results We identified 13 episodes of SGLT-2 inhibitor–associated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers.

Conclusions SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.

Introduction

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are the newest class of antihyperglycemic medications, first marketed in 2013 for the treatment of type 2 diabetes.[1] Limited studies suggest that SGLT-2 inhibitors may be effective in addressing many of the unmet needs of people with type 1 diabetes, including improving average glycemia, while reducing glycemic variability and postprandial hyperglycemia, without increasing hypoglycemia, as well as promoting weight loss while reducing insulin doses.[2–8] As a result, off-label use of SGLT-2 inhibitors in the setting of type 1 diabetes is increasing.[8]

Diabetic ketoacidosis (DKA) is a well recognized complication of management of type 1 diabetes; nearly 5% of 6,796 adult participants with type 1 diabetes in the T1D Exchange program experienced one or more episodes of DKA within the past 12 months.[9] DKA is traditionally defined by the triad of hyperglycemia (>250 mg/dL [>13.9 mmol/L]), anion-gap acidosis, and increased plasma ketones.[10] Euglycemic DKA (euDKA), defined as DKA without marked hyperglycemia, is classically considered rare but this is perhaps a result of underrecognition and underreporting.[10–12] euDKA is thought to be facilitated by factors such as partial treatment of DKA, food restriction, alcohol intake, and inhibition of gluconeogenesis.[10] Alcoholic ketoacidosis, a subtype of euglycemic ketoacidosis that occurs in individuals without diabetes, is thought to be underdiagnosed and is similar in presentation to euDKA although often with frankly low glucose values.[12] In both DKA and alcoholic ketoacidosis, there is a decreased insulin secretion in the setting of increased counterregulatory hormone secretion (cortisol, glucagon, catecholamines, and growth hormone).[13]

Here we describe 13 cases of SGLT-2 inhibitor–associated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these individuals delayed recognition of the emergent nature of the problem by patients and providers.

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