Euglycemic Diabetic Ketoacidosis With SGLT-2 Inhibitors
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.
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. 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. As a result, off-label use of SGLT-2 inhibitors in the setting of type 1 diabetes is increasing.
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. DKA is traditionally defined by the triad of hyperglycemia (>250 mg/dL [>13.9 mmol/L]), anion-gap acidosis, and increased plasma ketones. Euglycemic DKA (euDKA), defined as DKA without marked hyperglycemia, is classically considered rare but this is perhaps a result of underrecognition and underreporting. euDKA is thought to be facilitated by factors such as partial treatment of DKA, food restriction, alcohol intake, and inhibition of gluconeogenesis. 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. 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).
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.
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. 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. As a result, off-label use of SGLT-2 inhibitors in the setting of type 1 diabetes is increasing.
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. DKA is traditionally defined by the triad of hyperglycemia (>250 mg/dL [>13.9 mmol/L]), anion-gap acidosis, and increased plasma ketones. Euglycemic DKA (euDKA), defined as DKA without marked hyperglycemia, is classically considered rare but this is perhaps a result of underrecognition and underreporting. euDKA is thought to be facilitated by factors such as partial treatment of DKA, food restriction, alcohol intake, and inhibition of gluconeogenesis. 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. 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).
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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