Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition
Open accessAbstract
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.
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DKA in the setting of SGLT inhibitor use is often euglycemic DKA, with initial case reports describing admission glucose levels of 5.3-12.4 mmol/L (96-224 mg/dL).
“DKA in the setting of SGLT inhibitor use is often so-called euglycemic DKA, with initial case reports describing admission glucose levels of 5.3-12.4mmol/L (96-224 mg/dL) (218).”
From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [218]
The Results table and Conclusions describe euglycemic DKA associated with SGLT-2 inhibitor use. But the stated admission-glucose range is not accurate for these cases: the 96 mg/dL event was treated as an outpatient, while the table lists a presenting glucose of 233 mg/dL (12.9 mmol/L) for another case. (LLM, conf=0.89)
Experimental — accuracy not yet measuredDPP-4 inhibitors lack significant gastrointestinal adverse effects and can be used in early combination with metformin.
“DPP-4 inhibitors do not have significant GI adverse effects and may be used in early combination with metformin.1038–1043”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1043]
The Introduction discusses SGLT-2 inhibitors, and the Conclusions address their association with euglycemic ketoacidosis; neither addresses DPP-4 inhibitors. Searches for DPP-4 gastrointestinal adverse effects and early combination with metformin found no passage supporting either part of the claim. Page numbers were not available in our copy. (LLM, conf=0.77)
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References 22 · Cited by 849
- Authors
- Peters, A. L., Buschur, E. O., Buse, J. B., Cohan, P., Diner, J. C., & Hirsch, I. B.
- Affiliations
- University of Southern California (US)
- The Ohio State University (US)
- University of North Carolina at Chapel Hill (US)
- Specialized Endocrine Care Center, Beverly Hills, CA
- University of Washington (US)
- Corresponding author
- Peters, Anne L.
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2015-06-15
- Volume
- 38
- Issue
- 9
- Pages
- 1687-1693
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC4542270
- OpenAlex
- W1957004156
- Cited by
- 849
- References
- 22
- Citations by year
- 2026: 54 · 2025: 51 · 2024: 52 · 2023: 57 · 2022: 60 · 2021: 70 · 2020: 77 · 2019: 92 · 2018: 76 · 2017: 94 · 2016: 117 · 2015: 46 · 2014: 2 · 2013: 1
- FWCI
- 96.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Yale University
- Intarcia Therapeutics
- Halozyme
- Novo Nordisk
- Astellas Pharma
- National Institutes of Health (UL1TR001111)
- Abbott Diabetes Care
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- euglycemic diabetic ketoacidosis, SGLT2 inhibitors, adverse drug reactions, type 1 diabetes, type 2 diabetes, ketosis, hyperglucagonemia, hypovolemia, glucose clearance, metabolic acidosis, antihyperglycemic medications
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Adult, Aged, Benzhydryl Compounds, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Glucosides, Humans, Hypoglycemic Agents, Male, Middle Aged, Diabetic Ketoacidosis
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