Diabetes Metab J.  2024 Nov;48(6):1169-1175. 10.4093/dmj.2024.0036.

Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights

• Baek HS
• Jeong C
• Yang Y
• Lee J
• Lee J
• Lee SH
• Cho JH
• Sohn TS
• Son HS
• Yoon KH
• Lee EY

• KMID: 2561800
• DOI: http://doi.org/10.4093/dmj.2024.0036

Abstract

One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

Keyword

Diabetes mellitus; Diabetic ketoacidosis; Sodium-glucose transporter 2 inhibitors

Figure

• 

Reference

1. Palmer BF, Clegg DJ. Euglycemic ketoacidosis as a complication of SGLT2 inhibitor therapy. Clin J Am Soc Nephrol. 2021; 16:1284–91.

2. Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther. 2014; 5:355–66.

3. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 Update to: management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020; 43:487–93.

4. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2021. Diabetes Care. 2021; 44(Suppl 1):S125–50.

5. Fernandez-Fernandez B, Sarafidis P, Soler MJ, Ortiz A. EMPAKIDNEY: expanding the range of kidney protection by SGLT2 inhibitors. Clin Kidney J. 2023; 16:1187–98.

6. Goldenberg RM, Berard LD, Cheng AY, Gilbert JD, Verma S, Woo VC, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin Ther. 2016; 38:2654–64.

7. Douros A, Lix LM, Fralick M, Dell’Aniello S, Shah BR, Ronksley PE, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis: a multicenter cohort study. Ann Intern Med. 2020; 173:417–25.

8. U.S. Food and Drug Administration. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Available from: https://www.fda.gov/drugs/drug-safety-andavailability/fda-revises-labels-sglt2-inhibitors-diabetes-includewarnings-about-too-much-acid-blood-and-serious (cited 2024 Jun 3).

9. Ata F, Yousaf Z, Khan AA, Razok A, Akram J, Ali EA, et al. SGLT-2 inhibitors associated euglycemic and hyperglycemic DKA in a multicentric cohort. Sci Rep. 2021; 11:10293.

10. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J. 1973; 2:578–80.

11. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015; 38:1687–93.

12. American Diabetes Association. 15. Diabetes care in the hospital: standards of medical care in diabetes-2021. Diabetes Care. 2021; 44(Suppl 1):S211–20.

13. Patoulias D, Manafis A, Mitas C, Avranas K, Lales G, Zografou I, et al. Sodium-glucose cotransporter 2 inhibitors and the risk of diabetic ketoacidosis: from pathophysiology to clinical practice. Cardiovasc Hematol Disord Drug Targets. 2018; 18:139–46.

14. Huang J, Yeung AM, Bergenstal RM, Castorino K, Cengiz E, Dhatariya K, et al. Update on measuring ketones. J Diabetes Sci Technol. 2024; 18:714–26.

15. Han YM, Ramprasath T, Zou MH. β-Hydroxybutyrate and its metabolic effects on age-associated pathology. Exp Mol Med. 2020; 52:548–55.

16. Kolb H, Kempf K, Rohling M, Lenzen-Schulte M, Schloot NC, Martin S. Ketone bodies: from enemy to friend and guardian angel. BMC Med. 2021; 19:313.

17. Umapathysivam MM, Gunton J, Stranks SN, Jesudason D. Euglycemic ketoacidosis in two patients without diabetes after introduction of sodium-glucose cotransporter 2 inhibitor for heart failure with reduced ejection fraction. Diabetes Care. 2024; 47:140–3.