Possible risk factors for the development of sodium-glucose co-transporter 2 inhibitor- associated diabetic ketoacidosis in type 2 diabetes

Kate West, Lucy-Anne Webb, Matthew Fenech, Ketan Dhatariya


Background: In the summer of 2015 the Food and Drug Administration and European Medicines Agency reported that over 100 cases of diabetic ketoacidosis (DKA) had been identified and issued a warning of increasing concerns of a possible link between sodium-glucose co-transporter 2 (SGLT-2) inhibitor use and the development of DKA. Several mechanisms for this have been postulated, but precisely what factors predispose individuals to develop DKA remain unknown.

Methods: We conducted a literature search on Pubmed and Ovid databases and Google Scholar and report a further case of DKA occurring in a patient with a 16-year history of type 2 diabetes 10 months after starting dapagliflozin.

Results: Very few cases of DKA occurring in type 2 diabetes have been reported. Most cases of DKA have occurred in patients with type 1 diabetes taking part in clinical trials or given the drug ‘off licence’. Several potential mechanisms for developing DKA have been postulated. In addition to these, we suggest that a prolonged history of type 2 diabetes may lead to reduced beta cell reserve, increasing the probability of developing DKA.

Conclusion: Despite the insulin-independent mode of action, SGLT-2 inhibitors are currently only licensed for use in type 2 diabetes. If the duration of diabetes is long and/or if insulin doses are reduced on initiation, clinicians and patients should be wary of signs of DKA. Until further data are available, unlicensed use in type 1 diabetes should be avoided.


SGLT-2 inhibitors, diabetic ketoacidosis

Full Text:



US Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. 2015. [Last accessed 18 December 2015]

European Medicines Agency. Review of diabetes medicines called SGLT2 inhibitors started. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/Procedure_started/WC500187926.pdf. 2015. [Last accessed 18 December 2015]

Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015;38:1687-93. http://dx.doi.org/10.2337/dc15-0843

Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015;100:2849-52. http://dx.doi.org/10.1210/jc.2015-1884

Erondu N, Desai M, Ways K, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care 2015;38:1680-6. http://dx.doi.org/10.2337/dc15-1251

Dhatariya K. Comment on Erondu N et al – Does this data significantly underestimate the prevalence of SGLT-2 associated DKA? Diabetes Care 2016;39(1):e18.

Hine J, Paterson H, Abrol E, et al. SGLT inhibition and euglycaemic diabetic ketoacidosis. Lancet Diabetes Endocrinol 2015;3:503-04. http://dx.doi.org/10.1016/S2213-8587(15)00204-1

Burr K, Nguyen A-T, Rasouli N. A case report of ketoacidosis associated with canagliflozin (Invokana). http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2015.DGM.5.SAT-595. 2015. [Last accessed 18 December 2015]

Hayami T, Kato Y, Kamiya H, 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;6:587-90. http://dx.doi.org/10.1111/jdi.12330

Dhatariya K, Savage M, Kelly T, et al. Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults. Second edition. Update: September 2013. http://www.diabetologists-abcd.org.uk/JBDS/JBDS.htm. 2013 [Last accessed 18 December 2015]

Clar C, Gill JA, Court R, et al. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2012; 2. http://dx.doi.org/10.1136/bmjopen-2012-001007

Yokono M, Takasu T, Hayashizaki Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol 2014;727:66-74. http://dx.doi.org/10.1016/j.ejphar.2014.01.040

Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508. http://dx.doi.org/10.1172/JCI72227

Kaku K, Watada H, Iwamoto Y, et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc Diabetol 2014;13:65. http://dx.doi.org/10.1186/1475-2840-13-65

Nadel E. Metabolism and nutition. In: Medical Physiology. Boron W, Boulpaep E, eds. Philadelphia: Saunders/Elsevier, 2015, p.1230.

Bonner C, Kerr-conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nature Med 2015;21:512-17. http://dx.doi.org/10.1038/nm.3828

Holman RR. Assessing the potential for a-glucosidase inhibitors in prediabetic states. Diabetes Res Clin Pract 1998;40:S21-5. http://dx.doi.org/10.1016/S0168-8227(98)00038-2

Merovci A, Mari A, Solis C, et al. Dapagliflozin lowers plasma glucose concentration and improves ß-cell function. J Clin Endocrinol Metab 2015;100:1927-32. http://dx.doi.org/10.1210/jc.2014-3472

Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-9. http://dx.doi.org/10.2337/dc14-2441

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. http://dx.doi.org/10.1056/NEJMoa1504720

DOI: https://doi.org/10.15277/bjd.2016.079


  • There are currently no refbacks.

The Journal of the Association of British Clinical Diabetologists