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

Authors

  • Kate West Department of Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
  • Lucy-Anne Webb Department of Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
  • Matthew Fenech Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
  • Ketan Dhatariya Department of Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK

DOI:

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

Keywords:

SGLT-2 inhibitors, diabetic ketoacidosis

Abstract

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.

References

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

Downloads

Published

2016-06-12

Issue

Section

Current Topics

Most read articles by the same author(s)