Sodium–glucose cotransporter type 2 inhibitors: managing the small but critical risk of diabetic ketoacidosis

Hamblin, Peter S; Wong, Rosemary; Bach, Leon A

doi:10.5694/mja2.50525

Topics

Risk of SGLT2 inhibitor‐associated diabetic ketoacidosis in type 2 diabetes: some answers, but more questions

Prescribers have enthusiastically embraced sodium–glucose cotransporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes on the strength of accumulating data reporting improved cardiovascular and renal outcomes. In Australia, in 2016, 757 826 Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme prescriptions containing an SGLT2 inhibitor were dispensed. By 2019, that number had risen to 2.3 million.1 Assuming these scripts are dispensed monthly, an estimated 19% of all patients with type 2 diabetes (about 190 000 people) are currently being treated with SGLT2 inhibitors.

1 Western Health, Melbourne, VIC
2 University of Melbourne, Melbourne, VIC
3 Box Hill Hospital, Melbourne, VIC
4 Alfred Health, Melbourne, VIC
5 Monash University, Melbourne, VIC

Correspondence: peter.hamblin@wh.org.au

Competing interests:

Leon Bach was an investigator in the DECLARE study.

1. Australian Government, Department of Human Services. Medicare Australia statistics: Pharmaceutical Benefits Schedule item reports. http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp (viewed Feb 2020).
2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–2128.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: 347–357.
4. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–657.
5. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995–2008.
6. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–2306.
7. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–334.
8. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019; 7: 606–617.
9. Hamblin PS, Wong R, Ekinci EI, et al. SGLT2 inhibitors increase the risk of diabetic ketoacidosis developing in the community and during hospital admission. J Clin Endocrinol. Metab 2019; 104: 3077–3087.
10. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 2013; 15; 304: H1060–H1076.
11. Australian and New Zealand College of Anaesthetists. Severe euglycaemic ketoacidosis with SGLT2 inhibitor use in the perioperative period [alert]. Melbourne: ANZCA. http://www.anzca.edu.au/documents/alert-dka-and-oral-hypoglycaemics-20180215.pdf (viewed June 2019).
12. Australian Diabetes Society. Alert update January 2020: periprocedural diabetic ketoacidosis (DKA) with SGLT2 inhibitor use. https://diabetessociety.com.au/documents/ADS_DKA_SGLT2i_Alert_update_2020.pdf (viewed Feb 2020).
13. Therapeutic Goods Administration. Adverse Event Management System [accessed 4 June 2019]. Canberra: Australian Government Department of Health, 2019.
14. Daniele G, Xiong J, Solis‐Herrera C, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care 2016; 39: 2036–2041.
15. Al Jobori H, Daniele G, Adams J, et al. Determinants of the increase in ketone concentrations during SGLT2 inhibition in NGT, IFG and T2DM patients. Diabetes Obes Metab 2017; 19: 809–813.
16. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium‐glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016; 65: 1190–1195.
17. Hillier S, Grimmer‐Somers K, Merlin T, et al. FORM: an Australian method for formulating and grading recommendations in evidence‐based clinical guidelines. BMC Med Res Methodol 2011; 11: 23.

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