Perioperative Management of Glucose-lowering Drugs: Comment

We read with interest the review by Prieser et al. on the perioperative management of oral glucose-lowering agents in patients with type 2 diabetes mellitus.¹  The authors recommend (table 1) that sodium glucose cotransporter–2 inhibitors be ceased 24 h before elective interventions.¹  No allowance is made for the severity of the procedure (minor vs. major surgery) or type of procedure. However, the authors do acknowledge that other sources recommend a longer duration of withholding these medications before elective procedures. Ceasing them just on the day of the procedure may be suitable for minor interventions where early oral intake is possible. For procedures where return to preoperative state is expected to be delayed, some governing bodies recommend withholding these agents more than 24 h. The Australian Diabetes Society (Melbourne, Australia) recommends withholding 2 days before surgery and also on the day of the procedure in such scenarios.²  The half-lives of canagliflozin, dapagliflozin, and empagliflozin range between 12 to 13 h, and hence, withholding them for four to five half-lives (around 50 to 65 h) is likely to ensure complete washout of the drug at the time of surgery.³  As the half-life of ertugliflozin is 16 h, a more prolonged interruption may be required. The U.S. Food and Drug Administration (Silver Spring, Maryland) has recently approved a label change to sodium glucose cotransporter–2 inhibitors interruption before elective surgery. It recommends a 3-day cessation for canagliflozin, dapagliflozin, and empagliflozin, and 4 days for ertugliflozin.⁴ 

Euglycemic ketoacidosis is a rare, but serious complication associated with perioperative sodium glucose cotransporter–2 inhibitors therapy.⁵  Few reports have shown that the pharmacologic effects of sodium glucose cotransporter–2 inhibitors are likely to last beyond five half-lives of elimination (2 to 3 days).^6–8  Prolonged glycosuria and ketonemia persisting up to 9 to 10 days after discontinuation of sodium glucose cotransporter–2 inhibitors therapy have been described with euglycemic ketoacidosis presentations both in the surgical^6,7  and nonsurgical settings.⁸  Persistent glycosuria with minimal elevation of blood glucose was a key manifestation in those cases, highlighting an ongoing effect of these agents. Considering the half-lives of these agents, the renal effects should not have lasted beyond 2 to 3 days. Nonetheless, glycosuria (and metabolic effects) continued until 8 to 9 days with blood glucose values below the renal threshold of glucose. Sustained binding of these medications to renal transport proteins despite plasma elimination has been suggested as a possible mechanism of this prolonged effect.⁷ 

Supported by The Hospital Research Foundation Project Grant (Adelaide, Australia; grant is yet to be operative due to COVID-19 restrictions; to Drs. Jesudason, Meyer, and Thiruvenkatarajan), a Diabetes South Australia Research Grant (Adelaide, Australia; grant is yet to be operative due to COVID-19 restrictions; to Drs. Jesudason, Meyer, and Thiruvenkatarajan), and an A. R. Clarkson Scholarship, Royal Adelaide Hospital Research Fund (Adelaide, Australia; to Dr. Meyer). The remaining authors declare no competing interests.