Interruption of oral hypoglycemic agents before pediatric surgery

We thank Drs. Ahmed and Ingelmo for their excellent concise review on the perioperative management of diabetes mellitus in children.1 We feel that there is an update that must be brought to the readers' attention. The authors state that oral hypoglycemic agents should be discontinued on the day of the procedure. Recent developments have created one exception. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors (the “gliflozins”) are agents given to supplement metformin in type-2 diabetes. It lowers blood glucose by preventing renal reabsorption of glucose, causing osmotic diuresis, increased lipolysis, and increased ketogenesis in part due to increased levels of glucagon, corticosteroid, and catecholamines. SGLT-2 inhibitors also promote renal excretion of bicarbonate, predisposing to metabolic acidosis. Fasting and stress from illness, anxiety, and pain all promote ketogenesis. The U.S. Food and Drug Administration (FDA) recognized the increased risk of diabetic ketoacidosis (DKA), often without an extraordinary rise in blood glucose (euglycemic), in the perioperative period in patients on SGLT-2 inhibitors, and recommended in 2020 that this class of drug be held, instead of just on the day of surgery, for five half-lives (3 days before surgery; 4-days if on ertugliflozin which has a half-life of up to 17 h). Many other professional bodies (e.g., American Diabetes Association since 2021) have issued the same guidelines. Steinhorn et al.2 studied 463 (354 with diabetes, 109 without diabetes) adult patients who held their SGLT-2 inhibitor between 0 and 6 days before surgery. Using the anion gap (AG) as a surrogate for acidosis and a multivariable model, these authors found an independent association between SGLT-2 inhibitor hold time and postoperative AG change per day held [−0.43, 95% confidence interval (−0.76 to −0.11), p = 0.01]. They concluded that all SGLT-2 inhibitor-treated surgical patients develop some degree of ketoacidosis, the severity of which is inversely proportional to the duration of SGLT-2 inhibitor interruption, meaning holding only on the morning of surgery results in the highest risk. In a review of the literature, Seki et al.3 found 99 cases of SGLT2 inhibitor-associated perioperative ketoacidosis. In 59 of those cases, the preoperative SGLT-2 inhibitor interruption duration was reported, and in all cases, the interruption was <3 days preoperatively. All surgical and acutely ill patients on SGLT-2 inhibitors are at risk of developing some degree of acidosis, regardless of age and their diabetic status, but those with hold time of only 1–2 days and delayed resumption of caloric intake are at the highest risk. With adequate precautions and management, however, perioperative overt DKA associated with SGLT-2 inhibitor use remains rare.4 It may present from a few hours to up to several weeks later, depending on intercurrent illness, diet and therapeutic modifications, etc.4 The muted hyperglycemia and the similarities between the DKA and the post-surgical states (nausea, vomiting, malaise, decrease in mental acuity) increase the chance of delayed and/or missed diagnosis. Based on results from the DINAMO trial, which showed that empagliflozin (Jardiance®) treatment (vs. placebo) was associated with a statistically significant reduction of hemoglobin A1c levels at week 26 in patients 10–17 years old with type 2 diabetes,5 the FDA approved in June 2023 and the U.K. National Institute for Health and Care Excellence updated their guidelines in May 2023, to incorporate use of empagliflozin in type 2 diabetic children >10 years of age. SGLT-2 inhibitors confer cardiovascular and renal protection in diabetic and non-diabetic adults and have been incorporated into the practice of many pediatric heart failure centers as a fourth line agent.6 In a systematic review, Grube and Beckett found patients as young as 6 years on dapagliflozin for chronic kidney disease.7 Studies are also underway to determine if empagliflozin/dapagliflozin protects the kidneys in children with chronic kidney disease (e.g., NCT06430684, NCT05944016 in ClinicalTrials.gov). In summary, anesthesiologists should expect to encounter pediatric patients on a SGLT-2 inhibitor and need to recognize that the preoperative hold-time for them is ≥3 days, with possibly shorter interruption for minor procedures that do not lead to delayed resumption of full diet. Furthermore, SGLT-2 inhibitors should only be restarted postoperatively upon adequate caloric intake. Because the hyperglycemia could be muted, DKA could be missed if only blood glucose is measured. When in doubt, ketones and, if possible, bicarbonate, blood gases, and AG should be monitored.1 Support was provided solely from institutional and/or departmental sources. No external funding was acquired for the current work. The authors declare no conflict of interest. Not applicable.

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