A 61-year-old man is undergoing an elective open cholecystectomy. The surgical fellow has phoned you to ask for guidance on his medications perioperatively. In particular, the fellow is uncertain how to proceed with empagliflozin you commenced last month.
Background history includes the following:
Type 2 diabetes mellitus
Morbid obesity (BMI 41kg/m2)
Coronary artery disease:
Myocardial infarction 2012: PCI to LAD, mild diffuse disease elsewhere
Stress test 2019: 8 MET exercise tolerance
Current medications are:
Metformin 1g once daily
Perindopril 5mg once daily
Atorvastatin 80mg once daily
Ezetimibe 10mg once daily
Aspirin 100mg once daily
Empagliflozin 10mg once daily
Labs performed prior to her visit today reveal the following:
The surgical fellow tells you that the patient will fast from midnight the night before and anticipates the procedure occurring late morning. He anticipates the patient will be able to commence a light diet the following morning.
What is the most appropriate perioperative guidance for the empagliflozin?
The correct answer is: D. Hold 3 days prior to surgery, recommence when tolerating PO intake.
Patients who are planned for elective surgery should have their SGLT-2i ceased 3 days prior and recommenced when tolerating PO intake.5 It is considered reasonable to cease SGLT-2i approximately 3 days before (~5 half lives) before major surgery as the elimination half life ranges from 12-18 hours and the pharmacodynamics effects may persist for longer. For this reason, Option B is less correct.
While cardiologists are not routinely involved in the perioperative management of glucose-lowering drugs, increasing prescription of SGLT-2 inhibitors by cardiologists necessitates a knowledge of the safety profile and appropriate anticipatory guidance. Of particular concern is the potential risk, although low, of 'euglycemic' diabetic ketoacidosis (plasma glucose <14mmol/L).1 It needs to be noted that 'disproportionate' or 'lower than expected glucose level' diabetic ketoacidosis are the currently preferred terms as often the glucose is still mildly raised rather than being truly 'normal'.2
Rates of diabetic ketoacidosis remain low in patients on SGLT-2 inhibitors with contemporary estimates from claims data suggesting ~5 per 1000 patient years.3 This rate, however, is approximately two times more likely than with a DPP-4, for example.3 One of the strongest risk factors for diabetic ketoacidosis (DKA) on an SGLT-2i is a past history of DKA given the presence of existing beta cell dysfunction. Another important risk factor is acute illness, especially with decreased PO intake.
The mechanism for DKA is believed to be multifactorial.4 SGLT-2 inhibitors directly and indirectly reduce the normal feedback pathways of insulin secretion relative to glucagon, thereby resulting in enhanced lipolysis and ketogenesis at relatively 'normal' glucose levels. Further, inhibition of sodium reabsorption in the proximal convoluted tubule creates a favorable electrochemical gradient for negatively charged ketone bodies to be reabsorbed from the urine. Metabolic stress and reduced glycemic intake amplify these effects, which is why surgery is a 'double hit' of risk for DKA.2 Other important risk factors include diarrhea, excessive alcohol intake and abrupt decreases in (or holding) insulin doses.
Option C is incorrect as stopping for two weeks may destabilize glycemic control, which would be suboptimal in the context of planned surgery and wound healing. If there are concerns about glycemic control then questions about perioperative management of glycemia ought to be directed to their diabetologist or a perioperative physician.
Educational grant support provided by: Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC.
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Goldenberg RM, Berard LD, Cheng AY, et al. SGLT2 inhibitor‐associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clinical Therapeutics 2016;38:e1.
Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of Sglt‐2 inhibitors and diabetic ketoacidosis. Endocrine Practice 2016;22:753–62.
Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med 2017;376:2300–2.
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015;38:1638–42.
Milder DA, Milder TY, Kam PCA. Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations. Anaesthesia 2018;18:1008-18.