Issues for surgery
Increased risk of post-operative infection and delayed wound healing due to poor glycaemic control if omitted.
Risk of diabetic ketoacidosis (DKA) if continued (see Further information).
Risk of volume depletion, hypotension and/or electrolyte disturbances if continued (see Further information).
Combination product containing metformin – risk of lactic acidosis if continued (see Interactions with other common medicines used in the perioperative period and Further information).
Potential for hypoglycaemia when taken concomitantly with other blood glucose lowering medicines and continued during nil by mouth (NBM) period.
Advice in the perioperative period
Elective surgery
Omit on day before and day of surgery (including combination product).
Combination product:
- Vokanamet® - contains canagliflozin + metformin (follow advice for canagliflozin but also see metformin drug record)
Consideration should be given to prescribing the components of combination products as separate medicines perioperatively.
Patients undergoing surgery that requires liver reduction diet (LRD) (e.g. bariatric surgery, gallbladder surgery)
Patients with type 2 diabetes mellitus commencing liver reduction diet (LRD) are at increased risk of electrolyte disturbances and volume depletion during this period; hence, canagliflozin should be discontinued as the LRD commences (see Further information).
Patients with type 2 diabetes mellitus not following an LRD should follow the advice above for elective surgery.
Other patients who require reduced calorie intake prior to their procedure (e.g, those who require pre-operative bowel preparation)
Restricted food intake is a risk factor for DKA in patients taking canagliflozin. A longer period of treatment cessation may be necessary and, in general, should coincide with reduced food intake. Trusts/Health Boards should ensure they have clear guidance in place for these patients so that they can be appropriately managed.
Emergency surgery
Withhold canagliflozin on admission to hospital. Monitor capillary blood glucose (CBG) levels closely and treat any hypoglycaemia accordingly. Check ketones (preferably blood not urine) daily.
Perioperative considerations
Commence variable rate intravenous insulin infusion (VRIII) perioperatively where indicated (see Further information) and omit canagliflozin during VRIII treatment.
Ensure emergency treatment of hypoglycaemia is prescribed, i.e. Glucogel® and 20% dextrose. Rapid acting insulin should also be prescribed.
Post-operative advice
Do not restart until eating and drinking normally, any volume depletion has been corrected, VRIII (where applicable) has been stopped, ketone levels are normal, and patient is medically stable (see Further information). Once restarted check ketones (preferably blood not urine) daily whilst an inpatient, even if CBG is normal.
Monitor renal function post-operatively – a deterioration in renal function may require a review of canagliflozin (with or without metformin) – consult current product literature.
Patients undergoing bariatric surgery
Due to the nature of bariatric procedures, there is an increased risk of dehydration and overall improvement of glycaemic control due to weight loss. Discontinuation of canagliflozin should be considered after surgery. Blood glucose should be monitored until eating habits and food intake stabilises. Patients should have their need for ongoing pharmacological management of their diabetes reviewed by their GP or bariatric surgical team.
For combination product containing metformin, please refer to metformin drug record.
Interactions with common anaesthetic agents
Hypotension
Canagliflozin can increase the risk of hypotension when used concomitantly with inhalational or intravenous anaesthetics.
Interactions with other common medicines used in the perioperative period
Hypotension
Canagliflozin can increase the risk of hypotension when used concomitantly with the antiemetics droperidol and prochlorperazine.
Iodinated contrast agents
Caution with combination product containing metformin and concomitant use of iodinated contrast agents – see metformin drug record.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Caution with combination product containing metformin and concomitant use of NSAIDs – see metformin drug record.
Further information
MHRA / CHM Advice (Updated April 2016): Risk of diabetic ketoacidosis with sodium-glucose co-transporter 2 (SGLT2) inhibitors and SGLT2 inhibitors: monitor ketones in blood during treatment interruption for surgical procedures (March 2020)
Serious, life-threatening, and fatal cases of DKA have been reported rarely in patients taking an SGLT-2 inhibitor. The presentation can be atypical, with patients having only moderately elevated blood glucose levels. Patients undergoing surgery may be at higher risk of DKA. The following European Medicines Agency (EMA) advice should be followed during the perioperative period:
- Test for raised ketones in patients with signs and symptoms of DKA, even if plasma glucose levels are near-normal
- Discontinue treatment if DKA is suspected or diagnosed – do not restart unless another cause for DKA is identified and resolved (seek advice from specialist diabetes team)
- Monitor ketone levels during SGLT-2 inhibitor treatment interruption in patients who have been hospitalised for major surgery – measurement of blood ketones is preferred to urine
- Do not restart treatment following major surgery until ketone levels are normal and the patient’s condition has stabilised.
Rationale for recommendations
The practice of holding SGLT-2 inhibitors during the perioperative period has recently been questioned, due to the many benefits these medicines have, not only on blood glucose control but also cardiovascular and kidney function. However, a review of the available data continues to suggest there is an association between SGLT-2 inhibitor use and DKA. The benefits of holding SGLT-2 inhibitors pre-operatively to prevent DKA, must be weighed against the potential deterioration in glycaemic control, and a reduction in cardiac and renal function.
The US Food and Drug Administration (FDA) recommend ‘consideration’ of stopping SGLT-2 inhibitors at least 3 days pre-operatively. The UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Australian Therapeutics Goods Administration (TGA) recommend interruption of SGLT-2 inhibitors for patients undergoing major surgery, but do not state the period of interruption. The advice to hold SGLT-2 inhibitors 3 or more days prior to surgery does not consider the risk of prolonged cessation (i.e. poor glycaemic control, use of VRIII, decline in cardiac/renal function).
Therefore, until further evidence is available to support the safe continuation of SGLT-2 inhibitors perioperatively, the Centre for Perioperative Care (CPOC) advises that SGLT-2 inhibitors should be withheld the day before and on the day of surgery.
Volume depletion, hypotension and/or electrolyte imbalances
SGLT-2 inhibitors increase diuresis associated with a modest decrease in blood pressure, which may be more pronounced in patients with very high blood glucose concentrations. For patients receiving SGLT-2 inhibitors where there is risk of volume depletion (i.e. during surgery), careful monitoring of volume status and electrolytes is recommended. Temporary interruption of treatment with SGLT-2 inhibitors is recommended for patients who develop volume depletion until the depletion has been corrected.
Lactic acidosis
Risk of lactic acidosis with combination product containing metformin – see metformin drug record.
VRIII
Patients with a planned short starvation period (no more than one missed meal in total) should be managed by modification of their usual diabetes medication, avoiding VRIII wherever possible (although VRIII may be necessary if emergency surgery or in people with poorly controlled diabetes (HbA1c >69mmol/mol)). Patients with type 2 diabetes who are expected to miss more than one meal should have VRIII if they develop hyperglycaemia (CBG >12mmol/L).
Liver reduction diet (LRD)
Patients with a high BMI often have a large, fatty liver which can cause difficulty for laparoscopic surgery, as the stomach cannot be easily accessed. The LRD typically starts 10 – 15 days prior to surgery and is based on low calories, in particular low carbohydrate, and fat. This forces stored glycogen to be released from the liver (plus some water), making it softer, more flexible and easier to move. Due to the reduced calorie and carbohydrate intake, CBG levels will most likely be reduced. In addition, weight loss itself stimulates ketone production and can increase the risk of euglycaemic DKA developing. Therefore, SGLT-2 inhibitors should be discontinued at the start of the LRD.
References
Centre for Perioperative Care. Guideline for Perioperative Care for People with Diabetes Mellitus Undergoing Elective and Emergency Surgery (updated October 2023). Available at: https://cpoc.org.uk/guidelines-resources/guidelines [Accessed on 12th February 2024]
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 12th February 2024]
Mulla, CM, Baloch HM, & Hafida S. Management of Diabetes in Patients Undergoing Bariatric Surgery. Current Diabetes Reports (2019); 19(11): 112. DOI: 10.1007/s11892-019-1242-2.
Summary of Product Characteristics – Vokanamet® (canagliflozin + metformin) 50mg/1000mg film-coated tablets. A. Menarini Farmaceutica Internazionale SRL. Accessed via www.medicines.org.uk 12/02/2024 [date of revision of the text August 2023]
Canagliflozin. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 12th February 2024]
Summary of Product Characteristics – Invokana® (canagliflozin) 100mg film-coated tablets. A. Menarini Farmaceutica Internazionale SRL. Accessed via www.medicines.org.uk 12/02/2024 [date of revision of the text August 2023]
Elasha H, Elsheikh AM, Wafa W, et al. SGLT2 Inhibition May Precipitate Euglycemic DKA after Bariatric Surgery. Clin Diabetes Res 2018;2(1):40-42. DOI: 10.36959/647/492
Khunti K, Aroda VR, Bhatt DL, et al. Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence. Diabetes, Obesity and Metabolism 2022; 24(11): 2071-80. DOI: 10.1111/dom.14805
Dhatariya K, Levy N, Russon K et al. Perioperative use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for diabetes mellitus. BJA 2024. DOI: 10.1016/j.bja.2023.12.015