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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).

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.

EXCEPT:

• patients undertaking a liver reduction diet pre-operatively – see Patients undergoing surgery that requires liver reduction diet (LRD)

Patients undergoing surgery that requires liver reduction diet (LRD)

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, ertugliflozin should be discontinued as the LRD commences (see Further information).

Patients with type 2 diabetes mellitus not following a 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 ertugliflozin. 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 ertugliflozin 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 ertugliflozin 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 ertugliflozin – 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 ertugliflozin 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. 

Interactions with common anaesthetic agents

Hypotension

Ertugliflozin 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

Ertugliflozin can increase the risk of hypotension when used concomitantly with the antiemetics droperidol and prochlorperazine.

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.

Sick day rules

Patients undergoing surgery or who are acutely unwell, especially if they experience vomiting; diarrhoea; or fever perioperatively, should be advised to follow the 'Sick day rules':

• Temporarily stop ertugliflozin – also see ‘Advice in the perioperative period’

• Stay hydrated

• Maintain food intake, especially carbohydrates

• Increase frequency of blood glucose monitoring to 2 – 4 hourly, if they normally check it. If they don’t check their blood glucose, they should be advised to look out for symptoms of high blood sugars, such as thirst, passing more urine and tiredness

• Check blood ketones, irrespective of blood glucose levels, if they can. Or ask to have these checked at their GP surgery

• Seek medical advice if they have any concerns or their condition does not improve, especially if worsening vomiting or abdominal pain occurs, which may indicate raised ketone levels

• They can restart their ertugliflozin when any symptoms have resolved and they are able to eat and drink

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 ertugliflozin at least 4 days pre-operatively. The UK Medicines Healthcare products and 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.

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 12^th February 2024]

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 12^th 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

Ertugliflozin. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 12^th February 2024]

Summary of Product Characteristics – Steglatro® (ertugliflozin) 5mg Film-Coated Tablets. Merck Sharp & Dohme (UK) Limited. Accessed via www.medicines.org.uk 12/02/2024 [date of revision of the text April 2022]

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;132(2):435-436 doi: 10.1016/j.bja.2023.12.015