Metformin

  Issues for Surgery

For patients with diabetes – increased risk of post-operative infection and delayed wound healing due to poor glycaemic control if omitted.

Risk of lactic acidosis if continued (see Further Information).

Potential for hypoglycaemia when taken concomitantly with other blood glucose lowering medicines and continued during nil by mouth period.

Combination products containing Canagliflozin, Dapagliflozin or Empagliflozin – risk of diabetic ketoacidosis (DKA), volume depletion, hypotension and / or electrolyte disturbances if continued (see Further Information).

  Advice in the Perioperative period

Elective Surgery
Metformin should be taken as normal the day prior to surgery¹.

EXCEPT:

• Combination products containing canagliflozin (Vokanamet®), dapagliflozin (Xigduo®) or empagliflozin (Synjardy®) – see Sodium Glucose Co-transporter 2 (SGLT-2) monograph)¹.
  
  

Morning or Afternoon Surgery
If eGFR > 60 ml/min/1.73m²: -

• Once or Twice daily dosing: Continue^{1, 2}
• Three times daily dosing: Omit lunchtime dose on day of surgery^{1, 2}

If eGFR < 60 ml/min/1.73m²: -

• Contrast media: Omit on the day of the surgery and for 48 hours post-operatively^{1, 2}
• No contrast media: Follow advice above for eGFR > 60 ml/min/1.73m²
  
  

This advice should also be followed for: -

• Combination products containing pioglitazone (Competact®) – but also see Pioglitazone monograph
• Combination products containing alogliptin (Vipdomet®), linagliptin (Jentadueto®), saxagliptin (Komboglyze®), sitagliptin (Janumet®) or vildagliptin (Eucreas®) – but also see Dipeptidylpeptidase-4 (DPP-IV) Inhibitors monograph
• Modified release (MR/SR) preparations of metformin
• Patients taking metformin for Polycystic Ovary Syndrome (PCOS)

For combination products containing canagliflozin (Vokanamet®), dapagliflozin (Xigduo®) or empagliflozin (Synjardy®) - see Sodium Glucose Co-transporter 2 (SGLT-2) monograph).

Consideration should be given to prescribing the components of combination products as separate medicines perioperatively.

Patients undergoing Bariatric Surgery
Patients with type 2 diabetes mellitus commencing liver reduction diet (LRD): Metformin can be continued³ during the LRD as it does not cause hypoglycaemia providing other oral hypoglycaemics are reviewed. There should be close monitoring of CBG and if it falls below 4 mmol/L, metformin should be reviewed (See Further Information.

Patients with type 2 diabetes mellitus not following a LRD: Follow the advice above for Elective Surgery.

For information on combination products with Metformin, please refer to the individual monographs as above.

Emergency Surgery 
In the event of emergency surgery and the patient has already taken their metformin dose(s). Monitor capillary blood glucose (CBG) levels closely and treat any hypoglycaemia accordingly.

Perioperative Considerations
Commence variable rate intravenous insulin infusion (VRIII) perioperatively where indicated (see Further Information) and omit metformin during VRIII treatment¹.

Ensure emergency treatment of hypoglycaemia is prescribed i.e. Glucogel^® and 20% dextrose. Rapid acting insulin should also be prescribed^{1, 2}.

Post-operative Advice
Check renal function post-operatively; once eating and drinking normally and VRIII (where applicable) has been stopped¹ follow the advice below:-

• eGFR > 60ml/min/1.73m² (with or without use of contrast media) – restart metformin
• eGFR 30 – 60ml/min/1.73m² and no use of contrast media – restart metformin (BUT ensure that the dose is not increased above the patient’s usual pre-operative dose)
• eGFR 30 – 60ml/min/1.73m² and use of contrast media – do not restart metformin until 48 hours post-operatively.
• eGFR < 30ml/min/1.73m² (with or without use of contrast media) – do not restart metformin until renal function is stabilised. Seek advice from Diabetes Specialist Team

Combination Products
Follow advice above for restarting combination products containing pioglitazone or DPP-IV inhibitors. Combination products containing SGLT-2 inhibitors should not be restarted until patient eating and drinking normally and patient’s condition is stable (see Sodium Glucose Co-transporter 2 (SGLT-2) Inhibitors monograph).

Patients undergoing Bariatric Surgery
Improved glycaemic control is expected because of reduced calorie intake, early satiety and weight loss following bariatric surgery. However, depending on the preoperative HbA1c there may be a benefit to continuing a reduced dose of metformin post-operatively rather than discontinuing completely as metformin has been shown to reduce insulin resistance, which will further improve weight loss, and to have cardioprotective effects^{4, 5, 6}.

Providing renal function is stable metformin can be restarted from the third day post-operatively; however, if metformin is to continue, MR/SR formulations should be switched to immediate-release formulations (if tolerated) which are more appropriate to facilitate absorption and the dose may need to be reduced as bioavailability will increase following gastric bypass surgery³. Blood glucose should be monitored until eating habits and food intake stabilises³. Patients should have their need for ongoing pharmacological management of their diabetes reviewed by their General Practitioner / Bariatric Surgical Team.

For combination products containing metformin, please refer to individual monographs.

Patients taking metformin for PCOS may also continue it post-operatively.

Interaction(s) with Common Anaesthetic Agents

None for products containing metformin alone^{2, 7, 8, 9}.

Hypotension 
Combination products containing a SGLT-2 inhibitor can increase the risk of hypotension when used concomitantly with inhalational or intravenous anaesthetics².

  Interaction(s) with other Common Medicines used in the Perioperative Period

Iodinated Contrast Agents
Iodinated contrast agents can cause contrast-induced nephropathy (CIN). If CIN occurs, this can result in metformin accumulation and increased risk of lactic acidosis, although there is a lack of any valid evidence^{7, 8, 9, 10}. Ensure that renal function is checked prior to administration of iodinated contrast agents.

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)
Care with concomitant use of NSAIDs due to risk of impaired renal function and subsequent increased risk of lactic acidosis^{2, 7, 8}.

Hypotension
Combination products containing a SGLT-2 inhibitor can increase the risk of hypotension when used concomitantly with the antiemetics droperidol and prochlorperazine².

  Further Information

Lactic Acidosis
Lactic acidosis is a very rare but serious metabolic complication, which most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs as renal function deteriorates and increases the risk of lactic acidosis. Other risk factors include dehydration and prolonged fasting^{2, 7, 8}.

It should be noted that most manufacturers advise that metformin / metformin-containing products should be discontinued for all patients at the time of surgery under general, spinal or epidural anaesthesia, including those patient receiving iodinated contrast agents; and restarted no earlier than 48 hours after on resumption of oral nutrition and where renal function has been checked and is stable^{7, 8, 9}. However, current national guidance does not support this general restriction in patients with an eGFR > 60ml/min/1.73m² and the advice above should be followed^{1, 10}.

DKA, Volume Depletion, Hypotension and / or Electrolyte Imbalance
Risk of DKA, volume depletion, hypotension and / or electrolyte imbalance with combination product containing canagliflozin, dapagliflozin or empagliflozin – see Sodium Glucose Co-transporter 2 (SGLT-2) Inhibitors monograph.

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))¹. Patients with type 2 diabetes who are expected to miss more than one meal should have VRIII if they develop hyperglycaemia (CBG >12mmol/L)¹.

Use of VRIII is not indicated for patients taking metformin for PCOS.

Liver Reduction Diet (LRD)
Most people needing bariatric surgery have a large, fatty liver which can cause difficulty for laparoscopic surgery, as the stomach cannot be easily accessed. The LRD typically start 10 – 15 days prior to bariatric 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. Metformin can be continued during the LRD as it does not cause hypoglycaemia providing other oral hypoglycaemics are reviewed.

  References

1. Centre for Perioperative Care. Guideline for Perioperative Care for People with Diabetes Mellitus Undergoing Elective and Emergency Surgery (March 2021). Available at: https://cpoc.org.uk/guidelines-resources/guidelines [Accessed on 8^th March 2021]
2. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 28^th February 2021]
3. Busetto L, Dicker D, Aznar C et al. Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management. Obesity Facts 2017;10:597 – 632. DOI: 10.1159/000481825
4. Kooy A, de Jager J, Lehert P et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616–25. doi:10.1001/archinternmed.2009.20
5. Luo F, Das A, Chen J. et al. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol . 2019; 18(1):54. doi:10.1186/s12933-019-0860-y.
6. Drzewoski J, Hanefeld M. The Current and Potential Therapeutic Use of Metformin - The Good Old Drug. Pharmaceuticals (Basel). 2021; 14(2) 122 doi: 10.3390/ph14020122.
7. Summary of Product Characteristics – Glucophage^® (metformin) 500mg film coated tablets. Merck. Accessed via www.medicines.org.uk 28/02/2021 [date of revision of the text August 2019]
8. Summary of Product Characteristics – Glucophage^® SR (metformin) 1000mg prolonged release tablets. Merck. Accessed via www.medicines.org.uk 28/02/2021 [date of revision of the text December 2020]
9. Biguanide Antidiabetics. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. Electronic version. Truven Health Analytics, Greenwood Village, Colorado, USA. http://www.micromedexsolutions.com [Accessed 1^st March 2021]
10. The Royal College of Radiologists. Standards for intravascular contrast administration to adult patients, Third edition. London: The Royal College of Radiologists; 2015. www.rcr.ac.uk [Accessed 28th February 2021]