FRCA Notes

Metformin

Curriculum

"Diabetes mellitus: drugs used in... type 2 diabetes is the relevant curriculum item.

Resources

  • Metformin is a biguanide and the first-line drug for most adults with type 2 diabetes mellitus (T2DM)
  • It reduces hepatic glucose production and increases insulin sensitivity, but does not stimulate insulin secretion
    • It therefore does not cause hypoglycaemia when used alone
    • It is weight neutral and has evidence of long-term cardiovascular benefit

  • Type 2 diabetes mellitus
    • First-line, usually in combination with an SGLT2 inhibitor
    • Modified-release preparations are now preferred as they roughly halve the incidence of GI side-effects
    • Can be combined with other oral agents or insulin

  • Polycystic ovary syndrome (off-licence)

  • Reduces HbA1c by up to 13-14mmol/mol

  • The exact mechanism remains incompletely understood, but there are several proposed actions
  • Metformin only works in the presence of circulating insulin

Hepatic

  • In T2DM there is a failure to suppress hepatic gluconeogenesis in the fed state
  • Metformin activates hepatic AMP-activated protein kinase, suppressing gluconeogenesis
  • It also inhibits glucagon signalling, reducing glycogenolysis
  • Its predominant action is therefore to stop glucose rising rather than to lower it

Peripheral

  • Increases insulin receptor expression and tyrosine kinase activity, improving insulin sensitivity
  • Increases GLUT4-mediated glucose uptake into skeletal muscle
  • This insulin-sparing effect is seen when metformin is stopped in patients on insulin; insulin requirements rise by 25-35%

Gastrointestinal

  • Inhibits intestinal disaccharidase, delaying monosaccharide absorption (an 'acarbose-like' effect)
  • The resulting disaccharide load reaching the colon causes many of its GI side-effects

Absorption

  • Oral administration with slow GI absorption
  • Oral bioavailability 50-60%

Distribution

  • Negligible plasma protein binding

Metabolism

  • Not metabolised

Excretion

  • Excreted unchanged in the urine; elimination half-life approximately 6hrs
  • Accumulates in renal impairment
    • Dose should be reviewed if eGFR <45ml/min/1.73m2
    • Should be stopped if eGFR <30ml/min/1.73m2

Cardiovascular

  • Reduces macrovascular complications including stroke and death in overweight patients with T2DM

Gastrointestinal

  • Nausea, diarrhoea, bloating and flatulence are common
  • These usually settle with time; modified-release preparations reduce their incidence by approximately 50%

Nutritional and metabolic

  • Does not cause hypoglycaemia when used alone
  • Weight neutral
  • Lowers plasma cholesterol, triglycerides and LDL
  • Vitamin B12 deficiency with long-term use

Lactic acidosis

  • Metformin-associated lactic acidosis is rare
  • Concern is largely a legacy of older biguanides (phenformin, buformin) which were withdrawn for this reason
  • A Cochrane review found no evidence of increased lactate or lactic acidosis compared with other treatments
  • Most cases occur where there are contraindications or intercurrent illness, such as renal failure, tissue hypoperfusion, severe heart failure or overdose
  • When it does occur, mortality is significant and many patients require renal replacement therapy

Contraindications

  • eGFR <30ml/min/1.73m2
  • Conditions predisposing to tissue hypoxia or acute kidney injury e.g. dehydration, sepsis, shock, acute heart failure
  • Administration of iodinated contrast in patients with renal impairment
  • Hepatic impairment and alcohol excess

Perioperative management


Elective surgery

  • The manufacturer still advises stopping metformin at the time of surgery and restarting no earlier than 48hrs afterwards
  • However, UK guidance advocates continuing metformin given the low incidence of metformin-associated lactic acidosis:
    • Once or twice daily dosing: take as normal
    • Three times daily dosing: omit the lunchtime dose

  • Omit on the day of the procedure if there are risk factors for acute kidney injury, and for the following 48hrs
  • Combination products (e.g. with an SGLT2 inhibitor or DPP-4 inhibitor) should be prescribed as separate components peri-operatively so each can be managed individually

Emergency surgery

  • Omit in patients with renal derangement or those due to receive intravenous contrast

Evidence

  • Continuing metformin before elective surgery does not cause hypoglycaemia nor a clinically relevant rise in lactate
  • Observational data suggest continuation may be associated with less postoperative AKI and fewer complications
  • In the MOPED study (2026) only 12% of patients continued metformin on the day of surgery despite guidance
    • Continuation was associated with slightly more days alive and at home at 30 days (adjusted difference ~0.5 days), with less hypoglycaemia and ketoacidosis
    • No cases of lactic acidosis were recorded

  • Use a renoprotective anaesthetic technique by maintaining normotension and normovolaemia, and consider avoiding nephrotoxins

  • Restart once the patient is eating and drinking and renal function is stable
  • After bariatric surgery, modified-release preparations may need changing to immediate-release to aid absorption, and the dose reviewed
  • In critical care, metformin should usually be discontinued owing to the risks of tissue hypoperfusion and deteriorating renal function