Metformin

Common indications

• Type 2 diabetes mellitus, as first choice medication for control of blood glucose, used alone or in combination with other oral hypoglycaemic drugs (e.g. sulphonylureas) or insulin.

 

Mechanisms of action

• Metformin (a biguanide) lowers blood glucose by increasing the response (sensitivity) to insulin. It suppresses hepatic glucose production (glycogenolysis and gluconeogenesis), increases glucose uptake and utilisation by skeletal muscle and suppresses intestinal glucose absorption. It achieves this by diverse intracellular mechanisms, which are incompletely understood. It does not stimulate pancreatic insulin secretion and therefore does not cause hypoglycaemia. 
• It reduces weight gain and can induce weight loss, which can prevent worsening of insulin resistance and slow deterioration of diabetes mellitus.

 

Important adverse effects

• Metformin commonly causes gastrointestinal upset, including nausea, vomiting, taste disturbance, anorexia and diarrhoea. This adverse effect may contribute to weight loss in patients taking metformin. 
• Lactic acidosis is a rare adverse effect associated with metformin use, which can be fatal if untreated. It does not occur in stable patients, but can be precipitated by intercurrent illness that causes metformin accumulation (e.g. worsening renal impairment), increased lactate production (e.g. sepsis, hypoxia, cardiac failure) or reduced lactate metabolism (e.g. liver failure).

 

Warnings

• Metformin is excreted unchanged by the kidney. Metformin is therefore contraindicated in severe renal impairment and a dose reduction is required for patients with moderate renal impairment. Metformin should be withheld acutely where there is acute kidney injury, e.g. in sepsis, shock, or dehydration; or severe tissue hypoxia, e.g. in cardiac or respiratory failure, or myocardial infarction. 
• Caution is required in hepatic impairment as clearance of excess lactate may be impaired. 
• Metformin should be withheld during acute alcohol intoxication, when it may precipitate lactic acidosis, and be used with caution in chronic alcohol overuse, where there is a risk of hypoglycaemia.

 

Important interactions

• Metformin must be withheld before and for 48 hours after injection of IV contrast media (e.g. for CT scans, coronary angiography) when there is an increased risk of renal impairment, metformin accumulation and lactic acidosis. Other drugs (e.g. ACE inhibitors, NSAIDs, diuretics) with potential to impair renal function should also be used with caution (e.g. with renal function monitoring) in combination with metformin. Prednisolone, thiazide and loop diuretics elevate blood glucose, hence oppose the actions and reduce efficacy of metformin.