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Metformin has been used as a first line agent in the management of type 2 diabetes for over 40 years. It is inexpensive, effective (twelve patients need to be treated for 10 years to prevent one diabetes-related endpoint),1 and in contrast to other drugs used to treat diabetes, does not usually cause hypoglycaemia or weight gain.2 It is generally well tolerated, although it can produce mild gastrointestinal effects that usually settle with time. Sales of another biguanide (phenformin) were suspended in the 1970s as a result of a high rate of lactic acidosis associated with its use. Naturally this raised concerns of a class effect and metformin has been implicated in a number of case reports and case series of lactic acidosis, particularly in people with kidney disease.2 However, stopping metformin denies patients a drug with known patient oriented outcomes and often leads, at least temporarily, to deterioration in glycaemic control, weight gain and the need for insulin treatment. Many people believe that metformin has usually been an innocent bystander in cases of lactic acidosis, particularly in those patients with pre-existing chronic kidney disease who are already at high risk of sepsis and cardiorespiratory failure, the principal causes of lactic acidosis.3
Data from observational studies have been used to explore the association of lactic acidosis with metformin. For example, a Cochrane systematic review compared over 70,000 patient years of metformin exposure with a matched group receiving other hypoglycaemic agents and found no evidence of excess lactic acidosis.4 The upper estimate of incidence was in fact lower for those in the metformin group than in the non-metformin group. The authors concluded that “there is no evidence at present that metformin is associated with an increased risk for lactic acidosis when prescribed under the study conditions”. More recently, a UK case-control study also found higher rates of lactic acidosis in those on sulphonylureas (4.8/100,000 person-years) compared with metformin (3.3/100,000 person-years).5
Metformin is excreted unchanged by the kidney and therefore lower doses are needed as kidney function falls. Unfortunately for clinicians, advice and guidance on the use of metformin in renal disease from the British National Formulary (BNF), the National Institute for Health and Care Excellence (NICE) and the Summary of Product Characteristics (SPC) rather unhelpfully uses different terminology, measures of kidney function and thresholds. The SPC states that metformin is contraindicated in renal failure or renal dysfunction (creatinine clearance <60mL/min).6 The BNF advises ‘caution’ in renal impairment and that the drug should be avoided in ‘significant renal impairment’.2 NICE recommends that the dose is reviewed when estimated glomerular filtration rate (eGFR) <45mL/min/1.73m2 (or if serum creatinine >130μmol/L) and stopped when eGFR <30mL/min/1.73m2 (or if serum creatinine >150μmol/L).7 In addition, NICE advises that metformin should be withdrawn when there is a high risk of tissue hypoxia or acute kidney injury. Practical advice from the Renal Drug Handbook includes using 25–50% of the standard dose when GFR is 40–50mL/min, 25% of the standard dose when the GFR is 10–40mL/min and avoiding metformin when GFR <10mL/min, with annual monitoring of eGFR in people with normal renal function and 2–4 times a year in those with an eGFR at the lower end of normal and in older people.8
Balancing the benefits and risks of metformin and other hypoglycaemic agents it could be argued that metformin is one of the most effective hypoglycaemic agents, and that it has a valuable role even in patients with chronic kidney disease. There is a growing conviction amongst nephrologists and diabetologists that the current contraindication is too restrictive. It is time for standardisation of the prescribing advice on the use of metformin to maximise its use in people with renal disease supported by the development of a decision aid to enable patients to make an informed choice based on the risks and benefits of such treatment.
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