LAUSR

This year marks the 60th anniversary of the first clinical use of metformin for diabetes. From small beginnings (and despite a somewhat chequered history), metformin is currently recommended as the first-line oral glucose-lowering agent in most, if not all, clinical guidelines on the management of type 2 diabetes. Perhaps as a reflection of this, metformin was prescribed for 83.6% of individuals with type 2 diabetes in the UK in 2013 [1]. Meanwhile, in the USA, metformin was the eighth most commonly prescribed drug consistently from 2008 to 2012 [2], the number of prescriptions rising from 51.6 million in 2008 to 61.6 million in 2012. Metformin and gliclazide are the only two oral glucose-lowering agents on the WHO Model List of Essential Medications [3]. How did this drug reach such a commanding position and is such widespread use justified? If pharmacological therapy is really needed in addition to lifestyle measures, diabetes specialists and people with type 2 diabetes want medication that is effective at reducing blood glucose levels, easy to take, preferably has once-daily dosing, has no shortor long-term side effects, carries no risk of hypoglycaemia, does not cause weight gain and is affordable worldwide. In addition, the ideal drug would address the underlying pathophysiology of type 2 diabetes and have added value in terms of reducing non-glycaemic risk factors for, and the incidence of, microand macrovascular complications of diabetes. How does metformin match up to these demands? The medication is certainly an effective glucose-lowering agent, generally reducing HbA1c by approximately 10–15 mmol/mol (1.0–1.5%) in type 2 diabetes [4]. However, we are beginning to realise that not everyone responds to the drug equally and that genetic variation may influence individual response [5]. Further, many people with diabetes would argue that it is not easy to take, finding the large tablet size off-putting and the need for more than oncedaily consumption inconvenient. With 60 years of clinical use, we have a good understanding of metformin’s shortand longterm side effects. The common gastrointestinal side effects can be minimised by titrating the dose up slowly, taking the medication with/after food and, if necessary, switching to the extended-release preparation. With long-term use, fear of metformin-associated lactic acidosis initially blighted the use of metformin in some countries. However, a recent systematic review of prospective comparator trials and observational cohorts suggests that lactic acidosis is extremely rare, with a similar incidence in people with diabetes taking metformin or other glucose-lowering agents [6]. Indeed, many people have suggested that the contraindication of metformin use in chronic kidney disease stage 3 and beyond (estimated GFR [eGFR] <60 ml min [1.73 m]) is too restrictive. A further meta-analysis, however, supports the cautious use of metformin in individuals with chronic kidney disease with an eGFR as low as 30 ml min [1.73 m], with appropriate dose * Sally M. Marshall [email protected]