This narrative review, from a US perspective, examines current evidence for the relationship between metformin, plasma lactate levels, and the risk of lactic acidosis in patients with type 2 diabetes; from this, the authors suggest guidelines for the drug's use in patients with renal dysfunction.

Metformin has been used in Europe and most other countries for many years, and has long been accepted as a first line drug for patients with type 2 diabetes; in current European guidelines, it is considered to be the first-line drug treatment. It was only launched in the US in 1995, however, and although it has a similar place in US guidelines, it may be underused for fear of the alleged adverse effect of lactic acidosis, especially in patients with less severe renal dysfunction. The US prescribing information contra-indicates its use in patients with renal failure based on serum creatinine levels (1.5mg/100ml and above in men or 1.4mg/100ml and above in women). The authors therefore attempted to produce guidance on the use of metformin in renal dysfunction based on current evidence.

They describe lactic acidosis as a condition, and then review the literature on its potential association with metformin. An analysis of pooled clinical trial data, including all controlled trials lasting >1month, obtained data for 47,846 patient-years of metformin use and 38,221 patient-years of non-use. In this population, there were no cases of lactic acidosis; calculations suggested upper limits for incidence of 3.5 cases per 100,000 patient-years for all type 2 diabetics regardless of metformin use, 6.3 cases per 100,000 patient-years for metformin-treated patients and 7.8 cases per 100,000 patient-years in patients not treated with metformin. They also examine the evidence on risk of lactic acidosis  and renal function, and note that there are data indicating that significant numbers of patients are continued on metformin therapy despite having a level of renal dysfunction that should contra-indicate its use.

Based on current evidence and data on use in practice, the authors consider that causal association between lactic acidosis and use of metformin in patients who do not have other risk factors is weak. They conclude that raised serum creatinine should be considered as a risk factor, but not a contra-indication, and thus suggest that the contra-indication for use in patients with raised serum creatinine in US prescribing information should be removed and replaced with a caution in use.

[Editor's note: renal failure and dysfunction (creatinine clearance < 60 mL/min) is also a contra-indication in UK prescribing information for metformin.]