metformin in renal failure

JAMA just published a systematic review of the literature on the use of metformin in patients with chronic kidney disease (see dm metformin ckd jama 2014 in dropbox, or JAMA. 2014;312(24):2668-2675​). the major concern is that metformin is renally-cleared, and that its close cousin, phenformin, was used extensively in the US, caused large numbers of cases of fatal lactic acidosis and was pulled off the market in 1977. major points from the systematic review:

--65 studies identified, mostly case series and observational post-marketing surveillance but also some pharmacokinetic/metabolic ones

--though there is reduced metformin clearance with renal insufficiency, both  metformin and lactic acid levels are in safe ranges in patients with eGFR of 30-60 mL/min/1.73m²

--the incidence of lactic acidosis in metformin users is 3-10/100K person-years, "generally indistinguishable from the background rate". for example, an analysis of 347 studies of diabetics found no cases of lactic acidosis in 70,490 patient-years on metformin (nor in 55,451 in those not on metformin)

--small studies which have reported "metformin lactic acidosis" have typically been in hospitalized patients with supervening illnesses precipitating metabolic decompensation (eg infection, acute kidney/liver failure, cardiovasc collapse). unclear if the lactic acidosis was related to metformin. when metformin levels were measured, they were occasionally elevated but no consistent correlation with the lactic acidosis.

--observational studies suggest macrovascular benefit of metformin in patients with renal insufficiency. for example, a study of 19,691 diabetic patients with atherosclerotic disease found that mortality rates were 6.3% in those on metformin but 9.8% in those not.  this benefit persisted in the subgroup with eGFR of 30-60 mL/min/1.73m². this finding was confirmed in other observational studies  

--population-based studies have found that about 25% of patients prescribed metformin have renal dysfunction above the FDA guidelines (creat of >1.5 in men and >1.4 in women)..... and no clear increase in lactic acidosis.​ as a result of the current FDA prohibitions, about 2.5 million people in the US would not be eligible to take metformin.  the UK guidelines are to allow metformin if eGFR <60 mL/min/1.73m², with recommendation to review dosing if eGFR <45 mL/min/1.73m² and stop if eGFR < 30 mL/min/1.73m².

--however, it should be emphasized that no specific randomized controlled trials to check the safety of metformin in those with renal disease

my sense many years ago from European data was that metformin was very rarely associated with clinically significant lactic acidosis in patients with renal disease. in fact a survey i saw about 15 years ago in the US showed that the majority of physicians were using metformin up to creatinines of 1.7-1.8. so, since metformin is such an important diabetes drug for many reasons (eg, improves macrovascular/cardiac outcomes), i have been using it in men with creatinine of <2 and and women <1.8  for at least 10-15 years. that being said, i usually use lower doses of metformin anyway (only marginal improvement in diabetic control if use 2 gm/day over 1 gm/day), and many patients respond robustly to 500 mg (or even less, if 500 mg not tolerated). the authors of the systematic review suggest decreasing the max dose of metformin to 1000mg/day in those with eGFR of 30-45 mL/min/1.73m² range and not use if <30, since very limited data do suggest an increased risk of lactic acidosis at that point.