Metformin-induced lactic acidosis extremely rare

Journal of Family Practice, April, 2004

Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med 2003; 163:2594-2602.

* CLINICAL QUESTION

What is the risk of lactic acidosis accompanying metformin therapy for patients with type 2 diabetes?

* BOTTOM LINE

The link between metformin and lactic acidosis, when used as prescribed, is tenuous. The bigger question is whether lactic acidosis risk truly increases when we relax criteria and give it to patients previously forbidden to take it. (LOE=1a)

* STUDY DESIGN

Systematic review

* SETTING

Outpatient (any)

* SYNOPSIS

It's tricky to try to prove the nonexistence of a phenomenon. The adage holds: Absence of proof is not proof of absence. So, how much absence of proof do we need?

The authors of this study combined the results of all randomized controlled trials and observational studies to determine the risk of lactic acidosis with metformin. The literature search was thorough and included unpublished data. Two independent reviewers evaluated articles for inclusion. The methodologic quality of the studies was evaluated using modified quality criteria. Of the 194 studies in the analysis, 126 were randomized controlled studies and 68 were observational research. More than 18,000 participants in these studies received metformin for an average 2.1 years (36,893 patient-years).

There were no cases of lactic acidosis in the metformin-treated group or in the comparison group. Not surprising, since patients with risk factors for lactic acidosis were undoubtedly not enrolled in any of the studies, and monitoring was more intense than in typical practice. Population studies estimate the rate of lactic acidosis to be between 2 and 9 cases per 100,000 patient-years (which is also the rate of lactic acidosis in patients with diabetes not receiving metformin). Using these numbers, 1 to 3 cases of lactic acidosis would have been expected. Several studies evaluated lactic acid levels in metformin-treated patients, finding no difference in baseline lactic acid levels compared with those not treated with metformin.