Safety Issues on Metformin Use

We read with interest the letter by Faichney and Tate (1) in the May issue of Diabetes Care. We would like to comment on metformin and the risk of lactic acidosis; however, we do not have data to refute the hypothetical relevance of diabetic ketoacidosis to the risk of lactic acidosis (1). We believe that the aforementioned letter and relevant reports (2–4) may negatively affect the future use of metformin, not only in type 1 (1) but also in type 2 diabetic patients. In this regard, the report by Horlen et al. (2), which addressed physicians’ lack of adherence to metformin prescribing precautions, was received with strong opposition in the medical media (5) following the public support from the Associated Press (www.aace.com).

Lactic acidosis has been linked to the use of biguanides for decades. Although phenformin had been pulled from the market, metformin-associated lactic acidosis has since been believed to be the direct result of metformin use, especially in situations likely to precipitate lactic acidosis, e.g., congestive heart failure, chronic renal insufficiency, shock, etc. Although this “solid fact” of causative (etiologic) relation between metformin and lactic acidosis has not been challenged previously, recent relevant publications have appeared in the literature (6–8). Lalau and colleagues (6,7) found that metformin accumulation was not related to either lactic acidosis or the associated mortality in patients taking therapeutic doses of metformin who developed lactic acidosis in association with other precipitating conditions. Metformin overdose was an exception, they reported (6); the latter can cause genuine type B lactic acidosis, but only a few such cases have been reported (9). In the report on metformin-associated lactic acidosis published by FDA investigators (3), metformin levels were not measured.

Rachmani et al. (8) have recently reported no lactic acidosis in diabetic patients who were continued on metformin over 4 years of follow-up; these patients had traditional contraindications (congestive heart failure, chronic renal insufficiency, or chronic obstructive pulmonary disease) to metformin use. Furthermore, a recent meta-analysis of 176 studies with >35,000 patient-years of follow-up found no cases of lactic acidosis, although some of these studies included patients with renal insufficiency and cardiovascular conditions (4).

Finally, Jones and Macklin (10) have recently reported that evidence suggested it was time to amend the contraindication “list” of metformin prescribing. They pointed out that the limiting criteria for the use of metformin in diabetes had stemmed largely from reports in the 1970s of mortality and lactic acidosis associated with “phenformin.”

Therefore, one may wonder whether metformin is an “innocent bystander” in these clinically complex metformin-associated lactic acidosis cases.

In conclusion, in view of the aforementioned thoughts challenging the “apparently well-established” etiologic role of metformin in metformin-associated lactic acidosis, and pending further research, it is prudent to critically appraise published reports on the issue. We believe that the average dose of metformin currently used in clinical practice is reasonably safe, even in the presence of mild to moderate cases of the “traditional contraindications.” An exception to this is the safe practice of holding metformin before contrast studies and during acute, intercurrent illnesses.