Erythrocyte metformin levels in patients with type 2 diabetes and varying severity of chronic kidney disease

Abstract

On the basis on a novel metformin assay, Frid et al. published clinical recommendations on use of the drug in patients with type 2 diabetes and varying severity of chronic kidney disease (CKD). The researchers stated that a threshold of 20 μmol/L (2.8 mg/L) was a ‘preliminary upper therapeutic limit’ [1]. However, the latter work can be questioned for several reasons: (i) the patients with an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 were not given the full therapeutic dose (median: 1500 mg/day); (ii) 22% of the patient population had an eGFR <60 mL/min/1.73m2; (iii) the study reported median metformin concentrations rather than individual values and (iv) lastly, and most importantly, the metformin concentration was measured in plasma, although the erythrocyte level may provide a better estimation of the risk of accumulation [2]. Indeed, metformin has a longer half-life in erythrocytes than it does in plasma (23.4 ± 1.9 versus 2.7 ± 1.2 h [3]); this makes the interpretation of a single concentration time point less critical if the time of the last metformin intake is not known. Here, we report on the distribution of erythrocyte metformin levels measured in a larger population with a wider range of eGFRs. We sought to test two hypotheses. Firstly, our previous work suggesting that metformin accumulation is not dangerous per se [since metformin-associated lactic acidosis is related to the severity of concomitant pathologies (for a review, see [4])] may have prompted the physicians in our centre to continue metformin administration beyond the limit stated in the current guidelines. Secondly, this particular situation offered an opportunity to study the extent to which CKD may lead to significant elevation of the metformin level. Given that metformin clears four to five times more quickly than creatinine [5], we did not expect this phenomenon to be significant.