Relationship Between Plasmatic Metformin Concentration and Renal Replacement Therapy: A Multicenter Cohort Study

Background: Metformin is the first-line treatment used for type 2 diabetes mellitus for more than 60 years. Metformin-associated lactic acidosis is the most serious adverse effect of metformin and is most widely defined as metabolic acidosis with elevated lactate levels in the presence of metformin. However, there is no consensus regarding the role of metformin in metformin-associated lactic acidosis onset. This study aimed to determine the metformin toxicity threshold (the metformin plasma concentration that predicts the occurrence of lactic acidosis) and the metformin dialysis threshold (the metformin plasma concentration strongly correlated with dialysis introduction). Methods: This was a retrospective multicenter cohort study conducted from January 1, 2013, to December 31, 2020. All consecutive adult patients with at least one metformin-detectable blood concentration measurement were included. Results: In total, 169 patients (92 men; mean age, 70 ± 11 years) were included in this study. A receiver operating characteristic analysis using Youden index showed that a metformin plasma concentration threshold of 17.9 mg/L was associated with lactic acidosis (sensitivity: 43.8%; specificity: 90.5%). Another receiver operating characteristic analysis using Youden index showed that a metformin plasma concentration threshold of 17.5 mg/L was associated with dialysis (sensitivity, 53.0%; specificity: 94.2%). Conclusions: The retrospective study design, lack of clinical data, and selection bias (patients in whom metformin was prescribed owing to pathological conditions) were major limitations, resulting in only preliminary findings. However, this study could serve as a basis for future prospective clinical studies to evaluate the use of these clinical threshold values as therapeutic guides.