Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users:A GoDarts study

Aims: Metformin is renally excreted and has been associated with the development of lactic acidosis. Although current advice is to omit metformin during illnesses that may increase risk of acute kidney injury (AKI), the evidence supporting this is lacking. We investigated the relationship between AKI, lactate concentrations and the risk of lactic acidosis in those exposed to metformin.Methods: We undertook a population-based case-control study of lactic acidosis in 1,746 participants with Type 2 diabetes and 846 individuals without diabetes with clinically measured lactates with and without AKI between 1994-2014. AKI was stratified by severity according to Kidney Disease: Improving Global Outcomes guidelines. Mixed effects logistic and linear regression was used to analyse lactic acidosis risk and lactate concentrations respectively.Results: 82 cases of lactic acidosis were identified. In Type 2 diabetes, those treated with metformin had a greater incidence of lactic acidosis (45.7 per 100,000 patient years; 95% CI 35.9-58.3) compared to those not exposed to this drug (11.8 per 100,000 patient years; 95% CI 4.9-28.5). Lactate concentrations were 0.34 mmol/L higher in the metformin-exposed cohort (p < 0.001). The risk of lactic acidosis was higher in metformin users (OR 2.3; p = 0.002) and increased with AKI severity (stage 1: OR 3.0, p = 0.002; stage 2: OR 9.4, p < 0.001; stage 3: OR 16.1, p < 0.001).Conclusions: A clear association was found between metformin, lactate accumulation and the development of lactic acidosis. This relationship is strongest in those with AKI. These results provide robust evidence to support current recommendations to omit metformin in any illness that may precipitate AKI.