Effect of metformin on survival rate in experimental sepsis

Summary Aim Because "metformin-associated lactic acidosis" refers to metformin and concurrent pathologies as co-precipitating factors, the respective impact in the outcome of metformin therapy, metformin accumulation, and general diseases should be determined. We therefore constructed a model of sepsis in mice treated with metformin at a dose corresponding to clinical practice, or to accumulation. Methods 460 mice were separated in 3 groups: no metformin therapy, a 7-day metformin therapy at 50 mg.kg −1 .day −1 (MET50) or 500 mg.kg −1 .day 1 (MET500). Blood was drawn on day 7 in 40 met-formin-treated animals for determining metformin concentrations. The 420 other mice were divided in 14 subgroups according to the amount of an intra-peritoneal inoculum of E. coli ranging from 5.10 3 to 10 10 CFU/ml in order to construct a lethal dose curve. The survival rate was assessed at 7,13, 24, 36,60 and 120 hours thereafter. Results Plasma metformin concentrations were 0.26 ± 0.13 mg/l in MET50, and 4.63 ± 1.92 mg/l in MET500. The comparative analysis of the survival rates at 120 hours showed no difference of mortality, always occurring for an inoculum amount > 10 8 CFU/ml. Comparing the survival rates from time 0 to 120 hours using Kaplan-Meyer curves and the Logrank test, there was no difference between the different groups. Conclusion Metformin, even at a dose mimicking accumulation, does not aggravate the mortality rate in this model of sepsis. Consequently, metformin can not be considered as toxic in such a condition.