Relationship Between Metformin Use and Lactic Acidosis in Advanced Chronic Kidney Disease: The REMIND-TMU Study

Abstract

Background: Although current guidelines only suggest that metformin is safe with an estimated glomerular filtration rate (eGFR) of >30 ml/min/1.73 m 2 due to increased risk of lactic acidosis, [1] evidence of metformin-associated lactic acidosis (MALA) has been limited due to insufficient case numbers. Up to 27.6% of patients with advanced chronic kidney disease (CKD) were still treated with metformin in real world practice. [2] It is necessary to investigate the incidence of laboratory-defined MALA in advanced CKD. Methods: This study used data from Taipei Medical University (TMU) and its affiliated hospitals, which was a three million population-based, long-term, propensity score-matched cohort study based on clinical data from 2008 to 2016. Adults with type 2 diabetes and advanced CKD were stratified according to being metformin users or non-users. The primary outcome was laboratory-defined lactic acidosis (serum pH of 5mmol/L). Relationships between the probability of MALA and various eGFR values in advanced CKD patients are also presented in regression analysis. Findings: In total, 12,850 adults with type 2 diabetes whose eGFR was <30 ml/min/1.73 m 2 were enrolled in this study out of a database consisting of 3,305,711 persons. After the process of propensity score matching, 7707 patients were divided into metformin and non-metformin groups. In linear regression model, metformin significantly increased the risk of lactic acidosis ( p =0.0204) as the eGFR declined in advanced CKD over a mean follow up of over 600 days after confounder adjustment with age, sex and comorbidities. Interpretations: Metformin significantly increased risk of lactic acidosis as renal function declined in advanced CKD even after confounder adjustment. This “REMIND” study reminds us that metformin should be avoided in advanced CKD due to a significantly increased risk of lactic acidosis as renal function declined. Funding Statement: This study was partially supported by Center for Drug Evaluation, Taiwan (grant number: RC1051115) and Taipei Municipal Wanfang Hospital (managed by Taipei Medical University) (grant number: 107TMU-WFH-07). Declaration of Interest: The authors declare no competing interests. Ethics Approval Statement: The study has the approval of fast track review by TMU institutional review board (TMU-JIRB no. IRB N201709052).