948 Diabetes Care Volume 43, May 2020 Soie Kwon,1,2 Yong Chul Kim,1 The Long-term Effects of Jae Yoon Park,3 Jeonghwan Lee,2 Jung Nam An,4 Clara Tammy Kim,5 Metformin on Patients With Sohee Oh,6 Seokwoo Park,7,8 Dong KiKim,1,8 Yun Kyu Oh,2,8 Yon Su Kim,1 Chun Soo Lim,2,8 Type 2 Diabetic Kidney Disease and Jung Pyo Lee2,8 Diabetes Care 2020;43:948–955 | https://doi.org/10.2337/dc19-0936 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL OBJECTIVE Metformin is the first pharmacological option for treating type 2 diabetes. However, theuseofthis drugis notrecommendedinindividuals withimpairedkidneyfunction because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that 1Department of Internal Medicine, Seoul National patients with less severe disease were prescribed metformin, propensity score University Hospital, Seoul, Korea matching (PSM) was conducted. 2Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea RESULTS 3Department of Internal Medicine, Dongguk Uni- versity Ilsan Hospital, Goyang, Korea All-cause mortality and incident ESRD were lower in the metformin group according 4Department of Internal Medicine, Hallym Uni- to the multivariate Cox analysis. Because the two groups had significantly different versity Sacred Heart Hospital, Anyang, Gyeonggi- baseline characteristics, PSM was performed. After matching, metformin usage was do, Korea 5 still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% Institute of Life and Death Studies, Hallym Uni- – P < – P < versity, Chuncheon, Korea CI 0.57 0.73; 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58 0.77; 6Department of Biostatistics, Seoul Metropolitan 0.001).Only oneevent of metformin-associated lactic acidosis was recorded. In both Government, Seoul National University Boramae the original and PSM groups, metformin usage did not increase the risk of lactic Medical Center, Seoul, Korea 7 acidosis events from all causes (aHR 0.92; 95% CI 0.668–1.276; P 5 0.629). Department of Biomedical Sciences, Seoul Na- tional University College of Medicine, Seoul, Korea 8 CONCLUSIONS Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea In the present retrospective study, metformin usage in advanced chronic kidney Corresponding author:Jung Pyo Lee, nephrolee@ disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause gmail.com mortality and incident ESRD. Additionally, metformin did not increase the risk of Received 9 May 2019 and accepted 9 February lactic acidosis. However, considering the remaining biases even after PSM, further 2020 randomized controlled trials are needed to change real-world practice. This article contains Supplementary Data online at https://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-0936/-/DC1. Diabetes is the leading cause of chronic kidney disease (CKD) (1,2). According to the This article is featured in a podcast available at American Diabetes Association care guidelines, metformin is considered a first-line https://www.diabetesjournals.org/content/diabetes- treatment for type 2 diabetes because of its efficacy, low cost, weight neutrality, and core-update-podcasts. benefits regarding cardiovascular outcomes (3–5). In patients with CKD, however, the © 2020 by the American Diabetes Association. use of metformin is not recommended due to the risk of lactic acidosis (6,7). Readers may use this article as long as the work is properly cited, the use is educational and not for The risk of lactic acidosis and its fatal consequences have resulted in the withdrawal profit, and the work is not altered. More infor- of biguanide, phenformin and buformin, from the market (8,9). However, decades of mation is available at https://www.diabetesjournals clinical experience have provided clinicians with insights into the low incidence of .org/content/license. care.diabetesjournals.org Kwon and Associates 949 lactic acidosis resulting from the use of were investigated (ICD-E11, -E13, and -E14). concentration .5.0 mmol/L and serum metformin (10,11). A recent Cochrane We excluded patients with missing se- pH,7.35weresimultaneouslyrecorded. review reported a lack of evidence that rum creatinine levels (n 5 10), patients If more than 1 month had elapsed be- metformin treatment increases the in- with short follow-up periods (fewer than tween two lactic acidosis events, the cidence of lactic acidosis compared with 90 days of follow-up, n 5 306) and pa- second event was considered a separate other antidiabetic drugs (6). tients who received renal replacement event. After reviewing patient charts for Kidney Disease: Improving Global Out- (including hemodialysis, peritoneal dial- lactic acidosis events, we excluded pa- comes (KDIGO) recommended the con- ysis, and kidney transplantation) before tients who had other simultaneous causes tinuation of the use of metformin in or within 30 days of the first visit (n 5 of lactic acidosis (e.g., sepsis, cardiogenic people with an estimated glomerular fil- 499). Finally, 10,862 patients were in- shock, and hepatic failure) for drug- tration rate (eGFR) $45 mL/min/1.73 m2 cluded (Supplementary Fig. 1). induced lactic acidosis events. (eGFR categories G1–G3a), a review of its use in patients with an eGFR between Data Collection Statistical Analysis 30 and 44 mL/min/1.73 m2 (eGFR category A metformin user was defined as a patient We used the x2 test for categorical var- G3b), and its discontinuation in people who was prescribed metformin for longer iables and unpaired Student t tests for with an eGFR ,30 mL/min/1.73 m2 (eGFR than 90 days during the follow-up period. continuous variables to compare the categories G4–G5) (12). Moreover, the The start day was defined as the first baseline characteristics. We report the U.S.FoodandDrug Administration allows prescription date, and the stop date was categorical variables as percentages of all the use of metformin in individuals with defined as the last prescription date plus patients and continuous variables as the an eGFR $45 mL/min/1.73 m2 but still the last prescribed period. The definition means 6 SDs. A negative binomial regres- restrictsitsuseinpatientswithaneGFR criteria were also applied to sulfonylurea sion analysis was conducted to compare ,30 mL/min/1.73 m2 (13). Metformin andinsulinusers.TheeGFRwascalculated adverse events due to overdispersion. Mul- use in patients with an eGFR between 30 from the serum creatinine level using the tivariate Cox proportional hazards models and 45 mL/min/1.73 m2 is controversial Chronic Kidney Disease Epidemiology Col- were used to calculate the hazard ratios (12–14). laboration (CKD-EPI) equation (22), and (HRs) and 95% CIs for all-cause mortality Several recent studies revealed no dif- patients were divided into three groups andrenal outcomes. Additionally, we com- ference in the number of lactic acidosis based on the cutoff eGFR values of 30 pared the primary outcomes among the 2 events between patients with CKD who and 45 mL/min/1.73 m .HbA1c levels threegroupsdividedbyeGFRusingKaplan- were using metformin and those using were obtained to assess glycemic control. Meier curves and multivariate Cox pro- other antidiabetic drugs (15–19). How- This study was approved by the in- portional hazards models. A penalized spline ever, few studies have estimated the long- stitutional review board of Seoul National curve was used to summarize the effect of term advantages of metformin use, and University Hospital (no. 20180105/10– the metformin administration duration on the results are controversial (16,19–21). 2018–4/021), and the requirement for metformin users compared with nonmet- We performed a retrospective study with informed consent was waived due to the formin users. We used a multivariate Cox the hypothesis that metformin adminis- study’s retrospective design. All clinical regression to analyze the penalized spline tration to advanced CKD patients can be investigations were conducted in accor- curve with full adjustment (i.e., age, sex, beneficial in terms of all-cause mortality dance with the guidelines of the 2013 BMI, hypertension, liver disease, initial and incident end-stage renal disease (ESRD) Declaration of Helsinki. eGFR, initial HbA1c level, presence of pro- and cannot increase the incidence of lac- teinuria, and medication usage). tic acidosis. Outcomes The propensity scores were estimated The primary outcomeswere all-causemor- using logistic regression analyses and RESEARCH DESIGN AND METHODS tality and progression to ESRD. The in- were adjusted for the patient’s age, sex, Study Participants and Design formationondeathbeforeESRDwas BMI, hypertension, liver disease, initial eGFR, We performed a retrospective observa- obtained from the National Statistical initial HbA1c level, presence of proteinuria, tionalcohortstudyofpatientswithtype2 Office of Korea. ESRD was defined as a and medication usage (sulfonylurea, insulin, diabetes who were followed at the ne- requirement of dialysis longer than 3 angiotensin II receptor blocker, and ACE phrology clinics of two tertiary hospitals months