The Long-Term Effects of Metformin on Patients with Type 2 Diabetic

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 (either hemodialysis or peritoneal inhibitor). We performed propensity score in South Korea (Seoul National University dialysis) or preemptive renal transplanta- matching (PSM) using the MatchIt pack- Hospital and Seoul National University tion. The 3-month limit was designed to age by applying the nearest-neighbor Boramae Medical Center). Deidentified rule out acute renal failure that tempo- algorithm with 1:1 matching and discard- patient data retrieved from electronic rarily requires dialysis. The incident ESRD ing in both groups. Statistically significant medical records were used, including the information was ascertained through the differences in each variable after match- date of birth, sex, BMI, diagnostic codes Korean Society of Nephrology Database ing were tested using the x2 test and according to the ICD-10-Clinical Modifi- and electronic medical records of enrolled unpaired Student t tests. We also as- cation, drug prescriptions, and labora- hospitals. Both primary outcomes were sessed the standardized difference of tory results. The follow-up period for each censored by the date of the last serum each covariate, which defined the differ- patient was defined as the interval be- creatinine measurement. ence of the means or proportions. tween the first and last dates of creat- The secondary outcome was drug- All statistical analyses were performed ininemeasurements.From1January2001 inducedacidosisevents.Wedefinedalac- using R, version 3.5.0 (Comprehensive R to 31 December 2016, 11,677 patients tic acidosis event when a serum lactate Archive Network: https://cran.r-project.org) 950 Long-term Effects of Metformin on DKD Diabetes Care Volume 43, May 2020

and SPSS, version 22.0 (Armonk, NY). In all nonmetformin group (26.8%) died during # eGFR , 45 mL/min/1.73 m2 (aHR 0.77; analyses, P , 0.05 was considered statis- the follow-up period. All-cause mortality 95% CI 0.58–1.00; P 5 0.052); and eGFR tically significant. was significantly lower in the metformin #30 mL/min/1.73 m2 (aHR 0.88; 95% CI group than in the nonmetformin group 0.71–1.10; P 5 0.257) (Table 2). according to the multivariate Cox anal- In the Kaplan-Meier analysis, the RESULTS ysis (adjusted hazard ratio [aHR] 0.58; metformin group had a lower incidence Baseline Characteristics 95% CI 0.52–0.64; P , 0.001) (Table 2). of all-cause mortality and ESRD pro- According to the basic criterion of met- Also, 522 patients (11.4%) in the met- gression than the nonmetformin group formin usage for 90 days, 4,597 metformin group and 1,533 patients (24.5%) (Fig. 1 and Supplementary Figs. 2 and formin users and 6,265 nonmetformin in the nonmetformin group progressed 3). users were included in the current to ESRD. Compared with the nonmet- study. The median follow-up period formin group, the metformin group 6 All-Cause Mortality and Incidence of was 7.3 4.8 years in the whole pop- was less likely to develop ESRD (aHR 6 ESRD Progression After PSM ulation: 8.7 4.5 years for metformin 0.66; 95% CI 0.59–0.76; P , 0.001) To balance the differences in baseline char- 6 users and 6.3 4.7 years for nonmet- (Table 2). acteristics, we performed PSM. Metformin formin users (Table 1). We performed a subgroup analysis users still had lower all-cause mortality Before matching, the two groups had stratified according to renal function. We (aHR 0.65; 95% CI 0.57–0.73; P , 0.001) substantially different characteristics. Com- divided the patients into three groups and progression to ESRD (aHR 0.67; 95% pared with nonmetformin users, metfor- based on eGFR cutoff values of 30 and CI 0.58–0.77; P , 0.001) (Table 2). Met- min users had a higher mean BMI, higher 45 mL/min/1.73 m2, which represented formin usage was associated with low all- initial and mean HbA1c levels, and better CKD stages better than 3A and 3B and cause mortality in all three subgroups initial mean eGFR. Metformin users took worse than 4. The fully adjusted multivar- even after a fully adjusted multivariate more sulfonylurea than nonmetformin iate Cox regression analysis was conducted Cox regression model: eGFR $45 mL/ users, but no difference in insulin and for all eGFR groups. Compared with the min/1.73 m2 (aHR 0.70; 95% CI 0.60– renin-angiotensin system (RAS) blockade nonmetformin users, metformin users 0.82; P , 0.001); 30 mL/min/1.73 m2 # usage was observed between the two had lower all-cause mortality rates: eGFR , 45 mL/min/1.73 m2 (aHR 0.64; groups. After PSM for age, sex, BMI, eGFR $45 mL/min/1.73 m2 (aHR 0.61; 95% CI 0.47–0.86; P 5 0.003); and eGFR hypertension, liver disease, initial eGFR, 95% CI 0.54–0.70; P , 0.001); 30 mL/min/ #30 mL/min/1.73 m2 (aHR 0.55; 95% CI initial HbA1c level, the presence of pro- 1.73 m2 # eGFR , 45 mL/min/1.73 m2 0.37–0.81; P 5 0.003) (Table 2). Metfor- teinuria according to the dipstick tests, (aHR 0.58; 95% CI 0.45–0.75; P , 0.001); min users with an eGFR .30 mL/min/ and other medication usage, the differ- and eGFR #30 mL/min/1.73 m2 (aHR 1.73 m2 had a significantly lower inci- ences in baseline characteristics disap- 0.49; 95% CI 0.35–0.69; P , 0.001) dence of ESRD progression; eGFR $45 peared (Table 1). (Table 2) after full adjustment. Addi- mL/min/1.73 m2 (aHR 0.62; 95% CI 0.51– tionally, metformin users had a signifi- 0.76; P , 0.001); 30 mL/min/1.73 m2 # 2 All-Cause Mortality and Incidence of cantly lower incidence of ESRD in the CKD eGFR , 45 mL/min/1.73 m (aHR 0.73; ESRD Progression Before PSM stage than in the 3A stage: eGFR $45 95% CI 0.54–0.99; P 5 0.049); and eGFR In total, 634 patients (13.8%) in the met- mL/min/1.73 m2 (aHR 0.62; 95% CI 0.53– #30 mL/min/1.73 m2 (aHR 0.87; 95% CI formin group and 1,678 patients in the 0.73; P , 0.001); 30 mL/min/1.73 m2 0.67–1.12; P 5 0.278) (Table 2).

Table 1—Demographics before and after PSM Before matching After matching Metformin Nonmetformin Standardized Metformin Nonmetformin Standardized (n 5 4,597) (n 5 6,265) P value difference (n 5 2,704) (n 5 2,704) P value difference Follow-up duration, years 8.7 6 4.5 6.3 6 4.7 ,0.001 2.2982 8.2 6 4.5 7.4 6 4.7 ,0.001 0.8437 Age, years 67.8 6 11.6 66.2 6 12.9 ,0.001 1.0626 67.5 6 11.5 67.4 6 12.9 0.687 0.1335 Female 2,034(44.2) 2,459 (39.2) ,0.001 20.0563 1,180(43.6) 1,117 (41.3) 0.088 20.0233 Hypertension 2,307(50.2) 3,036 (48.5) 0.076 0.0021 1,322(48.9) 1,327 (49.1) 0.892 20.0018 Liver disease 163 (3.5) 305 (4.9) 0.001 20.0143 112 (4.1) 117 (4.3) 0.787 20.0018 BMI, kg/m2 19.9 6 10.9 17.9 6 10.9 ,0.001 1.5617 19.2 6 10.8 18.7 6 10.4 0.121 0.4469

Initial HbA1c, % 7.7 6 1.8 7.2 6 1.8 0.005 0.5150 7.4 6 1.9 7.4 6 1.7 0.720 0.0176

Initial HbA1c, mmol/mol 61 6 19.5 55 6 19.5 0.005 0.5150 57 6 20.5 57 6 18.5 0.720 0.0176 Initial eGFR, mL/min/1.73 m2 66.6 6 21.3 51.4 6 27.2 ,0.001 15.5865 61.2 6 25.1 61.4 6 21.9 0.801 0.1618 Urine proteinuria* 2,686(58.5) 2,680 (43.5) ,0.001 20.1542 1,456(53.8) 1,245 (46.0) 0.643 20.0067 Sulfonylurea 3,243(70.5) 1,812 (28.9) ,0.001 0.3990 1,419(52.5) 1,390 (51.4) 0.430 20.0107 Insulin 2,118(46.1) 2,806 (44.8) 0.184 20.0100 1,188(43.9) 1,179 (43.6) 0.805 20.0033 ARB and ACEi 709 (15.4) 899 (14.3) 0.126 0.0121 363 (13.5) 354 (13.1) 0.660 0.0044 Data are n (%) and mean 6 SD. ACEi, ACE inhibitor; ARB, angiotensin II receptor blocker. *Urine proteinuria was deﬁned as a value greater than 11 in urine dipstick results. care.diabetesjournals.org Kwon and Associates 951

Table 2—Multivariate Cox regression analysis of all-cause mortality and ESRD progression according to metformin usage in the whole population (models 1–3) and the PSM cohort (model 4) 30 mL/min/1.73 m2 # All eGFR $45 mL/min/1.73 m2 eGFR , 45 mL/min/1.73 m2 eGFR ,30 mL/min/1.73 m2 HR 95% CI P value HR 95% CI P value HR 95% CI P value HR 95% CI P value All-cause mortality Model 1a 0.44 0.41–0.49 ,0.001 0.67 0.60–0.75 ,0.001 0.56 0.45–0.71 ,0.001 0.35 0.25–0.49 ,0.001 Model 2b 0.45 0.41–0.49 ,0.001 0.66 0.59–0.74 ,0.001 0.59 0.47–0.75 ,0.001 0.42 0.30–0.59 ,0.001 Model 3c 0.58 0.52–0.64 ,0.001 0.61 0.54–0.70 ,0.001 0.58 0.45–0.75 ,0.001 0.49 0.35–0.69 ,0.001 Model 4d 0.65 0.57–0.73 ,0.001 0.70 0.60–0.82 ,0.001 0.64 0.47–0.86 0.003 0.55 0.37–0.81 0.003 ESRD progression Model 1a 0.38 0.35–0.42 ,0.001 0.69 0.60–0.80 ,0.001 0.69 0.54–0.88 0.003 0.90 0.73–1.10 0.300 Model 2b 0.38 0.34–0.42 ,0.001 0.68 0.59–0.79 ,0.001 0.71 0.55–0.91 0.007 0.85 0.69–1.50 0.135 Model 3c 0.66 0.59–0.76 ,0.001 0.62 0.53–0.73 ,0.001 0.77 0.58–1.00 0.052 0.88 0.71–1.10 0.257 Model 4d 0.67 0.58–0.77 ,0.001 0.62 0.51–0.76 ,0.001 0.73 0.54–0.99 0.049 0.87 0.67–1.12 0.278 aUnadjusted. bAdjusted for age, sex, BMI, hypertension, and liver disease. cAdjusted for age, sex, BMI, hypertension, liver disease, initial eGFR, initial HbA1c level, the presence of proteinuria according to the urine dipstick test, and other medication use (sulfonylurea, insulin, angiotensin II receptor d blocker, and ACE inhibitor). PSM covariates: age, sex, BMI, hypertension, liver disease, initial eGFR, initial HbA1c level, presence of proteinuria according to the dipstick test, and other medication use (sulfonylurea, insulin, angiotensin II receptor blocker, and ACE inhibitor).

Subgroup Analysis After PSM metformin treatment duration in both P 5 0.777), and insulin (aHR 5.37; 95% CI When performing a subgroup analysis primary outcomes. The correlations be- 3.222–8.954; P , 0.001) (Supplementary of the PSM cohort, the metformin group tween the daily mean metformin dose and Table 1). Additionally, there was no dif- still had a lower risk of all-cause mortality the predicted risks of all-cause mortality ference in the maximal lactate level be- and ESRD progression (Supplementary and ESRD progression are presented in tween metformin users and nonmetformin Figs. 4 and 5). Metformin usage showed Supplementary Fig. 6. users (P 5 0.440). more risk reduction in obese patients in all-cause mortality and ESRD progres- Sensitivity Analysis of Lactic Acidosis Sensitivity Analysis of Glycemic sion. Patients who used metformin and Events Control fi sulfonylurea at the same time bene ted Overall, 249 lactic acidosis events were Becauseglycemiccontrolcanaffectpatient more than those who used metformin recorded for 228 patients, regardless of outcomes, we conducted two sensitivity alone. In contrast, compared with met- the cause of lactic acidosis. When we analyses of glycemic control. First, we formin therapy alone, the simulta- reviewed all 249 events, only one patient adjusted HbA1c levels as a time-varying neous use of metformin with insulin experienced a metformin-induced lactic covariate based on a fully adjusted mul- fi or RAS blockers had less bene t. acidosis event. The patient was 80 years tivariate Cox regression model. Metfor- . old, and she had CKD stage 4 (eGFR of min users with an eGFR 30 mL/min/ 2 Sensitivity Analysis of the Duration of ;25mL/min/1.73m2)atthetimeofdrug- 1.73 m still had low all-cause mortality Metformin Administration induced lactic acidosis. She had started and low ESRD incidence (Supplementary We additionally constructed a penalized metformin 20 months before the event, Tables 2 and 3). spline to investigate the trend between when her eGFR was 40 mL/min/1.73 m2. Second, we investigated severe hypo- the predicted risks of each outcome ac- Because only one drug-induced lactic glycemic events that caused an emer- cording to the duration of metformin acidosis event was recorded, we addi- gency department visit. A total of 535 administration. In the whole population tionally analyzed the risk of lactic acidosis events were recorded in the whole co- without classification according to eGFR, events from all causes for patients re- hort, and 294 events were recorded in the overall mortality rate was decreased ceiving metformin, sulfonylurea, and in- the PSM cohort. Metformin did not in- in patients treated with metformin for sulin treatment. In all patients without crease the number of severe hypoglycemic more than 2.7 years, and the ESRD pro- PSM, metformin and sulfonylurea did not events for either the whole population – 5 gression rate decreased in patients trea- increase the risk of lactic acidosis events (HR 0.83; 95% CI 0.653 1.051; P 0.121) ted with metformin for more than 2.5 from all causes: metformin (aHR 0.92; or the PSM cohort (HR 0.83; 95% CI – 5 years (Fig. 2A and E). When a subgroup 95% CI 0.668–1.276; P 5 0.629) and 0.627 1.109; P 0.211) (Supplementary analysis stratified by an eGFR of 30 mL/min/ sulfonylurea (aHR 1.25; 95% CI 0.924– Table 4). 1.73 m2 and 45 mL/min/1.73 m2 was 1.697; P 5 0.147) (Supplementary Table performed,longer metforminusage was 1). In contrast, insulin usage was asso- CONCLUSIONS associated with a lower risk of all-cause ciated with a greater risk (aHR 5.13; 95% In the current study, metformin usage mortality and ESRD progression, with CI 3.543–7.421; P , 0.001). Even when was associated with a lower risk of all- the exception of the risk of ESRD pro- analyzed in a PSM cohort, metformin did cause mortality and ESRD progression in gression in the group with an eGFR not increase the risk of lactic acidosis CKD patients, particularly those with an ,30 mL/min/1.73 m2. Additionally, pa- from all causes: metformin (aHR 0.80; eGFR .30 mL/min/1.73 m2.Because tients with more advancedCKDtendedto 95% CI 0.546–1.162; P 5 0.238), sulfo- baseline characteristics were significantly experience more benefitfromashorter nylurea (aHR 1.06; 95% CI 0.710–1.580; different between metformin users and 952 Long-term Effects of Metformin on DKD Diabetes Care Volume 43, May 2020

Figure 1—Kaplan-Meier curves for all-cause mortality in the total group of patients (before PSM) (A), all-cause mortality in PSM patients (B), ESRD progression in the total group of patients (before PSM) (C), and ESRD progression in PSM patients (D).

nonmetformin users, we performed sub- on patients with stage 5 CKD. Because infection (16). Moreover, there were no group analyses and PSM to close the gap. we analyzed patients with various stages increased risks ofall-cause mortality, CVD, In patients whose eGFR was .30 mL/ of CKD, the current study is likely to be acidosis, or serious infection in patients min/1.73 m2, metformin users still had more clinically informative. Although this with an eGFR of 30–45 mL/min/1.73 m2. lower risks at both primary outcomes. To Taiwanese study and many other studies As a nationwide cohort study, the authors the best of our knowledge, this study is (15–19) have shown a low incidence of presented subanalysis results about drug the first to show the beneficial effects of metformin-associated lactic acidosis, a usage (metformin, other oral hypoglyce- metformin on a large Asian population debate about metformin usage in pa- mic drugs, insulin, and combinations of with a long-term follow-up period. tientswithadvancedCKDpersists.Ourstudy drugs) and outcomes (CVD, acidosis, in- An observational study of patients with showed a low incidence of metformin- fection, and all-cause mortality), although type 2 diabetes and stage 5 CKD by Hung associated acidosis events. Moreover, the median follow-up period was short et al. (20) showed that metformin usage compared with other antidiabetic drugs, (3.9 years). In the subgroup analysis pre- did not increase the risk of metabolic metformin usage did not increase the sented in the Swedish study, patients who acidosis. Moreover, metformin users were incidence of all-cause lactic acidosis used metformin alone had lower risks of less likely to develop ESRD even after events.Theseresultsimplythat compared all-cause mortality and CVD than patients accounting for competing risks of mor- with other antidiabetic agents, metformin treated with monotherapy of other drugs tality. However, because the authors may not increase the risk of lactic acidosis (other oral hypoglycemic agents and in- showeda dose-dependent increase in all- in CKD patients. sulin), and metformin monotherapy had cause mortality, they did not recommend Our results support the findings from a a better outcome than the combination a metformin prescription for patients previous nationwide observational study therapy with other drugs. whose serum creatinine concentration is in Sweden suggesting protective effects However, as an observational study, .530 mmol/L (6.00 mg/dL). Although this of metformin on cardiovascular disease the baseline characteristics of each treat- well-organized study presented meaningful (CVD) and all-cause mortality in patients ment group were unbalanced. The met- results, a limitation in its clinical appli- with an eGFR of 45–60 mL/min/1.73 m2, formin monotherapygrouppresented cation exists, as the authors only focused without increases in acidosis or serious a lower initial HbA1c concentration, higher care.diabetesjournals.org Kwon and Associates 953

Figure 2—Penalized spline curve for the predicted risks of all-cause mortality (A–D) and ESRD progression (E–H) according to the duration of metformin administration. Results from the analyses of all patients (A and E) and subgroups: eGFR $45 mL/min/1.73 m2 (B and F); 30 mL/min/1.73 m2 # eGFR , 45 mL/min/1.73 m2 (C and G); and eGFR ,30 mL/min/1.73 m2 (D and H). All-cause mortality of all patients (A), patients with an eGFR $45 mL/min/ 1.73 m2 (B), patients with 30 mL/min/1.73 m2 # eGFR , 45 mL/min/1.73 m2 (C), and patients with an eGFR ,30 mL/min/1.73 m2 (D). ESRD progression in all patients (E), patients with an eGFR $45 mL/min/1.73 m2 (F), patients with 30 mL/min/1.73 m2 # eGFR , 45 mL/min/1.73 m2 (G), and patients with an eGFR ,30 mL/min/1.73 m2 (H). eGFR, and lower microalbuminuria than the current study. Considering the results models have recently revealed the pleio- the other groups. For a balanced com- of our sensitivity analysis of metformin tropic beneficial action of metformin. Cur- parison, a subgroup analysis was per- prescription duration, we thought that rently, CKD is understood to be a process formed in the PSM group in the current the duration could explain this opposite of glomerulosclerosis and tubulointer- study. Compared with the patients who result about ESRD progression in the stitial fibrosis involving the epithelial- received combination treatment with in- TREAT study and the current study. At an to-mesenchymal transition, regardless sulin or RAS blockers, those who received eGFR of 30–45 mL/min/m2, treatment of cause (24,25). Metformin has the po- metformin-only treatment had a reduced with metformin for more than 2.6 years tential to attenuate tubulointerstitial fibro- risk of all-cause mortality and ESRD pro- (when considering the 95% CI, it was 4.5 sis and the epithelial-to-mesenchymal gression. In contrast, combination therapy years) was needed to reduce the risk. The transition byactivating AMPKanddown- with metformin and sulfonylurea reduced meanfollow-up periodwas2.5years, and regulating transforming growth factor- the risks further than the metformin-only the maximal follow-up period was 4.5 b1(26–30).Additionally,Nevenetal.(31) treatment. This different result of com- years in the TREAT study, which might reported that metformin not only prevented bination therapy with metformin might be too short to benefit from metformin the development of severe CKD but also come from remaining biases even after usage based on the current study. More- preserved calcium phosphorus homeosta- PSM, and further investigations are needed. over, our results from patients with an sis, which is related to CKD mineral and Recently, the Trial to Reduce Cardio- eGFR ,30 mL/min/1.73 m2 (Fig. 2D and bond disorder. When they treated adenine- vascular Events with Aranesp (darbepoetin H) suggest a possible effect of metformin induced and warfarin-induced CKD rats a) Therapy (TREAT) study group reported usage on reducing the risks of all-cause with 200 mg/kg/day metformin com- that metformin usage independently re- mortality and ESRD progression, although pared with vehicle treatment as a con- duced the risks of all-cause mortality, the significance was very low due to the trol, the metformin-treated rats showed cardiovascular death,cardiovascularcom- small number of patients (n 5 208). lower serum creatinine, phosphorus, and posite, and kidney disease composite Because a prospective randomized co- parathyroid hormone concentrations. Ad- (ESRD or death) in patients with an eGFR hortstudyisdifficulttoperform,research- ditionally, the metformin group showed of 20–60 mL/min/1.73 m2 (23). In the ers have used many different approaches less renal cellular infiltration, renal fibro- TREAT study, the combined end point to clarify the benefits of metformin use. sis, vascular calcification, and progression was lower in metformin users than in In addition, many researchers are wary of tohigh boneturnover status at pathology. nonusers. However, metformin use did accepting the benefits of metformin be- After a novel assay was introduced to not significantly reduce the risk of the cause the exact mechanism of action of calculate the metformin concentration, a ESRD-only outcome (aHR 1.01; 95% CI metformin has not been clearly eluci- few studies regarding metformin concen- 0.65–1.55; P 5 0.98), which is contrary to dated. However, many in vitro and in vivo tration in CKD patients were conducted 954 Long-term Effects of Metformin on DKD Diabetes Care Volume 43, May 2020

(31–35). Recently, Lalau et al. (34) reported randomized controlled trials are needed 12. Kidney Disease: Improving Global Outcomes an interesting study about metformin to change real-world practice. (KDIGO). Chapter 4: other complications of CKD: dose and safety validation in advanced CVD, medication dosage, patient safety, infec- tions, hospitalizations, and caveats for investi- CKD patients. In the dose-finding study, This research project was supported gating complications of CKD. Kidney Int Suppl there was a significant inverse correlation Funding. – by a grant from the Korea Health Technology (2011) 2013;3:91 111 between eGFR and metformin levels. On R&D Project through the Korea Health Industry 13. Inzucchi SE, Bergenstal RM, Buse JB, et al. the basis of this result, they selected a Development Institute funded by the Ministry Management of hyperglycemia in type 2 di- daily metformin dose of 1,500 mg in CKD of Health and Welfare, Republic of Korea (grant abetes, 2015: a patient-centered approach: update to a position statement of the American stage 3A, 1,000 mg in CKD stage 3B, and number HC15C1129). fl Diabetes Association and the European Asso- 500 mg in CKD stage 4 for a 4-month Duality of Interest. No potential con icts of interest relevant to this article were reported. ciation for the Study of Diabetes. Diabetes Care validation. In the validation period, only Author Contributions. All authors contributed 2015;38:140–149 one case of lactic acidosis was defined, to this study and made substantial contribu- 14. Schernthaner G, Schernthaner-Reiter MH. but the patient had myocardial infarc- tions to the conception and design of the study, Therapy: risk of metformin use in patients with tion. Also, the peak metformin concen- acquisition of data, or analysis and interpretation T2DM and advanced CKD. Nat Rev Endocrinol of data. All authors participated in drafting the 2015;11:697–699 tration in all patients was quite below article and revising it critically for important 15. Bodmer M, Meier C, Krahenb¨ uhl¨ S, Jick SS, the U.S. Food and Drug Administration’s intellectual content. All authors provided their Meier CR. Metformin, sulfonylureas, or other maximum plasma safety concentration final approval of this version of the manuscript antidiabetes drugs and the risk of lactic acidosis of 5 mg/L. Additionally, there was no for publication. J.P.L. is the guarantor of this work or hypoglycemia: a nested case-control analysis. – correlation between metformin and lac- and, as such, had full access to all the data in the Diabetes Care 2008;31:2086 2091 study and takes responsibility for the integrity of 16. Ekstrom¨ N, Schioler¨ L, Svensson AM, et al. tate concentration. Even though more the data and the accuracy of the data analysis. Effectiveness and safety of metformin in 51 675 validations are needed, this study presents Prior Presentation. Parts of this study were patients with type 2 diabetes and different levels the possibility of metformin usage in ad- presented as an oral presentation at the Amer- of renal function: a cohort study from the Swedish vanced CKD patients with a reduced dose. ican Society of Nephrology’s Kidney Week, San National Diabetes Register. BMJ Open 2012;2: – Although our results are informative, Diego, CA, 23 28 October 2018. e001076 our study has several limitations. First, 17. 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