Comparative effectiveness of incident oral antidiabetic drugs on kidney function
Authors: Adriana M. Hung, Christianne L. Roumie, Robert A. Greevy, Xulei Liu, Carlos G. Grijalva, Harvey J. Murff, T Alp Ikizler, Marie R. Griffin
Journal: Kidney International (2012)

Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who filled an incident oral antidiabetic drug prescription for metformin, sulfonylurea, or rosiglitazone, and had an estimated glomerular filtration rate (eGFR) of 60ml/min or better. The primary composite outcome was a persistent decline in eGFR from baseline of 25% or more (eGFR event) or a diagnosis of end-stage renal disease (ESRD). The secondary outcome was an eGFR event, ESRD, or death. Sensitivity analyses included using a more stringent definition of the eGFR event requiring an eGFR <60ml/min per 1.73m2 in addition to the 25% or more decline; controlling for baseline proteinuria thereby restricting data to 15,065 patients; and not requiring persistent treatment with the initial oral antidiabetic drug. Compared to patients using metformin, sulfonylurea users had an increased risk for both the primary and the secondary outcome, each with an adjusted hazard ratio of 1.20. Results of sensitivity analyses were consistent with the main findings. The risk associated with rosiglitazone was similar to metformin for both outcomes. Thus, compared to metformin, oral antidiabetic drug treatment with sulfonylureas increased the risk of a decline in eGFR, ESRD, or death. Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who filled an incident oral antidiabetic drug prescription for metformin, sulfonylurea, or rosiglitazone, and had an estimated glomerular filtration rate (eGFR) of 60ml/min or better. The primary composite outcome was a persistent decline in eGFR from baseline of 25% or more (eGFR event) or a diagnosis of end-stage renal disease (ESRD). The secondary outcome was an eGFR event, ESRD, or death. Sensitivity analyses included using a more stringent definition of the eGFR event requiring an eGFR <60ml/min per 1.73m2 in addition to the 25% or more decline; controlling for baseline proteinuria thereby restricting data to 15,065 patients; and not requiring persistent treatment with the initial oral antidiabetic drug. Compared to patients using metformin, sulfonylurea users had an increased risk for both the primary and the secondary outcome, each with an adjusted hazard ratio of 1.20. Results of sensitivity analyses were consistent with the main findings. The risk associated with rosiglitazone was similar to metformin for both outcomes. Thus, compared to metformin, oral antidiabetic drug treatment with sulfonylureas increased the risk of a decline in eGFR, ESRD, or death. Chronic kidney disease (CKD) is a major public health problem. CKD prevalence is increasing worldwide,1.Levey A.S. Atkins R. Coresh J. et al.Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.Kidney Int. 2007; 72: 247-259Abstract Full Text Full Text PDF PubMed Scopus (1036) Google Scholar partly related to the epidemic of obesity and Type 2 diabetes mellitus (DM). In the United States, diabetes accounts for 45% of incident end-stage renal disease (ESRD).2.Collins A.J. Foley R.N. Herzog C. et al.Excerpts from the US renal data system 2009 annual data report.Am J Kidney Dis. 2010; 55 (A426–427): S1-420Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar In 2006, the US federal government estimated cost was $23 billion for ESRD treatment, and the corresponding CKD treatment cost was $49 billion.2.Collins A.J. Foley R.N. Herzog C. et al.Excerpts from the US renal data system 2009 annual data report.Am J Kidney Dis. 2010; 55 (A426–427): S1-420Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Patients with CKD have an increased risk of premature death,3.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8976) Google Scholar,4.Hallan S.I. Dahl K. Oien C.M. et al.Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey.BMJ. 2006; 333: 1047Crossref PubMed Scopus (281) Google Scholar which is further increased by the presence of DM. A number of randomized clinical trials have shown that control of hyperglycemia,5.Brocco E. Velussi M. Cernigoi A.M. et al.Evidence of a threshold value of glycated hemoglobin to improve the course of renal function in type 2 diabetes with typical diabetic glomerulopathy.J Nephrol. 2001; 14: 461-471PubMed Google Scholar, 6.Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3865) Google Scholar, 7.Levin S.R. Coburn J.W. Abraira C. et al.Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. veterans affairs cooperative study on glycemic control and complications in type 2 diabetes feasibility trial investigators.Diabetes Care. 2000; 23: 1478-1485Crossref PubMed Scopus (80) Google Scholar, 8.Patel A. MacMahon S. Chalmers J. et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (44) Google Scholar blood pressure, and blockade of the renin–angiotensin–aldosterone system9.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (5039) Google Scholar,10.Parving H.H. Lehnert H. Brochner-Mortensen J. et al.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2938) Google Scholar can slow the progression of diabetic kidney disease. Most previous studies focused on the effect of achieving glycemic targets5.Brocco E. Velussi M. Cernigoi A.M. et al.Evidence of a threshold value of glycated hemoglobin to improve the course of renal function in type 2 diabetes with typical diabetic glomerulopathy.J Nephrol. 2001; 14: 461-471PubMed Google Scholar, 6.Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3865) Google Scholar, 7.Levin S.R. Coburn J.W. Abraira C. et al.Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. veterans affairs cooperative study on glycemic control and complications in type 2 diabetes feasibility trial investigators.Diabetes Care. 2000; 23: 1478-1485Crossref PubMed Scopus (80) Google Scholar, 8.Patel A. MacMahon S. Chalmers J. et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (44) Google Scholar on CKD progression regardless of the oral antidiabetic drug (OAD) used, or on the effect of OADs on proteinuria (an early marker of the development of diabetic kidney disease).11.Bakris G. Viberti G. Weston W.M. et al.Rosiglitazone reduces urinary albumin excretion in type II diabetes.J Hum Hypertens. 2003; 17: 7-12Crossref PubMed Scopus (240) Google Scholar,12.Bakris G.L. Ruilope L.M. McMorn S.O. et al.Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria.J Hypertens. 2006; 24: 2047-2055Crossref PubMed Scopus (91) Google Scholar Few studies have compared the effects of individual OADs on kidney function decline. A recent systematic review on the 'Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes', sponsored by the Agency for Healthcare Research and Quality, concluded that there was insufficient and low-quality evidence on the effectiveness of individual OADs on the development or progression of nephropathy.13.Bennett W.L. Maruthur N.M. Singh S. et al.Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.Ann Intern Med. 2011; 154: 602-613Crossref PubMed Scopus (441) Google Scholar The aim of this study was to determine whether initial treatment with different OAD monotherapies was associated with differential declines in kidney function. Using regional Veterans Health Administration (VHA) data, we recently reported that sulfonylurea users had worse kidney outcomes than metformin users.14.Hung A.M. Roumie C.L. Greevy R.A. et al.Comparative effectiveness of incident oral antidiabetic drugs on kidney function in veterans with type 2 diabetes mellitus.Am Soc Nephrol. 2010Google Scholar The aim of the present study was to evaluate a larger national VHA cohort of OAD initiators, to increase the precision of our estimates, and to extend our assessment to include rosiglitazone. Of the 343,612 Type 2 DM veterans identified as incident users of OADs (Figure 1), we excluded 24% for missing race, 13% with severe medical conditions, 13% for missing baseline estimated glomerular filtration rate (eGFR)/creatinine, 9% because of an eGFR<60 or a creatinine >1.5mg/dl, and 3% who were not on OAD monotherapy. Of the 129,821 patients who met the eligibility criteria, 72% (93,577) had complete baseline covariates and were included in the final analyses. Of those patients, 65% (61,104) initiated metformin, 33% (30,550) initiated sulfonylureas, and 2% (1923) initiated rosiglitazone. The characteristics of the patients excluded from the analytical data set owing to missing covariates were similar to the 72% included in the analysis (Supplementary Table 1 online). Download .doc (.1 MB) Help with doc files Supplementary Tables 1-5 Baseline characteristics were similar across OAD groups (Table 1). Overall, 78% were white, and 96% were men, and median serum creatinine was 1.0mg/dl (interquartile range (IQR)=0.9, 1.1). Metformin initiators had the highest body mass index median (32.3kg/m2; IQR=29, 37) compared with rosiglitazone (31kg/m2; IQR=28, 35) and sulfonylurea (31kg/m2; 27, 35) initiators. Median HbA1c was lowest among rosiglitazone (6.8; IQR=6.2, 7.6) compared with sulfonylurea (7.3; IQR=6.6, 8.4) and metformin (7.1; IQR=6.5, 7.9) initiators. The median length of follow-up by exposure group was 0.9 years for metformin (range=0.25–5.5 years/IQR=0.5, 1.8), 0.8 years for sulfonylureas (range=0.25–5.5 years/IQR=0.4–1.7), and 0.7 for rosiglitazone (range=0.25–5.3/IQR=0.3, 1.5). The percentage of patients on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) increased over time and was similar across groups at baseline and during follow-up (Figure 2).Table 1Baseline characteristics of the study cohortCharacteristicsMetformin (N=61,104)Sulfonylurea (N=30,550)Rosiglitazone (N=1923)Age, median (IQR, year)60 (55, 69)62 (56, 72)64 (57,72)Male, %959797Race, % White797672 Black161816 Hispanic4511 Other111Baseline creatinine, mg/dl, median (IQR)1.0 (0.9, 1.1)1.0 (0.9, 1.1)1.0 (0.9, 1.1)Glomerular filtration rate, ml/min81 (72, 93)80 (70, 93)79 (69, 91)Urine microalbumin–creatinine ratio test available, %182219Microalbuminuria present, %334HbA1c, median (IQR)7.1 (6.5, 7.9)7.3 (6.6, 8.4)6.8 (6.2, 7.6)Systolic blood pressure, median (IQR)134 (124, 144)135 (124, 146)133 (122, 143)Diastolic blood pressure, median (IQR)77 (70, 84)76 (69, 84)74 (67, 81)Body mass index (kg/m2), median (IQR)32.3 (28.8, 36.7)30.7 (27.3, 34.7)30.9 (27.5, 34.7)Coronary artery disease, %212323Cerebrovascular disease, %9118Peripheral vascular disease, %333Smoking, %12118ACEI or ARBs, %575657Thiazides, %333028Loop diuretics, %81210Statins, %625559Number of outpatient medications, median (IQR)5 (3, 8)5 (3, 8)5 (3, 7)Number of outpatient visits, median (IQR)5 (3, 8)5 (3, 8)4 (2, 7.5)Hospitalized in the prior year, %8108Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; IQR, interquartile range. Open table in a new tab Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; IQR, interquartile range. The annual rate of the primary composite end point of a persistent 25% decline in eGFR or ESRD was 3.8%, 5.0%, and 3.2% in metformin, sulfonylurea, and rosiglitazone initiators, respectively. eGFR events accounted for 97% of the primary composite end points (97%, 97%, and 95% in the metformin, sulfonylurea, and rosiglitazone initiators groups, respectively). The annual rate of the secondary composite end point, which included all-cause mortality, was 4.1, 5.5, and 3.4% in the respective three OAD groups (Table 2).Table 2Event rates and adjusted hazard ratios for primary and secondary outcomes among incident OAD usersMetformin (N=61,104)Sulfonylurea (N=30,550)Rosiglitazone (N=1923)Primary analysis–Persistent exposure required (PER)aPER: considers patients persistent on their incident regimen until they have a gap in use of medications that reaches 90 days, or have added or switched to a different OAD or insulin, have a study outcome, have left the Veterans Affairs (VA), reached the end of the study or reached a creatinine of 1.5mg/dl or higher. Person time (years)77,42036,5922014 Number of GFR or ESRD events2926184164 Rate/1000 person-years3.853.2 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the primary outcomeReference1.20 (1.13, 1.28)0.92 (0.71, 1.18) Number of GFR, ESRD or death events3149202768 Rate/100 person-years4.15.53.4 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the secondary outcomeReference1.20 (1.13, 1.28)0.89 (0.69, 1.12)Sensitivity analysesPER with a more stringent definition of GFR eventcGFR event defined as a persistent decline of 25% of baseline GFR plus reaching a GFR<60ml/min. Person time (years)79,19737,50820,44 Number of GFR or ESRD events139090834 Rate/100 person-years1.762.421.66 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the primary outcomeReference1.17 (1.07, 1.27)0.90 (0.64, 1.27) Number of GFR, ESRD or death events1622110238 Rate/1000 person-years2.052.941.86 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the secondary outcomeReference1.16 (1.08, 1.27)0.83 (0.60, 1.15)PER adjusted for ACR10,2934366401 Person Time (years)122914959415 Number of GFR or ESRD events46124511 Rate/100 person-years3.84.92.7 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the primary outcomeReference1.22 (1.03, 1.44)0.67 (0.37, 1.25) Number of GFR, ESRD, or death events49326312 Rate/1000 person-years4.05.32.9 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the secondary outcomeReference1.20 (1.02, 1.41)0.70 (0.39, 1.24)Persistent exposure not required (PENR)dPENR: patients remain in their initial OAD exposure group, regardless of their persistence on drug therapy, until a study outcome, or end of the study patients remain in their original exposure group regardless of changes in therapy after cohort entry (akin to an intent to treat analysis). Person time (years)139,77376,2444492 Number of GFR or ESRD events57523787170 Rate/100 person-years4.15.03.8 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the primary outcomeReference1.11 (1.06, 1.16)1.01 (0.87, 1.18) Number of GFR, ESRD, or death events64034405188 Rate/100 person-years4.65.84.2 aHRbCox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials. (95% CI) for the secondary outcomeReference1.13 (1.08, 1.18)0.97 (0.84, 1.12)Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ACR, albumin to creatinine ratio; aHR, adjusted hazard ratio; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; ESRD, end-stage renal disease; GFR, glomerular filtration rate; LDL, low-density lipoprotein; OAD, oral antidiabetic drug.a PER: considers patients persistent on their incident regimen until they have a gap in use of medications that reaches 90 days, or have added or switched to a different OAD or insulin, have a study outcome, have left the Veterans Affairs (VA), reached the end of the study or reached a creatinine of 1.5mg/dl or higher.b Cox proportional hazards model for time to renal disease. Adjusted hazard ratio is for each exposure compared with metformin as reference. All models were adjusted for age, sex, race, fiscal year of cohort entry, number of medications, number of outpatient visits, history of hospitalization, baseline HbA1c, BMI, serum creatinine, LDL cholesterol, use of medications (ACEI or ARBs, thiazide or loop diuretics, or statins), smoking-related illness, myocardial infarction; obstructive coronary disease, or prescription for a long acting nitrate; stroke/transient ischemic attack; atrial fibrillation/flutter; mitral/aortic or rheumatic heart disease; asthma/obstructive pulmonary disease; procedures for carotid/peripheral artery revascularization or bypass or lower extremity amputation. All continuous variables were modeled as third degree polynomials.c GFR event defined as a persistent decline of 25% of baseline GFR plus reaching a GFR<60ml/min.d PENR: patients remain in their initial OAD exposure group, regardless of their persistence on drug therapy, until a study outcome, or end of the study patients remain in their original exposure group regardless of changes in therapy after cohort entry (akin to an intent to treat analysis). Open table in a new tab Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ACR, albumin to creatinine ratio; aHR, adjusted hazard ratio; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; ESRD, end-stage renal disease; GFR, glomerular filtration rate; LDL, low-density lipoprotein; OAD, oral antidiabetic drug. Compared with metformin, sulfonylurea use was associated with an increased risk of reaching the primary composite end point (adjusted hazard ratio (aHR)=1.20 (95% confidence interval (CI): 1.13, 1.28)), as well as the secondary outcome (aHR=1.20 (95% CI: 1.13, 1.28)). Compared with metformin, rosiglitazone use was not significantly associated with the primary or secondary outcome (Table 2). We also made a direct comparison of rosiglitazone and sulfonylurea use. Compared with sulfonylureas, rosiglitazone use was associated with a decreased risk for both the primary (aHR=0.76 (95% CI: 0.59, 0.99)) and secondary outcome (aHR=0.73 (95% CI: 0.57, 0.94)). Unadjusted cumulative incidence curves are shown in Figure 2. The percentage of patients who remained at risk at each time interval was similar across all exposure groups. In addition, the percentage of patients who remained on ACE inhibitors or ARBs was also similar. Propensity score–matched analyses yielded similar results. Compared with metformin, sulfonylurea use (1 to 1 greedy matching n=57,904) was associated with an increased risk for the primary outcome (aHR=1.23 (95% CI: 1.15, 1.31); P<0.0001); compared with metformin, rosiglitazone use (1 to 3 greedy matching n=7648) was not statistically associated with a higher or lower risk for the primary outcome (aHR=0.92 (95% CI: 0.67, 1.25); P=0.59)). Results were consistent with the primary analysis across all sensitivity and subgroup analyses. When the requirement of achieving a GFR<60ml/min was added to the 25% GFR decline, the number of events was substantially reduced (from 4831 to 2332). However, results of this sensitivity analysis were similar to those from the main analyses. Sulfonylurea use was associated with a higher risk for both the primary outcome (aHR=1.17 (95% CI: 1.07, 1.27)) and the secondary outcome (aHR=1.17 (95% CI: 1.10, 1.25); P<0.0001) compared with metformin. There were no differences between rosiglitazone and metformin for either the primary or secondary outcome. Among the 15,065 patients with a baseline ACR measurement, OAD-specific rates of both primary and secondary end points were similar to those of the entire cohort. Compared with metformin, sulfonylurea use was associated with an increased risk of both the primary (aHR=1.22 (95% CI: 1.03, 1.44)) and secondary (aHR=1.20 (95% CI: 1.02, 1.481)) outcomes. There was no significant difference observed between rosiglitazone use and metformin use for either the primary or the secondary outcome (Table 2). In this analysis, each individual remained in their incident OAD regimen exposure group throughout follow-up regardless of changes to their regimen (similar to an intention-to-treat analysis). The strength of the observed associations was attenuated but consistent with the primary analysis such that sulfonylurea use was associated with a higher risk of reaching the primary outcome (aHR=1.11 (95% CI: 1.06, 1.16)) and secondary outcome (aHR=1.13 (95% CI: 1.08, 1.18; P<0.0001)) compared with metformin. There were no differences between the rosiglitazone therapy and metformin for either the primary or the secondary outcome in this analysis (Table 2). Prespecified assessments were performed and no significant interactions were identified between OAD categories and the a priori subgroups: age, race, use of ACE inhibitors/ARBs, and HbA1c levels (Figure 3). DM is the most common cause of CKD and progression to ESRD in the United States.2.Collins A.J. Foley R.N. Herzog C. et al.Excerpts from the US renal data system 2009 annual data report.Am J Kidney Dis. 2010; 55 (A426–427): S1-420Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Patients with CKD and ESRD experience an increased risk of premature death even at early disease stages.3.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8976) Google Scholar,4.Hallan S.I. Dahl K. Oien C.M. et al.Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey.BMJ. 2006; 333: 1047Crossref PubMed Scopus (281) Google Scholar In addition to the human costs, treatment costs pose an enormous burden on the health-care system. Although the efficacy of OADs on glucose control is well established,13.Bennett W.L. Maruthur N.M. Singh S. et al.Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.Ann Intern Med. 2011; 154: 602-613Crossref PubMed Scopus (441) Google Scholar their effects on long-term kidney function outcomes are less clear.13.Bennett W.L. Maruthur N.M. Singh S. et al.Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.Ann Intern Med. 2011; 154: 602-613Crossref PubMed Scopus (441) Google Scholar,15.Bolen S. Feldman L. Vassy J. et al.Systematic review