BMJ

Confidential: For Review Only

Should D iabetes Mellitus be a Compelling Indication for System Blockers?

Journal: BMJ

Manuscript ID: BMJ.2015.028226

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 19-Jul-2015

Complete List of Authors: Bangalore, Sripal; New York University School of Medicine Fakheri, Robert; New York University School of Medicine, Toklu, Bora; New York University, Division of Cardiology Messerli, Franz; St. Luke's-Roosevelt Hospital Center,

angiotensin converting enzyme inhibitors, angiotensin receptor blockers, Keywords: diabetes, outcomes

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1 2 3 Should Diabetes Mellitus be a Compelling Indication for Renin Angiotensin System 4 5 Blockers? 6 Insights from a Systematic Review and MetaAnalysis of Randomized Trials 7 8 Confidential: For Review Only 9 10 11 Sripal Bangalore, MD, MHA, Robert Fakheri, MD, Bora Toklu, MD, Franz H. Messerli, MD 12 13 14 15 16 New York University School of Medicine, New York, NY [SB, RF, BT] 17 18 Mount Sinai Health Medical Center, Icahn School of Medicine, New York, NY [FHM] 19 20 21 22 Word Count: 2751 23 24 25 26 27 28 Running Title: RAS for Diabetes 29 30 31 The Corresponding Author has the right to grant on behalf of all authors and does grant on 32 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all 33 forms, formats and media (whether known now or created in the future), to i) publish, reproduce, 34 distribute, display and store the Contribution, ii) translate the Contribution into other languages, 35 create adaptations, reprints, include within collections and create summaries, extracts and/or, 36 37 abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, 38 iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from 39 the Contribution to third party material whereever it may be located; and, vi) licence any third 40 party to do any or all of the above. 41 42 43 44 45 46 Author Correspondence: 47 Sripal Bangalore, MD, MHA, FACC, FSCAI, 48 Director of Research, Cardiac Catheterization Laboratory, 49 50 Director, Cardiovascular Outcomes Group, 51 Cardiovascular Clinical Research Center, 52 Associate Professor of Medicine, 53 New York University School of Medicine, 54 The Leon H. Charney Division of Cardiology, 55 56 New York, NY 10016. 57 Email: [email protected] 58 59 60 1

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1 2 3 ABSTRACT 4 5 6 Objectives Most national and international guidelines consider diabetes mellitus as a compelling 7 8 indicationConfidential: for renin angiotensin system (RAS) For block ers.Review However, it is not known Only if RAS 9 10 11 blockers provide superior cardio protection when compared with other antihypertensive agents in 12 13 patients with diabetes. Our objective was to evaluate the outcomes with RAS blockers versus 14 15 other antihypertensive agents in patients with diabetes. 16 17 18 19 20 Design Metaanalysis. 21 22 23 24 25 Data Sources and Study Selection We searched Pubmed, EMBASE, CENTRAL databases for 26 27 randomized trials of RAS blockers vs. other antihypertensive agents in patients with diabetes 28 29 mellitus. Outcomes were death, cardiovascular death, (MI), angina, , 30 31 32 , revascularization, and end stage renal disease (ESRD). 33 34 35 36 37 Results Our search yielded 19 RCTs which enrolled 25,414 subjects with diabetes for a total of 38 39 95,910 patient years of followup. When compared with other antihypertensive agents, RAS 40 41 blockers were associated with similar risk of death (RR=0.99; 95% CI 0.931.05), cardiovascular 42 43 44 death (RR=1.02; 95% CI 0.831.24), MI (RR=0.87; 95% CI 0.641.18), angina pectoris 45 46 (RR=0.80; 95% CI 0.581.11), stroke (RR=1.04; 95% CI 0.921.17), heart failure (RR=0.90; 47 48 95% CI 0.761.07), and revascularization (RR=0.97; 95% CI 0.771.22). There was also no 49 50 51 difference in the hard renal outcome of ESRD (RR=0.99; 95% CI 0.781.28) (power of 94% to 52 53 show a 23% reduction in ESRD). 54 55 56 57 58 59 60 2

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1 2 3 Conclusions In patients with diabetes, RAS blockers are not superior to other antihypertensive 4 5 6 agents at reducing the risk of hard cardiovascular and renovascular endpoints. Diabetes should be 7 8 reconsideredConfidential: as a compelling indication forFor RAS blo ckade.Review Only 9 10 11 12 13 Keywords: angiotensin converting enzyme inhibitors, angiotensin receptor blockers, diabetes, 14 15 outcomes 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52

53 54 55 56 57 58 59 60 3

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1 2 3 4 5 6 Introduction 7 8 PatientsConfidential: with diabetes are at increased risk For of cardiovascular Review and renovascular Only events.[1] Early 9 10 placebo controlled trials (such as HOPE and EUROPA) have shown significant benefits of 11 12 13 blockers of renin angiotensin system (RAS) on cardiovascular and renovascular events in 14 15 patients with diabetes, benefits touted to be independent of the lowering efficacy. 16 17 As such the 2015 American Diabetes Association guidelines recommend RAS blockers 18 19 20 (angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)) as 21 22 first line therapy for patients with diabetes and .[2] Similarly, the 2013 American 23 24 25 Society of Hypertension/International Society of Hypertension guidelines favor RAS blockers as 26 27 a first line therapy in patients with diabetes.[3] The National Kidney FoundationKidney Disease 28 29 Outcomes Quality Initiative (NKFKDOQI) Clinical Practice Guidelines state in their executive 30 31 32 summary that “Hypertensive people with diabetes and chronic kidney disease stages 14 should 33 34 be treated with an ACEi or an ARB, usually in combination with a diuretic .”[4] In contrast, the 35 36 2013 European Society of Cardiology (ESC)European Society of Hypertension (ESH) 37 38 39 guidelines[5] and the 2014 evidence based guidelines from the panel members of the eight Joint 40 41 National Committee (JNC 8)[6] recommend any class of antihypertensive agents in patients with 42 43 diabetes with a preference for RAS blockers only in the presence of proteinuria or 44 45 46 microalbuminuria. This seemingly discordant set of recommendations begs the questions about 47 48 the evidence base to support superior cardioprotective/renoprotective effects of RAS blockers in 49 50 51 patients with diabetes. 52 53 54 55 56 57 58 59 60 4

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1 2 3 The objective of the study was therefore to explore whether RAS blockers are superior to 4 5 6 other antihypertensive agents for the prevention of hard cardiovascular and renovascular events 7 8 in Confidential:patients with diabetes. For Review Only 9 10 11 Methods 12 13 14 Eligibility Criteria 15 16 We conducted PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials 17 18 (CENTRAL) searches until July 2015 (Week 1) for randomized controlled trials (RCTs) of RAS 19 20 21 blockers (ACEi or ARB) (MeSH terms in Table S1) in patients with diabetes or impaired fasting 22 23 glucose. There were no language restrictions for the search. In addition, we searched the 24 25 26 bibliography of original trials, metaanalyses and review articles identified to find other eligible 27 28 trials (‘snowball search’). The search was kept uptodate by weekly reminders from PUBMED. 29 30 Eligible trials had to fulfill the following criteria: (1) RCTs comparing RAS blockers versus 31 32 33 other antihypertensive agents in subjects with diabetes or impaired fasting glucose; and (2) 34 35 sample size of at least 100 subjects with diabetes with followup of at least 1 year (to minimize 36 37 small study effect). Studies conducted in heart failure cohort were excluded. In addition, studies 38 39 40 were excluded if they were redacted for any reason, compared ACEi vs. ARB, RAS vs. placebo 41 42 or randomized to a combination of ACEi plus an ARB. 43 44 45 46 47 Trial Selection and Bias Assessment 48 49 Trial eligibility, trial bias risk and data extraction were performed independently by three authors 50 51 52 (R.F., B.T., and S.B.) with disagreements resolved by consensus. The bias risk of trials was 53 54 assessed using the components for randomized trials recommended by the Cochrane 55 56 Collaboration[7]: allocation sequence generation, allocation concealment, and blinding of 57 58 59 60 5

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1 2 3 outcome assessors. For each component, trials were categorized as low, high or unclear risk of 4 5 6 bias. We considered trials with high or unclear risk for bias for any one of the above components 7 8 as Confidential:trials with high risk of bias. For Review Only 9 10 11 12 13 Outcomes 14 15 Outcomes were death, cardiovascular death, myocardial infarction (MI), angina, stroke, heart 16 17 18 failure, revascularization, end stage renal disease (ESRD), major adverse cardiovascular events 19 20 (MACE) and drug withdrawal due to adverse events. 21 22 23 24 25 Statistical Analyses 26 27 Statistical analyses were performed using an intentiontotreat approach and in line with 28 29 recommendations from the Cochrane Collaboration and the Preferred Reporting Items for 30 31 32 Systematic reviews and MetaAnalyses (PRISMA) statement.[7 8] Analyses were performed 33 34 comparing RAS blockers (ACEi or ARB) versus other agents. Subgroup analyses were 35 36 37 performed comparing RAS blockers versus each class of the comparative agent (CCB, diuretics 38 39 or βblockers). The metaanalytic summary estimates (relative riskRR) was calculated using the 40 41 fixedeffect model and the randomeffects model of DerSimonian and Laird.[9] Heterogeneity, 42 43 44 which is the proportion of total variation observed between the trials attributable to differences 45 46 between trials rather than sampling error (chance), was assessed using the I 2 statistic,[10] with I 2 47 48 < 25% considered low and I 2 >75% high. Small study effect was assessed using the Begg’s and 49 50 51 the Egger’s test and by visual evaluation of the funnel plots for asymmetry. 52 53 A metaregression analysis was performed to evaluate the relationship of percent patients 54 55 with nephropathy at baseline on the outcomes. We used a residual maximum likelihood (REML) 56 57 58 59 60 6

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1 2 3 to estimate the additive (betweenstudy) component of variance tau 2 for the metaregression 4 5 6 analysis. Bootstrap analyses were performed using a Monte Carlo permutation test for meta 7 8 regressionConfidential: using 10000 random permutations.[11] For Ana Reviewlyses were performed usingOnly standard 9 10 11 statistical software (Stata 12.1, Stata corporation, Texas)[12] with P <0.05 used to denote 12 13 statistical significance. 14 15 16 17 18 Role of the funding source 19 20 21 This work was not funded and hence there was no role of any funding source in the conception, 22 23 data synthesis, analysis, data interpretation, or in drafting of the manuscript. 24 25 26 27 28 29 Results 30 31 Study Selection and Baseline Characteristics 32 33 34 Our search yielded 19 RCTs (Figure S1) which enrolled a total of 25,414 subjects with diabetes 35 36 and were followed for a mean of 3.8 years for a total of 95, 910 patient years of followup. 37 38 Fifteen trials compared RAS blockers with a calcium channel blocker (CCB), three trials 39 40 41 compared RAS blockers with a thiazide diuretic whereas two trials compared them with a β 42 43 blocker. The RAS blockers were an ACEi in fourteen trials and an ARB in six trials. All trials 44 45 enrolled patients with type 2 diabetes. In addition, the majority of trials (17 trials) enrolled 46 47 48 patients with diabetes and hypertension. 49 50 The baseline characteristics of the included trials are outlined in Table S2S3. Blacks were a 51 52 minority of the enrolled patients in the studies that reported race/ethnicity. 53 54 55 56 57 RAS Blockers versus Other Antihypertensive Agents: Outcomes 58 59 60 7

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1 2 3 When compared with other antihypertensive agents, RAS blockers were associated with similar 4 5 6 risk of death (RR=0.99; 95% CI 0.931.05), cardiovascular death (RR=1.02; 95% CI 0.831.24), 7 8 MIConfidential: (RR=0.87; 95% CI 0.641.18), angina Forpectoris (RR Review=0.80; 95% CI 0.581.11), Only stroke 9 10 11 (RR=1.04; 95% CI 0.921.17), heart failure (RR=0.90; 95% CI 0.761.07) and revascularization 12 13 (RR=0.97; 95% CI 0.771.22) (Figure 1). There was no difference in the outcome of MACE 14 15 (RR=0.97; 95% CI=0.891.06) between the two groups. In addition there was no difference in 16 17 18 drug withdrawal due to adverse effects and ESRD (RR=0.99; 95% CI 0.781.28) (Figure 1). The 19 20 results were consistent using fixedeffect model (Figure 1). There was low to moderate 21 22 heterogeneity (Figure 1) with no evidence of small study effect/publication bias. 23 24 25 26 27 RAS Blockers versus CCBs: Outcomes 28 29 When compared with CCBs, RAS blockers were associated with similar risk of death (RR=1.01; 30 31 32 95% CI 0.921.10), cardiovascular death (RR=1.17; 95% CI 0.901.50), MI (RR=0.84; 95% CI 33 34 0.541.30), angina pectoris (RR=0.69; 95% CI 0.331.42), stroke (RR=1.08; 95% CI 0.901.28) 35 36 37 and revascularization (RR=1.01; 95% CI 0.741.39) (Figure 2). However, RAS blockers were 38 39 associated with significant reduction in the risk of heart failure when compared with CCBs 40 41 (RR=0.78; 95% CI 0.700.88) (Figure 2). There was no difference in drug withdrawal due to 42 43 44 adverse effects and ESRD (Figure 2). There was low to moderate heterogeneity (Figure 2) with 45 46 no evidence of small study effect/publication bias. 47 48 49 50 51 RAS Blockers versus Thiazide Diuretics: Outcomes 52 53 When compared with thiazide diuretics, RAS blockers were associated with similar risk of death 54 55 (RR=0.99; 95% CI 0.901.08), cardiovascular death (RR=0.50; 95% CI 0.055.46) and other 56 57 58 59 60 8

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1 2 3 outcomes (Figure 3). There were only three trials comparing RAS blockers versus diuretics and 4 5 6 hence the confidence interval for most outcomes was wide. There was low to moderate 7 8 heterogeneityConfidential: (Figure 3) with no evidence For of small study Review effect/publication bias.Only 9 10 11 12 13 RAS Blockers versus βblockers: Outcomes 14 15 When compared with βblockers, RAS blockers were associated with similar risk of death 16 17 18 (RR=0.84; 95% CI 0.471.51), cardiovascular death (RR=0.87; 95% CI 0.471.60) and other 19 20 outcomes tested (Figure 4). There were only two trials comparing RAS blockers versus β 21 22 blockers and hence the confidence interval for most outcomes was wide. There was high 23 24 25 heterogeneity for the outcome of death but low to moderate heterogeneity for other outcomes 26 27 (Figure 4) with no evidence of small study effect/publication bias. 28 29 30 31 32 Influence of Nephropathy 33 34 Metaregression analysis aimed to assess the relationship of percent patients with nephropathy at 35 36 baseline on the outcomes showed no statistically significant relationship (P>0.05) for all 37 38 39 outcomes. 40 41 42 43 44 45 Discussion 46 47 48 This analysis of patients with diabetes with 95, 910 patient years of followup from randomized 49 50 trials failed to show a superiority of RAS blockade over other antihypertensive agents for 51 52 reduction of cardiovascular and renovascular outcomes, except perhaps a reduction in heart 53 54 55 failure when compared with CCBs alone. More importantly, there was no benefit in reducing the 56 57 risk of death or MI and ESRD with RAS blockers when compared with other agents. The results 58 59 60 9

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1 2 3 were consistent when RAS blockers were compared with all controls and also when compared 4 5 6 with individual antihypertensive agents. 7 8 Confidential: For Review Only 9 10 11 RAS Blockers for Diabetes 12 13 14 Patients with diabetes mellitus are at increased risk of hypertension and the concomitant 15 16 17 presence of both diabetes and hypertension is associated with an exponential increase in the risk 18 19 of cardiovascular, cerebrovascular and renovascular events.[13] Prior trials have shown that BP 20 21 22 reduction in such patients leads to significant reduction in cardiovascular events, emphasizing 23 24 the need for aggressive management of hypertension in this cohort. [14] However, whether one 25 26 class is superior to the other is controversial. Early studies of RAS 27 28 29 blockade in patients with diabetes and microalbuminuria showed a significant ‘renoprotective’ 30 31 effect (mainly by slowing progression to clinical proteinuria) when compared to placebo,[15] 32 33 leading to recommendation of RAS blockers for this indication. This was later extended to all 34 35 36 patients with diabetes. In addition, small headtohead comparison trials of RAS blockers 37 38 () versus CCBs (amlodipine) such as the FACET trial (380 patients) showed a 39 40 significant reduction in cardiovascular events (secondary endpoint of combined outcome of MI, 41 42 43 stroke or hospitalization for angina) with RAS blockers compared with CCB.[16] However, there 44 45 was no difference in hard endpoints of death or MI in this trial. Subsequent guidelines, including 46 47 48 the JNC7 promoted diabetes as a compelling indication for RAS blockade. The American 49 50 Diabetic Association guidelines states “In people with diabetes, inhibitors of the renin 51 52 angiotensin system (RAS) may have unique advantages for initial or early treatment of 53 54 55 hypertension”. However, more recent trials have failed to show superiority of RAS blockers 56 57 when compared with other antihypertensive agents for hard cardiovascular outcomes. [17] In 58 59 60 10

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1 2 3 addition, studies with larger sample size (e.g., ALLHAT study with 13,101 patients with 4 5 6 diabetes) also failed to show the superiority of RAS blockers when compared with other 7 8 antihypertensiveConfidential: agents for cardiovascular For outcomes .[18]Review Indeed, Ritz stated Only two decades ago 9 10 11 about CKD progression that “despite some discrepancies in experimental studies, recent 12 13 controlled clinical trials show a similar slowing of progression with either ACEi or CCB”.[19] 14 15 Consequently there is now divergence of opinion among various guidelines regarding the role of 16 17 18 RAS blockade in subjects with diabetes, with most guidelines still recommending RAS blockers 19 20 as a preferred drugs whereas some relegating it to be on par with other antihypertensive drug 21 22 classes. 23 24 25 26 Given the controversy and the discordance in various guideline recommendations about the 27 28 role of RAS blockers in subjects with diabetes we aimed to evaluate the comparative 29 30 effectiveness of RAS blockers when compared with other antihypertensive agents in patients 31 32 33 with diabetes, excluding cohorts where RAS blockers are shown to provide benefit (i.e. heart 34 35 failure). We also excluded placebo controlled trials since placebo is not the standard of care in 36 37 such patients. The results of this study with over 95,000 patientyears of followup from headto 38 39 40 head randomized trials of RAS blockers versus other antihypertensive agents failed to show a 41 42 superiority of RAS blockers over other antihypertensive agents for the prevention of hard 43 44 cardiovascular or renovascular outcomes. The notable exception in our analysis was that the 45 46 47 RAS blockers were superior to CCB for the prevention of heart failure. This outcome (heart 48 49 failure) was mainly driven by the ALLHAT trial, the findings of which has been criticized.[20] 50 51 52 Although various guideline recommendations in patients with diabetes but without 53 54 55 nephropathy are somewhat discordant, most of them still recommend a RAS blocker in patients 56 57 with diabetes and nephropathy. In the IDNT trial (1715 patients with diabetic nephropathy) RAS 58 59 60 11

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1 2 3 blocker () when compared with CCB (amlodipine) was associated with significant 4 5 6 reduction in the risk of primary composite end point (32.6% vs. 41.1%; P=0.006) of a doubling 7 8 of Confidential:serum creatinine concentration, the development For ofReview ESRD, or death from anyOnly cause, driven by 9 10 11 differences in doubling of serum creatinine concentration (16.9% vs. 25.4%; P<0.001) and 12 13 development of ESRD (14.2% vs. 18.3%; P=0.07) with no difference in death (15.0% vs. 14.6%; 14 15 P>0.05). [21] The ‘renoprotective’ benefit of ACEi and ARBs in patients with diabetic 16 17 18 nephropathy has been attributed solely to a decrease in angiotensin activity. [21] However, in our 19 20 meta regression analysis, there was no superiority of RAS blockers for any of the outcomes 21 22 tested with in trials with higher proportion of patients with nephropathy at baseline. Moreover, 23 24 25 with data from eight RCTs with 17,626 patients there was no difference between RAS blockers 26 27 and other antihypertensive agents for the ‘hard’ renal outcome of ESRD. Although IDNT trial 28 29 showed a trend (P=0.07) towards a 23% reduction in ESRD with RAS blocker when compared 30 31 32 with CCB, the trial was not powered for this endpoint given a sample size of only 1146 patients. 33 34 Our analysis with 17,626 patients (for the outcome of ESRD) had a power of 94% to show a 35 36 37 23% reduction in ESRD with RAS blockers when compared with controls and is thus sufficiently 38 39 powered to show a difference if one existed. We did not evaluate the outcome of doubling of 40 41 serum creatinine as this was reported in only one trial. 42 43 44 45 46 47 48 Study Limitations 49 50 51 We used trial level data only for the analyses and hence were unable to control for between trial 52 53 differences. Although a separate analysis in the cohort of patients with nephropathy is desirable 54 55 56 trials did not report outcomes separately for this cohort. There were only few trials for the RAS 57 58 59 60 12

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1 2 3 blocker vs. diuretics and RAS blockers vs. βblocker comparisons and the analyses is likely 4 5 6 underpowered. For the renovascular outcomes, we only evaluated ESRD as an outcome as this is 7 8 consideredConfidential: a ‘hard’ renal endpoint. While Forone can argue Review that doubling of serum Only creatinine is a 9 10 11 stringent renal endpoint, this outcome was only reported in one trial. 12 13 14 15 Conclusions 16 17 18 This analysis of headtohead comparison trials of RAS blockers vs. other antihypertensive 19 20 agents in patients with diabetes failed to show a superiority of RAS blockers when compared 21 22 with other antihypertensive agents for the prevention of hard cardiovascular and renovascular 23 24 25 outcomes. National and international guidelines should reconsider diabetes as a compelling 26 27 indication for RAS blockers. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13

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1 2 3 Author Contributions: 4 5 6 7 Dr. Bangalore had full access to all of the data in the study and takes responsibility for the 8 Confidential: For Review Only 9 integrity of the data and the accuracy of the data analysis. 10 11 12 Study concept and design: Dr. Bangalore 13 14 15 Acquisition of data: Drs. Fakheri and Toklu 16 17 18 19 Analysis and interpretation of data: Drs. Bangalore, Fakheri, Toklu, and Messerli 20 21 22 Drafting of the manuscript: Dr. Bangalore 23 24 25 Critical revision of the manuscript for important intellectual content: Drs. Bangalore, Fakheri, 26 27 28 Toklu, and Messerli 29 30 31 Statistical analysis: Dr. Bangalore 32 33 34 Study supervision: Dr. Bangalore 35 36 37 38 39 40 Disclosures: 41 42 43 Dr. Bangalore: Honorarium from Abbott, Boehringher Ingelheim, Daiichi Sankyo, Merck, 44 45 Gilead and Pfizer 46 47 48 Dr. Messerli consulting for Daiichi, Sankyo, Pfizer, Takeda, Abbott, AbbVie, Servier, Medtronic 49 50 51 and Ipca Laboratories. 52 53 54 Other authors report no relevant conflict of interest. 55 56 57 58 59 60 14

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1 2 3 1. Wingard DL, BarrettConnor EL, ScheidtNave C, McPhillips JB. Prevalence of 4 5 6 cardiovascular and renal complications in older adults with normal or impaired glucose 7 8 Confidential:tolerance or NIDDM. A populationbased For study. Review Diabetes Care 1993;16:10225. Only 9 10 11 2. Standards of medical care in diabetes2015: summary of revisions. Diabetes Care 2015;38 12 13 Suppl:S4. 14 15 3. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical 16 17 18 practice guidelines for the management of hypertension in the community a statement by 19 20 the American Society of Hypertension and the International Society of Hypertension. 21 22 Journal of hypertension 2014;32:315. 23 24 25 4. Kdoqi. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 26 27 Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49:S12154. 28 29 5. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC 30 31 32 Guidelines for the management of arterial hypertension: the Task Force for the 33 34 management of arterial hypertension of the European Society of Hypertension (ESH) and 35 36 37 of the European Society of Cardiology (ESC). Journal of hypertension 2013;31:1281 38 39 357. 40 41 6. James PA, Oparil S, Carter BL, Cushman WC, DennisonHimmelfarb C, Handler J, et al. 42 43 44 2014 evidencebased guideline for the management of high blood pressure in adults: 45 46 report from the panel members appointed to the Eighth Joint National Committee (JNC 47 48 8). JAMA 2014;311:50720. 49 50 51 7. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 52 53 5.0.0 ed: The Cochrane Collaboration 2008. www.cochranehandbook.org . Accessed Dec 54 55 12, 2013. 56 57 58 59 60 15

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1 2 3 8. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of 4 5 6 reports of metaanalyses of randomised controlled trials: the QUOROM statement. 7 8 Confidential:Quality of Reporting of Metaanalyses. For Lancet Review 1999;354:1896900. Only 9 10 11 9. DerSimonian R, Laird N. Metaanalysis in clinical trials. Control Clin Trials 1986;7:17788. 12 13 10. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical 14 15 trials. Stat.Med. 1988;7:88994. 16 17 18 11. Higgins JP, Thompson SG. Controlling the risk of spurious findings from metaregression. 19 20 Statistics in medicine 2004;23:166382. 21 22 12. Bradburn MJ, Deeks JJ, Altman DG. Sbe24: metan an alternative metaanalysis command. 23 24 25 Stata Technical Bulletin Reprints 1998;8 86100. 26 27 13. Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992;19:40318. 28 29 14. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive antihypertensive 30 31 32 treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 33 34 1983;1:11759. 35 36 37 15. Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of on progression to clinical 38 39 proteinuria in patients with insulindependent diabetes mellitus and microalbuminuria. 40 41 European Microalbuminuria Captopril Study Group. JAMA 1994;271:2759. 42 43 44 16. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, et al. Outcome results of 45 46 the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in 47 48 patients with hypertension and NIDDM. Diabetes Care 1998;21:597603. 49 50 51 17. Muramatsu T, Matsushita K, Yamashita K, Kondo T, Maeda K, Shintani S, et al. 52 53 Comparison between and amlodipine regarding cardiovascular morbidity and 54 55 56 57 58 59 60 16

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1 2 3 mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study. 4 5 6 Hypertension 2012;59:5806. 7 8 18.Confidential: Whelton PK, Barzilay J, Cushman WC, For Davis BR, Review Iiamathi E, Kostis JB, Only et al. Clinical 9 10 11 outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose 12 13 concentration, and normoglycemia: Antihypertensive and LipidLowering Treatment to 14 15 Prevent Heart Attack Trial (ALLHAT). Archives of internal medicine 2005;165:14019. 16 17 18 19. Ritz E. Are antihypertensive drugs similar in protecting the kidney? Am J Hypertens 19 20 1995;8:53S58S. 21 22 20. Messerli FH. ALLHAT, or the soft science of the secondary end point. Annals of internal 23 24 25 medicine 2003;139:77780. 26 27 21. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective 28 29 effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due 30 31 32 to type 2 diabetes. N Engl J Med 2001;345:85160. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17

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1 2 3 FIGURE LEGENDS 4 5 6 Figure 1. Outcomes with RAS blockers when compared with other antihypertensive agents in 7 8 Confidential:subjects with diabetes For Review Only 9 10 Figure 2. Outcomes with RAS blockers when compared with CCBs in subjects with diabetes 11 12 13 Figure 3. Outcomes with RAS blockers when compared with diuretics in subjects with diabetes 14 15 Figure 4. Outcomes with RAS blockers when compared with βblockers in subjects with 16 17 diabetes 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 18

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1 2 3 Figure 1. Outcomes with RAS blockers when compared with other antihypertensive agents in 4 5 subjects with diabetes 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 19

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1 2 3 Figure 2. Outcomes with RAS blockers when compared with CCBs in subjects with diabetes 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 20

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1 2 3 Figure 3. Outcomes with RAS blockers when compared with diuretics in subjects with diabetes 4 5 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

49 50 51 52 53 54 55 56 57 58 59 60 21

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1 2 3 Figure 4. Outcomes with RAS blockers when compared with βblockers in subjects with 4 5 diabetes 6 7 8 Confidential: For Review Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 22

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1 2 3 4 Supplementary Appendix 5 6 Should Diabetes Mellitus be a Compelling Indication for Renin Angiotensin 7 System Blockers? 8 Confidential: For Review Only 9 Insights from a Systematic Review and Meta-Analysis of Randomized Trials 10 11 12 13 Sripal Bangalore, MD, MHA, Robert Fakheri, MD, Bora Toklu, MD, Franz H. Messerli, 14 MD 15 16 17 18 19 This appendix has been provided by the authors to give readers additional information 20 about their work. 21 22 23 24 25 26 Contents 27

28 29 30 Figure S1. Study selection...... 2 31 Table S1. Details of Search Terms ...... 3 32 33 Table S2. Summary of Clinical Trials included in the Meta-analysis ...... 4 34 35 Table S3. Baseline Characteristics of the Clinical Trials included in the Meta-analysis ...... 6 36 References ...... 7 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1

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1 2 3 4 5 Figure S1. Study selection 6 7 8 Confidential: For Review Only Records identified through database 9 10 search using terms “Angiotensin-

11 Converting enzyme inhibitor”, “angiotensin

12 receptor antagonist”, and limited to RCT,

13 Humans (n=11120) 14 15 Duplicate studies (n=2010) 16 Records excluded on the basis of title 17 and/or abstract (n=8545) 18 19 20 21 Full-text articles assessed for eligibility (n=565) 22 23 24 Sample size <100 or follow-up <1-year 25 (n=232) 26 Not reporting relevant findings (n=212) 27 28 29 121 articles retrieved for detailed 30 evaluation 31 Children cohort (n=3) 32 Cancer cohort (n=2) 33 Transplant cohort (n=3) 34 Retracted studies (n=4) 35 Concomitant ACEi and ARB use (n=3) 36 37 Non-diabetic cohorts (n=87) 38 Studies included in the final meta- 39 analysis (n=19) 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2

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1 2 3 4 Table S1. Details of Search Terms 5 Search terms used 6 7 or Irbesartan or or or Valsartan or or or 8 AzilsartanConfidential: or Fimasartan or or ForCaptopril orReview or Onlyor or Fosinopril 9 or or or or or or or or 10 11 or or 12 Angiotensin-Converting Enzyme Inhibitor; Angiotensin-Converting Enzyme Inhibitors; angiotensin 13 14 receptor antagonist; angiotensin receptor antagonists; angiotensin receptor blocker; angiotensin 15 receptor blockers 16 17 18 19 20 21 22 23 24 25

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1 2 3 4 Table S2. Summary of Clinical Trials included in the Meta-analysis 5 Trial Year Sample Follow -up Cohort Age Male Black 6 Size (years) (years) (%) (%) 7 RAS Blockers vs CCB 8 Confidential: For Review Only 9 ABCD 1998 470 5.6 DM and HTN 58 68 14 10 1,2 11 (Hypertensive) ABCD 2002 354 5.3 DM and 59 55 7 12 3 13 (Normotensive) Normotensive 4,5 14 ALLHAT (DM 2002 7107 4.9 DM and HTN 67 51 39 15 subgroup) 16 ALLHAT 4-6 (IFG 2002 771 4.9 IFG and HTN 67 62 30 17 subgroup) 18 BENEDICT 7 2004 604 3.6 DM and HTN 62 53 NR 19 CAMELOT 8 (DM 2004 233 2 DM and CAD 58 73 NR 20 subgroup) 21 CAMELOT 8 (IFG 2004 233 2 IFG and CAD 58 73 NR 22 subgroup) 23 9-11 24 CASE-J (DM 2008 1195 3.2 DM and HTN 67 47 NR 25 subgroup) 12 26 FACET 1998 380 2.9 DM and HTN 63 60 NR 13 27 Fogari et al 2002 205 4 DM with proteinuria 63 58 NR 28 and HTN 29 IDNT 14 -16 2001 1146 2.6 DM with 60 64 13 30 nephropathy and 31 HTN 32 JMIC-B17 ,18 (DM 2004 372 3 DM, HTN and CAD 64 69 NR 33 subgroup) 34 J-MIND 19 2001 436 2 DM and HTN 60 51 NR 35 MITEC 20 2009 209 2 DM and HTN 60 64 NR 36 21 ,22 37 MOSES (DM 2005 498 2.5 DM, HTN and CVA 70 70 NR 38 subgroup) 23 39 NAGOYA HEART 2012 1150 3.2 Glucose intolerance 63 66 NR 40 and HTN 41 STOP-Hypertension- 1999 466 5 DM and Elderly HTN 76 38 NR 42 224 (DM subgroup) 43 RAS Blockers vs Diuretic 44 ALLHAT 4,5 (DM 2002 9504 4.9 DM and HTN 67 51 39 45 subgroup) 46 ALLHAT 4-6 (IFG 2002 1035 4.9 IFG and HTN 67 62 30 47 subgroup) 48 25 ,26 49 ANBP2 (DM 2003 441 4.1 DM and Elderly HTN 72 57 NR subgroup) 50 27 51 NESTOR 2003 569 1 DM with 60 65 5 52 microalbuminuria 53 and HTN 54 RAS Blockers vs βblocker 55 56 UKPDS 39 28 1998 758 8.4 DM and HTN 56 54 8 57 LIFE 29 -32 (DM 2002 1195 4.8 DM and HTN with 67 46 12 58 59 60 4

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1 2 3 subgroup) LVH 4 ABCD=Appropriate Blood Pressure Control in Diabetes; ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2= Second 5 Australian National Blood Pressure Study; BENEDICT=Bergamo Nephrologic Diabetes Complications Trial; β-blocker=Beta-blocker; CAD=Coronary artery disease; 6 CAMELOT=Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis; CASE-J= Candesartan Antihypertensive Survival Evaluation in Japan; CCB=Calcium 7 channel blocker; CVA=Cerebrovascular accident; DM=Diabetes mellitus; FACET= Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial; 8 HTN=Hypertension;Confidential: IDNT=Irbesartan Type II Diabetic Nephropathy Trial; IFG=ImpairedFor fasting Review glucose; JMIC-B=Japan Multicenter Only Investigation for Cardiovascular 9 Diseases-B; J-MIND=Japan Multicenter Investigation of Antihypertensive Treatment for Nephropathy in Diabetics; LIFE=Losartan Intervention For Endpoint reduction; LVH=Left ventricular hypertrophy; MITEC=Media Intima Thickness Evaluation with Candesartan cilexetil; MOSES=Morbidity and Mortality After Stroke, Eprosartan 10 Compared With Nitrendipine for Secondary Prevention; NAGOYA HEART=Comparison between valsartan and amlodipine regarding morbidity and mortality in patients 11 with hypertension and glucose intolerance; NESTOR=Natrilix SR versus Enalapril Study in Type 2 diabetic hypertensives with micrOalbuminuRia; NR=not reported; RAS- 12 inh=Renin-Angiotensin System inhibitor; STOP-Hypertension=Swedish Trial in Old Patients with Hypertension; UKPDS=UK Prospective Diabetes Study Group. 13 14 15 16 17 18 19

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

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1 2 3 4 Table S3. Baseline Characteristics of the Clinical Trials included in the Meta- 5 analysis 6 Trial Treatment Comparison Nephropathy Quality of 7 (treatment vs comparison) Trial* 8 Confidential: For Review Only ABCD Enalapril Nisoldipine 18% vs 19% +++ 9 1,2 10 (Hypertensive) 11 ABCD Enalapril Nisoldipine 34% vs 34% +++ 3 12 (Normotensive) 4-6 13 ALLHAT Lisinopril Amlodipine NR +++ 14 BENEDICT 7 Trandalopril Verapamil None ±±+ 15 CAMELOT 8 (DM Enalapril Amlodipine NR +++ 16 subgroup) 17 CASE-J9-11 (DM Candesartan Amlodipine 23% vs 22% +++ 18 subgroup) 19 FACET 12 Fosinopril Amlodipine None +±+ 20 13 21 Fogari et al Fosinopril Amlodipine 100% vs 100% +±± 14 -16 22 IDNT Irbesartan Amlodipine 100% vs 100% ±++ 23 JMIC-B17 ,18 (DM Enalapril, Nifedipine NR +++ 24 subgroup) Imidapril, 25 Lisinopril 26 J-MIND 19 Enalapril Nifedipine 36% vs 38% ++± 27 MITEC 20 Candesartan Amlodipine NR +±+ 28 MOSES 21 ,22 (DM Eprosartan Nitrendipine 6% vs 8% +++ 29 subgroup) 30 23 31 NAGOYA HEART Valsartan Amlodipine NR +±+ 32 STOP- Enalapril, Felodipine, NR ±++ 33 Hypertension-224 Lisinopril Isradipine 34 (DM subgroup) 35 ALLHAT 4-6 Lisinopril Chlorthalidone NR +++ 36 ANBP2 25 ,26 (DM Enalapril HCTZ 13% ±++ 37 subgroup) 38 NESTOR 27 Enalapril Indapamide 100% vs 100% +±+ 39 UKPDS 39 28 Captopril Atenolol 16% vs 20% +++ 40 LIFE 29 -32 (DM Losartan Atenolol 11% vs 12% +++ 41 42 subgroup) See foot note of Table 1 for abbreviations and expansion of trial names. 43 *Represents risk of bias based on: sequence generation of allocation; allocation concealment and blinding. ‘+’ represents low bias risk, ‘-‘ high bias risk, 44 and “±” unclear bias risk. 45 46 47 48 49

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