Confidential: For Review Only · Sripal Bangalore, MD, MHA, FACC, FSCAI, Director of Research,...

Confidential: For Review O

nly

Should Diabetes Mellitus be a Compelling Indication for

Renin Angiotensin 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,

Keywords: angiotensin converting enzyme inhibitors, angiotensin receptor blockers,

diabetes, outcomes

https://mc.manuscriptcentral.com/bmj

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Should Diabetes Mellitus be a Compelling Indication for Renin Angiotensin System

Blockers?

Insights from a Systematic Review and Meta-Analysis of Randomized Trials

Sripal Bangalore, MD, MHA, Robert Fakheri, MD, Bora Toklu, MD, Franz H. Messerli, MD

New York University School of Medicine, New York, NY [SB, RF, BT]

Mount Sinai Health Medical Center, Icahn School of Medicine, New York, NY [FHM]

Word Count: 2751

Running Title: RAS for Diabetes

The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all

forms, formats and media (whether known now or created in the future), to i) publish, reproduce,

distribute, display and store the Contribution, ii) translate the Contribution into other languages,

create adaptations, reprints, include within collections and create summaries, extracts and/or,

abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution,

iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from

the Contribution to third party material where-ever it may be located; and, vi) licence any third

party to do any or all of the above.

Author Correspondence:

Sripal Bangalore, MD, MHA, FACC, FSCAI,

Director of Research, Cardiac Catheterization Laboratory,

Director, Cardiovascular Outcomes Group,

Cardiovascular Clinical Research Center,

Associate Professor of Medicine,

New York University School of Medicine,

The Leon H. Charney Division of Cardiology,

New York, NY 10016.

Email: [email protected]

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ABSTRACT

Objectives Most national and international guidelines consider diabetes mellitus as a compelling

indication for renin angiotensin system (RAS) blockers. However, it is not known if RAS

blockers provide superior cardio protection when compared with other antihypertensive agents in

patients with diabetes. Our objective was to evaluate the outcomes with RAS blockers versus

other antihypertensive agents in patients with diabetes.

Design Meta-analysis.

Data Sources and Study Selection We searched Pubmed, EMBASE, CENTRAL databases for

randomized trials of RAS blockers vs. other antihypertensive agents in patients with diabetes

mellitus. Outcomes were death, cardiovascular death, myocardial infarction (MI), angina, stroke,

heart failure, revascularization, and end stage renal disease (ESRD).

Results Our search yielded 19 RCTs which enrolled 25,414 subjects with diabetes for a total of

95,910 patient years of follow-up. When compared with other antihypertensive agents, RAS

blockers were associated with similar risk of death (RR=0.99; 95% CI 0.93-1.05), cardiovascular

death (RR=1.02; 95% CI 0.83-1.24), MI (RR=0.87; 95% CI 0.64-1.18), angina pectoris

(RR=0.80; 95% CI 0.58-1.11), stroke (RR=1.04; 95% CI 0.92-1.17), heart failure (RR=0.90;

95% CI 0.76-1.07), and revascularization (RR=0.97; 95% CI 0.77-1.22). There was also no

difference in the hard renal outcome of ESRD (RR=0.99; 95% CI 0.78-1.28) (power of 94% to

show a 23% reduction in ESRD).

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Conclusions In patients with diabetes, RAS blockers are not superior to other antihypertensive

agents at reducing the risk of hard cardiovascular and renovascular endpoints. Diabetes should be

reconsidered as a compelling indication for RAS blockade.

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

outcomes

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Introduction

Patients with diabetes are at increased risk of cardiovascular and renovascular events.[1] Early

placebo controlled trials (such as HOPE and EUROPA) have shown significant benefits of

blockers of renin angiotensin system (RAS) on cardiovascular and renovascular events in

patients with diabetes, benefits touted to be independent of the blood pressure lowering efficacy.

As such the 2015 American Diabetes Association guidelines recommend RAS blockers

(angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)) as

first line therapy for patients with diabetes and hypertension.[2] Similarly, the 2013 American

Society of Hypertension/International Society of Hypertension guidelines favor RAS blockers as

a first line therapy in patients with diabetes.[3] The National Kidney Foundation-Kidney Disease

Outcomes Quality Initiative (NKF-KDOQI) Clinical Practice Guidelines state in their executive

summary that “Hypertensive people with diabetes and chronic kidney disease stages 1-4 should

be treated with an ACEi or an ARB, usually in combination with a diuretic.”[4] In contrast, the

2013 European Society of Cardiology (ESC)-European Society of Hypertension (ESH)

guidelines[5] and the 2014 evidence based guidelines from the panel members of the eight Joint

National Committee (JNC 8)[6] recommend any class of antihypertensive agents in patients with

diabetes with a preference for RAS blockers only in the presence of proteinuria or

microalbuminuria. This seemingly discordant set of recommendations begs the questions about

the evidence base to support superior cardioprotective/renoprotective effects of RAS blockers in

patients with diabetes.

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The objective of the study was therefore to explore whether RAS blockers are superior to

other antihypertensive agents for the prevention of hard cardiovascular and renovascular events

in patients with diabetes.

Methods

Eligibility Criteria

We conducted PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials

(CENTRAL) searches until July 2015 (Week 1) for randomized controlled trials (RCTs) of RAS

blockers (ACEi or ARB) (MeSH terms in Table S1) in patients with diabetes or impaired fasting

glucose. There were no language restrictions for the search. In addition, we searched the

bibliography of original trials, meta-analyses and review articles identified to find other eligible

trials (‘snowball search’). The search was kept up-to-date by weekly reminders from PUBMED.

Eligible trials had to fulfill the following criteria: (1) RCTs comparing RAS blockers versus

other antihypertensive agents in subjects with diabetes or impaired fasting glucose; and (2)

sample size of at least 100 subjects with diabetes with follow-up of at least 1 year (to minimize

small study effect). Studies conducted in heart failure cohort were excluded. In addition, studies

were excluded if they were redacted for any reason, compared ACEi vs. ARB, RAS vs. placebo

or randomized to a combination of ACEi plus an ARB.

Trial Selection and Bias Assessment

Trial eligibility, trial bias risk and data extraction were performed independently by three authors

(R.F., B.T., and S.B.) with disagreements resolved by consensus. The bias risk of trials was

assessed using the components for randomized trials recommended by the Cochrane

Collaboration[7]: allocation sequence generation, allocation concealment, and blinding of

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outcome assessors. For each component, trials were categorized as low, high or unclear risk of

bias. We considered trials with high or unclear risk for bias for any one of the above components

as trials with high risk of bias.

Outcomes

Outcomes were death, cardiovascular death, myocardial infarction (MI), angina, stroke, heart

failure, revascularization, end stage renal disease (ESRD), major adverse cardiovascular events

(MACE) and drug withdrawal due to adverse events.

Statistical Analyses

Statistical analyses were performed using an intention-to-treat approach and in line with

recommendations from the Cochrane Collaboration and the Preferred Reporting Items for

Systematic reviews and Meta-Analyses (PRISMA) statement.[7 8] Analyses were performed

comparing RAS blockers (ACEi or ARB) versus other agents. Subgroup analyses were

performed comparing RAS blockers versus each class of the comparative agent (CCB, diuretics

or β-blockers). The meta-analytic summary estimates (relative risk-RR) was calculated using the

fixed-effect model and the random-effects model of DerSimonian and Laird.[9] Heterogeneity,

which is the proportion of total variation observed between the trials attributable to differences

between trials rather than sampling error (chance), was assessed using the I2 statistic,[10] with I

2

< 25% considered low and I2 >75% high. Small study effect was assessed using the Begg’s and

the Egger’s test and by visual evaluation of the funnel plots for asymmetry.

A meta-regression analysis was performed to evaluate the relationship of percent patients

with nephropathy at baseline on the outcomes. We used a residual maximum likelihood (REML)

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to estimate the additive (between-study) component of variance tau2 for the meta-regression

analysis. Bootstrap analyses were performed using a Monte Carlo permutation test for meta-

regression using 10000 random permutations.[11] Analyses were performed using standard

statistical software (Stata 12.1, Stata corporation, Texas)[12] with P <0.05 used to denote

statistical significance.

Role of the funding source

This work was not funded and hence there was no role of any funding source in the conception,

data synthesis, analysis, data interpretation, or in drafting of the manuscript.

Results

Study Selection and Baseline Characteristics

Our search yielded 19 RCTs (Figure S1) which enrolled a total of 25,414 subjects with diabetes

and were followed for a mean of 3.8 years for a total of 95, 910 patient years of follow-up.

Fifteen trials compared RAS blockers with a calcium channel blocker (CCB), three trials

compared RAS blockers with a thiazide diuretic whereas two trials compared them with a β-

blocker. The RAS blockers were an ACEi in fourteen trials and an ARB in six trials. All trials

enrolled patients with type 2 diabetes. In addition, the majority of trials (17 trials) enrolled

patients with diabetes and hypertension.

The baseline characteristics of the included trials are outlined in Table S2-S3. Blacks were a

minority of the enrolled patients in the studies that reported race/ethnicity.

RAS Blockers versus Other Antihypertensive Agents: Outcomes

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When compared with other antihypertensive agents, RAS blockers were associated with similar

risk of death (RR=0.99; 95% CI 0.93-1.05), cardiovascular death (RR=1.02; 95% CI 0.83-1.24),

MI (RR=0.87; 95% CI 0.64-1.18), angina pectoris (RR=0.80; 95% CI 0.58-1.11), stroke

(RR=1.04; 95% CI 0.92-1.17), heart failure (RR=0.90; 95% CI 0.76-1.07) and revascularization

(RR=0.97; 95% CI 0.77-1.22) (Figure 1). There was no difference in the outcome of MACE

(RR=0.97; 95% CI=0.89-1.06) between the two groups. In addition there was no difference in

drug withdrawal due to adverse effects and ESRD (RR=0.99; 95% CI 0.78-1.28) (Figure 1). The

results were consistent using fixed-effect model (Figure 1). There was low to moderate

heterogeneity (Figure 1) with no evidence of small study effect/publication bias.

RAS Blockers versus CCBs: Outcomes

When compared with CCBs, RAS blockers were associated with similar risk of death (RR=1.01;

95% CI 0.92-1.10), cardiovascular death (RR=1.17; 95% CI 0.90-1.50), MI (RR=0.84; 95% CI

0.54-1.30), angina pectoris (RR=0.69; 95% CI 0.33-1.42), stroke (RR=1.08; 95% CI 0.90-1.28)

and revascularization (RR=1.01; 95% CI 0.74-1.39) (Figure 2). However, RAS blockers were

associated with significant reduction in the risk of heart failure when compared with CCBs

(RR=0.78; 95% CI 0.70-0.88) (Figure 2). There was no difference in drug withdrawal due to

adverse effects and ESRD (Figure 2). There was low to moderate heterogeneity (Figure 2) with

no evidence of small study effect/publication bias.

RAS Blockers versus Thiazide Diuretics: Outcomes

When compared with thiazide diuretics, RAS blockers were associated with similar risk of death

(RR=0.99; 95% CI 0.90-1.08), cardiovascular death (RR=0.50; 95% CI 0.05-5.46) and other

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outcomes (Figure 3). There were only three trials comparing RAS blockers versus diuretics and

hence the confidence interval for most outcomes was wide. There was low to moderate

heterogeneity (Figure 3) with no evidence of small study effect/publication bias.

RAS Blockers versus β-blockers: Outcomes

When compared with β-blockers, RAS blockers were associated with similar risk of death

(RR=0.84; 95% CI 0.47-1.51), cardiovascular death (RR=0.87; 95% CI 0.47-1.60) and other

outcomes tested (Figure 4). There were only two trials comparing RAS blockers versus β-

blockers and hence the confidence interval for most outcomes was wide. There was high

heterogeneity for the outcome of death but low to moderate heterogeneity for other outcomes

(Figure 4) with no evidence of small study effect/publication bias.

Influence of Nephropathy

Meta-regression analysis aimed to assess the relationship of percent patients with nephropathy at

baseline on the outcomes showed no statistically significant relationship (P>0.05) for all

outcomes.

Discussion

This analysis of patients with diabetes with 95, 910 patient years of follow-up from randomized

trials failed to show a superiority of RAS blockade over other antihypertensive agents for

reduction of cardiovascular and renovascular outcomes, except perhaps a reduction in heart

failure when compared with CCBs alone. More importantly, there was no benefit in reducing the

risk of death or MI and ESRD with RAS blockers when compared with other agents. The results

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were consistent when RAS blockers were compared with all controls and also when compared

with individual antihypertensive agents.

RAS Blockers for Diabetes

Patients with diabetes mellitus are at increased risk of hypertension and the concomitant

presence of both diabetes and hypertension is associated with an exponential increase in the risk

of cardiovascular, cerebrovascular and renovascular events.[13] Prior trials have shown that BP

reduction in such patients leads to significant reduction in cardiovascular events, emphasizing

the need for aggressive management of hypertension in this cohort. [14] However, whether one

antihypertensive drug class is superior to the other is controversial. Early studies of RAS

blockade in patients with diabetes and microalbuminuria showed a significant ‘renoprotective’

effect (mainly by slowing progression to clinical proteinuria) when compared to placebo,[15]

leading to recommendation of RAS blockers for this indication. This was later extended to all

patients with diabetes. In addition, small head-to-head comparison trials of RAS blockers

(Fosinopril) versus CCBs (amlodipine) such as the FACET trial (380 patients) showed a

significant reduction in cardiovascular events (secondary endpoint of combined outcome of MI,

stroke or hospitalization for angina) with RAS blockers compared with CCB.[16] However, there

was no difference in hard endpoints of death or MI in this trial. Subsequent guidelines, including

the JNC-7 promoted diabetes as a compelling indication for RAS blockade. The American

Diabetic Association guidelines states “In people with diabetes, inhibitors of the renin-

angiotensin system (RAS) may have unique advantages for initial or early treatment of

hypertension”. However, more recent trials have failed to show superiority of RAS blockers

when compared with other antihypertensive agents for hard cardiovascular outcomes. [17] In

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addition, studies with larger sample size (e.g., ALLHAT study with 13,101 patients with

diabetes) also failed to show the superiority of RAS blockers when compared with other

antihypertensive agents for cardiovascular outcomes.[18] Indeed, Ritz stated two decades ago

about CKD progression that “despite some discrepancies in experimental studies, recent

controlled clinical trials show a similar slowing of progression with either ACEi or CCB”.[19]

Consequently there is now divergence of opinion among various guidelines regarding the role of

RAS blockade in subjects with diabetes, with most guidelines still recommending RAS blockers

as a preferred drugs whereas some relegating it to be on par with other antihypertensive drug

classes.

Given the controversy and the discordance in various guideline recommendations about the

role of RAS blockers in subjects with diabetes we aimed to evaluate the comparative

effectiveness of RAS blockers when compared with other antihypertensive agents in patients

with diabetes, excluding cohorts where RAS blockers are shown to provide benefit (i.e. heart

failure). We also excluded placebo controlled trials since placebo is not the standard of care in

such patients. The results of this study with over 95,000 patient-years of follow-up from head-to-

head randomized trials of RAS blockers versus other antihypertensive agents failed to show a

superiority of RAS blockers over other antihypertensive agents for the prevention of hard

cardiovascular or renovascular outcomes. The notable exception in our analysis was that the

RAS blockers were superior to CCB for the prevention of heart failure. This outcome (heart

failure) was mainly driven by the ALLHAT trial, the findings of which has been criticized.[20]

Although various guideline recommendations in patients with diabetes but without

nephropathy are somewhat discordant, most of them still recommend a RAS blocker in patients

with diabetes and nephropathy. In the IDNT trial (1715 patients with diabetic nephropathy) RAS

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blocker (irbesartan) when compared with CCB (amlodipine) was associated with significant

reduction in the risk of primary composite end point (32.6% vs. 41.1%; P=0.006) of a doubling

of serum creatinine concentration, the development of ESRD, or death from any cause, driven by

differences in doubling of serum creatinine concentration (16.9% vs. 25.4%; P<0.001) and

development of ESRD (14.2% vs. 18.3%; P=0.07) with no difference in death (15.0% vs. 14.6%;

P>0.05). [21] The ‘renoprotective’ benefit of ACEi and ARBs in patients with diabetic

nephropathy has been attributed solely to a decrease in angiotensin activity. [21] However, in our

meta regression analysis, there was no superiority of RAS blockers for any of the outcomes

tested with in trials with higher proportion of patients with nephropathy at baseline. Moreover,

with data from eight RCTs with 17,626 patients there was no difference between RAS blockers

and other antihypertensive agents for the ‘hard’ renal outcome of ESRD. Although IDNT trial

showed a trend (P=0.07) towards a 23% reduction in ESRD with RAS blocker when compared

with CCB, the trial was not powered for this endpoint given a sample size of only 1146 patients.

Our analysis with 17,626 patients (for the outcome of ESRD) had a power of 94% to show a

23% reduction in ESRD with RAS blockers when compared with controls and is thus sufficiently

powered to show a difference if one existed. We did not evaluate the outcome of doubling of

serum creatinine as this was reported in only one trial.

Study Limitations

We used trial level data only for the analyses and hence were unable to control for between trial

differences. Although a separate analysis in the cohort of patients with nephropathy is desirable

trials did not report outcomes separately for this cohort. There were only few trials for the RAS

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blocker vs. diuretics and RAS blockers vs. β-blocker comparisons and the analyses is likely

underpowered. For the renovascular outcomes, we only evaluated ESRD as an outcome as this is

considered a ‘hard’ renal endpoint. While one can argue that doubling of serum creatinine is a

stringent renal endpoint, this outcome was only reported in one trial.

Conclusions

This analysis of head-to-head comparison trials of RAS blockers vs. other antihypertensive

agents in patients with diabetes failed to show a superiority of RAS blockers when compared

with other antihypertensive agents for the prevention of hard cardiovascular and renovascular

outcomes. National and international guidelines should reconsider diabetes as a compelling

indication for RAS blockers.

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Author Contributions:

Dr. Bangalore had full access to all of the data in the study and takes responsibility for the

integrity of the data and the accuracy of the data analysis.

Study concept and design: Dr. Bangalore

Acquisition of data: Drs. Fakheri and Toklu

Analysis and interpretation of data: Drs. Bangalore, Fakheri, Toklu, and Messerli

Drafting of the manuscript: Dr. Bangalore

Critical revision of the manuscript for important intellectual content: Drs. Bangalore, Fakheri,

Toklu, and Messerli

Statistical analysis: Dr. Bangalore

Study supervision: Dr. Bangalore

Disclosures:

Dr. Bangalore: Honorarium from Abbott, Boehringher Ingelheim, Daiichi Sankyo, Merck,

Gilead and Pfizer

Dr. Messerli consulting for Daiichi, Sankyo, Pfizer, Takeda, Abbott, AbbVie, Servier, Medtronic

and Ipca Laboratories.

Other authors report no relevant conflict of interest.

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FIGURE LEGENDS

Figure 1. Outcomes with RAS blockers when compared with other antihypertensive agents in

subjects with diabetes

Figure 2. Outcomes with RAS blockers when compared with CCBs in subjects with diabetes

Figure 3. Outcomes with RAS blockers when compared with diuretics in subjects with diabetes

Figure 4. Outcomes with RAS blockers when compared with β-blockers in subjects with

diabetes

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Figure 1. Outcomes with RAS blockers when compared with other antihypertensive agents in

subjects with diabetes

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Figure 2. Outcomes with RAS blockers when compared with CCBs in subjects with diabetes

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Figure 3. Outcomes with RAS blockers when compared with diuretics in subjects with diabetes

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Figure 4. Outcomes with RAS blockers when compared with β-blockers in subjects with

diabetes

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Supplementary Appendix

Should Diabetes Mellitus be a Compelling Indication for Renin Angiotensin System Blockers?

Insights from a Systematic Review and Meta-Analysis of Randomized Trials

Sripal Bangalore, MD, MHA, Robert Fakheri, MD, Bora Toklu, MD, Franz H. Messerli, MD

This appendix has been provided by the authors to give readers additional information

about their work.

Contents

Figure S1. Study selection......................................................................................................... 2

Table S1. Details of Search Terms ............................................................................................ 3

Table S2. Summary of Clinical Trials included in the Meta-analysis ........................................... 4

Table S3. Baseline Characteristics of the Clinical Trials included in the Meta-analysis .............. 6

References ............................................................................................................................... 7

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Figure S1. Study selection

Full-text articles assessed for eligibility (n=565)

Records identified through database search using terms “Angiotensin-

Converting enzyme inhibitor”, “angiotensin receptor antagonist”, and limited to RCT,

Humans (n=11120)

121 articles retrieved for detailed evaluation

Studies included in the final meta-analysis (n=19)

Sample size <100 or follow-up <1-year (n=232) Not reporting relevant findings (n=212)

Duplicate studies (n=2010) Records excluded on the basis of title and/or abstract (n=8545)

Children cohort (n=3) Cancer cohort (n=2) Transplant cohort (n=3) Retracted studies (n=4) Concomitant ACEi and ARB use (n=3) Non-diabetic cohorts (n=87)

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Table S1. Details of Search Terms

Search terms used

Candesartan or Irbesartan or Losartan or Telmisartan or Valsartan or Olmesartan or Eprosartan or

Azilsartan or Fimasartan or Benazepril or Captopril or Enalapril or Cilazapril or Delapril or Fosinopril

or Imidapril or Lisinopril or Moexipril or Perindopril or Quinapril or Ramipril or Spirapril or Temocapril

or Trandolapril or Zofenopril

Angiotensin-Converting Enzyme Inhibitor; Angiotensin-Converting Enzyme Inhibitors; angiotensin

receptor antagonist; angiotensin receptor antagonists; angiotensin receptor blocker; angiotensin

receptor blockers

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Table S2. Summary of Clinical Trials included in the Meta-analysis

Trial Year Sample Size

Follow-up (years)

Cohort Age (years)

Male (%)

Black (%)

RAS Blockers vs CCB

ABCD (Hypertensive)1,2

1998 470 5.6 DM and HTN 58 68 14

ABCD (Normotensive)3

2002 354 5.3 DM and Normotensive

59 55 7

ALLHAT4,5 (DM subgroup)

2002 7107 4.9 DM and HTN 67 51 39

ALLHAT4-6 (IFG subgroup)

2002 771 4.9 IFG and HTN 67 62 30

BENEDICT7 2004 604 3.6 DM and HTN 62 53 NR CAMELOT8 (DM subgroup)

2004 233 2 DM and CAD 58 73 NR

CAMELOT8 (IFG subgroup)

2004 233 2 IFG and CAD 58 73 NR

CASE-J9-11 (DM subgroup)

2008 1195 3.2 DM and HTN 67 47 NR

FACET12 1998 380 2.9 DM and HTN 63 60 NR Fogari et al13 2002 205 4 DM with proteinuria

and HTN 63 58 NR

IDNT14-16 2001 1146 2.6 DM with nephropathy and

HTN

60 64 13

JMIC-B17,18 (DM subgroup)

2004 372 3 DM, HTN and CAD 64 69 NR

J-MIND19 2001 436 2 DM and HTN 60 51 NR MITEC20 2009 209 2 DM and HTN 60 64 NR MOSES21,22 (DM subgroup)

2005 498 2.5 DM, HTN and CVA 70 70 NR

NAGOYA HEART23 2012 1150 3.2 Glucose intolerance and HTN

63 66 NR

STOP-Hypertension-224 (DM subgroup)

1999 466 5 DM and Elderly HTN 76 38 NR

RAS Blockers vs Diuretic ALLHAT4,5 (DM subgroup)

2002 9504 4.9 DM and HTN 67 51 39

ALLHAT4-6 (IFG subgroup)

2002 1035 4.9 IFG and HTN 67 62 30

ANBP225,26 (DM subgroup)

2003 441 4.1 DM and Elderly HTN 72 57 NR

NESTOR27 2003 569 1 DM with microalbuminuria

and HTN

60 65 5

RAS Blockers vs β-blocker

UKPDS 3928 1998 758 8.4 DM and HTN 56 54 8 LIFE29-32 (DM 2002 1195 4.8 DM and HTN with 67 46 12

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subgroup) LVH ABCD=Appropriate Blood Pressure Control in Diabetes; ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2= Second

Australian National Blood Pressure Study; BENEDICT=Bergamo Nephrologic Diabetes Complications Trial; β-blocker=Beta-blocker; CAD=Coronary artery disease;

CAMELOT=Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis; CASE-J= Candesartan Antihypertensive Survival Evaluation in Japan; CCB=Calcium

channel blocker; CVA=Cerebrovascular accident; DM=Diabetes mellitus; FACET= Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial;

HTN=Hypertension; IDNT=Irbesartan Type II Diabetic Nephropathy Trial; IFG=Impaired fasting glucose; JMIC-B=Japan Multicenter Investigation for Cardiovascular

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

Compared With Nitrendipine for Secondary Prevention; NAGOYA HEART=Comparison between valsartan and amlodipine regarding morbidity and mortality in patients

with hypertension and glucose intolerance; NESTOR=Natrilix SR versus Enalapril Study in Type 2 diabetic hypertensives with micrOalbuminuRia; NR=not reported; RAS-

inh=Renin-Angiotensin System inhibitor; STOP-Hypertension=Swedish Trial in Old Patients with Hypertension; UKPDS=UK Prospective Diabetes Study Group.

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Table S3. Baseline Characteristics of the Clinical Trials included in the Meta-

analysis Trial Treatment Comparison Nephropathy

(treatment vs comparison) Quality of Trial*

ABCD (Hypertensive)1,2

Enalapril Nisoldipine 18% vs 19% +++

ABCD (Normotensive)3

Enalapril Nisoldipine 34% vs 34% +++

ALLHAT4-6 Lisinopril Amlodipine NR +++

BENEDICT7 Trandalopril Verapamil None ±±+

CAMELOT8 (DM subgroup)

Enalapril Amlodipine NR +++

CASE-J9-11 (DM subgroup)

Candesartan Amlodipine 23% vs 22% +++

FACET12 Fosinopril Amlodipine None +±+

Fogari et al13 Fosinopril Amlodipine 100% vs 100% +±±

IDNT14-16 Irbesartan Amlodipine 100% vs 100% ±++

JMIC-B17,18 (DM subgroup)

Enalapril, Imidapril, Lisinopril

Nifedipine NR +++

J-MIND19 Enalapril Nifedipine 36% vs 38% ++±

MITEC20 Candesartan Amlodipine NR +±+

MOSES21,22 (DM subgroup)

Eprosartan Nitrendipine 6% vs 8% +++

NAGOYA HEART23 Valsartan Amlodipine NR +±+

STOP-Hypertension-224 (DM subgroup)

Enalapril, Lisinopril

Felodipine, Isradipine

NR ±++

ALLHAT4-6 Lisinopril Chlorthalidone NR +++ ANBP225,26 (DM subgroup)

Enalapril HCTZ 13% ±++

NESTOR27 Enalapril Indapamide 100% vs 100% +±+ UKPDS 3928 Captopril Atenolol 16% vs 20% +++ LIFE29-32 (DM subgroup)

Losartan Atenolol 11% vs 12% +++

See foot note of Table 1 for abbreviations and expansion of trial names.

*Represents risk of bias based on: sequence generation of allocation; allocation concealment and blinding. ‘+’ represents low bias risk, ‘-‘ high bias risk,

and “±” unclear bias risk.

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