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