Diabetes

RESEARCH
open access
Diabetes mellitus as a compelling indication for use of renin

angiotensin system blockers: systematic review and meta-analysis
of randomized trials
Sripal Bangalore,1 Robert Fakheri,1 Bora Toklu,2 Franz H Messerli3
1New
York University School of

Medicine, New York, NY, USA
2Mount Sinai Beth Israel Medical
Center, New York, NY, USA
3Mount Sinai Health Medical
Center, Icahn School of
Medicine, New York, NY, USA
Correspondence to: S Bangalore
sripalbangalore@gmail.com
Additional material is published
online only. To view please visit
the journal online.
Cite this as: BMJ 2016;352:i438
http://dx.doi.org/10.1136/bmj.i438
Accepted: 08 January 2016
ABSTRACT
Objective
To evaluate the outcomes with use of renin
angiotensin system (RAS) blockers compared with
other antihypertensive agents in people with diabetes.
Design
Meta-analysis.
Data sources and study selection
PubMed, Embase, and the Cochrane central register of
controlled trials databases for randomized trials of RAS
blockers versus other antihypertensive agents in
people with diabetes mellitus. Outcomes were death,
cardiovascular death, myocardial infarction, angina,
stroke, heart failure, revascularization, and end stage
renal disease.
Results
The search yielded 19 randomized controlled trials that
enrolled 25414 participants with diabetes for a total of
95910 patient years of follow-up. When compared with
other antihypertensive agents, RAS blockers were
associated with a similar risk of death (relative risk 0.99,
95% confidence interval 0.93 to 1.05), cardiovascular
death (1.02, 0.83 to 1.24), myocardial infarction (0.87,
0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke
(1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and
revascularization (0.97, 0.77 to 1.22). There was also no
difference in the hard renal outcome of end stage renal
disease (0.99, 0.78 to 1.28) (power of 94% to show a
23% reduction in end stage renal disease).
Conclusions
In people with diabetes, RAS blockers are not superior
to other antihypertensive drug classes such as
thiazides, calcium channel blockers, and blockers at
reducing the risk of hard cardiovascular and renal
What is already known on this topic

Various guidelines recommend renin angiotensin system (RAS) blockers as first line
treatment for people with diabetes, predominantly based on placebo controlled
trials done 20 years ago
However, other guidelines recommend RAS blockers on a par with other
antihypertensives based on more recent trials comparing RAS blockers versus
active comparators
What this study adds

Our study suggests that in people with diabetes, RAS blockers are similar to other
antihypertensives at reducing the risk of hard cardiovascular and renal endpoints
These findings support the European Society of Cardiology/European Society of
Hypertension and eighth Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure guideline recommendations
Those guidelines recommend using any antihypertensives in people with diabetes
but without kidney disease
thebmj|BMJ 2016;352:i438|doi: 10.1136/bmj.i438
endpoints. These findings support the

recommendations of the guidelines of the European
Society of Cardiology/European Society of Hypertension
and eighth Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood
Pressure to also use other antihypertensive agents in
people with diabetes but without kidney disease.
Introduction
People with diabetes are at increased risk of cardiovascular and renal events.1 Early placebo controlled trials
(such as the Heart Outcomes Prevention Evaluation and
European Trial on Reduction of Cardiac Events With
Perindopril in Stable Coronary Artery Disease) have
shown significant benefits from use of renin angiotensin system (RAS) blockers on cardiovascular and renal
events in people with diabetes, benefits touted to be
independent of the drugs blood pressure lowering efficacy. As such, the 2015 American Diabetes Association
guidelines recommend RAS blockers (angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor
blockers (ARBs)) as first line treatment for people with
diabetes and hypertension.2 Similarly, the 2013 American Society of Hypertension/International Society of
Hypertension guidelines favor RAS blockers as a first
line treatment in people with diabetes.3 The National
Kidney Foundation-Kidney Disease Outcomes Quality
Initiative clinical practice guidelines state in its executive summary that Hypertensive people with diabetes
and chronic kidney disease stages 1-4 should be treated
with an ACE inhibitor or an ARB, usually in combination with a diuretic.4 In contrast, the 2013 European
Society of Cardiology/European Society of Hypertension guidelines5 and the 2014 evidence based guidelines from the panel members of the eighth Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure6 recommend any class of antihypertensive agents in people
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 and renoprotective effects of
RAS blockers in people with diabetes.
We explored whether RAS blockers are superior to
other antihypertensive agents for the prevention of hard
cardiovascular and renal events in people with diabetes.
Methods
Eligibility criteria
We searched PubMed, Embase, and the Cochrane central
register of controlled trials until December 2015 (week 1)
1
RESEARCH
for randomized controlled trials of RAS blockers (ACE
inhibitor or ARB) (see supplementary table S1 for MeSH
terms) in people with diabetes or impaired fasting glucose. There were no language restrictions for the search.
In addition, we searched the bibliography of identified
original trials, meta-analyses, and review articles to find
other eligible trials (snowball search). Weekly reminders from PubMed kept the search up to date.
Eligible trials had to fulfill two criteria: randomized
controlled trials comparing RAS blockers with other
antihypertensive agents in participants with diabetes or
impaired fasting glucose, and a sample size of at least
100 participants with diabetes with follow-up of at least
one year (to minimize small study effect). We excluded
studies conducted in cohorts with heart failure given
the known efficacy of RAS blockers in this patient
group. In addition, we excluded studies that had been
redacted for any reason, compared ACE inhibitors with
ARBs, RAS blockers with placebo, or randomized participants to an ACE inhibitor plus ARB.
Trial selection and bias assessment

Three authors (RF, BT, SB) independently assessed trial
eligibility, trial bias risk, and data extraction, with disagreements resolved by consensus. The bias risk of trials was assessed using the components for randomized
trials recommended by the Cochrane Collaboration7:
allocation sequence generation, allocation concealment, and blinding of outcome assessors. For each
component, we categorized trials as being at low, high,
or unclear risk of bias. We considered trials with high or
unclear risk of bias for any one of the above components as trials with high risk of bias.
Outcomes
Outcomes were death, cardiovascular death, myocardial
infarction, angina, stroke, heart failure, revascularization, end stage renal disease, major adverse cardiovascular events, and drug withdrawal owing 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 statement.78 We carried out analyses to compare
RAS blockers (ACE inhibitor or ARB) with other agents.
Subgroup analyses compared RAS blockers with each
class of comparative agent (calcium channel blockers,
diuretics, and blockers). The meta-analytic summary
estimates (relative risk) were calculated using the fixed
effect model and the random-effects model of DerSimonian and Laird.9 Continuity correction was used for trials with zero events. We used the I2 statistic to assess
heterogeneitythe proportion of total variation
observed between the trials attributable to differences
between trials rather than to sampling error (chance),10
with an I2 value less than 25% considered low and more
than 75% high. We assessed small study effect using the
Beggs and the Eggers test and by visual evaluation of
the funnel plots for asymmetry.
2
A metaregression analysis was performed to evaluate

the relation of percent of participants with nephropathy
at baseline on the outcomes. We used a residual maximum likelihood to estimate the additive (between
study) component of variance 2 for the metaregression
analysis. Bootstrap analyses were performed using a
Monte Carlo permutation test for metaregression, using
10000 random permutations.11 Sensitivity analyses
were done after excluding trials that included participants with impaired fasting glucose. Analyses were performed using standard statistical software (Stata 12.1,
Stata, TX),12 with P<0.05 used to denote statistical
significance.
Patient involvement
No patients were involved in setting the research question or the outcome measures, nor were they involved in
developing plans for design or implementation of the
study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants
or the relevant patient community.
Results
Study selection and baseline characteristics
Our search yielded 19 randomized controlled trials (see
supplementary figure S1), enrolling 25414 people with
diabetes. The participants were followed for a mean of
3.8 years, totalling 95910 patient years of follow-up. Fifteen trials compared RAS blockers with a calcium channel blocker, three with a thiazide diuretic, and two with a
blocker. In 14 trials the RAS blockers were an ACE
inhibitor and in six an ARB. All trials enrolled people
with type 2 diabetes. In addition, the majority of the trials
(n=17) enrolled people with diabetes and hypertension.
Table 1 outlines the baseline characteristics of the
included trials. In the studies that reported race/ethnicity, black people were a minority of the enrolled
patients. The primary endpoint for the trials was heterogeneous (see supplementary table S2). Only three
trials enrolled patients with microalbuminuria or
proteinuria.
Outcomes
RAS blockers versus other antihypertensives
When compared with other antihypertensive agents,
RAS blockers were associated with a similar risk of
death (relative risk 0.99, 95% confidence interval 0.93 to
1.05, fig 1), cardiovascular death (1.02, 0.83 to 1.24, fig
2), myocardial infarction (0.87, 0.64 to 1.18, fig 3),
angina pectoris (0.80, 0.58 to 1.11, fig 4), stroke (1.04,
0.92 to 1.17, fig 5), heart failure (0.90, 0.76 to 1.07, fig 6),
and revascularization (0.97, 0.77 to 1.22, fig 7). The outcome of major adverse cardiovascular events (0.97, 0.89
to 1.06) did not differ between the two groups. In addition, there was no difference in end stage renal disease
(0.99, 0.78 to 1.28, fig 8) or drug withdrawal owing to
adverse effects (fig 9). The results were consistent when
using a fixed effect model (figs 1-9). Heterogeneity was
low to moderate, with no evidence of small study effect/
publication bias (see supplementary figures S2-S10).
doi: 10.1136/bmj.i438|BMJ 2016;352:i438|thebmj
RESEARCH
Table 1 | Baseline characteristics and risk of bias assessment of included trials

Trials
Year
Sample
size
Follow-up
(years)
RAS blockers versus calcium channel blockers:

ABCD (hypertensive)13, 14
ABCD (normotensive)15
ALLHAT16, 17 (diabetes mellitus)
ALLHAT16, 17, 18 (impaired fasting glucose)
BENEDICT19
CAMELOT20 (diabetes mellitus)
CAMELOT20 (impaired fasting glucose)
CASE-J21, 22, 23 (diabetes mellitus)
FACET24
Fogari etal25
IDNT26, 27, 28
JMIC-B29, 30 (diabetes mellitus)
1998
2002
2002
2002
2004
2004
2004
2008
1998
2002
2001
2004
470
354
7107
771
604
233
233
1195
380
205
1146
372
5.6
5.3
4.9
4.9
3.6
2
2
3.2
2.9
4
2.6
3
J-MIND31
MITEC32
MOSES33, 34 (diabetes mellitus)
2001
2009
2005
436
209
498
2
2
2.5
NAGOYA HEART 35
STOP-Hypertension-236 (diabetes mellitus)
RAS blockers versus diuretic:
ALLHAT16, 17 (diabetes mellitus)
ALLHAT16, 17, 18 (impaired fasting glucose)
ANBP237, 38 (diabetes mellitus)
NESTOR 39
2012
1999
1150
466
3.2
5
2002
2002
2003
2003
9504
1035
441
569
4.9
4.9
4.1
1
1998
2002
758
1195
8.4
4.8
RAS blockers versus blockers:

UKPDS 3940
LIFE41, 42, 43, 44 (diabetes mellitus)
Age
(years)
Black
people (%)
Risk of
bias*
58
59
67
67
62
58
58
67
63
63
60
64
14
7
39
30
NR
NR
NR
NR
NR
NR
13
NR
+++
+++
+++
+++
+
+++
+++
+++
++
+
++
+++
60
60
70
NR
NR
NR
++
++
+++
63
76
NR
NR
++
++
Diabetes mellitus and hypertension

Impaired fasting glucose and hypertension
Diabetes mellitus and elderly hypertension
Diabetes mellitus with microalbuminuria and
hypertension
67
67
72
60
39
30
NR
5
+++
+++
++
++

Diabetes mellitus and hypertension with left
ventricular hypertrophy
56
67
8
12
+++
+++
Cohort

Diabetes mellitus and normotensive
Impaired fasting glucose and hypertension
Diabetes mellitus and coronary artery disease
Impaired fasting glucose and coronary artery disease
Diabetes mellitus with proteinuria and hypertension
Diabetes mellitus with nephropathy and hypertension
Diabetes mellitus, hypertension, and coronary artery
disease
Diabetes mellitus, hypertension, and cerebrovascular
accident
Diabetes mellitus and elderly hypertension
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; CAMELOT=Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis; CASE-J=Candesartan
Antihypertensive Survival Evaluation in Japan; FACET=Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial; IDNT=Irbesartan Type II Diabetic Nephropathy Trial; 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; 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.
*Represents risk of bias based on: sequence generation of allocation; allocation concealment and blinding. + represents low bias risk and unclear bias risk.
RAS blockers versus calcium channel blockers

When compared with calcium channel blockers, RAS
blockers were associated with a similar risk of death
(1.01, 0.92 to 1.10, fig 1), cardiovascular death (1.17, 0.90 to
1.50, fig 2), myocardial infarction (0.84, 0.54 to 1.30,
fig3), angina pectoris (0.69, 0.33 to 1.42, fig 4), stroke
(1.08, 0.90 to 1.28, fig 5), and revascularization (1.01, 0.74
to 1.39, figs 7 and 10). However, RAS blockers were associated with a significant reduction in the risk of heart
failure compared with calcium channel blockers (0.78,
0.70 to 0.88, figs 6 and 10). There was no difference in
drug withdrawal owing to adverse effects (fig 9) or end
stage renal disease (figs 8 and 10). Heterogeneity was low
to moderate (fig 10), with no evidence of small study
effect/publication bias (see supplementary figures S2-10).
RAS blockers versus thiazide diuretics
Compared with thiazide diuretics, RAS blockers were
associated with a similar risk of death (0.99, 0.90 to
1.08, fig 1), cardiovascular death (0.50, 0.05 to 5.46,
fig2), and other outcomes (figs 3-9 and 11). Only three
trials compared RAS blockers with diuretics and hence
the confidence interval for most outcomes was wide.

Heterogeneity was low to moderate (fig 11), with no evidence of small study effect/publication bias (see supplementary figures S2-10).
RAS blockers versus blockers

Compared with blockers, RAS blockers were associated with a similar risk of death (0.84, 0.47 to 1.51, fig 1),
cardiovascular death (0.87, 0.47 to 1.60, fig 2), and other
outcomes tested (figs 3-9 and 12). Only two trials compared RAS blockers with blockers and hence the confidence interval for most outcomes was wide.
Heterogeneity was high for the outcome of death but
low to moderate for other outcomes (fig 12), with no evidence of small study effect/publication bias (see supplementary figures S2-10).
Influence of nephropathy
Metaregression analysis, aimed to assess the relation of
percent of patients with nephropathy at baseline on the
outcomes, showed no significant relation (P>0.05) for
all outcomes.
3
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No of events/total
RAS
blockers
Control
ABCD (hypertensive)
14/235
ABCD (normotensive)
19/181
Death
RAS blockers v calcium channel blockers
ALLHAT (diabetes mellitus)

ALLHAT (impaired fasting glucos)
Relative risk
(95% CI)
Weight
(%)
Relative risk
(95% CI)
18/235
0.77
0.78 (0.39 to 1.56)
19/173
0.93
0.96 (0.51 to1.81)
674/3510
683/3597
33.04
1.01 (0.91 to1.13)
58/407
55/364
2.75
0.94 (0.65 to 1.36)
BENEDICT
3/301
2/303
0.12
1.51 (0.25 to 9.04)
CASE-J
40/586
49/609
2.15
0.85 (0.56 to 1.29)
FACET
4/189
5/191
0.22
0.81 (0.22 to 3.01)
Fogari et al
3/103
4/102
0.17
0.74 (0.17 to 3.32)
IDNT
87/579
83/567
4.14
1.03 (0.76 to 1.39)
JMIC-B
5/173
2/199
0.14
2.88 (0.56 to 14.82)
MITEC
0/100
0/109
0.02
1.09 (0.02 to 54.93)
NAGOYA HEART
22/575
16/575
0.90
1.38 (0.72 to 2.62)
STOP-2
56/235
50/231
2.57
1.10 (0.75 to 1.61)
47.91
1.01 (0.92 to 1.10)
D+L Subtotal: P=0.973, I2=0%
1.01 (0.92 to 1.10)
I-V Subtotal
RAS blockers v diuretics
674/3510
1145/5994
41.33
1.01 (0.91 to 1.11)
ALLHAT (impaired fasting glucose)
58/407
107/628
3.66
0.84 (0.61 to 1.15)
NESTOR
1/286
2/283
0.06
0.50 (0.05 to 5.46)
45.05
0.99 (0.90 to 1.08)
0.99 (0.90 to 1.08)
I-V Subtotal
RAS blockers v blockers
LIFE (diabetes mellitus)
63/586
104/609
3.82
0.63 (0.46 to 0.86)
UKPDS 39
75/400
59/358
3.22
1.14 (0.81 to 1.60)
7.04
0.84 (0.47 to 1.51)
D+L Subtotal: P=0.012, I2=84.1%
0.83 (0.66 to 1.04)
I-V Subtotal
D+L Overall: P=0.611, I2=0%
100.00
0.99 (0.93 to 1.05)

0.99 (0.93 to 1.05)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
Fig 1 | Outcomes of death with renin angiotensin system (RAS) blockers compared with other antihypertensives in people
with diabetes
Sensitivity analysis
Results were largely similar in sensitivity analysis
excluding trials of participants with impaired fasting
glucose (see supplementary table S3).
Discussion
This analysis of patients with diabetes (largely without
microalbuminuria or proteinuria) with 95910 patient
years of follow-up from randomized trials failed to show
a superiority of renin angiotensin system (RAS) blockade over other antihypertensive agents for reduction of
cardiovascular and renal outcomes. More importantly,
compared with other agents RAS blockers showed no
benefit in reducing the risk of death or myocardial
infarction and end stage renal disease. The results were
consistent in comparisons of RAS blockers with all controls and with individual antihypertensive agents.
RAS blockers for diabetes
People with diabetes mellitus are at increased risk of
hypertension, and the concomitant presence of diabetes and hypertension is associated with an exponential
increase in the risk of cardiovascular, cerebrovascular,
4
and renal events.45 Previous trials have shown that

blood pressure reduction in such patients leads to a
significant reduction in cardiovascular events, emphasizing the need for aggressive management of hypertension in this cohort. 46 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) compared with
placebo,47 leading to the recommendation of RAS
blockers for this indication. This recommendation was
later extended to all people with diabetes. In addition,
small head to head comparison trials of RAS blockers
(fosinopril) versus calcium channel blockers (amlodipine) such as the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (380 participants)
showed a significant reduction in cardiovascular
events (secondary endpoint of combined outcome of
myocardial infarction, stroke, or hospital admission for
angina) with RAS blockers compared with calcium
channel blockers.24 However, hard endpoints of death
or myocardial infarction did not differ in this trial.
RESEARCH
No of events/total
RAS
blockers
Control
ABCD (hypertensive)
6/235
ABCD (normotensive)
14/181
Cardiovascular death
Weight
(%)
Relative risk
(95% CI)
11/235
4.06
0.55 (0.20 to 1.48)
8/173
5.31
1.67 (0.70 to 3.99)
1/3.1
1/303
0.53
1.01 (0.06 to 16.09)
CASE-J
11/586
15/609
6.58
0.76 (0.35 to 1.66)
Fogari et al
2/103
2/102
1.06
0.99 (0.14 to 7.03)
IDNT
52/579
37/567
21.26
1.38 (0.90 to 2.10)
JMIC-B
3/173
1/199
0.79
3.45 (0.36 to 33.18)
MITEC
0/100
0/109
0.27
1.09 (0.02 to 54.93)
NAGOYA HEART
4/575
4/575
2.11
1.00 (0.25 to 4.00)
STOP-2
39/235
33/231
17.8
1.16 (0.73 to 1.85)
59.77
1.17 (0.90 to 1.50)
BENEDICT
Relative risk
(95% CI)
1.17 (0.90 to 1.50)
I-V Subtotal
NESTOR
1/286
2/283
D+L Subtotal: Not applicable
0.71
0.50 (0.05 to 5.46)
0.71
0.50 (0.05 to 5.46)

0.50 (0.05 to 5.46)
I-V Subtotal
LIFE
38/586
61/609
22.88
0.65 (0.43 to 0.97)
UKPDS 39
39/400
29/358
16.64
1.20 (0.74 to 1.95)
39.52
0.87 (0.47 to 1.60)
D+L Subtotal: P=0.053, I2=73.3%
0.84 (0.61 to 1.14)
I-V Subtotal
Fig 2 | Outcome of
cardiovascular death with
renin angiotensin system
(RAS) blockers compared
with other antihypertensives
in people with diabetes
D+L Overall: P=0.421, I2=2.5%
100.00
1.02 (0.83 to 1.24)

1.02 (0.83 to 1.24)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
No of events/total
RAS
blockers
Control
ABCD (hypertensive)
9/235
ABCD (normotensive)
16/181
FACET
Weight
(%)
Relative risk
(95% CI)
27/235
9.38
0.33 (0.16 to 0.71)
18/173
10.59
0.85 (0.43 to 1.67)
10/189
13/191
8.46
0.78 (0.34 to 1.77)
Fogari et al
3/103
4/102
3.55
0.74 (0.17 to 3.32)
IDNT
44/579
27/567
14.09
1.60 (0.99 to 2.58)
J-MIND
1/208
1/228
1.17
1.10 (0.07 to 17.53)
JMIC-B
4/173
4/199
4.03
1.15 (0.29 to 4.60)
NAGOYA HEART
7/575
3/575
4.19
2.33 (0.60 to 9.02)
STOP-2
/235
32/231
12.02
0.52 (0.29 to 0.94)
67.48
0.84 (0.54 to 1.30)
Myocardial infarction
Relative risk
(95% CI)
D+L Subtotal: P=0.024, I2=54.6%
0.86 (0.66 to 1.13)
I-V Subtotal
NESTOR
0/286
3/283
1.03
0.14 (0.01 to 2.74)
1.03
0.14 (0.01 to 2.74)

0.14 (0.01 to 2.74)
I-V Subtotal
LIFE
41/586
50/609
15.43
0.85 (0.56 to 1.29)
UKPDS 39
61/400
46/358
16.05
1.19 (0.81 to 1.74)
31.48
1.02 (0.73 to 1.40)
D+L Subtotal: P=0.249, I2=24.8%
1.02 (0.77 to 1.35)
I-V Subtotal
Fig 3 | Outcome of
myocardial infarction with
renin angiotensin system
(RAS) blockers compared
with other antihypertensives
in people with diabetes
D+L Overall: P=0.032, I2=48.1%
100.00
0.87 (0.64 to 1.18)

0.93 (0.76 to 1.12)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
RESEARCH
No of events/total
Angina pectoris
RAS
blockers
Control
Relative risk
(95% CI)
Weight
(%)
Relative risk
(95% CI)
0.11 (0.01 to 2.09)
FACET
0/189
4/191
1.24
IDNT
8/579
15/567
13.79
0.52 (0.22 to 1.23)
J-MIND
2/208
0/228
1.14
5.48 (0.26 to 114.16)
JMIC-B
12/173
16/199
17.89
0.86 (0.41 to 1.82)
34.05
0.69 (0.33 to 1.42)
D+L Subtotal: P=0.259, I2=25.3%
0.70 (0.40 to 1.20)
I-V Subtotal
NESTOR
0/286
2/283
1.14
0.20 (0.01 to 4.12)
1.14
0.20 (0.01 to 4.12)

0.20 (0.01 to 4.12)
I-V Subtotal
LIFE
30/586
30/609
36.76
1.04 (0.63 to 1.72)
UKPDS 39
20/400
25/358
28.04
0.72 (0.40 to 1.29)
64.80
0.89 (0.60 to 1.30)
0.89 (0.60 to 1.30)
I-V Subtotal
Fig 4 | Outcome of angina

pectoris with renin
angiotensin system (RAS)
blockers compared with
other antihypertensives in
people with diabetes
D+L Overall: P=0.397, I2=3.8%
100.00
0.80 (0.58 to 1.11)

0.81 (0.59 to 1.10)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
No of events/total
RAS
blockers
Control
ABCD (hypertensive)
7/235
ABCD (normotensive)
6/181
Stroke
Weight
(%)
Relative risk
(95% CI)
11/235
1.51
0.64 (0.25 to 1.64)
11/173
1.37
0.52 (0.19 to 1.41)
260/3510
230/3597
23.75
1.16 (0.97 to 1.38)
21/407
15/364
3.00
1.25 (0.65 to 2.43)
CASE-J
31/586
26/609
4.67
1.24 (0.74 to 2.09)
FACET
4/189
10/191
1.02
0.40 (0.13 to 1.29)
Fogari et al
3/103
2/102
0.43
1.49 (0.25 to 8.89)
IDNT
28/579
15/567
3.32
1.83 (0.98 to 3.42)
J-MIND
5/208
2/228
0.51
2.74 (0.53 to 14.13)
Relative risk
(95% CI)
JMIC-B
6/173
4/199
0.86
1.73 (0.49 to 6.11)
MOSES
49/245
61/253
8.28
0.83 (0.57 to 1.21)
NAGOYA HEART
13/575
16/575
2.48
0.81 (0.39 to 1.69)
STOP-2
34/235
29/231
5.12
1.15 (0.70 to 1.89)
56.33
1.08 (0.90 to 1.28)
D+L Subtotal: P=0.292, I2=15.2%
1.10 (0.96 to 1.25)
I-V Subtotal
260/3510
414/5994
27.18
1.07 (0.92 to 1.25)
21/407
38/628
4.49
0.85 (0.50 to 1.45)
NESTOR
0/286
4/283
0.16
0.11 (0.01 to 2.04)
31.83
0.98 (0.69 to 1.38)
D+L Subtotal: P=0.229, I2=32.2%
1.05 (0.90 to 1.22)
I-V Subtotal
LIFE
51/586
65/609
8.64
0.82 (0.57 to 1.18)
UKPDS 39
21/400
17/358
3.20
1.11 (0.58 to 2.10)
11.84
0.88 (0.64 to 1.21)
0.88 (0.64 to 1.21)
I-V Subtotal
Fig 5 | Outcome of stroke

with renin angiotensin
system (RAS) blockers
compared with other
antihypertensives in people
with diabetes
6
D+L Overall: P=0.308, I2=12.2%
100.00
1.04 (0.92 to 1.17)

1.06 (0.96 to 1.16)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
RESEARCH
No of events/total
Heart failure
RAS
blockers
Control
Relative risk
(95% CI)
Weight
(%)
Relative risk
(95% CI)
ABCD (hypertensive)
10/235
8/235
3.08
1.25 (0.49 to 3.17)
ABCD (normotensive)
12/181
11/173
3.86
1.04 (0.46 to 2.36)
365/3510
468/3597
24.70
0.80 (0.70 to 0.92)
27/407
37/364
8.56
0.65 (0.40 to 1.07)
IDNT
58/579
86/567
14.00
0.66 (0.47 to 0.92)
J-MIND
0/208
1/228
0.29
0.37 (0.02 to 8.97)
JMIC-B
5/173
8/199
2.21
0.72 (0.24 to 2.20)
STOP-2
22/235
24/231
6.83
0.90 (0.51 to 1.61)
63.54
0.78 (0.70 to 0.88)
0.78 (0.70 to 0.88)
I-V Subtotal
365/3510
581/5994
25.03
1.07 (0.94 to 1.22)
27/407
29/628
7.91
1.44 (0.85 to 2.43)
32.95
1.11 (0.93 to 1.32)
D+L Subtotal: P=0.289, I2=10.9%
1.09 (0.96 to 1.24)
I-V Subtotal
UKPDS 39
12/400
9/358
3.51
1.19 (0.50 to 2.83)
3.51
1.19 (0.50 to 2.83)

1.19 (0.50 to 2.83)
I-V Subtotal
D+L Overall: P=0.039, I2=47.7%
100.00
0.90 (0.76 to 1.07)

0.92 (0.84 to 1.00)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
Fig 6 | Outcome of heart failure with renin angiotensin system (RAS) blockers compared with other antihypertensives in
No of events/total
Revascularization
RAS
blockers
Control
Relative risk
(95% CI)
Weight
(%)
Relative risk
(95% CI)
FACET
3/189
3/191
2.13
1.01 (0.20 to 5.01)
IDNT
27/579
28/567
19.49
0.94 (0.56 to 1.60)
JMIC-B
16/173
19/199
12.32
0.97 (0.50 to 1.88)
NAGOYA HEART
29/575
26/575
19.44
1.12 (0.66 to 1.89)
53.38
1.01 (0.74 to 1.39)
1.01 (0.74 to 1.39)
I-V Subtotal
LIFE
62/586
70/609
46.62
0.92 (0.65 to 1.30)
46.62
0.92 (0.65 to 1.30)

0.92 (0.65 to 1.30)
I-V Subtotal
D+L Overall: P=0.985, I2=0%
100.00
0.97 (0.77 to 1.22)

0.97 (0.77 to 1.22)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
Fig 7 | Outcome of revascularization with renin angiotensin system (RAS) blockers compared with antihypertensives in
ubsequent guidelines, including the seventh report of

S
the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure 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 compared with other antihypertensive agents for hard cardiovascular outcomes.35 In
addition, studies with larger sample size (for example, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with
13101 patients with diabetes) also failed to show the
superiority of RAS blockers compared with other
7
RESEARCH
No of events/total
End stage renal disease
RAS
blockers
Control
Relative risk
(95% CI)
Weight
(%)
Relative risk
(95% CI)
105/3510
126/3597
29.45
0.85 (0.66 to 1.11)
10/407
3/364
3.44
2.98 (0.82 to 10.83)
IDNT
82/579
104/567
27.29
0.77 (0.58 to 1.03)
60.18
0.88 (0.64 to 1.21)
D+L Subtotal: P=0.132, I2=50.5%
0.84 (0.69 to 1.02)
I-V Subtotal
105/3510
156/5994
30.29
1.15 (0.90 to 1.47)
10/407
9/628
6.51
1.71 (0.70 to 4.22)
36.80
1.18 (0.93 to 1.50)
1.18 (0.93 to 1.50)
I-V Subtotal
UKPDS 39
4/400
4/358
3.01
0.90 (0.22 to 3.58)
3.01
0.90 (0.22 to 3.58)

0.90 (0.22 to 3.58)
I-V Subtotal
D+L Overall: P=0.089, I2=47.7%
100.00
0.99 (0.78 to 1.28)

0.96 (0.83 to 1.11)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
Fig 8 | Outcome of end stage renal disease with renin angiotensin system (RAS) blockers compared with other
antihypertensives in people with diabetes
No of events/total
RAS
blockers
Control
ABCD (hypertensive)
41/235
Fogari et al
26/103
IDNT
Weight
(%)
Relative risk
(95% CI)
54/235
17.60
0.76 (0.51 to 1.14)
27/102
13.50
0.95 (0.56 to 1.63)
43/579
44/567
17.11
0.96 (0.63 to 1.46)
J-MIND
23/208
17/228
11.33
1.48 (0.79 to 2.78)
MITEC
5/100
16/109
5.78
0.34 (0.13 to 0.93)
65.32
0.89 (0.65 to 1.22)
Drug withdrawal owing to side effects

Relative risk
(95% CI)
D+L Subtotal: P=0.145, I2=41.4%
0.89 (0.71 to 1.12)
I-V Subtotal
NESTOR
15/286
14/283
9.33
1.06 (0.51 to 2.20)
9.33
1.06 (0.51 to 2.20)

1.06 (0.51 to 2.20)
I-V Subtotal
LIFE
2/586
9/609
2.79
0.23 (0.05 to 1.07)
UKPDS 39
88/400
125/358
22.56
0.63 (0.48 to 0.83)
25.35
0.51 (0.23 to 1.14)
D+L Subtotal: P=0.206, I2=37.4%
0.61 (0.47 to 0.80)
I-V Subtotal
D+L Overall: P=0.060, I2=48.4%
100.00
0.80 (0.61 to 1.05)

0.77 (0.65 to 0.92)
I-V Overall
0.1
Favours
RAS blockers
10
Favours
control
Fig 9 | Outcome of drug withdrawal owing to adverse effects with renin angiotensin system (RAS) blockers compared with
other antihypertensives in people with diabetes
ntihypertensive agents for cardiovascular outcomes.18

a
Indeed, two decades ago one author stated about the
progression of chronic kidney disease that despite
some discrepancies in experimental studies, recent
controlled clinical trials show a similar slowing of progression with either ACEi [ACE inhibitor] or CCB
8
[calcium channel blocker].48 Consequently opinion

now diverges among various guidelines about the role
of RAS blockade in people with diabetes, with some
guidelines still recommending RAS blockers as preferred drugs and some relegating them to be on a par
with other antihypertensive drug classes.
RESEARCH
No of events/
No of participants
Outcomes
Relative risk (95% CI)
Calcium
No of
I2
RAS
studies blockers channel blockers
Random
Fixed
13
985/7174
986/7255
0.0
1.01 (0.92 to 1.10) 1.01 (0.92 to 1.10)
Cardiovascular mortality 10
132/3068
112/3103
0.0
1.17 (0.90 to 1.50) 1.17 (0.90 to 1.50)
111/2478
129/2501
54.6
0.84 (0.54 to 1.30) 0.86 (0.66 to 1.13)
Angina
22/1149
35/1185
25.3
0.69 (0.33 to 1.42) 0.70 (0.40 to 1.20)
Stroke
13
467/7226
432/7324
15.2
1.08 (0.90 to 1.28) 1.10 (0.96 to 1.25)
Heart failure
499/5528
643/5594
0.0
0.78 (0.70 to 0.88) 0.78 (0.70 to 0.88)
Revascularization
75/1516
76/1532
0.0
1.01 (0.74 to 1.39) 1.01 (0.74 to 1.39)
Drug withdrawal
138/1225
158/1241
41.4
0.89 (0.65 to 1.22) 0.89 (0.71 to 1.12)
197/4496
233/4528
50.5
All cause mortality
0.88 (0.64 to 1.21) 0.84 (0.69 to 1.02)

0.3
3.3
Calcium
channel blockers
RAS
blockers
Fig 10 | Outcomes with renin angiotensin system (RAS) blockers compared with calcium channel blockers in people with
diabetes
No of events/
No of participants
Outcomes
No of
RAS
studies blockers
Diuretics

I2
1254/6905 0.0
Random
Fixed
All cause mortality
733/4203
0.99 (0.90 to 1.08)
0.99 (0.90 to 1.08)
Cardiovascular mortality
1/286
2/283
NA
0.50 (0.05 to 5.46)
0.50 (0.05 to 5.46)
0/286
3/283
NA
0.14 (0.01 to 2.74)
0.14 (0.01 to 2.74)
Angina
0/286
2/283
NA
0.20 (0.01 to 4.12)
0.20 (0.01 to 4.12)
Stroke
281/4203
456/6905 32.2
0.98 (0.69 to 1.38)
1.05 (0.90 to 1.22)
Heart failure
392/3917
610/6622 10.9
1.11 (0.93 to 1.32)
1.09 (0.96 to 1.24)
Drug withdrawal
15/286
14/283
NA
1.06 (0.51 to 2.20)
1.06 (0.51 to 2.20)
115/3917
165/6622
0.0
1.18 (0.93 to 1.50)
1.18 (0.93 to 1.50)
0.01
RAS blockers
100
Diuretics
Fig 11 | Outcomes with renin angiotensin system (RAS) blockers compared with diuretics in people with diabetes
No of events/
No of participants
Outcomes
No of
RAS
studies blockers
blockers
I2
Random
Fixed
All cause mortality
138/986
163/967
84.1
0.84 (0.47 to 1.51)
0.83 (0.66 to 1.04)
Cardiovascular mortality
77/986
90/967
73.3
0.87 (0.47 to 1.60)
0.84 (0.61 to 1.14)
102/986
96/967
24.8
1.02 (0.73 to 1.40)
1.02 (0.77 to 1.35)
Angina
50/986
55/967
0.0
0.89 (0.60 to 1.30)
0.89 (0.60 to 1.30)
Stroke
72/986
82/967
0.0
0.88 (0.64 to 1.21)
0.88 (0.64 to 1.21)
Heart failure
12/400
9/358
NA
1.19 (0.50 to 2.83)
1.19 (0.50 to 2.83)
Revascularization
62/586
70/609
NA
0.92 (0.65 to 1.30)
0.92 (0.65 to 1.30)
Drug withdrawal
90/986
134/967
37.4
0.51 (0.23 to 1.14)
0.61 (0.47 to 0.80)
4/400
4/358
NA
0.90 (0.22 to 3.58)
0.90 (0.22 to 3.58)
0.2
RAS blockers
5
blockers
Fig 12 | Outcomes with renin angiotensin system (RAS) blockers compared with blockers in people with diabetes
Given the controversy and the discordance in various guideline recommendations about the role of RAS
blockers in people with diabetes we evaluated the
comparative effectiveness of RAS blockers compared
with other antihypertensive agents in people with diabetes, excluding cohorts where RAS blockers are
shown to provide benefit (that is, 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 95000 patient years of follow-up from head to head randomized trials of RAS
blockers versus other antihypertensive agents failed to
9
RESEARCH
show a superiority of RAS blockers over other antihypertensive agents for the prevention of hard
cardiovascular or renal outcomes. The notable exception in our analysis was that the RAS blockers were
superior to calcium channel blockers for the prevention of heart failure. This outcome (heart failure) was
mainly driven by the ALLHAT trial, the findings of
which have been criticized.49 Our findings of similar
outcomes with RAS blockers compared with other
antihypertensive agents therefore supports both the
2013 Society of Cardiology/European Society of Hypertension guidelines5 and the 2014 eighth Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure6 recommendation
that any class of antihypertensive agents can be used
in people with diabetes.
Diabetes with proteinuria or microalbuminuria

Both the 2013 Society of Cardiology/European Society
of Hypertension guidelines5 and the 2014 eighth Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure6 recommend RAS blockers in the presence of proteinuria or
microalbuminuria. The guideline recommendations
favoring RAS blockers in those with diabetes and
chronic kidney disease are driven mainly by placebo
controlled trials of RAS blockers where there was a
reduction in doubling of serum creatinine concentration (the Microalbuminuria, Cardiovascular, and
Renal Outcomes substudy of the Heart Outcomes Prevention Evaluation study (MICRO-HOPE) and the
Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study (RENAAL) and end
stage renal disease (RENAAL) compared with placebo.5051 Casas and colleagues showed a greater benefit of RAS blockers on renal outcomes in placebo
controlled trials than active comparison trials and
concluded that the benefits of RAS blockers on renal
outcomes probably results from a blood pressure lowering effect.52 Palmer and colleagues, in a meta-analysis of trials enrolling patients with diabetes and
kidney disease, found that no drug regimen was more
effective than placebo for reducing all cause mortality.53 However, end stage renal disease and a doubling
of creatinine concentration was less likely and regression of albuminuria was more likely with ACE inhibitors or ARBs compared with placebo.53 Limited trials
have shown this superiority in active comparator trials. In the Irbesartan Type II Diabetic Nephropathy
Trial (1715 patients with diabetic nephropathy) the
RAS blocker irbesartan compared with the calcium
channel blocker amlodipine was associated with a
significant reduction in the risk of the primary composite end point (32.6%v 41.1%; P=0.006) of a doubling of serum creatinine concentration, the
development of end stage renal disease, or death from
any cause, driven by differences in doubling of serum
creatinine concentration (16.9%v 25.4%; P<0.001),
with numerically lower end stage renal disease
(14.2%v 18.3%; P=0.07) but with no difference in
death (15.0%v 14.6%; P>0.05). 28 Finally, Wu and
10
c olleagues in a meta-analysis of RAS blockers in

patients with diabetes showed no statistically significant difference among treatments for the hard endpoint of end stage renal disease even in the placebo
comparisons.54 However, an ACE inhibitor reduced
the risk of doubling of serum creatinine compared
with placebo. 54 Our study excluded placebo controlled trials and failed to show a benefit for the outcome of end stage renal disease with RAS blockers
compared with other antihypertensive agents. Our
analysis with 17626 patients (for the outcome of end
stage renal disease) had a power of 94% to show a
23% reduction in end stage renal disease with RAS
blockers compared with controls and is thus sufficiently powered to show a difference if one existed.
Limitations of this study

We used trial level data only for the analyses and hence
were unable to control for differences between trials.
Although a separate analysis in the cohort of patients
with nephropathy is desirable, trials did not report outcomes separately for this cohort. Moreover, the definition of nephropathy was variable. In addition, most of
the studies in patients with diabetes and nephropathy
were placebo controlled trials and excluded in the current analysis. There were only a few trials for the RAS
blocker compared with diuretics and RAS blockers
compared with blocker, and the analyses are likely
underpowered. For the renal outcomes, we only evaluated end stage renal disease as an outcome as this is
considered a hard renal endpoint. While one can
argue that a doubling of serum creatinine concentration is a stringent renal endpoint, only one trial
reported this outcome. Most patients with diabetes and
hypertension require on an average two antihypertensive agents and thus which agent should be first may
not be critical. The results were partly driven by the
ALLHAT trial, given the sample size. However, this trial
did not monitor urine protein.
Conclusions
This analysis of head to head comparison trials of RAS
blockers versus other antihypertensive agents in people with diabetes (and largely without microalbuminuria or proteinuria) failed to show a superiority of
RAS blockers compared with other antihypertensive
agents for the prevention of hard outcomes. The
results support the recommendation of both the 2013
European Society of Cardiology/European Society of
Hypertension guidelines5 and the 2014 eighth report
of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure6 that any class of antihypertensive agents can be
used in people with diabetes especially in those without renal impairment.
Contributors: SB conceived, designed, and supervised the study,
carried out the statistical analysis, and drafted the manuscript. RF and
BT acquired the data. All authors analyses and interpreted the data
and critically revised the manuscript for important intellectual content.
SB is the guarantor. He 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.
RESEARCH
Funding: None.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare: the
following financial relationships with organisations that might have an
interest in the submitted work in the previous three years: SB receives
honorariums from Abbott, Boehringher Ingelheim, Daiichi Sankyo,
Merck, Gilead, and Pfizer. FHM is a consultant for Daiichi, Sankyo,
Pfizer, Takeda, Abbott, AbbVie, Servier, Medtronic, and Ipca
Laboratories.
Ethical approval: Not required.
Data sharing: No additional data available.
Transparency: The guarantor (SB) affirms that the manuscript is an
honest, accurate, and transparent account of the study being reported;
that no important aspects of the study have been omitted; and that
any discrepancies from the study as planned have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on different terms,
provided the original work is properly cited and the use is noncommercial. See:http://creativecommons.org/licenses/by-nc/3.0/.
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Diabetes mellitus as a compelling indication for use of renin

York University School of

Accepted: 08 January 2016

What is already known on this topic

What this study adds

endpoints. These findings support the

Trial selection and bias assessment

A metaregression analysis was performed to evaluate

Table 1 | Baseline characteristics and risk of bias assessment of included trials

RAS blockers versus calcium channel blockers:

RAS blockers versus blockers:

Diabetes mellitus and hypertension

Diabetes mellitus and hypertension

Diabetes mellitus and hypertension

RAS blockers versus calcium channel blockers

the confidence interval for most outcomes was wide.

RAS blockers versus blockers

ALLHAT (diabetes mellitus)

0.78 (0.39 to 1.56)

0.96 (0.51 to1.81)

1.01 (0.91 to1.13)

0.94 (0.65 to 1.36)

1.51 (0.25 to 9.04)

0.85 (0.56 to 1.29)

0.81 (0.22 to 3.01)

0.74 (0.17 to 3.32)

1.03 (0.76 to 1.39)

2.88 (0.56 to 14.82)

1.09 (0.02 to 54.93)

1.38 (0.72 to 2.62)

1.10 (0.75 to 1.61)

1.01 (0.92 to 1.10)

D+L Subtotal: P=0.973, I2=0%

1.01 (0.92 to 1.10)

1.01 (0.91 to 1.11)

ALLHAT (impaired fasting glucose)

0.84 (0.61 to 1.15)

0.50 (0.05 to 5.46)

0.99 (0.90 to 1.08)

ALLHAT (diabetes mellitus)

D+L Subtotal: P=0.475, I2=0%

0.99 (0.90 to 1.08)

0.63 (0.46 to 0.86)

1.14 (0.81 to 1.60)

0.84 (0.47 to 1.51)

D+L Subtotal: P=0.012, I2=84.1%

0.83 (0.66 to 1.04)

0.99 (0.93 to 1.05)

and renal events.45 Previous trials have shown that

0.55 (0.20 to 1.48)

1.67 (0.70 to 3.99)

1.01 (0.06 to 16.09)

0.76 (0.35 to 1.66)

0.99 (0.14 to 7.03)

1.38 (0.90 to 2.10)

3.45 (0.36 to 33.18)

1.09 (0.02 to 54.93)

1.00 (0.25 to 4.00)

1.16 (0.73 to 1.85)

1.17 (0.90 to 1.50)

RAS blockers v calcium channel blockers

D+L Subtotal: P=0.778, I2=0%

1.17 (0.90 to 1.50)