see commentary on page 615

The impact of reninangiotensinaldosterone system

inhibitors on Type 1 and Type 2 diabetic patients
with and without early diabetic nephropathy
Jennifer A. Hirst
1,2
, Kathryn S. Taylor
1,2
, Richard J. Stevens
1,2
, Claire L. Blacklock
1,2
, Nia W. Roberts
2,3
,
Christopher W. Pugh
4
and Andrew J. Farmer
1,2
1
Department of Primary Care Health Sciences, University of Oxford, Oxford, UK;
2
National Institute for Health Research School for
Primary Care Research, Oxford, UK;
3
Bodleian Health Care Libraries, University of Oxford, Oxford, UK and
4
Nuffield Department of
Clinical Medicine, University of Oxford, Oxford, UK
Reninangiotensinaldosterone system inhibitors prevent
the progression of kidney disease in patients with diabetic
nephropathy, and we studied how that benefit varies by
the type of diabetes and baseline urinary albumin. We pooled
data from 49 randomized controlled trials in a meta-analysis
using the ratio of endpoint urinary albumin levels in those
treated compared to those untreated with reninangiotensin
aldosterone system inhibitors in both fixed- and random-
effects models. The urinary albumin excretion for treated
microalbuminuric patients with Type 1 diabetes was on
average 60% lower at the end of the trial compared with
patients not treated with reninangiotensinaldosterone
system inhibitors using the fixed-effects model and 67%
lower using the random-effects model. There was no
significant effect of treatment in patients with normal
albumin excretion. For normoalbuminuric patients with
Type 2 diabetes, urinary albumin excretion was on average
12% lower after treatment using the fixed-effects model
compared to 21% lower using the random-effects model. For
microalbuminuric patients, urinary albumin excretion was on
average 23% lower using the fixed-effects model and 27%
lower using the random-effects model. Thus, renin
angiotensinaldosterone system inhibition reduced urinary
albumin excretion for Type 1 diabetic patients with
micro-, but not those with normoalbuminuria. Treatment
reduced urinary albumin excretion for Type 2 diabetic
patients with and without microalbuminuria.
Kidney International (2012) 81, 674683; doi:10.1038/ki.2011.413;
published online 21 December 2011
KEYWORDS: ACE inhibitors; diabetes; diabetic nephropathy; microalbumi-
nuria; reninangiotensin system
Kidney disease affecting people with diabetes is a major
global health issue.
1,2
Factors contributing to the burden of
the disease include an increasing prevalence of diabetes and
improved survival from cardiovascular disease through better
risk management and treatment. Early diabetic kidney disease
(diabetic nephropathy) is characterized by higher than
normal excretion of urinary albumin in the presence of
otherwise normal renal function. Reninangiotensinaldo-
sterone system inhibitors (RAASIs) have proven benet
3,4
for
preventing the progression of established diabetic nephrop-
athy. Angiotensin-converting enzyme inhibitors (ACEIs)
are recommended as rst-line treatment, and angiotensin
receptor blockers (ARBs) are used where there is ACEI
intolerance. Treatment is initiated on detection and diagnosis
of microalbuminuria (raised urinary albumin excretion).
Devising the optimal strategy for surveillance, detection,
and treatment of diabetic nephropathy and other forms of
renal disease is hampered by a lack of understanding about
the benets of available treatments and the extent to which
they differ in the settings of Type 1 and Type 2 diabetes.
5
The complications associated with diabetes differ depending
on the type of diabetes: in young-onset (Type 1) diabetes,
incidence of microvascular complications such as retinopathy
is more frequent, whereas in adult-onset diabetes (Type 2)
cardiovascular outcomes predominate.
6
In patients with
diabetes, elevated urinary albumin excretion is independently
associated with increased morbidity and mortality.
7,8
The
extent to which current treatment improves outcomes has
not been explored in systematic reviews of the effect in
subgroups of Type 1 and Type 2 diabetes patients with
elevated urinary albumin excretion (30300 mg per 24 h,
microalbuminuria) and normal urinary albumin excretion
(o30 mg per 24 h, normoalbuminuria).
We therefore carried out a systematic review, meta-
analysis, and meta-regression of randomized controlled trials
of RAASI to provide information about outcomes stratied
by the type of diabetes and the presence or absence of
microalbuminuria. The objectives were to examine the effects
of treatment on urinary albumin excretion and determine
or i gi nal ar t i cl e http://www.kidney-international.org
& 2012 International Society of Nephrology
Received 18 March 2011; revised 9 September 2011; accepted 27
September 2011; published online 21 December 2011
Correspondence: Jennifer A. Hirst, Department of Primary Care Health
Sciences, University of Oxford, Hythe Bridge Street, Oxford, OX1 2ET, UK.
E-mail: jennifer.hirst@phc.ox.ac.uk
674 Kidney International (2012) 81, 674683
whether these effects varied with type of diabetes, baseline
urinary albumin levels, and treatment type.
RESULTS
Description of studies
Reference lists of two Cochrane systematic reviews
9,10
identied 65 trials of which 38 were assessed for full eligi-
bility. Of these, three trials could not be included in the meta-
analysis because they measured urinary protein instead
of urinary albumin,
1113
and a fourth trial because consistent
data could not be extracted,
14
leaving 34 trials that fully met
our inclusion criteria. In addition, 7849 articles were
identied from the search of MEDLINE, EMBASE, and the
Cochrane library from January 2005 to August 2010. Of these
articles, 1450 were duplicates (Figure 1), leaving 6399 articles
for review. After screening on title and abstract, 671 articles
were examined in more detail for eligibility and a further 659
articles were excluded, leaving 12 papers (15 trials) that met
our inclusion criteria. A total of 49 trials were therefore
identied for the meta-analysis, of which three had multiple
arms,
1517
which were included as separate comparisons,
resulting in 52 comparisons (Figure 1).
Seven trials were included in the analysis of patients with
Type 1 diabetes and normoalbuminuria (eight comparisons).
Fifteen trials were included in the analysis of patients with
Type 1 diabetes and microalbuminuria or macroalbuminuria.
One trial was included for both normoalbuminuria and
microalbuminuria,
18
giving a total of 21 trials of Type 1
diabetes patients. Ten trials were included in the analysis of
patients with Type 2 diabetes and normoalbuminuria.
Twenty-two trials were included in the analysis of patients
with Type 2 diabetes and microalbuminuria or macro-
albuminuria (24 comparisons). Four trials were included in
both the normoalbuminuria and microalbuminuria
1922
groups, giving a total of 28 included trials for Type 2
diabetes. One trial could not be included in the analysis
because only one patient was left in the comparator group at
the end of the trial.
23
Of the 21 trials of RAASI carried out in people with Type 1
diabetes, only three used ARBs
15,24
(Table 1). All three ARB
trials were carried out in patients with normoalbuminuria,
the remaining trials of Type 1 diabetes patients used ACEI.
All trials of Type 1 diabetes included normotensive or
controlled hypertensive patients, and the majority of trials
allowed patients to take antihypertensive medications (other
than RAASI; Table 1). In contrast to this, nearly all trials
of patients with Type 2 diabetes and normoalbuminuria
included hypertensive patients, whereas 6 of the 21 trials of
Type 2 diabetes patients with microalbuminuria specically
selected hypertensive patients (Table 1). In Type 2 diabetes,
three trials of normoalbuminuric patients used ARBs, and
nine trials of microalbuminuric patients used ARBs; the
remaining trials that were included all used ACEI (Table 1).
Only one trial in Type 1 diabetes
18
and two trials in Type 2
diabetes
20,21
directly compared patients with normoalbumin-
uria and microalbuminuria.
Urinary albumin excretion
Trials of Type 1 diabetes. The ratio of mean urinary
albumin excretion in treatment vs. comparator groups at the
end of the trial for Type 1 diabetes is shown in Figure 2a.
In patients who were normoalbuminuric at baseline, the ratio
65 Trials identified
through previous
systematic reviews
(Strippoli 2005 and
2006)
5728 Excluded
Not humans,
not all diabetes,
not RCT,
not randomized to ACE/ARB
1450 Duplicates excluded
27 Excluded
Mixed Type 1 and Type
2 diabetes, normo- and
microalbuminuria not
analyzed separately
659 Excluded
ACE/ARB in both arms
Normo- and micro not
separated
repeat trial
Trial < 6 months
Mixed Type 1 and Type 2
diabetes
Four excluded
proteinuria measured,
data inconsistent
within paper
7849 Records identified
through searching 20052009
38 Assessed for full
eligibility
6399 Records after
duplicates removed
671 Articles assessed for
eligibility
34 Trials
included
12 Papers -15 trials
included
49 Trials
included
(52 comparisons)
Figure 1 | Flow chart of the literature search. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; RCT, randomized
controlled trial.
Kidney International (2012) 81, 674683 675
JA Hirst et al.: The impact of RAASI on diabetic patients or i gi nal ar t i cl e
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or i gi nal ar t i cl e JA Hirst et al.: The impact of RAASI on diabetic patients
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Kidney International (2012) 81, 674683 677
JA Hirst et al.: The impact of RAASI on diabetic patients or i gi nal ar t i cl e
of means was 0.96 (4% lower urinary albumin excretion in
the treatment vs. comparator groups) using a xed-effects
model (inverse variance) and 0.94 (6% lower) using a
random-effects model
34
with corresponding 95% condence
intervals (CIs) of 0.940.99 and 0.791.12. In microalbumin-
uric patients, ratio of means was 0.40 (60% lower) using a
xed-effects model and 0.33 (67% lower) using a random-
effects model, with corresponding 95% CIs 0.360.44 and
0.230.46, respectively. A subgroup analysis by comparator
type was conducted to explore the difference between RAASI
and antihypertensive comparator, and RAASI and placebo or
no treatment comparator groups. The subgroup analysis was
not possible in patients with normoalbuminuria, as all trials
used placebo as the comparator. The subgroup analysis
of trials of patients with microalbuminuria yielded a ratio of
means of 0.44 (95% CI 0.390.48) in 12 placebo or no
treatment trials and a ratio of means of 0.20 (95% CI
0.140.27) in two active-comparator trials. This and other
sensitivity analyses are listed in full in the online Supple-
mentary Appendix A1.
Trials of Type 2 diabetes. The ratio of mean urinary
albumin excretion in treatment vs. comparator groups at
the end of the trial for Type 2 diabetes is shown in Figure 2b.
In patients who were normoalbuminuric at baseline, the ratio
of means was 0.88 (12% lower urinary albumin excretion in
treatment vs. comparator group) using a xed-effects model
(inverse variance) and 0.79 (21% lower) using a random-
effects model,
34
with corresponding 95% CIs of 0.840.92 and
0.680.93, respectively. In microalbuminuric patients, ratio of
means was 0.77 (23% lower) using a xed-effects model and
0.73 (27% lower) using a random-effects model, with
corresponding 95% CI 0.740.80 and 0.620.85, respectively.
A subgroup analysis by comparator type was conducted to
explore the difference between RAASI and antihypertensive
comparator, and RAASI and placebo or no treatment
comparator groups. The subgroup analysis in patients with
normoalbuminuria yielded a ratio of means of 0.89 (95% CI
0.850.93) in ve placebo or no treatment trials and a ratio of
means of 0.65 (95% CI 0.510.83) in two active-comparator
trials. The subgroup analysis of trials of microalbuminuric
patients yielded a ratio of means of 0.70 (95% CI 0.660.75)
in 13 placebo or no treatment trials and a ratio of means of
0.82 (95% CI 0.780.86) in seven active-comparator trials. A
sensitivity analysis restricted to trials of at least 200 patients
shows that effects remained statistically signicant but
smaller in magnitude (summary ratio of means 0.92, 95%
CI 0.880.96) in trials of normoalbuminuric patients. These
and other sensitivity analyses are listed in full in the online
Supplementary Appendix A1.
Other outcomes
Type 1 diabetes. Results for progression and regression of
albuminuria are presented in Figure 3. RAASI treatment of
normoalbuminuric patients led to no signicant difference in the
number of patients who progressed to microalbuminuria from
the comparator group, with a relative risk of 0.96 (95% CI
0.761.23, P0.25, I
2
24%). Trials using ACEI all favored the
treatment group, although the effect was not signicant, whereas
trials using ARBs all favored the comparator group, although not
signicantly. ACEI treatment of patients with microalbuminuria
resulted in fewer progressing to macroalbuminuria (urinary
albumin excretion 4300mg per 24h) than in comparator
groups with a relative risk of 0.39 (CI 0.230.64, P0.0005,
I
2
0%). Treatment with ACEI also resulted in more patients
regressing from microalbuminuria to normoalbuminuria, with a
relative risk of 5.81 (CI 2.0516.43, P0.001, I
2
0%). There
was no signicant effect of treatment on mortality (Figure 4) or
glomerular ltration rate (data not shown).
Type 2 diabetes. Results for progression and regression
of albuminuria are presented in Figure 3. Patients with
a b
Figure 2 | Ratio of mean urinary albumin excretion at the end of trials of reninangiotensinaldosterone system inhibitor treatment
vs. comparator (boxes) and pooled estimates across trials (diamonds) calculated by the fixed-effects inverse variance (IV)
method and by the DerSimonian and Laird random-effects (DL) method, in patients with (a, left) Type 1 and (b, right) Type 2
diabetes, stratified by baseline urine albumin status. Horizontal bars and diamond widths denote 95% confidence intervals (CI), and box
sizes indicate relative weight in the IV analysis. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ccb, calcium
channel blocker; nt, no treatment.
678 Kidney International (2012) 81, 674683
or i gi nal ar t i cl e JA Hirst et al.: The impact of RAASI on diabetic patients
Type 2 diabetes with both normoalbuminuria and micro-
albuminuria benetted from treatment with RAASI in
terms of progression or regression of urinary albumin, but
the effect was larger for patients with microalbumin-
uria. Fewer Type 2 diabetes patients with normoalbumin-
uria treated with RAASI progressed to microalbuminuria,
with a relative risk of 0.84 (95% CI 0.790.89 P0.002,
I
2
19%). RAASI treatment resulted in fewer patients
progressing from microalbuminuria to macroalbuminuria
with a relative risk of 0.52 (CI 0.430.63, P 0.00001,
I
2
48%). More patients regressed from microalbuminuria
to normoalbuminuria in the treated group than in compa-
rator groups, with a relative risk of 1.20 (CI 1.121.29,
P0.03, I
2
75%). There was no signicant effect of
treatment on mortality (Figure 4) or glomerular ltration
rate (data not shown).
Trial N RR (95% CI)
Trial
44
65
66
73
92
23
15
N RR (95% CI)
Trial
Chase 3.75 (0.18, 80.19)
11.79 (0.75, 184.66)
4.80 (1.10, 21.03)
5.31 (0.66, 43.04)
5.81 (2.05, 16.43)
5.44 (1.92, 15.38)
Jerums
Atlantis
Crepaldi
M-H overall (I
2
= 0.0%, P = 0.940)
D+L overall
23
65
66
15
N RR (95% CI)
Trial N RR (95% CI)
Trial N RR (95% CI)
0.84 (0.23, 3.06) Chan 34
43
49
76
103
342
395
2548
Ogawa ACE
Ogawa ARB
Baba
Ahmad
Makino
Parving
ADVANCE
M-H overall (I
2
= 47.8%, P = 0.062)
D-L overall
Chan 2.11 (0.44, 10.02)
1.32 (0.18, 9.95)
2.47 (0.36, 16.80)
0.68 (0.38, 1.22)
2.24 (1.03, 4.87)
18.64 (4.56, 76.21)
1.63 (1.17, 2.27)
1.13 (1.05, 1.21)
1.20 (1.12, 1.29)
1.62 (1.05, 2.51)
Ogawa ACE
Ogawa ARB
Baba
Shiga
34
43
49
76
150
342
395
2548
Makino
Parving
ADVANCE
M-H overall (I
2
= 75.3%, P = 0.000)
D-L overall
Chase
Jerums
Mathiesen
Atlantis
Crepaldi
Ahmad
Viberti
M-H overall (I
2
= 0.0%, P = 0.477)
D+L overall
0.79 (0.19, 3.29)
0.45 (0.10, 2.09)
0.88 (0.21, 3.66)
0.33 (0.11, 0.95)
0.33 (0.23, 0.48)
0.35 (0.17, 0.69)
0.69 (0.53, 0.89)
0.52 (0.43, 0.63)
0.49 (0.34, 0.70)
2.57 (0.29, 22.93)
0.26 (0.03, 2.11)
0.24 (0.06, 1.00)
0.85 (0.24, 2.98)
0.30 (0.07, 1.35)
0.27 (0.08, 0.87)
0.33 (0.12, 0.96)
0.39 (0.23, 0.64)
0.39 (0.23, 0.67)
Trial
Lebovitz
Chan
Baba
UKPDS
DIRECT P2
BENEDICT
ROADMAP
ADVANCE
M-H overall (I
2
= 19.2%, P = 0.278)
D+L overall
0.0813 1 1
1
12.3
Favors comparator Favors intervention
37
43
135
788
4440
6827
299
725
N RR (95% CI)
0.35 (0.08, 1.52)
0.79 (0.27, 2.31)
0.73 (0.40, 1.31)
1.21 (0.84, 1.73)
0.93 (0.73, 1.19)
0.58 (0.36, 0.93)
0.85 (0.70, 1.03)
0.83 (0.78, 0.89)
0.84 (0.79, 0.89)
0.85 (0.77, 0.94)
0.23 (0.01, 4.40)
0.08 (0.00, 1.28)
0.68 (0.16, 2.92)
2.61 (0.80, 8.52)
0.73 (0.37, 1.45)
1.11 (0.59, 2.08)
1.02 (0.74, 1.39)
0.96 (0.76, 1.23)
0.96 (0.67, 1.38)
24
75
142
143
384
1421
1905
0.00449
Favors intervention Favors comparator
223
0.0312
Favors intervention Favors comparator
0.0969 1 10.3
Favors intervention Favors comparator
32.1
0.00542 1
Favors intervention Favors comparator
185 0.0131 76.2 1
Favors intervention Favors comparator
Tuominen
Kvetny
Mauer ACE
Mauer ARB
EUCLID
Direct Prevent 1
Direct Protect 1
M-H overall (I
2
= 23.9%, P = 0.246)
D+L overall
a b
Figure 3| Relative risk (RR) of progression and regression of albuminuria during trials of reninangiotensinaldosterone system
inhibitor treatment vs. comparator (boxes) and pooled estimates across trials (diamonds) calculated by the fixed-effects
Mantel-Haenszel (M-H) method and by the DerSimonian and Laird random-effects (DL) method, in patients with (a, left) Type 1
and (b, right) Type 2 diabetes, stratified by baseline urine albumin status. Horizontal bars and diamond widths denote 95% confidence
intervals (CI), and box sizes indicate relative weight in the M-H analysis. (a) Type 1 diabetes: progression from normoalbuminuria to
microalbuminuria (top); progression from microalbuminuria to macroalbuminuria (middle); and regression from microalbuminuria to
normoalbuminuria (bottom). (b) Type 2 diabetes: progression from normoalbuminuria to microalbuminuria (top); progression from
microalbuminuria to macroalbuminuria (middle); and regression from microalbuminuria to normoalbuminuria (bottom).
Kidney International (2012) 81, 674683 679
JA Hirst et al.: The impact of RAASI on diabetic patients or i gi nal ar t i cl e
Meta-regression
In a univariate meta-regression, it was found that treatment
effect in trials of microalbuminuric patients was signicantly
greater than in trials of normoalbuminuric patients in studies
of Type 1 diabetes (P0.006). Differences in treatment effect
size between microalbuminuria and normoalbuminuria were
not signicant in studies of Type 2 diabetes (P0.65). Meta-
regression of the Type of medication (ACEI or ARB) could
not be performed in Type 1 diabetes as very few trials used
ARB; however, medication type was not found to signi-
cantly affect urinary albumin levels in Type 2 diabetes
(P0.43). Investigations into comparator found that
comparator type (antihypertensive medication vs. no anti-
hypertensive medication) did not signicantly affect treat-
ment effect size either for Type 1 diabetes (P 0.34) or for
Type 2 diabetes (P0.86). In multivariate meta-regression,
the effect of the following factors on heterogeneity was
explored: baseline urinary albumin, medication type, trial
country, age, differences in baseline urinary albumin levels,
trial size, data extraction method, and dose of RAASI. None
of these factors was found individually to reduce the
I
2
statistic by more than 20%, with trial country having
the biggest impact on the heterogeneity in both Type 1 and
Type 2 diabetes trials.
DISCUSSION
This is the rst systematic review of RAASI designed to look
for possible differences in benets between Type 1 and Type 2
diabetes. Previous reviews
10,25
on microalbuminuric patients
found that RAASI reduced disease progression: we have
conrmed this, and further shown that there is benet in
both Type 1 and Type 2 diabetes. However, the benet of
RAASI in primary prevention of microalbuminuria that was
found by a previous review in patients with normoalbumin-
uria
9
was only conrmed in our review for patients with Type
2 diabetes, and not for Type 1 diabetes. These separate
analyses by type of diabetes have been made possible by a
number of new trials, including the largest, ADVANCE,
19
which were not included in the previous systematic reviews.
In addition, we found no evidence of a difference in response
between ARB and ACEI in Type 2 diabetes, but this result
should be treated with caution as it is largely based on
comparisons across trials of either treatment against placebo,
rather than head-to-head trials of ACEI vs. ARB. We were
unable to make a similar comparison in Type 1 diabetes
because of insufcient ARB trial numbers. Results were
consistent across both the continuous and dichotomous
outcomes.
We have used a systematic search strategy to ensure that all
relevant published trials have been included in the review.
Conning the search to those trials separately reporting
outcomes for Type 1 and Type 2 patients allows us to explore
potential differences between the conditions. In the analysis
of continuous outcomes, heterogeneity between the trials is
large, even within subgroups dened by type of diabetes and
baseline urinary albumin levels. The meta-regression suggests
Trial Weight (%) Weight (%)
Weight (%)
RR (95% CI)
Trial
Atlantis (2000)
Laffel (1995)
Lewis (1993)
Parving (2001)
Overall (I
2
= 13.1%, P = 0.327)
3.98
3.07
87.08
5.87
100.00
RR (95% CI)
6.24 (0.35, 109.77)
0.91 (0.45, 1.84)
1.13 (0.08, 16.55)
0.57 (0.25, 1.34)
3.08 (0.13, 74.45)
Trial RR (95% CI)
Trial RR (95% CI)
DIRECT-prevent 1 1.40 (0.45, 4.38)
Direct - Protect 2
Overall (I
2
= 55.2%, P = 0.107)
Benedict (2004a)
Roadmap (2010) 1.72 (0.92, 3.25)
0.17 (0.02, 1.61)
1.06 (0.67, 1.67)
1.18 (0.82, 1.68)
34.93
55.77
9.30
100.00 1.07 (0.52, 2.19)
1.00 (0.09, 10.89)
0.88 (0.32, 2.41) DIRECT-protect 1
Mauer 2009-ACE
Overall (I
2
= 0.0%, P = 0.834)
0.0918 1 10.9
Favors intervention Favors comparator
0.00911 1 110
Favors intervention Favors comparator
0.62
Overall (I
2
= 0.0%, P = 0.950)
Rennal (2001)
Marre (2004)
Berl (2003) 1.10 (0.75, 1.61)
Weight (%)
27.84
7.39
64.77
100.00
8.89
61.66
28.45
100.00 1.04 (0.93, 1.16)
1.03 (0.84, 1.26)
1.04 (0.90, 1.20)
1 1.61
Favors intervention Favors comparator
1 57.1 0.0175
Favors intervention Favors comparator
a
b
Figure 4| Relative risk (RR) of all-cause mortality during trials of reninangiotensinaldosterone system inhibitor treatment vs.
comparator (boxes) and pooled estimates across trials (diamonds) calculated by the fixed-effects Mantel-Haenszel (M-H) method
in patients with (a, left) Type 1 and (b, right) Type 2 diabetes, stratified by baseline urine albumin status. Horizontal bars and
diamond widths denote 95% confidence intervals (CIs) and box sizes indicate relative weight in the M-H analysis. (a) Type 1 diabetes:
normoalbuminuria (top) and microalbuminuria (bottom). (b) Type 2 diabetes: normoalbuminuria (top) and microalbuminuria (bottom).
680 Kidney International (2012) 81, 674683
or i gi nal ar t i cl e JA Hirst et al.: The impact of RAASI on diabetic patients
that no single factor could explain the heterogeneity between
the trials, and the heterogeneity is attributable to multiple
factors that may include geographic setting, treatment type,
treatment dose, trial size, type of comparator, or baseline
imbalance between randomization groups. However, the
greater impact of baseline urinary albumin on treatment
effect size in Type 1 diabetes than in Type 2 diabetes was
conrmed by the analysis of dichotomous outcomes, which
showed relatively little heterogeneity.
The appropriate use of xed- or random-effects models in
meta-analysis continues to be discussed.
26
In xed-effects
analyses, CIs do not reect heterogeneity between studies.
27
Thus, in Figure 2, the narrow CIs for xed-effects analyses
better reects the large quantity of data available than the
degree of heterogeneity between the trials. Random-effects
analyses incorporate heterogeneity when calculating CIs, but
arguably give too much weight to small studies: for example,
in the random-effects analysis in Figure 2b, the largest study
is over 100 times the size of the smallest, but has less than
10 times the weight in the analysis. In presenting results
from both analyses, we demonstrate that our broad clinical
conclusions are not sensitive to the choice of method.
Regardless of the method of analysis, RAASI protects against
onset and progression of microalbuminuria in Type 2
diabetes, but in Type 1 diabetes it is only benecial to
patients with established microalbuminuria.
No signicant effect of treatment on glomerular ltration
rate or mortality was found. Few trials reported these
outcomes; of those that did, the largest trials were of a
duration of 5 years. In the absence of longer-term outcome
data, any conclusions drawn about the benets of RAASI from
our results are dependent on acceptance of urinary albumin
excretion as a surrogate measure.
2830
The evidence to date for
and against using urinary albumin as a surrogate for long-
term outcomes has recently been summarized elsewhere.
31
There are some remaining concerns that the benets of
RAASI may be mediated solely by their antihypertensive
effect, but these have not been substantiated.
28
In two of
three analyses that stratied trials by comparator type, the
effect was larger in the trials that compared RAASI with
active antihypertensive treatment.
The randomization method was not reported in the
majority of the included trials, which is a limitation of our
review in that it could be a potential source of bias in the
meta-analysis. In a sensitivity analysis restricted to the largest
trials (nX200), Type 2 diabetes patients who were normo-
albuminuric at baseline had a lower treatment-effect size than
in the main analysis (online Supplementary Appendix A1);
however, the effect was not large compared with the
uncertainty in the CIs. In other analyses, there was little or
no evidence of publication bias.
This review does not provide evidence for routine use of
RAASI for Type 1 normoalbuminuric diabetes patients. Our
conclusions are based on an analysis that includes two trials
intended to prevent microalbuminuria in this group, with
neither providing evidence of slowing of progression to
microalbuminuria.
15,24
The high rate of comorbidity among
people with diabetes may mean that, in practice, many people
without microalbuminuria have other indications for RAASI
use. A recent study among individuals above 55 years of age
with diabetes
32
suggests that virtually all individuals of this
group have additional indications for treatment with RAASI,
including hypertension and other cardiovascular risk factors.
However, in otherwise well younger people with Type 1
diabetes, there is no indication for treatment with RAASI.
A recent trial of losartan and lisinopril vs. placebo suggested
that treatment of this group of patients may even be poten-
tially harmful,
15
although this may be a drug-specic effect or
a chance nding.
The current practice is to monitor urinary albumin in all
adults with diabetes in order to initiate RAASI treatment when
nephropathy is detected. In Type 1 diabetes, our results
support this strategy of targeting RAASI at those with
nephropathy. However, in Type 2 diabetes, we nd that RAASI
has similar albumin-lowering effects in those with and without
nephropathy. Our ndings suggest that RAASI treatment of
Type 2 diabetes patients with normoalbuminuria may be
benecial to patients in terms of fewer patients progressing to
microalbuminuria. This raises the possibility that monitoring
for Type 2 diabetes could be replaced by routine treatment
with RAASI for Type 2 diabetes. Before determining whether
the current monitoring program is the best strategy for
managing this group of patients, further work, including cost-
effectiveness and a full health economic analysis, is needed.
MATERIALS AND METHODS
Search strategy
Trials published up to January 2005 were identied from reference
lists of two Cochrane systematic reviews on this topic.
9,10
Articles
from January 2005 onward were identied as follows: MEDLINE
(January 2005 to August 2010), EMBASE (January 2005 to August
2010), and the Cochrane Controlled Trials Register (issue 1 2005 to
issue 8 2010) were searched using the search strategy described in a
previous Cochrane systematic review
9
for diabetes and randomized
controlled trials, plus terms to identify diabetes, urinary albumin,
ACEI, or ARBs (see online Supplementary Appendix A2 for the full
search strategy in MEDLINE). Reference lists of identied trials and
relevant reviews were also searched.
Trial selection criteria
Included trials met the following criteria: (i) randomized controlled
design; (ii) outcomes for patients with Type 1 and Type 2 diabetes
were reported separately; (iii) the intervention used was either an
ACEI or an ARB; the comparator group was either placebo, no
treatment, or antihypertensive (other than ACEI or ARB); (iv) trial
duration was at least 6 months; (v) at least one outcome was separately
reported for patients with normoalbuminuria or micro/macroalbu-
minuria, and urinary albumin levels were reported either as a timed
albumin excretion rate or as a spot test albumincreatinine ratio.
The outcomes evaluated were (i) urinary albumin excretion at the
end of the trial; (ii) progression to microalbuminuria (30300 mg per
24 h); (iii) progression to macroalbuminuria (4300 mg per 24 h);
(iv) regression to normoalbuminuria (o30 mg per 24h); (v) change
in glomerular ltration rate in ml/min per 1.73 m
2
; and (vi) death.
Kidney International (2012) 81, 674683 681
JA Hirst et al.: The impact of RAASI on diabetic patients or i gi nal ar t i cl e
Data extraction
Two reviewers (JAH and CLB) identied relevant publications and
two (JAH and KST) independently extracted the data, and disagree-
ments were resolved by consensus with a third author (AJF).
Structured forms were used for data extraction. Trials that compared
two doses of the same intervention with placebo, no treatment, or
other antihypertensives were also included, but only the data from the
higher dose was included in the meta-analysis, as a parallel study has
demonstrated a dose dependency of effects.
33
Trials that considered
both an ACEI and an ARB in comparison with placebo, no treatment,
or other antihypertensive treatment were included in the meta-analysis
by splitting the data from the comparator group between the required
comparisons using a standard method.
27
Unpublished trial data were
sought from authors of trials published since 2000.
Statistical methods
Statistical analysis was carried out using STATA version 11.1
(StataCorp, College Station, TX). Data on progression to micro/
macroalbuminuria and regression to normoalbuminuria were
analyzed as dichotomous data using the MantelHaenszel method,
with a xed-effects model, specifying the relative risk as the effect
measure. The analysis of continuous urinary albumin data was based
on an inverse variance method using a xed-effects model.
27
We also
report results and CIs from random-effects analyses based on the
DerSimonian and Laird method
34
for comparison. A ratio of means
effect measure
3537
was used, which allowed us to combine 35 trials
that reported urinary albumin excretion as albumin excretion rate
(mg per 24 h) and ve trials of albumincreatinine ratio (mg/mmol
or mg/g) in a single analysis. We took ratio of means to be the ratio
of nal value in the intervention group to the nal value in the
comparator group, so that ratio of means o1 favors intervention.
Comparison with standard analysis methods using mean difference
and standardized mean difference veried that ratio of means was a
suitable analysis method. The following sensitivity analyses were
carried out to verify that our results were not sensitive to these
approximations or to trials in which the comparator group was not
an antihypertensive; double-blinding was not clearly stated; it was
not clearly stated that at least two measurements of urinary albumin
were made to categorize patients as normoalbuminuric, micro-
albuminuric, and macroalbuminuric (applied both at baseline and
endpoint); and the number of participants was o200. Statistical
heterogeneity between studies was assessed with the I
2
statistic. For
the glomerular ltration rate data, we used inverse variance, xed-
effect model, and ratio of means. For a few studies it was necessary
to impute or approximate data.
We undertook random-effects meta-regression to evaluate the
explanatory value of baseline urinary albumin (microalbuminuria
vs. normoalbuminuria), and medication type (ACEI vs. ARB) on
effect size separately for Type 1 and Type 2 diabetes. Because a high
degree of statistical heterogeneity was observed between studies in
the analysis of continuous data, a post-hoc multivariate meta-
regression analysis was carried out to test whether the heterogeneity
was explained by the following: study length; trial size; average
participant age; country of trial; comparator type (no treatment,
placebo, or active comparator); medication type (ACEI or ARB);
treatment dose (categorized as high dose vs. low dose based on usual
dose in the British National Formulary and excluding one study of a
drug not licensed in the UK, temocapril); difference in baseline
urinary albumin excretion between the treatment and comparator
groups, whether or not approximations were made, or year of trial
publication. In addition, the effect of comparator type (placebo
or no treatment vs. another antihypertensive) on effect size was
investigated using subgroup analyses and meta-regression.
Univariate and multivariate meta-regression was carried out using
the metareg routine in STATA version 11.1, applying the method of
DerSimonian and Laird,
34
and estimating heterogeneity from the
MantelHaenszel model and reporting the I
2
statistic for heterogeneity.
27
DISCLOSURE
All the authors declared no competing interests.
ACKNOWLEDGMENTS
This systematic review was funded by the Health Technology
Assessment programme (HTA). AJF is funded by the National Institute
of Health Oxford Biomedical Research Centre. We thank Professor
Jan Kvetny, Naestved Hospital, Professor Vlado Perkovic, and the
ADVANCE team, and Piero Ruggenenti and Annalisa Perna from the
BENEDICT trial, for supplying unpublished data for inclusion in the
meta-analysis. We are grateful to anonymous reviewers for comments
resulting in substantial improvements to this paper.
Disclaimer
This report is the result of an independent research commissioned
by the National Institute for Health Research. The views expressed in
this publication are those of the authors and not necessarily those
of the NHS, the National Institute for Health Research, or the
Department of Health.
SUPPLEMENTARY MATERIAL
Appendix.
Supplementary material is linked to the online version of the paper at
http://www.nature.com/ki
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