See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/7624979

Antihypertensive Agents for Primary

Prevention of Diabetic Nephropathy

Article in Journal of the American Society of Nephrology November 2005

DOI: 10.1681/ASN.2004080634 Source: PubMed

CITATIONS READS

60 49

4 authors:

Giovanni Strippoli Maria Craig

Diaverum UNSW Sydney
244 PUBLICATIONS 6,702 CITATIONS 257 PUBLICATIONS 4,894 CITATIONS

SEE PROFILE SEE PROFILE

Francesco Paolo Schena Jonathan Craig

Universit degli Studi di Bari Aldo Moro University of Sydney
521 PUBLICATIONS 14,819 CITATIONS 894 PUBLICATIONS 27,214 CITATIONS

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

The resilience of urban Aboriginal children and their caregivers View project

Growth Hormone for Children with Renal Failure View project

All content following this page was uploaded by Maria Craig on 22 July 2014.

The user has requested enhancement of the downloaded file.

Antihypertensive Agents for Primary Prevention of
Diabetic Nephropathy
Giovanni F.M. Strippoli, Maria Craig, Francesco P. Schena, and Jonathan C. Craig
Centre for Kidney Research, Cochrane Renal Group, The Childrens Hospital at Westmead, School of Public Health,
University of Sydney, Sydney, Australia

The objective of this study was to evaluate the comparative effects of antihypertensive agents in patients with diabetes and
normoalbuminuria. Randomized, controlled trials that compared any antihypertensive agent with placebo or another agent in
hypertensive or normotensive patients with diabetes and normoalbuminuria (albumin excretion rate <30 mg/d) were
identified on Medline, in Embase, on the Cochrane Controlled Trials Register, in conference proceedings, and by contacting
investigators. Two authors independently extracted data on renal outcomes and other patient-relevant outcomes (e.g., mor-
tality, serious cardiovascular events) and assessed quality of trials. Analysis was by a random-effects model, and results were
expressed as relative risk (RR) and 95% confidence intervals (CI). Sixteen trials (7603 patients) were identified, six of
angiotensin-converting enzyme inhibitors (ACEi) versus placebo, six of ACEi versus calcium antagonists, one of ACEi versus
calcium antagonists or combined ACEi and calcium antagonist, and three of ACEi versus other agents. Compared with placebo,
ACEi significantly reduced the development of microalbuminuria (six trials, 3840 patients; RR 0.60; 95% CI 0.43 to 0.84) but
not doubling of creatinine (three trials, 2683 patients; RR 0.81; 95% CI 0.24 to 2.71) or all-cause mortality (four trials, 3284
patients; RR 0.81; 95% CI 0.64 to 1.03). Compared with calcium antagonists, ACEi significantly reduced progression to
microalbuminuria (four trials, 1210 patients; RR 0.58; 95% CI 0.40 to 0.84). A significant reduction in the risk for developing
microalbuminuria in normoalbuminuric patients with diabetes has been demonstrated for ACEi only. It seems that the effect
of ACEi is independent of baseline BP, renal function, and type of diabetes, but data are too sparse to be confident that these
are not important effect modifiers, and an individual patient data meta-analysis is required.
J Am Soc Nephrol 16: 30813091, 2005. doi: 10.1681/ASN.2004080634

iabetes is a global epidemic with 150 million people develops in approximately 50% of cases within 10 yr and in 75%

D affected, a number that is expected to double by 2025.

It is a progressively debilitating condition; a major
cause of death in the world; and a leading cause of heart
disease, adult blindness, and amputations of the lower extrem-
ities (1). Diabetes also represents the most common single cause
of ESRD in the United States and Europe (2,3).
Renal involvement in patients with diabetes is defined by the
appearance of low but abnormal levels (30 mg/d, or 20
g/min) of albumin in the urine (microalbuminuria). This oc-
curs in 40 to 80% of patients with diabetes 20 to 25 yr after the
onset of diabetes (4). Without specific interventions, microalbu-
minuria (also called incipient nephropathy) progresses to the
next stage of diabetic nephropathymacroalbuminuria, or
overt nephropathywhich is characterized by urinary albumin
excretion 300 mg/d, or 200 g/min. This stage generally
develops over a period of 10 to 15 yr. If a patient has microalbu-
minuria, then the risk for progression to ESRD is 20 to 40% within
15 to 20 yr (59). If a patient has macroalbuminuria, then ESRD
Received August 3, 2004. Accepted July 8, 2005.
within 20 yr. In parallel, there is a two- to four-fold increased risk
for cardiovascular events and death for both conditions (9).
Recently, much attention has been given to secondary pre-
vention strategies for patients with diabetes and nephropathy
by attempting to prevent the progression of micro and mac-
roalbuminuria to ESRD (10). Using available trial data, most
national guideline groups have recommended angiotensin-con-
verting enzyme inhibitors (ACEi) and angiotensin receptor
blockers (ARB) in preference to other antihypertensive agents
in patients who have diabetes with micro- or macroalbumin-
uria (Table 1) (1116). In comparison, these same guidelines
groups generally do not preferentially recommend any class of
antihypertensive agents in patients who have diabetes without
microalbuminuria or any antihypertensive agent in patients
who have diabetes without hypertension.
This systematic review was undertaken to evaluate the rela-
tive effects of antihypertensive agents in the primary preven-
tion of nephropathy in patients who have diabetes without
microalbuminuria. We also sought to determine whether the
effects of these agents varied with baseline BP, renal function,
and type of diabetes.

Published online ahead of print. Publication date available at www.jasn.org.

Address correspondence to: Dr. Giovanni F.M. Strippoli, Editor and Regional Coor-
dinator of the Cochrane Renal Group, Centre for Kidney Research, Locked Bag 4001,
Childrens Hospital at Westmead, Westmead, NSW 2145, Australia. Phone: 39-349-
5705884; Fax: 39-080-5580776; E-mail: gfmstrippoli@aliceposta.it
Materials and Methods
Inclusion Criteria
We included data from trials (adult or pediatric) in which any anti-
hypertensive agent was given for at least 6 mo, compared with placebo

Copyright 2005 by the American Society of Nephrology ISSN: 1046-6673/1610-3081

3082 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 30813091, 2005

Table 1. Guidelines on pharmacologic management of hypertension in patients with diabetes

Recommended Agent
Guideline Country Year Indication
ACEi ARB -Blockers CA Diuretic -Blockers

JNC-7 United States 2003 Hypertension X X X X X X

Diabetic nephropathy X X
(type 1 diabetes)
Diabetic nephropathy X X
(type 2 diabetes)
ADA United States 2003 Hypertension X X X Xb X
Diabetic nephropathy X X
(type 1 diabetes)
Diabetic nephropathy X X
(type 2 diabetes)
K-DOQI United States 2003 Hypertension
Diabetic nephropathy X X
(type 1 diabetes)
Diabetic nephropathy X X
(type 2 diabetes)
Canadian Diabetes Canada 2003 Hypertension X
Association
Diabetic nephropathy X
(type 1 diabetes)
Diabetic nephropathy X Xc
(type 2 diabetes)
European Society of Europe 2003 Hypertension X Xd X X X X
Hypertension
Diabetic nephropathy X X
(type 1 diabetes)
Diabetic nephropathy X X
(type 2 diabetes)
British Hypertension United Kingdom 2004 Hypertension Xe X
Society
Diabetic nephropathy X
(type 1 diabetes)
Diabetic nephropathy X
(type 2 diabetes)
CARI Guidelines Australia 2000 Hypertension X
Diabetic nephropathy X Xf
(type 1 diabetes)
Diabetic nephropathy X Xf
(type 2 diabetes)
a
ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CA, calcium antagonists; JNC-7, Joint
National Committee on Prevention, Diagnosis and Management of Hypertension; ADA, American Diabetes Association; K-
DOQI, Kidney Disease Outcome Quality Initiative; CARI, Caring for Australians with Renal Impairment; X, suggested agent.
b
Second-line agent.
c
Either ACEi or ARB but ARB only if creatinine clearance is 60 ml/min.
d
Use CA for hypertension when can be managed with monotherapy; use any agent for hypertension that requires
combination treatment.
e
If intolerant to other agents.
f
Only if intolerant to ACEi.

(or no treatment) or with other antihypertensive agents directly, in Those that included only patients who had diabetes without nephrop-
patients with diabetes and no diabetic nephropathy (defined as the athy; trials primarily of patients who had diabetes with nephropathy
absence of micro- or macroalbuminuria, i.e., urinary albumin excretion when the data of the patients without diabetic nephropathy were
30 mg/d). These data were extracted from three groups of trials: available or could be obtained by contacting the authors; and trials of
J Am Soc Nephrol 16: 30813091, 2005 Antihypertensive Agents for Prevention of Diabetic Nephropathy 3083

primarily hypertensive patients, including some patients with diabetes, dard criteria (allocation concealment, intention-to-treat analysis, loss to
when the data of the patients with diabetes and without diabetic follow-up, and blinding). Any differences in data extraction were re-
nephropathy could be extracted or obtained. solved by discussion among authors.
To compare the consistency of these findings with results obtained in
large-scale, randomized trials of different antihypertensive agents con- Statistical Analyses
ducted in general population settings, we searched for trials using the Treatment effects were summarized as relative risks (RR) with 95%
criteria of the Blood Pressure Lowering Treatment Trialists Collabora- confidence intervals (CI) and pooled using the DerSimonian and Laird
tion (n 4000 with a planned minimum of 1000 patient-years of random-effects model (18). Heterogeneity of treatment effects between
follow-up; http://www.thegeorgeinstitute.org/bplttc/resources.html). studies was examined using Cochran Q and the I2 statistics (19). Sub-
These trials were analyzed separately because data on baseline albu- group analysis and random-effects meta-regression were planned to
minuria for the patients with diabetes were not provided (i.e., the explore the influence of possible sources of heterogeneity (duration of
outcomes for normoalbuminuric patients with diabetes could not be follow-up, type of diabetes, type of drug, baseline renal function and
isolated). A separate systematic review of the relative effects of antihy- hypertension, and specific trial quality items) on treatment effect, pro-
pertensive agents in patients with established diabetic nephropathy has vided that a sufficient number of trials were identified.
been published elsewhere (10). In trials of populations with mixed-causation hypertension, the raw
data were used whenever available to summarize treatment effect with
the RR measure and its 95% CI. Estimates of treatment effect were
Literature Search
obtained for the overall population, the patients with diabetes, and the
Electronic searches were performed in Medline (1966 through Sep-
patients without diabetes. Differences in the estimate of effect of treat-
tember 2003) and Embase (1988 through September 2003) using opti-
ment between patients with and without diabetes were tested with a
mally sensitive search strategies developed by the Cochrane Collabo-
formal test of interaction whenever these data were available.
ration for the identification of trials (17). The Cochrane Renal Group
Specialized Register and the Cochrane CENTRAL registry of random-
ized trials were also searched. The following medical subject heading Results
terms and text words were used: AT 2 receptor blockers, angiotensin II Literature Search
receptor antagonist(s), angiotensin receptor antagonist(s), chlorothia- The literature search identified 4723 articles, 4424 of which
zide, chlorthalidone, hydralazine, hydrochlorothiazide, indapamide, were excluded after title and abstract review (Figure 1). The
minoxidil, losartan, imidazole, irbesartan, candesartan, eprosartan, val-
sartan, olmesartan, telmisartan, angiotensin converting enzyme inhib-
itors, captopril, enalapril, cilazapril, enalaprilat, fosinopril, lisinopril,
perindopril, ramipril, saralasin, teprotide, calcium channel blockers,
amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nimodipine,
nisoldipine, nitrendipine, verapamil, adrenergic -antagonists, alpre-
nolol, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol,
adrenergic -antagonists, labetalol, prazosin, beta blocker, diuretics,
spironolactone, triamterene, bumetanide, furosemide, combined with
diabetes mellitus or diabetic nephropathy.
Trials were considered without language restriction. The results of
the searches were analyzed in title and abstract form by two indepen-
dent authors (G.F.M.S., M.C.) according to the inclusion criteria. Ref-
erence lists from identified articles were also searched. Information
about unpublished or additional trials were sought from experts in the
field (authors of identified trials) and the Internet (international med-
ical societies web sites, on-line guidelines, and health promotion orga-
nizations).

Data Extraction, Definition of Outcomes, and

Quality Assessment
Each trial was assessed by two independent authors (G.F.M.S., M.C.).
From all included trials, data were extracted on characteristics of the
participants, interventions, comparisons, and outcomes (progression
from normo- to micro- or macroalbuminuria, ESRD, doubling of creat-
inine, all-cause mortality, fatal and nonfatal myocardial infarction, fatal
and nonfatal stroke, cough, headache, and hyperkalemia). Whenever
data were not reported in the publications, authors were contacted by
at least two methods from the primary investigator (G.F.M.S.) and the
Cochrane Renal Group editorial office. Authors were also contacted
when trials enrolled mixed populations of normo- and micro-/mac-
roalbuminuric patients with diabetes to obtain individual data of the
normoalbuminuric individuals only, as per the inclusion criteria and Figure 1. Flowchart indicating the number of citations retrieved
objectives of this analysis. by individual searches and the final number of trials included
The quality of included randomized trials was assessed using stan- in this analysis. Reasons for exclusion are provided.
3084 Journal of the American Society of Nephrology
major reasons for exclusion were a nonrandomized design,
nonantihypertensive interventions, nondiabetic study popula-
tions, patients with diabetes and established nephropathy (ei-
ther micro- or macroalbuminuria), and duplicate publications.
Full-text assessment of 299 potentially eligible studies identi-
fied 16 eligible trials (25 publications) that enrolled 7603 pa-
tients (20 35).
Supplemental data on design features and outcomes were
asked of all authors of the trials. Authors of the 10 trials that
enrolled both patients with and without nephropathy were also
asked for the data sets of the normoalbuminuric patients only,
with seven replying to our requests (2328,32).
Study Characteristics
The characteristics of the populations and interventions of
the studies included in this systematic review are presented in
Table 2. Of the 16 trials, seven trials or trial arms (4925 patients)
compared ACEi with placebo or no treatment, seven trials or
trial arms (1161 patients) compared ACEi with calcium antag-
onists, and four trials or trials arms compared ACEi with
-blockers, combined ACEi and calcium antagonists, -block-
ers, or conventional treatment (note: one trial had four arms
and so contributed data to more than one group of trials).
Most trials enrolled only patients with type 2 diabetes (12
trials, 3381 patients). Three trials (645 patients) of ACEi versus
placebo/no treatment enrolled only patients with type 1 dia-
betes, and one trial (3577 patients) of ACEi versus placebo
enrolled both patients with type 1 and type 2 diabetes (24). Ten
trials enrolled mixed populations of normo- and micro-/macro-
albuminuric patients. Fourteen trials enrolled hypertensive in-
dividuals, and BP equalization between the experimental and
control group of the trials was obtained in eight by adminis-
tration of additional antihypertensive co-interventions besides
the randomized intervention. Follow-up of the studies ranged
from 6.0 to 63.6 mo.
Co-interventions for blood glucose control were adminis-
tered in all but one trial, but the agents used were often not
specified. In general, tight control of blood glucose was ad-
dressed with end-of-treatment values of HbA1c reported in 10
trials and ranging between 5 and 9%.
Study Quality
Trial quality was variable. Allocation concealment was ade-
quate in four (25%) of 16 trials and unclear in the remaining
trials. Participants were blinded in nine (56%) of 16 trials,
investigators were blinded in seven (44%) of 16 trials, and
outcome assessors were blinded in two (13%) of 16 trials. In-
tention-to-treat analysis was used in six (38%) of 16 trials. The
percentage of patients who were lost to follow-up ranged be-
tween 0.0 and 20.0%.
Quantitative Data Synthesis
ACEi versus Placebo/No Treatment. Compared with pla-
cebo/no treatment, ACEi significantly reduced the risk for
microalbuminuria (six trials, 3840 patients; RR 0.60; 95% CI 0.43
to 0.84). A test of interaction did not demonstrate any difference
in the effect of ACEi versus placebo in hypertensive and non-
J Am Soc Nephrol 16: 30813091, 2005
hypertensive patients (21 0.854, P 0.36), type 1 and type 2
diabetes (21 0.3408, P 0.56), and normal and abnormal
renal function (21 1.4158, P 0.23), but given the relatively
sparse data, dominated by three trials, important quantitative
interactions have not been excluded (Figure 2).
For other outcomes, trial data were sparse, with the Micro-
HOPE trial dominating all analyses. There was no significant
difference in the risk for doubling of creatinine with ACEi
compared with placebo (three trials, 2558 patients; RR, 0.81;
95% CI, 0.24 to 2.71; Figure 3). This analysis presented signifi-
cant heterogeneity (heterogeneity 2 2.84, P 0.09, I2
64.8%), which may be explained by competing risks between
the different trial outcomes (Table 1). ESRD (one trial, n 2683;
RR, 2.35, 95% CI, 0.46 to 12.10) and all-cause mortality (three
trials, 2683 patients; RR, 0.80; 95% CI, 0.63 to 1.02) were not
significantly different with ACEi compared with placebo (Fig-
ure 4).
The risk for cough was significantly increased with ACEi
compared with placebo/no treatment (four trials, 3725 patients;
RR, 1.79; 95% CI, 1.19 to 2.69), whereas there was no significant
difference in the risk for headache (one trial, 2438 patients; RR,
1.25; 95% CI, 0.44 to 3.61) or hyperkalemia (two trials, 2594
patients; RR, 2.95; 95% CI, 0.31 to 28.18). There were no data on
other cardiovascular end-points.
ACEi versus Calcium Antagonists. Compared with cal-
cium antagonists, ACEi reduced the risk for micro- or mac-
roalbuminuria (four trials, 1210 patients; RR, 0.58; 95% CI, 0.40
to 0.84; Figure 5). There was no significant difference in the risk
for all-cause mortality with ACEi compared with calcium an-
tagonists (six trials, 1286 patients; RR, 0.84; 95% CI, 0.26 to 2.73)
and no data on other cardiovascular end points.
ACEi versus Other Agents. There was no statistically sig-
nificant difference in risk for nephropathy with ACEi compared
with -blockers (one trial, 299 patients; RR, 1.01; 95% CI, 0.74 to
1.37) and with combination ACEi and calcium antagonist ther-
apy compared with ACEi alone (one trial, 901 patients; RR, 1.03;
95% CI, 0.59 to 1.80).
Other Potentially Relevant Trials
Eight large trials that were performed in patients with mixed-
causation hypertension met the criteria for analysis in this review
(36 43). These trials included varying proportions of patients
with diabetes (10 to 35%). Patients with renal impairment were
systematically excluded from the trials, and baseline data on ne-
phropathy were not available, so we were not able to separate out
the data of patients with diabetes and normoalbuminuria and
could not include these data in our main analyses. The character-
istics of these trials interventions, a quantitative description of
treatment effects in the overall trial population, and a comparison
of effect estimates in the patients with and without diabetes with
a formal test of interaction are reported in Table 3. In general, all
trials reported that patients with diabetes had a two to three times
higher rate of cardiovascular events compared with the trial pop-
ulation as a whole, but the relative effects of the antihypertensive
agents used in the trial did not differ significantly between pa-
tients with diabetes and the entire trial population for the out-
comes of death and a range of composite cardiovascular end
J Am Soc Nephrol 16: 30813091, 2005 Antihypertensive Agents for Prevention of Diabetic Nephropathy 3085

Table 2. Characteristics of populations and interventions in the studies of antihypertensive agents to prevent
diabetic nephropathy included in this systematic review
Level of Type of
Albuminuria Diabetes
Baseline Renal Baseline End-of-
BP Target Experimental Antihypertensive Follow-Up
Study Function Hyper- Control Treatment N
Micro/ Equalization Intervention Co-Interventionsb (mo)
Normo (Mean SD) tension HbA1c (%)
Macro 1 2
(N)
(N/N)

ACEi versus placebo/no

treatment

ABCD 2002c (21) NA NA X NA X X Enalapril 5 to 40 mg/d Placebo X NA 246 63.6

EUCLID 1997 (22) 227 (22) 34/269 X NA Lisinopril 10 to 20 Placebo NA 530 24

mg/d

Kvetny 2001 (23) 89 X NA X Perindopril 2 mg Placebo X NA 89 36

2/d

HOPE 2000 (24) 2438 1139/NA X X Creatinine 1.05 X Ramipril 10 mg/d Placebo X 2.2 versus 3577 54
0.2 mg/dl 2.0 changed

Ravid 1998 (25) 156 X Creatinine 1.3 X X Enalapril 5 to 10 mg/d Placebo X 8.7 versus 8.5 156 72

0.1 mg/dl

Tuominen 1998 (26) 26 X Creatinine 1.0 Lisinopril 15 to 20 Placebo NA 26 24

0.1 mg/d

ACEi versus calcium

channel blocker

Baba 2001 (27) NA NA X Creatinine 0.7 X X Enalapril 5 to 20 Nifedipine 20 to X No difference 464 24

0.3 mg/dl mg/d 60 mg/d

Chan 2000 (28) 44 36/NA X Creatinine clearance 62.0 X X Enalapril 10 to 40 Nifedipine SF 40 to 80 X 7.6 versus 7.1 102 66

23.0 ml/min mg/d mg/d

Crepaldi 1995 (29) 55 24/NA X Creatinine clearance X Lisinopril 10 to 20 Nifedipine 20 to 0.4 versus 82 6
120 10 ml/min mg/d 60 mg/d 0.2 changed
per 1.73 m2

FACET 1998 (30) 42 X Creatinine 1.0 X Fosinopril 20 mg/d Amlodipine 10 mg/d X 6.8 versus 7.0 103 42

0.1 ml/min

Ruggenenti 2004e (20) 1204 X Creatinine 0.9 X X Trandolapril 2 mg/d Verapamil SR 240 X NA 1204 36

0.2 mg/dl mg/d

Scognamiglio 1997 (31) 73 X NA X X Captopril 50 to 100 Nitrendipine 20 to X 6.6 versus 6.8 73 6

mg/d 40 mg/d

Velussi 1996 (32) 26 18/0 X Creatinine 1.0 X X Cilazapril 2.5 mg/d Amlodipine 5 mg/d X 8.0 versus 8.0 44 24

0.1 mg/dl

ACEi versus other

UKPDS 1998 (33) NA NA X NA X X Captopril 25 to 50 mg Atenolol 500 to X 8.3 versus 8.4 758 48

2/d 100 mg/d

Joglekar 1998 (34) NA NA X NA X Enalapril 5 to Prazosin GITS NA 89 6

10 mg/d 2.55 mg/d

Lin 1995 (35) NA NA X Creatinine 1.2 X X Captopril 25 to Conventionalf X 7.0 versus 7.6 60 12
0.4 mg/dl 150 mg/d

a
NA, not available; X, presence of the factor.
b
Co-interventions were calcium antagonists, -blockers, -blockers, or diuretics.
c
This trial included not only a placebo/no treatment control arm but also an additional treatment arm (non-ACEi, non
angiotensin receptor antagonist).
d
From baseline value.
e
This trial included not only a calcium antagonist control arm but also two additional arms, one of placebo and one of the
combination of an ACEi and a CA.
f
Unclear; the term conventional was not defined.

points. The only exception was the HOT study, in which patients greater RR reduction in cardiovascular mortality and major car-
were randomized to three diastolic BP targets (90, 85, and 80 diovascular events with lower target BP than patients without
mmHg) and which showed that patients with diabetes had a diabetes (38). There was no evidence of significant differences in
3086 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 30813091, 2005

Figure 2. Effect of angiotensin converting enzyme inhibitors (ACEi) versus placebo/no treatment on development of micro- or
macroalbuminuria in patients with diabetes and normoalbuminuria (note: data on normoalbuminuric patients only were not
provided from the authors of the EUCLID trial).

Figure 3. Effect of ACEi versus placebo/no treatment on doubling of creatinine in patients with diabetes and normoalbuminuria.

Figure 4. Effect of ACEi versus placebo/no treatment on all-cause mortality in patients with diabetes and normoalbuminuria.

all-cause mortality or cardiovascular end points among the classes
of antihypertensive agents trialled (Table 3). The only exception
was the CAPPP trial, which showed a significant reduction in the
risk for all-cause mortality with captopril compared with conven-
tional treatment only in the subgroup of patients with diabetes.
Discussion
In currently available randomized trials, only one class of
antihypertensive agentsACEi has been found to be effec-
tive for the primary prevention of nephropathy in patients with
diabetes. With ACEi, an RR reduction of 42% has been demon-
strated (95% CI, 16 to 60%). Given a 10% risk for the develop-
ment of microalbuminuria in hypertensive patients with diabe-
tes over 3 to 4 yr, approximately 25 people would need to be
treated to prevent one new case of microalbuminuria (2). Com-
paring the effects of ACEi against other classes of antihyper-
tensive agents is more difficult because of the relative sparse-
ness of data, except for calcium antagonists. Compared with
these agents, ACEi reduce the risk for nephropathy and by a
similar degree than for the placebo-comparison trials (40%).
J Am Soc Nephrol 16: 30813091, 2005 Antihypertensive Agents for Prevention of Diabetic Nephropathy
Figure 5. Effect of ACEi versus calcium antagonists on development of micro- or macroalbuminuria in patients with diabetes and
normoalbuminuria.
What our review also shows is considerable areas of residual
uncertainty regarding the effects of antihypertensive agents in
normoalbuminuric patients with diabetes. The existing uncer-
tainties cluster around four main areas: the comparative effects
of different antihypertensive agents; the presence of hyperten-
sion, type of diabetes, and renal function as potential effect
modifiers of ACEi therapy; the other renal and nonrenal effects
of ACEi in this population; and the identification and reporting
of renal disease as a relevant outcome for microvascular dis-
ease.
First, there are few available trial data comparing -blockers
or other antihypertensive agents for patients with diabetes and
no renal disease. There are no trial data on the relative effects of
ARB and ACEi, even though these agents are recommended
interchangeably by most guidelines groups once nephropathy
has occurred (Table 1).
Second, patients with diabetes, even without microalbumin-
uria, are a heterogenous population, most have hypertension
but some do not, most have type 2 diabetes but some have type
1 diabetes, the level of renal function is variable, and patients
have different diabetes-associated comorbidities. Is the benefi-
cial effect of ACEi on preventing nephropathy constant across
these groups, or is there a qualitative (different effect but only
in terms of the size of the effect, not direction) or quantitative
(different effect in terms of direction) interaction? Here, the
variability in design of the ACEi versus placebo trials is mod-
erately informative. In our analysis, the point estimates for all
trials favored ACEi, irrespective of design, and we could not
detect statistically significant interactions between ACEi and
differences in baseline characteristics across trials. However,
given the small number of trials, our power to detect significant
differences is low, and because comparisons are made across
trials and not within trials, these comparisons are potentially
confounded. Given such uncertainty, we may conclude at best
that there is no evidence that the effect of ACEi varies with
baseline BP, renal function, or type of diabetes and that any
variability is likely to be quantitative and not qualitative. This
uncertainty could be reduced by an individual patient data
meta-analysis.
Third, these trials are relatively uninformative about out-
comes other than the development of microalbuminuria and
macroalbuminuria, such as side effects, effects on cardiovascu-
lar end points, and mortality. Clinicians and patients would
3087
want to know the effect of ACEi on all patient-centered out-
comes, not just surrogate outcomes, such as urinary protein
excretion. Only three (of six) trials reported these outcomes,
and no statistically significant reduction in the risk for ESRD,
doubling of creatinine, or all-cause mortality was demon-
strated. There was considerable imprecision around these esti-
mates as a result of low event rates and low sample sizes,
except for the micro-HOPE trial, which dominates all analyses.
The lack of beneficial effect on ESRD and doubling of serum
creatinine shown in micro-HOPE could be explainable by the
competing risks of these renal outcomes and overall survival
(which was improved in HOPE with ramipril therapy). It is
plausible that fewer patients developed ESRD in the ramipril
arm because fewer patients survived long enough. A reduction
in these outcomes is plausible given that microalbuminuria is
an independent risk factor for kidney failure and cardiovascu-
lar deaths, ACEi have been shown to reduce microalbuminuria
more than other antihypertensive agents, and a reduction in
these outcomes with ACEi treatment has also been demon-
strated in patients with diabetes and overt nephropathy (10).
However, summarizing the nonalbuminuria outcomes of these
trials, we conclude that no statistically significant benefit of
ACEi on ESRD, doubling of serum creatinine, and all-cause
mortality has been demonstrated.
Fourth, as Table 3 demonstrates, many large-scale trials have
been done in hypertensive patients, with patients with diabetes
making up a significant proportion. Unfortunately for clini-
cians and patients who want to know the comparative effects of
these agents with kidney disease as an outcome, these trials are
largely uninformative, because this outcome (onset of micro- or
macroalbuminuria) was not reported. In our review, we sought
to extract data for patients with and without diabetes to deter-
mine whether the diabetic state is an effect modifier for all-
cause mortality and cardiovascular and renal outcomes, but
this was possible only for the first two outcomes. No evidence
of effect modification (significant variation in the estimates of
treatment effect in patients with diabetes compared with pa-
tients without diabetes) was demonstrated for drug classes, but
tighter control was found to be more effective for patients with
diabetes than for patients without diabetes in the HOT trial
(38). In short, from the large-scale antihypertensive trials, it is
unclear whether any class of antihypertensive agent is more
effective in preventing nephropathy control than any other, but
 3088

Table 3. Effect of antihypertensive agents in randomized, controlled trials that enrolled hypertensive patients (n 4000, planned minimum of 1000 patient-
years) and included patients who had diabetes with or without nephropathy (estimates of treatment effect where calculated from raw data of the trials)
All-Cause Mortality (RR and 95% CI) Major Cardiovascular Events (RR and 95% CI)
No. of % with Follow-Up
Study Intervention
Patients Diabetes a a (mo)
All Patients Diabetes No Diabetes P All Patients Diabetes No Diabetes P

m m
ALLHAT 2002 (36) Lisinopril versus 24309 35.9 1.00 (0.94 to 1.08) 1.02 (0.91 to 1.13) NA 1.05 (0.98 to 1.11)b 1.03 (0.93 to 1.14)b NA 58.8
chlorthalidone
m m
Amlodipine versus 24303 36.4 0.96 (0.89 to 1.02) 0.96 (0.89 to 1.07) NA 1.10 (0.90 to 1.33)b 0.98 (0.69 to 1.41)b NA
chlorthalidone
m m
CAPPP 1999 (37) Captopril versus 10985 6.5 0.80 (0.59 to 1.07) 0.54 (0.31 to 0.96)d NA 1.13 (0.98 to 1.30)e 0.59 (0.38 to 0.91)e NA 73.2
conventionalc
HOT 1998 (38) DBP 90 versus 85 12528 8.0 0.97 (0.79 to 1.19) 1.03 (0.62 to 1.71) 0.96 (0.78 to 1.19) 0.78 0.99 (0.83 to 1.19)g 1.32 (0.84 to 2.06)g 0.94 (0.77 to 1.14)g 0.15 45.6
DBP 85 versus 80 12526 8.0 0.93 (0.77 to 1.14) 1.69 (0.94 to 1.05) 0.82 (0.67 to 1.01) 0.02 1.08 (0.89 to 1.29)g 1.54 (0.91 to 2.60)g 1.04 (0.86 to 1.27)g 0.17
DBP 90 versus 80 12526 8.0 0.91 (0.74 to 1.10) 1.76 (0.98 to 3.15) 0.82 (0.68 to 1.02) 0.02 1.07 (0.89 to 1.28)3 2.04 (1.24 to 3.34)g 0.97 (0.80 to 1.19)g 0.01
n n
INSIGHT 2000 (39) Nifedipine versus 6321 20.6 1.01 (0.81 to 1.26) NA NA 0.97 (0.85 to 1.10)h NA NA 48
co-amilozide

NORDIL 2000 (40) Diltiazem versus 10881 6.7 1.41 (1.20 to 1.68) 1.15 (0.69 to 1.92) 1.01 (0.84 to 1.23) 0.64 1.01 (0.89 to 1.16)i 1.15 (0.78 to 1.72)i 1.03 (0.90 to 1.12)i 0.60 60
Journal of the American Society of Nephrology

conventionalc
SHEP 1996 (41) Chlorthalidone/ 4763 12.3 0.88 (0.74 to 1.01) 0.86 (0.58 to 1.27) 0.89 (0.73 to 1.01) 0.88 0.70 (0.61 to 0.80)j 0.73 (0.54 to 0.98)j 0.70 (0.56 to 0.81)j 0.79 60
atenolo/reserpine
versus placebo
m m
STOP-Hypertension2 Enalapril versus 4418 11.0 1.02 (0.89 to 1.18) NA NA 0.90 (0.72 to 1.13)k NA NA 72
1999 (42) conventionalc
m m
Calcium antagonist 4409 10.9 0.99 (0.87 to 1.12) NA NA 1.18 (0.95 to 1.47)k NA NA
versus conventionalc
Syst-EUR 1999 (43) Nitrendipine, 4695 10.5 0.86 (0.68 to 1.09) 0.59 (0.32 to 1.06) 0.92 (0.71 to 1.12) 0.79 0.86 (0.68 to 1.01)l 0.40 (0.21 to 0.75)l 0.77 (0.61 to 0.96)l 0.06 24
possible enalapril,
hydrochlorothiazide
or both versus
placebo

a
X2 test with 1 degree of freedom for interaction between cohort of patients with diabetes versus cohort of patients without diabetes.
b
Fatal coronary heart disease and nonfatal myocardial infarction.
c
Diuretic, -blocker, or both.
d
Data adjusted for age, gender, systolic BP, and previous treatment.
e
Fatal and nonfatal myocardial infarction, stroke, and other cardiovascular deaths.
f
Diastolic BP in mmHg.
g
Major cardiovascular events, including all fatal and nonfatal myocardial infarctions, all fatal and nonfatal strokes, and all other cardiovascular deaths.
h
Myocardial infarction, stroke, heart failure and cardiovascular death, noncardiovascular death, renal failure, angina, and transient ischemic attach.
i
Fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, and other cardiovascular death.
j
Cardiovascular disease including nonfatal or fatal myocardial infarction, sudden cardiac death, rapid cardiac death, coronary artery bypass graft, angioplasty,
nonfatal or fatal stroke, transient ischemic attach, aneurysm, and endarterectomy.
k
Fatal and nonfatal myocardial infarction.
l
Fatal and nonfatal heart failure, fatal and nonfatal myocardial infarction, and sudden death
m
Raw data not available to evaluate interaction; however, trialists reported no interaction.
n
Patients with diabetes required more treatment and were the group in which nifedipine and co-amilozide were most effective for all outcomes.
J Am Soc Nephrol 16: 30813091, 2005
J Am Soc Nephrol 16: 30813091, 2005 Antihypertensive Agents for Prevention of Diabetic Nephropathy
any additional downstream effect on all-cause mortality and
cardiovascular events is very unlikely.
The strength of this study is that it represents the first com-
prehensive systematic review in this area, on the basis of pre-
vious publication of a detailed protocol (44); rigid inclusion
criteria for randomized, controlled trials only; and a compre-
hensive MEDLINE, EMBASE, and Cochrane Controlled Trial
Registry search. Data extraction, data analysis, and method
quality assessment were performed by two independent inves-
tigators, and consistency was checked with an additional in-
vestigator. This method contrasts with strategies adopted in
previous nonsystematic reviews, reports, and guidelines (11
16,45,46). We presented an explicit comparison of trial data
with current guidelines and of data from trials that were con-
ducted in patients with diabetes with those of large-scale trials
that were conducted in hypertensive individuals and that in-
cluded a proportion of patients with diabetes to check for
consistency of findings. We also obtained previously unpub-
lished data from trialists.
Our study shares the limitations of most systematic reviews,
being susceptible to publication bias and outcomes reporting
bias. These biases tend to favor the intervention being consid-
ered. We have attempted to reduce these biases by an extensive
search for relevant papers and contacting authors for additional
information. The reduction in microalbuminuria with ACEi is
only a surrogate for the clinically important outcome of ESRD.
We were unable to demonstrate any concomitant reduction in
ESRD, but given the low-risk population for this outcome in
these trials, this is not surprising. Evidence that microalbumin-
uria is a good surrogate for ESRD can be found in other trials,
in patients with microalbuminuria, in whom ACEi have been
shown to prevent macroalbuminuria, reverse microalbumin-
uria (to normoalbuminuria), and prevent ESRD (or doubling of
serum creatinine) (10).
How do the results of our study compare with published
guidelines on the treatment of patients with diabetes? Most
guidelines recommend any agent in patients with diabetes and
hypertension and without nephropathy, and only ACEi or ARB
once nephropathy occurs. The use of any class of antihyperten-
sive agents in patients with diabetes targeting tight BP control
is justified by significant reduction in mortality and cardiovas-
cular outcomes from the primarily nondiabetic trials of hyper-
tension, but only ACEi have been proved to reduce the onset of
microalbuminuria in this population compared with placebo,
and the results of ACEi look more favorable than the only other
class of drug evaluated, the calcium channel blockers. Our data
therefore suggest that ACEi have an incremental effect on renal
outcomes in patients with diabetes, compared with other
agents, and so should be the treatment of choice unless other
antihypertensive agents are evaluated against ACEi in the set-
ting of a randomized, controlled trial. Future trials of antihy-
pertensive agents in patients with diabetes and no renal disease
should report microalbuminuria and other renal outcomes as
well as the usually reported outcomes: all-cause mortality and
cardiovascular end points.
3089
Acknowledgments
Funding for this study was provided by an NHMRC Centre for
Clinical Research Excellence grant, the University of Sydney, a Univer-
sity of Sydney Program Grant PhD Scholarship (2004 to 2005), the
Italian Society of Nephrology Young Investigator Scholarship granted
to G.F.M.S. in 2003, and the Australia-Europe Endeavour Scholarship
granted to G.F.M.S. in 2005.
We acknowledge the contribution of Dr. Salvatore di Paolo (Univer-
sity of Bari, Bari, Italy) for useful suggestions on design at the time of
study inception and critical discussion of the draft manuscript. We
acknowledge the editorial and administrative support of Narelle Willis,
Sharn Gokalp, and Sandra Puckeridge. Ruth Mitchell, Linda Heslop,
and Gail Higgins, trial search coordinators of the Cochrane Renal
Group, provided search strategies for this review. We are particularly
indebted to Janice Pogue and the HOPE trialists, Dr. Ravid, Dr. Kvetny,
Dr. Tuominen, Dr. Baba, Dr. Velussi, and Dr. Lin, who provided data of
normoalbuminuric patients with diabetes in their study or information
about study design and conduct upon request.
References
1. Anderson RN: Deaths: Leading causes for 1999. Natl Vital
Stat Rep 49: 1 87, 2001
2. American Diabetes Association: Hypertension manage-
ment in adults with diabetes. Diabetes Care 27: S65S67,
2004
3. Canadian Organ Replacement Registry (CORR): 2001 An-
nual Report, Ottawa, Canadian Institute for Health Infor-
mation, 2001
4. Ritz E, Orth SR: Nephropathy in patients with type 2
diabetes mellitus. N Engl J Med 341: 11271133, 1999
5. Gerstein HC, Mann JFE, Yi Q, Zinman B, Dinneen SF,
Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C,
Nawaz S, Yusuf S; HOPE Study Investigators: Albumin-
uria and risk of CV events, death, and heart failure in
diabetic and non diabetic individuals. JAMA 286: 421 426,
2001
6. Dinneen SF, Gerstein HC: The association of microalbu-
minuria and mortality in non-insulin-dependent diabetes
mellitus. A systematic overview of the literature. Arch In-
tern Med 157: 14131418, 1997
7. Borch-Johnsen K, Andersen PK, Deckert T: The effect of
proteinuria on relative mortality in type 1 (insulin-depen-
dent) diabetes mellitus. Diabetologia 28: 590 596, 1985
8. Mattock MB, Morrish NJ, Viberti G, Keen H, Fitzgerald AP,
Jackson G: Prospective study of microalbuminuria as pre-
dictor of mortality in NIDDM. Diabetes 41: 736 741, 1992
9. Gall MA, Borch-Johnsen K, Hougaard P, Nielsen FS, Par-
ving HH: Albuminuria and poor glycemic control predict
mortality in NIDDM. Diabetes 44: 13031309, 1995
10. Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC: Effect
of angiotensin converting enzyme inhibitors and angioten-
sin II receptor antagonists on mortality and renal outcomes
in diabetic nephropathy: Systematic review. BMJ 329: 828
831, 2004
11. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green
LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT
Jr, Roccella EJ; National Heart, Lung, and Blood Institute
Joint National Committee on Prevention, Detection, Eval-
uation, and Treatment of High Blood Pressure; National
High Blood Pressure Education Program Coordinating
Committee: The Seventh Report of the Joint National Com-
3090 Journal of the American Society of Nephrology
mittee on Prevention, Detection, Evaluation, and Treat-
ment of High Blood Pressure: The JNC 7 report. JAMA 289:
2560 2572, 2003
12. K-DOQI Clinical Practice Guidelines on Blood Pressure
Management and Use of Antihypertensive Agents in
Chronic Kidney Disease. Executive Summary, October
2003. Available: http://www.kidney.org. Accessed Au-
gust 3, 2004
13. Canadian Diabetes Association Clinical Practice Guide-
lines Expert Committee: Nephropathy. Available: http://
mdm.ca/cpgsnew/cpgs/search/english/results.asp. Ac-
cessed August 3, 2004
14. 2003 European Society of Hypertension-European Society
of Cardiology guidelines for the management of arterial
hypertension. J Hypertens 21: 10111053, 2003
15. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT,
Potter JF, Sever PS, Thom SM; BHS guidelines working
party, for the British Hypertension Society: British Hyper-
tension Society guidelines for hypertension management
2004 (BHS-IV): Summary. BMJ 328: 634 640, 2004
16. Caring for Australians with Renal Impairment Guidelines.
Available: http://www.kidney.org.au/cari/drafts/new/
prevention.html. Accessed August 3, 2004
17. Dickersin K, Scherer R, Lefebvre C: Identifying relevant
studies for systematic reviews. BMJ 309: 1286 1291, 1994
18. DerSimonian R, Laird N: Meta-analysis in clinical trials.
Control Clin Trials 7: 177188, 1986
19. Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measur-
ing inconsistency in meta-analyses. BMJ 327: 557560, 2003
20. Ruggenenti P, Fassi A, Parvanova Ilieva A, Bruno S, Iliev
IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva
M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan
R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabe-
tes Complications Trial (BENEDICT) Investigators: The
BENEDICT Investigators. Preventing microalbuminuria in
type 2 diabetes. N Engl J Med 351: 19411951, 2004
21. Schrier RW, Estacio RO, Esler A, Mehler P: Effects of
aggressive blood pressure control in normotensive type 2
diabetic patients on albuminuria, retinopathy and strokes.
Kidney Int 61: 1086 1097, 2002
22. The EUCLID Study Group: Randomised placebo-con-
trolled trial of lisinopril in normotensive patients with
insulin-dependent diabetes and normoalbuminuria or mi-
croalbuminuria. Lancet 349: 17871792, 1997
23. Kvetny J, Gregersen G, Pedersen RS: Randomized placebo-
controlled trial of perindopril in normotensive, nor-
moalbuminuric patients with type 1 diabetes mellitus. QJM
94: 89 94, 2001
24. Heart Outcomes Prevention Evaluation (HOPE) Study In-
vestigators: Effects of ramipril on cardiovascular and mi-
crovascular outcomes in people with diabetes mellitus:
Results of the HOPE study and MICRO-HOPE substudy.
Lancet 355: 253259, 2000
25. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rach-
mani R: Use of enalapril to attenuate decline in renal
function in normotensive, normoalbuminuric patients with
type 2 diabetes mellitus: A randomized controlled trial.
Ann Intern Med 128: 982988, 1998
26. Tuominen JA, Ebeling P, Koivisto VA: Long term lisinopril
therapy reduces exercise-induced albuminuria in nor-
moalbuminuric normotensive IDDM patients. Diabetes
Care 21: 13451348, 1998
J Am Soc Nephrol 16: 30813091, 2005
27. Baba S; the J-MIND Study Group: Nifedipine and enalapril
equally reduce the progression of nephropathy in hyper-
tensive type 2 diabetics. Diabetes Res Clin Pract 54: 191201,
2001
28. Chan JCN, Ko GTC, Leung DHY, Cheung RC, Cheung MY,
So WY, Swaminathan R, Nicholls MG, Critchley JA, Cock-
ram CS: Long-term effects of angiotensin-converting en-
zyme inhibition and metabolic control in hypertensive
type 2 diabetic patients. Kidney Int 57: 590 600, 2000
29. Crepaldi G, CArraro A, Brocco E, Adezati L, Andreani D,
Bompiani G, Brunetti P, Fedele D, Giorgino R, Giustina G,
et al.: Hypertension and non-insulin-dependent diabetes.
Acta Diabetol 32: 203208, 1995
30. Tatti P, Pahor M, Byington R, Di Mauro P, Guarisco R,
Strollo G, Strollo F: Outcome results of the fosinopril ver-
sus amlodipine cardiovascular events randomized trial
(FACET) in patients with hypertension and NIDDM. Dia-
betes Care 21: 597 603, 1998
31. Scognamiglio R, Nosadini R, Marin M, Nisti S, Fasoli G,
Palisi M, Frigato F, Virgili F, Carraro A, Crepaldi G: Eval-
uation of the efficacy and tolerability of nitrendipine in
reducing both pressure and left ventricular mass in hyper-
tensive type 2 diabetic patients. Diabetes Care 20: 1290
1292, 1997
32. Velussi M, Brocco E, Frigato F, Zolli M, Muollo B, Maioli
M, Carraro A, Tonolo G, Fresu P, Cernigoi AM, Fioretto P,
Nosadini R: Effects of cilazapril and amlodipine on kidney
function in hypertensive NIDDM patients. Diabetes 45:
216 222, 1996
33. UK Prospective Diabetes Study Group: Efficacy of atenolol
and captopril in reducing risk of macrovascular and mi-
crovascular complications in type 2 diabetes: UKPDS 39.
BMJ 317: 713720, 1998
34. Joglekar SJ, Nanivadekar AS: The Bombay Hypertension
Study Group. A randomized, controlled, multicenter study
to compare prazosin GITS with enalapril in hypertensive
patients with diabetes mellitus. J Assoc Physicians India
1[Suppl]: 52 62, 1998
35. Lin M, Yang YF, Chiang HT, Lee D, Wang SP, Chang MS,
Cheitlin MD: Beneficial effects of angiotensin-converting
enzyme inhibitors on cardiovascular and renal functions in
patients with hypertension and diabetes. Acta Cardiol Sing
11: 30 38, 1995
36. ALLHAT Officers and Coordinators for the ALLHAT Col-
laborative Research Group: Major outcomes in high-risk
hypertensive patients randomized to angiotensin-convert-
ing enzyme inhibitor or calcium channel blocker vs di-
uretic. The antihypertensive and lipid-lowering treatment
to prevent heart attack trial (ALLHAT). JAMA 288: 2981
2997, 2002
37. Hansson L, Lindholm L, Niskanen L, Lanke J, Hedner T,
Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin
C, Karlberg BE, Wester PO, Bjorck JE: Effect of angiotensin-
converting-enzyme inhibition compared with conven-
tional therapy on cardiovascular morbidity and mortality
in hypertension: The Captopril Prevention Project (CAPPP)
randomised trial. Lancet 353: 611 616, 1999
38. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt
D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S:
Effects of intensive blood-pressure lowering and low-dose
aspirin in patients with hypertension: Principal results of
J Am Soc Nephrol 16: 30813091, 2005 Antihypertensive Agents for Prevention of Diabetic Nephropathy 3091

the Hypertension Optimal Treatment (HOT) randomised
trial. Lancet 351: 17551762, 1998
39. Brown M, Palmer C, Castaigne A, de Leeuw PW, Mancia G,
Rosenthal T, Ruilope LM: Morbidity and mortality in patients
randomised to double-blind treatment with a long-acting
calcium-channel blocker or diuretic in the International Ni-
fedipine GITS study: Intervention as a Goal in Hypertension
Treatment (INSIGHT). Lancet 356: 366 372, 2000
40. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE,
Lindholm LH, Syvertsen JO, Lanke J, de Faire U, Dahlof B,
Karlberg BE: Randomised trial of effects of calcium antag-
onists compared with diuretics and beta-blockers on cardio-
vascular morbidity and mortality in hypertension: The Nor-
dic Diltiazem (NORDIL) study. Lancet 356: 359 365, 2000
41. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB,
Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guth-
rie G, Oberman A, Rutan GH, Stamler J: Effect of diuretic-
based antihypertensive treatment on cardiovascular dis-
ease risk in older diabetic patients with isolated systolic
hypertension. JAMA 276: 1886 1892, 1996
42. Hansson L, Lindholm L, Ekbom T, Dahlof B, Lanke J,
Schersten B, Wester PO, Hedner T, de Faire U: Randomised
trial of old and new antihypertensive drugs in elderly
patients: Cardiovascular mortality and morbidity the
Swedish Trial in Old Patients with Hypertension-2 study.
Lancet 354: 17511756, 1999
43. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, An-
tikainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A,
Palatini P, Sarti C, Fagard R: Effects of calcium-channel
blockade in older patients with diabetes and systolic hy-
pertension. N Engl J Med 340: 677 684, 1999
44. Strippoli GFM, Craig M, Schena FP, Craig JC: Antihyper-
tensive agents for preventing diabetic kidney disease (Pro-
tocol for a Cochrane Review). In: The Cochrane Library,
Issue 3, Chichester, John Wiley & Sons, Ltd, 2004
45. Arauz-Pacheco C, Parrot MA, Raskin P: The treatment of
hypertension in adult patients with diabetes. Diabetes Care
25: 134 147, 2002
46. Messerli HF: Implications of discontinuation of doxazosin
arm of ALLHAT. Lancet 355: 863 864, 2000

Access to UpToDate on-line is available for additional clinical information

at http://www.jasn.org/

View publication stats