Clinical Care/Education/Nutrition

O R I G I N A L A R T I C L E

Therapeutic Benefits of ACE Inhibitors

and Other Antihypertensive Drugs in
Patients With Type 2 Diabetes
MARCO PAHOR, MD WILLIAM B. APPLEGATE, MD, MPH Hypertension Optimal Treatment trial and
BRUCE M. PSATY, MD, PHD JEFF D. WILLIAMSON, MD, MHS the U.K. Prospective Diabetes Study
MICHAEL H. ALDERMAN, MD CURT D. FURBERG, MD, PHD (UKPDS) suggest that, in patients with dia-
betes, greater blood pressure reduction
results in greater clinical benefits (3,4).
Although these studies document that treat-
ment of high blood pressure is beneficial in
OBJECTIVE — To assess whether ACE inhibitors are superior to alternative agents for the hypertensive patients with type 2 diabetes,
prevention of cardiovascular events in patients with hypertension and type 2 diabetes.
none of these trials provides information on
RESEARCH DESIGN AND METHODS — This study is a review and meta-analysis of the relative therapeutic benefit of individual
randomized controlled trials that included patients with type 2 diabetes and hypertension who antihypertensive agents.
were randomized to an ACE inhibitor or an alternative drug, were followed for 2 years, and Recent comparative trials and observa-
had adjudicated cardiovascular events. tional studies in diabetes have suggested
that, for the prevention of cardiovascular
RESULTS — A total of 4 trials were eligible. The Appropriate Blood Pressure Control in Dia- events, ACE inhibitors may be superior to
betes (ABCD) trial (n = 470) compared enalapril with nisoldipine, the Captopril Prevention alternative antihypertensive agents (5,6).
Project (CAPPP) (n = 572) compared captopril with diuretics or -blockers, the Fosinopril Ver- That the greater benefit of ACE inhibitors
sus Amlodipine Cardiovascular Events Trial (FACET) (n = 380) compared fosinopril with was not explained by better blood pressure
amlodipine, and the U.K. Prospective Diabetes Study (UKPDS) (n = 758) compared captopril
with atenolol. The cumulative results of the first 3 trials showed a significant benefit of ACE
control indicates that other mechanisms
inhibitors compared with alternative treatments on the outcomes of acute myocardial infarc- linked to ACE inhibition may have played
tion (63% reduction, P  0.001), cardiovascular events (51% reduction, P  0.001), and all- an additional role in the prevention of major
cause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS. clinical events. The purpose of the present
The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in review and meta-analysis is to summarize
any of the trials. None of the findings were explained by differences in blood pressure control. the current evidence from randomized clin-
ical trials with clinical outcomes that
CONCLUSIONS — Compared with the alternative agents tested, ACE inhibitors may pro- directly compared ACE inhibitors to alter-
vide a special advantage in addition to blood pressure control. The question of whether atenolol native antihypertensive agents in patients
is equivalent to captopril remains open. Conclusive evidence on the comparative effects of anti- with hypertension and type 2 diabetes.
hypertensive treatments will come from large prospective randomized trials.

Diabetes Care 23:888–892, 2000 RESEARCH DESIGN AND

METHODS — To be included in the
meta-analysis, a study had to be a random-
ized controlled trial published in a peer-
he primary goal of antihypertensive gram and the Systolic Hypertension in reviewed journal that included patients

T treatment is to prevent clinical com-

plications and not simply to lower ele-
vated blood pressure. Evidence from the
Systolic Hypertension in the Elderly Pro-
Europe Trial showed that, compared with
placebo, treatment of hypertension in
patients with type 2 diabetes prevents major
clinical complications (1,2). Data from the
with type 2 diabetes and hypertension,
evaluated an ACE inhibitor versus an active
treatment, followed the participants for 2
years to allow the occurrence of a sufficient
number of clinical events, and used prede-
fined criteria to adjudicate the cardiovas-
From the Sticht Center on Aging (M.P., W.B.A., J.D.W.), Department of Internal Medicine, and the Depart- cular events. Studies were identified
ment of Public Health Sciences (C.D.F.), Wake Forest University, Winston-Salem, North Carolina; the Car- through PubMed searches using the fol-
diovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Services, lowing key words: “ACE inhibitors,” “dia-
University of Washington, Seattle, Washington; and the Department of Epidemiology and Social Medicine betes,” “hypertension,” and “clinical trial.”
(M.H.A.), Albert Einstein College of Medicine, Bronx, New York.
Address correspondence and reprint requests to Marco Pahor, MD, Sticht Center on Aging, Department
The searches were extended through Janu-
of Internal Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston- ary 2000. Letters to the editor, commen-
Salem, NC 27157. E-mail: mpahor@wfubmc.edu. taries, review articles, editorials, and
Received for publication 21 October 1999 and accepted in revised form 1 February 2000. observational studies were not included.
Abbreviations: ABCD, Appropriate Blood Pressure Control in Diabetes; CAPPP, Captopril Prevention Pro- Bibliographies of the retrieved articles were
ject; FACET, Fosinopril Versus Amlodipine Cardiovascular Events Trial; HOPE, Heart Outcomes Prevention
Evaluation; RR, relative risk; UKPDS, U.K. Prospective Diabetes Study. searched to identify other eligible studies,
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion and information from colleagues was used
factors for many substances. to identify more recently published articles.

888 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000

 Pahor and Associates

Table 1—Baseline characteristics according to treatment

Age Men BMI Macroalbuminuria Duration of Systolic blood Diastolic blood

Trial Agent n (years) (%) (kg/m2) (%) diabetes (years) pressure (mmHg) pressure (mmHg)
ABCD (7) Enalapril 235 57.7 ± 8.4 67 31.9 ± 5.9 19 8.5 ± 6.8 156 ± 17 98 ± 7
Nisoldipine 235 57.2 ± 8.2 68 31.3 ± 5.9 18 8.7 ± 6.6 155 ± 19 98 ± 7
CAPPP (8) Captopril 309 55.0 ± 7.6 63 30.9 164 ± 19 97 ± 10
Diuretic/-blockers 263 55.7 ± 7.4 60 30.3 163 ± 21 97 ± 10
FACET (9) Fosinopril 189 62.8 ± 7.0 64 30.7 ± 4.6 0 10.7 ± 9.1 170 ± 16 95 ± 10
Amlodipine 191 63.3 ± 6.1 56 30.5 ± 5.4 0 10.5 ± 8.6 171 ± 18 94 ± 8
UKPDS (10) Captopril 400 56.3 ± 8.1 51 29.8 ± 5.6 2 2.6 159 ± 20 94 ± 10
Atenolol 358 56.0 ± 8.2 57 29.7 ± 5.3 3 2.7 159 ± 19 93 ± 10
Data are means ± SEM, unless otherwise indicated.

The following elements were abstracted:
design, sample size, randomized treat-
ments, follow-up time, average age, sex
distribution, average BMI, proportion of
participants with macroalbuminuria, dura-
tion of diabetes, baseline systolic and dias-
tolic arterial pressures, and the number of
events (including acute myocardial infarc-
tion, stroke, combined cardiovascular
events, and all-cause mortality) occurring
in each treatment group.
The initial search identified 195 arti-
cles. Of those, 4 trials met all of the inclusion
criteria. Those trials were the Appropriate
Blood Pressure Control in Diabetes (ABCD)
trial (7), the diabetic group of the Captopril
Prevention Project (CAPPP) (8), the Fosino-
pril Versus Amlodipine Cardiovascular
Events Trial (FACET) (9), and the UKPDS
(Table 1) (10). The recently published
Swedish Trial in Old Patients with Hyper-
tension-2 compared the use of -blockers
or diuretics with the use of ACE inhibitors
or Ca antagonists and was not included
because outcome data in the subgroup of
patients with diabetes in that study were
not published and were not available
from the authors (B. Dalhof, personal
communication) (11).
For the combined outcome of cardio-
vascular events, we adopted the definition
used in each trial. In the ABCD trial, the
cardiovascular events included cardiovas-
cular death, fatal and nonfatal acute
myocardial infarction, congestive heart fail-
ure requiring hospitalization, fatal or non-
fatal stroke, and pulmonary infarction.
Because the number of events in patients
with diabetes was not reported in the
CAPPP, we estimated these numbers by
using the sample size, the relative risk (RR)
(95% CI), and the P value of the difference
between the 2 treatment groups. In the
CAPPP, the cardiovascular events included
cardiovascular deaths, fatal and nonfatal
acute myocardial infarction, and fatal or
nonfatal stroke. In the FACET, the cardio-
vascular events included fatal and nonfatal
acute myocardial infarction, fatal and non-
fatal stroke, and angina requiring hospital-
ization. In the UKPDS, the combined end
point of cardiovascular events was not
reported. We calculated the total number of
cardiovascular events by adding the num-
ber of fatal and nonfatal acute myocardial
infarctions and strokes, the number of con-
gestive heart failure events, and the number
of sudden deaths. Because more than 1
event may have occurred in a single patient,
this method is likely to have slightly over-
estimated the number of patients with car-
diovascular events in the UKPDS.
The overall relative risk (85% CI) of
each outcome was calculated with Peto’s
method (12). Cochran’s test for heterogene-
ity was used to assess the extent to which
the differences among the trial results were
because of random fluctuations (13).
RESULTS — In the 4 eligible trials (the
ABCD trial, the CAPPP, the FACET, and
the UKPDS), the total number of partici-
pants was 2,180 (1,133 randomized to an
ACE inhibitor and 1,047 randomized to
an alternative active agent) with a total fol-
low-up experience of 13,300 person-
years. The participants’ characteristics
according to treatment are shown in Table 1.
In the ABCD trial, the medication daily
dose was 10–60 mg for nisoldipine and
5–40 mg for enalapril. In the CAPPP, 50
mg captopril was given once or twice a
day, and 50–100 mg atenolol or metopro-
lol, 25 mg hydrochlorothiazide, or 2.5 mg
bendrofluazide was given once a day. In
the FACET, 20 mg fosinopril or 10 mg
amlodipine was given once a day. In the
UKPDS, the dose of captopril was 25–50
mg twice a day, and the dose of atenolol
was 50–100 mg once a day.
In the ABCD trial, the FACET, and the
UKPDS, systolic (Fig. 1) and diastolic
blood pressure decreased significantly with
both treatments. In the ABCD trial and the
UKPDS, no significant differences were evi-
dent in blood pressure control among the
randomized treatment groups. In the
FACET, the patients randomized to
amlodipine achieved a significantly lower
systolic blood pressure level than patients
randomized to fosinopril. Data on blood
pressure control in the diabetic patients of
the CAPPP have not been reported.
The number of events by treatment
group in each trial is shown in Table 2, and
the relative risks (95% CIs) of outcomes for
ACE inhibitors versus other agents are
depicted in Fig. 2. In the ACE inhibitor
group, the risk of acute myocardial infarc-
tion was significantly decreased in the
ABCD trial and the CAPPP, was nonsignif-
icantly lower in the FACET, and was non-
significantly higher in the UKPDS
compared with the alternative treatment.
For the outcome of stroke, no significant
differences were evident among treatments
in any of the trials. In the ACE inhibitor
group, the risk of combined cardiovascular
events was significantly decreased in the
ABCD trial, the CAPPP, and the FACET,
and was nonsignificantly increased in the
UKPDS compared with the alternative
treatment; the risk of all-cause mortality
was significantly decreased in the CAPPP,
was nonsignificantly lower in the ABCD
trial and the FACET, and was nonsignifi-
cantly higher in the UKPDS.
In initial analyses, the data of the 4 tri-
als were combined. For ACE inhibitors ver-
sus other treatments, the RRs (95% CIs) of
acute myocardial infarction, stroke, cardio-
vascular events, and all-cause mortality

DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000 889

Therapeutic benefits of ACE inhibitors

Why do the results of the UKPDS differ

Figure 1—Systolic blood pressure changes during follow-up according to treatment in the ABCD trial,
the FACET, and the UKPDS. The data of the CAPPP have not been reported.
were 0.73 (0.54–0.99), 0.86 (0.59–1.26),
0.77 (0.61–0.91), and 0.85 (0.64–1.12),
respectively. To identify potential outliers,
we tested the heterogeneity of the results of
the trials for individual outcomes of inter-
est through iterative analyses. The test for
heterogeneity was significant for the out-
comes of acute myocardial infarction and
cardiovascular events when the data of the
UKPDS were combined with the other 3
trials (P  0.001 for both outcomes) but
not when the UKPDS was excluded from
the meta-analysis. Thus, only the data for
the ABCD trial, the CAPPP, and the FACET
were used in the formal meta-analytic cal-
culations. When the data of the ABCD trial,
the CAPPP, and the FACET were com-
bined, the patients randomized to an ACE
inhibitor had a significantly lower risk of
acute myocardial infarction, cardiovascular
events, and all-cause mortality than those
randomized to an alternative treatment
(P  0.001, P  0.001, and P = 0.010,
respectively) (Fig. 2). Moreover, no hetero-
geneity was found with the reduced
dataset. No such differences were evident
for the outcome of stroke.
CONCLUSIONS — This review identi-
fied 4 trials in which patients with type 2
diabetes and hypertension were random-
ized to either an ACE inhibitor or to an
alternative antihypertensive treatment and
were followed for 2 years. The results of
these trials have been previously reviewed
(5), but to our knowledge, this is the first
quantitative meta-analysis of their outcome
data. The cumulative results of 3 trials (the
ABCD trial, the CAPPP, and the FACET)
showed a significant benefit of ACE
inhibitors compared with alternative treat-
ments on the outcomes of acute myocardial
infarction (63% reduction, P  0.001), car-
diovascular events (51% reduction, P 
0.001), and all-cause mortality (62% reduc-
tion, P = 0.010). These findings were not
observed in the UKPDS, which compared
captopril with atenolol. The ACE inhibitors
did not appear to be superior to other agents
for the outcome of stroke in any of the trials.
from those of the other trials? One possible
explanation may be because of differences in
population characteristics. In the UKPDS,
diabetes was newly diagnosed compared
with the other studies (Table 1). The dura-
tion of follow-up in the UKPDS is another
difference from the other trials. Another
explanation is the selective dropout from
the trial. Patients randomized to atenolol
were more likely to drop out of the ran-
domized treatment (10), and they possibly
received an ACE inhibitor if they had a com-
pelling indication such as albuminuria or left
ventricular dysfunction. The net effect of
such a selective dropout would be to dimin-
ish any differences between atenolol and
captopril. The potential frequent crossover
between groups renders many aspects of
the UKPDS difficult to interpret (14).
Another plausible hypothesis is that the
selective -blocker atenolol is equivalent to
captopril. Recent reports indicate in both
normotensive and hypertensive individuals
that the suppression of angiotensin II levels
achieved with -blockade is similar to that
obtained with an ACE inhibitor (15). To
confirm the hypothesis of equivalence of
captopril and atenolol, one must assess the
relative risk of events in the CAPPP by using
diuretics and individual -blockers. The
divergent effects found in the UKPDS com-
pared with the other 3 trials indicate that the
overall evidence of the comparative effects of
ACE inhibitors is not yet conclusive.
If ACE inhibitors are truly more bene-
ficial than other agents for the treatment of
hypertension in patients with diabetes,
then what are the potential mechanisms?
Blood pressure control did not differ
significantly between treatments in the
ABCD trial. In the FACET, the amlodipine
group achieved a significantly lower sys-
tolic blood pressure level than the ACE
inhibitor group. Total cholesterol levels
were similar in both treatment groups in
the ABCD trial and the FACET. Microal-

Table 2— Number of clinical events according to treatment

Mean
follow-up ACE inhibitors Other therapies
Trial (years) Agent n AMI Stroke CV Death Agent n AMI Stroke CV Death
ABCD (7) 5 Enalapril 235 5 7 20 13 Nisoldipine 235 25 11 43 17
CAPPP (8) 6.1 Captopril 309 10 24 30 17 Diuretic/-blocker 263 25 20 43 27
FACET (9) 2.8 Fosinopril 189 10 4 14 4 Amlodipine 191 13 10 27 5
UKPDS (10) 8.4 Captopril 400 61 21 102 75 Atenolol 358 46 17 75 59
Data are n. AMI, acute myocardial infarction; CV, cardiovascular events.

890 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000


Figure 2—RR (95% CI) of outcomes for ACE inhibitors compared with other agents in the ABCD trial,
the CAPPP, the FACET, the UKPDS, and in combined analyses.
buminuria and serum creatinine levels
during follow-up were similar in both
treatment groups in the FACET. Metabolic
control is another important factor that
may affect cardiovascular outcomes. In the
ABCD trial, the participants had poor
metabolic control at baseline and during
the 5 years of follow-up, but metabolic
control was not significantly different
between the ACE inhibitor and the Ca
antagonist–treated group. In the FACET,
the patients randomized to the ACE
inhibitor or the Ca antagonist achieved
similar HbA1c and fasting glucose levels
during follow-up. Changes in blood pres-
sure, metabolic control, or other risk fac-
tors during follow-up were not reported
for diabetic patients enrolled in the CAPPP.
Thus, from the published data, differences
in blood pressure control, metabolic con-
trol, or other measured risk factors likely
explain the substantial difference in major
cardiovascular events.
Several other mechanisms not mea-
sured in the reviewed trials may account for
a greater therapeutic benefit of ACE
inhibitors. ACE inhibitors may reduce car-
diovascular risk by improving endothelial
dysfunction (16), by reducing inflamma-
tion (17), and by promoting fibrinolysis
through inhibition of plasminogen activa-
tor inhibitor 1 (18,19). The recently pub-
lished Heart Outcomes Prevention
Evaluation (HOPE) trial showed that the
reduction in cardiovascular events with an
ACE inhibitor was much greater than that
expected from blood pressure reduction
DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000
Acknowledgments — The results of this study
were presented at the 59th Annual Meeting of
the American Diabetes Association, San Diego,
CA, 19 June 1999.
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