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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
BRUCE M. PSATY, MD, PHD
MICHAEL H. ALDERMAN, MD
WILLIAM B. APPLEGATE, MD, MPH
JEFF D. WILLIAMSON, MD, MHS
CURT D. FURBERG, MD, PHD
OBJECTIVE — To assess whether ACE inhibitors are superior to alternative agents for the
prevention of cardiovascular events in patients with hypertension and type 2 diabetes.
RESEARCH DESIGN AND METHODS — This study is a review and meta-analysis of
randomized controlled trials that included patients with type 2 diabetes and hypertension who
were randomized to an ACE inhibitor or an alternative drug, were followed for 2 years, and
had adjudicated cardiovascular events.
RESULTS — A total of 4 trials were eligible. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial (n = 470) compared enalapril with nisoldipine, the Captopril Prevention
Project (CAPPP) (n = 572) compared captopril with diuretics or -blockers, the Fosinopril Versus Amlodipine Cardiovascular Events Trial (FACET) (n = 380) compared fosinopril with
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
inhibitors compared with alternative treatments on the outcomes of acute myocardial infarction (63% reduction, P 0.001), cardiovascular events (51% reduction, P 0.001), and allcause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS.
The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in
any of the trials. None of the findings were explained by differences in blood pressure control.
CONCLUSIONS — Compared with the alternative agents tested, ACE inhibitors may provide a special advantage in addition to blood pressure control. The question of whether atenolol
is equivalent to captopril remains open. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials.
Diabetes Care 23:888–892, 2000
he primary goal of antihypertensive
treatment is to prevent clinical complications and not simply to lower elevated blood pressure. Evidence from the
Systolic Hypertension in the Elderly Pro-
T
gram and the Systolic Hypertension in
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
From the Sticht Center on Aging (M.P., W.B.A., J.D.W.), Department of Internal Medicine, and the Department of Public Health Sciences (C.D.F.), Wake Forest University, Winston-Salem, North Carolina; the Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Services,
University of Washington, Seattle, Washington; and the Department of Epidemiology and Social Medicine
(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
of Internal Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, WinstonSalem, NC 27157. E-mail: [email protected].
Received for publication 21 October 1999 and accepted in revised form 1 February 2000.
Abbreviations: ABCD, Appropriate Blood Pressure Control in Diabetes; CAPPP, Captopril Prevention Project; FACET, Fosinopril Versus Amlodipine Cardiovascular Events Trial; HOPE, Heart Outcomes Prevention
Evaluation; RR, relative risk; UKPDS, U.K. Prospective Diabetes Study.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion
factors for many substances.
888
Hypertension Optimal Treatment trial and
the U.K. Prospective Diabetes Study
(UKPDS) suggest that, in patients with diabetes, greater blood pressure reduction
results in greater clinical benefits (3,4).
Although these studies document that treatment of high blood pressure is beneficial in
hypertensive patients with type 2 diabetes,
none of these trials provides information on
the relative therapeutic benefit of individual
antihypertensive agents.
Recent comparative trials and observational studies in diabetes have suggested
that, for the prevention of cardiovascular
events, ACE inhibitors may be superior to
alternative antihypertensive agents (5,6).
That the greater benefit of ACE inhibitors
was not explained by better blood pressure
control indicates that other mechanisms
linked to ACE inhibition may have played
an additional role in the prevention of major
clinical events. The purpose of the present
review and meta-analysis is to summarize
the current evidence from randomized clinical trials with clinical outcomes that
directly compared ACE inhibitors to alternative antihypertensive agents in patients
with hypertension and type 2 diabetes.
RESEARCH DESIGN AND
METHODS — To be included in the
meta-analysis, a study had to be a randomized controlled trial published in a peerreviewed journal that included patients
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 predefined criteria to adjudicate the cardiovascular events. Studies were identified
through PubMed searches using the following key words: “ACE inhibitors,” “diabetes,” “hypertension,” and “clinical trial.”
The searches were extended through January 2000. Letters to the editor, commentaries, review articles, editorials, and
observational studies were not included.
Bibliographies of the retrieved articles were
searched to identify other eligible studies,
and information from colleagues was used
to identify more recently published articles.
DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000
Pahor and Associates
Table 1—Baseline characteristics according to treatment
Trial
ABCD (7)
Agent
Enalapril
Nisoldipine
CAPPP (8)
Captopril
Diuretic/-blockers
FACET (9)
Fosinopril
Amlodipine
UKPDS (10)
Captopril
Atenolol
n
Age
(years)
Men
(%)
BMI
(kg/m2)
235
235
309
263
189
191
400
358
57.7 ± 8.4
57.2 ± 8.2
55.0 ± 7.6
55.7 ± 7.4
62.8 ± 7.0
63.3 ± 6.1
56.3 ± 8.1
56.0 ± 8.2
67
68
63
60
64
56
51
57
31.9 ± 5.9
31.3 ± 5.9
30.9
30.3
30.7 ± 4.6
30.5 ± 5.4
29.8 ± 5.6
29.7 ± 5.3
Macroalbuminuria Duration of
Systolic blood
Diastolic blood
(%)
diabetes (years) pressure (mmHg) pressure (mmHg)
19
18
8.5 ± 6.8
8.7 ± 6.6
0
0
2
3
10.7 ± 9.1
10.5 ± 8.6
2.6
2.7
156 ± 17
155 ± 19
164 ± 19
163 ± 21
170 ± 16
171 ± 18
159 ± 20
159 ± 19
98 ± 7
98 ± 7
97 ± 10
97 ± 10
95 ± 10
94 ± 8
94 ± 10
93 ± 10
Data are means ± SEM, unless otherwise indicated.
The following elements were abstracted:
design, sample size, randomized treatments, follow-up time, average age, sex
distribution, average BMI, proportion of
participants with macroalbuminuria, duration of diabetes, baseline systolic and diastolic arterial pressures, and the number of
events (including acute myocardial infarction, stroke, combined cardiovascular
events, and all-cause mortality) occurring
in each treatment group.
The initial search identified 195 articles. 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 Fosinopril Versus Amlodipine Cardiovascular
Events Trial (FACET) (9), and the UKPDS
(Table 1) (10). The recently published
Swedish Trial in Old Patients with Hypertension-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 cardiovascular events, we adopted the definition
used in each trial. In the ABCD trial, the
cardiovascular events included cardiovascular death, fatal and nonfatal acute
myocardial infarction, congestive heart failure requiring hospitalization, fatal or nonfatal 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
DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000
cardiovascular deaths, fatal and nonfatal
acute myocardial infarction, and fatal or
nonfatal stroke. In the FACET, the cardiovascular events included fatal and nonfatal
acute myocardial infarction, fatal and nonfatal stroke, and angina requiring hospitalization. In the UKPDS, the combined end
point of cardiovascular events was not
reported. We calculated the total number of
cardiovascular events by adding the number of fatal and nonfatal acute myocardial
infarctions and strokes, the number of congestive 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 overestimated the number of patients with cardiovascular events in the UKPDS.
The overall relative risk (85% CI) of
each outcome was calculated with Peto’s
method (12). Cochran’s test for heterogeneity 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 participants was 2,180 (1,133 randomized to an
ACE inhibitor and 1,047 randomized to
an alternative active agent) with a total follow-up experience of 13,300 personyears. 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 metoprolol, 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 evident 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 infarction was significantly decreased in the
ABCD trial and the CAPPP, was nonsignificantly lower in the FACET, and was nonsignificantly 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 nonsignificantly higher in the UKPDS.
In initial analyses, the data of the 4 trials were combined. For ACE inhibitors versus other treatments, the RRs (95% CIs) of
acute myocardial infarction, stroke, cardiovascular events, and all-cause mortality
889
Therapeutic benefits of ACE inhibitors
Why do the results of the UKPDS differ
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 duration 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 randomized treatment (10), and they possibly
received an ACE inhibitor if they had a compelling indication such as albuminuria or left
ventricular dysfunction. The net effect of
such a selective dropout would be to diminish 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 compared 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 beneficial 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 systolic 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-
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 interest through iterative analyses. The test for
heterogeneity was significant for the outcomes 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 calculations. When the data of the ABCD trial,
the CAPPP, and the FACET were combined, 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 heterogeneity was found with the reduced
dataset. No such differences were evident
for the outcome of stroke.
CONCLUSIONS — This review identified 4 trials in which patients with type 2
diabetes and hypertension were randomized 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 treatments on the outcomes of acute myocardial
infarction (63% reduction, P 0.001), cardiovascular events (51% reduction, P 0.001), and all-cause mortality (62% reduction, 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.
Table 2— Number of clinical events according to treatment
Trial
ABCD (7)
CAPPP (8)
FACET (9)
UKPDS (10)
Mean
follow-up
(years)
Agent
5
6.1
2.8
8.4
Enalapril
Captopril
Fosinopril
Captopril
ACE inhibitors
n
AMI Stroke
235
309
189
400
5
10
10
61
7
24
4
21
CV
Death
Agent
20
30
14
102
13
17
4
75
Nisoldipine
Diuretic/-blocker
Amlodipine
Atenolol
Other therapies
n
AMI Stroke
235
263
191
358
25
25
13
46
11
20
10
17
CV
Death
43
43
27
75
17
27
5
59
Data are n. AMI, acute myocardial infarction; CV, cardiovascular events.
890
DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000
Pahor and Associates
Acknowledgments — The results of this study
were presented at the 59th Annual Meeting of
the American Diabetes Association, San Diego,
CA, 19 June 1999.
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 pressure, metabolic control, or other risk factors during follow-up were not reported
for diabetic patients enrolled in the CAPPP.
Thus, from the published data, differences
in blood pressure control, metabolic control, or other measured risk factors likely
explain the substantial difference in major
cardiovascular events.
Several other mechanisms not measured in the reviewed trials may account for
a greater therapeutic benefit of ACE
inhibitors. ACE inhibitors may reduce cardiovascular risk by improving endothelial
dysfunction (16), by reducing inflammation (17), and by promoting fibrinolysis
through inhibition of plasminogen activator inhibitor 1 (18,19). The recently published 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
alone compared with placebo, which supports the view that additional mechanisms
contribute to the prevention of cardiovascular events with ACE inhibition (20). The
main findings of the HOPE trial were confirmed in patients with and without diabetes. The HOPE trial was not included in
the present meta-analysis because the comparison group was treated with a placebo
and not with an active agent as required by
the inclusion criteria.
In summary, blood pressure reduction per se is necessary to prevent clinical
complications in hypertensive patients
(21), but additional clinical benefits can
be achieved by non–blood pressure mechanisms. The evidence from the present
review and meta-analysis of comparative
trials in patients with hypertension and
diabetes should not be considered conclusive. The available data support the
view that, compared with the alternative
agents tested, ACE inhibitors appear to
provide a special advantage in addition to
blood pressure control. The question of
whether atenolol is equivalent to captopril
remains open. Based on available data
from comparative trials, using ACE
inhibitors may be prudent as a first-line
agent for the treatment of hypertension in
patients with type 2 diabetes. Conclusive
evidence on the comparative effects of
antihypertensive treatments will come
from large prospective randomized trials
such as the Antihypertensive and Lipid
Lowering Treatment To Prevent Heart
Attack Trial (22).
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