1. health and fitness
2. disease
3. diabetes

CARDIOVASCULAR DRUGS IN DIABETES
Should all diabetic patients receive an ACE
inhibitor? Results from recent trials
CLAIRE MCDOUGALL, GILLIAN MARSHALL, ADRIAN JB BRADY, MILES FISHER
Br J Cardiol 2005;12:130–4
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Many studies have confirmed the excessive cardiovascular morbidity and mortality in people with diabetes.1,2 In addition,
between 25–50% of diabetic patients develop kidney disease.
Only a proportion of these will require dialysis or transplantation
Diabetes Clinic, Glasgow Royal Infirmary, 84 Castle Street, Glasgow,
G4 0SF.
Claire McDougall, Research Fellow
Miles Fisher, Consultant Physician
Department of Cardiology, Queen Elizabeth Building, Glasgow Royal
Infirmary, Alexandra Parade, Glasgow, G4 0SF.
Gillian Marshall, Research Fellow
Adrian JB Brady, Consultant Cardiologist
Correspondence to: Dr M Fisher
(email: [email protected])
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Key word s : diabetes, angiotensin-converting enzyme (ACE)
inhibitors, angiotensin II receptor blocker.
Introduction
as many die from premature cardiovascular disease prior to needing renal replacement therapy.3 Diabetic nephropathy is a progressive condition with early glomerular hyperfiltration followed
by microalbuminuria, which progresses to frank proteinuria and
end-stage renal disease. Microalbuminuria is also an independent marker of cardiovascular risk in patients with both type 1
and type 2 diabetes.
We discuss the rationale for inhibition of the re n i n angiotensin system using angiotensin-converting enzyme (ACE)
inhibitors or angiotensin II receptor blockers (ARBs) in patients
with type 1 and 2 diabetes, and examine the benefits of blockade of the renin-angiotensin system on the progression of diabetic nephropathy and cardiovascular disease. We pose the
question “should all diabetic patients receive an ACE inhibitor?”
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iabetes is associated with both premature
cardiovascular disease and renal disease. The
presence of microalbuminuria is itself an
independent risk factor for the development of
cardiovascular disease. Angiotensin-converting enzyme
(ACE) inhibitors were initially shown to slow the
progression of established renal disease in patients with
type 1 diabetes. Subsequent trials have demonstrated a
similar benefit in patients with type 2 diabetes and
with the use of angiotensin II receptor blockers (ARBs).
The use of ACE inhibitors to prevent cardiovascular
events in patients with established cardiovascular
disease but not left ventricular dysfunction was
established in two large randomised trials – HOPE and
EUROPA. These benefits were maintained within the
diabetic subgroups of these trials and appear to be
independent of blood pressure lowering. The LIFE trial
also provides evidence of the benefits of ARBs in
reducing cardiovascular events in a high-risk population
of diabetic patients with hypertension and left
ventricular hypertrophy. Ideally, therefore, all diabetic
patients with renal or cardiovascular disease should be
treated with ACE inhibitors or ARBs.
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Abstract
Landmark studies
ACE inhibitors were introduced initially for the treatment of
hypertension. Early trials measuring microalbuminuria suggested
that ACE inhibitors were reno-protective independent of their
hypotensive actions. The Collaborative Study Group examined
the effects of captopril on the progression of renal disease in
patients with type 1 diabetes and overt proteinuria.4 The study
demonstrated a significant reduction in the primary end point of
a two-fold increase in serum creatinine, although there was a
small but greater mean blood pressure reduction in the treatment group of 2–3 mmHg. Reductions were also seen in the
combined end point of dialysis, renal transplantation and death.
The reductions in both the primary and secondary end points
were maintained after correction for blood pressure differences.
The benefits of ACE inhibitor therapy in reducing cardiovascular end points in patients with myocardial infarction (MI) or left
ventricular (LV) dysfunction have been demonstrated in many
studies e.g. the SAVE (Survival And Ventricular Enlargement),
AIRE (Acute Infarction Ramipril Efficacy) and ISIS-4 (Fourt h
I n t e rnational Study of Infarct Survival) studies, including post-hoc
subgroup analyses in diabetic patients.5-7 The HOPE (Heart
Outcomes Prevention Evaluation) study examined the potential
benefits of ramipril in a wider population of patients with vascular disease but no history of LV systolic dysfunction.8 Patients with
diabetes and at least one other cardiovascular risk factor were
also eligible. Analysis of the diabetic cohort of the 3,577 patients
(38% of total) enrolled in the HOPE study demonstrated a statistically significant 25% relative risk reduction in the combined prim a ry end point of MI, stroke and cardiovascular death
(p=0.0004). These reductions were seen re g a rdless of whether
the patients had type 1 or type 2 diabetes (although the vast
THE BRITISH JOURNAL OF CARDIOLOGY
Table 1.
Results of end points for all subjects and subjects with diabetes in recent cardiovascular and renal studies with angiotensin-converting enzyme
inhibitors or angiotensin II receptor blockers
Drug
Total
subjects
n
Diabetic
subjects
n (%)
Primary
end point
all
Primary
end point
diabetes
Perindopril 8 mg
or placebo
12,218
1,502
(12%)
Reduced CV events
Reduced CV
(CV death, MI, cardiac
events from
arrest) from 9.9% to 8.0% 15.5% to 12.6%
PEACE
Trandolapril 4 mg
or placebo
8,290
17%
No effect on combined
end point (CV death, MI,
coronary revascularisation)
LIFE
Losartan-based vs.
atenolol-based
treatment
9,193
1,195
(13%)
Reduced composite
end point (CV death,
MI, stroke) from
13% with atenolol
to 11% with losartan
Other
events
all
Other
events
diabetes
Comments
Cardiovascular studies
D
Data not
provided
IDNT
Reduced composite
Reduced stroke
Reduced CV
end point from (fatal and non-fatal) mortality
23% with atenolol
with losartan
with
to 18% with
losartan
losartan
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Renal studies
Open label ACE
inhibitors for
diabetes patients
with overt
proteinuria or
hypertension and
microalbuminuria
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EUROPA/
PERSUADE
Irbesartan 300 mg
vs. amlodipine 10 mg
vs. placebo
1,715
1,715
(100%)
Reduced combined
end point (doubling
of creatinine, end-stage
renal disease, death)
from 39% placebo,
41% amlodipine to 33%
Ditto
No effect
on all-cause
mortality
Ditto
No significant
reduction in CV
composite
RENAAL
Losartan 100 mg
vs. placebo
1,513
1,513
(100%)
Reduced combined
end point (doubling of
creatinine, end-stage
renal disease, death)
from 47% to 43%
Ditto
No effect
on all-cause
mortality
Ditto
No significant
reduction in CV
composite, reduced
first hospitalisation
with heart failure
DETAIL
Telmisartan 80 mg
vs. enalapril 20 mg
250
250
(100%)
No difference
in the change in
glomerular filtration rate
Ditto
No difference in
CV events or
all-cause mortality
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Key: EUROPA = EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease; PERSUADE = PERindopril SUbstudy in coronary Artery
DiseasE and diabetes; PEACE = Prevention of Events with Angiotensin Converting Enzyme Inhibition; LIFE = Losartan Intervention For Endpoint reduction in hypertension;
IDNT = Irbesartan Diabetic Nephropathy Trial; RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; DETAIL = Diabetics Exposed to
Telmisartan and Enalapril; CV = cardiovascular; MI = myocardial infarction; ACE = angiotensin-converting enzyme
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majority of patients had type 2 diabetes), previous cardiovascular
events, hypertension or microalbuminuria. The reduction in the
primary end point remained significant after adjustment for the
slight reduction in blood pressure seen in the treatment group.
In addition to HOPE, the MICRO-HOPE substudy examined
the effects of ramipril on the development of renal disease within the same diabetic cohort.9 There was a 24% relative risk
reduction (p=0.027) in the development of overt nephropathy,
defined as an albumin:creatinine ratio of > 36 mg/mmol. The
incidence of overt nephropathy was reduced even in those
patients without microalbuminuria at baseline but this was not
statistically significant. When the incidence of other micro v a s c ular complications were analysed, ramipril was shown to cause a
significant reduction in the combined incidence of overt
VOLUME 12 ISSUE 2 . MARCH/APRIL 2005
nephropathy, requirement for dialysis and laser treatment for
retinopathy (RRR 16% p=0.036).
Recent cardiovascular studies
The EUROPA (EURopean trial On reduction of cardiac events with
Perindopril in stable coronary Art e ry disease) trial studied the
effects of perindopril, a long-acting ACE inhibitor, on cardiovascular events in 12,218 male and female patients with documented history of coronary art e ry disease but no clinical evidence
of heart failure.10 Over a mean follow-up of 3.7 years there was
a 20% relative risk reduction in the composite primary end point
of cardiovascular death, non-fatal MI and successfully resuscitated cardiac arrest (table 1), (p=0.0003).
The PERSUADE (PERindopril SUbstudy in coronary Art e ry
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reduction was observed in the overall study. Significant reductions were seen in cardiovascular and total mortality compared
to atenolol, but reductions in stroke and myocardial infarction
were not significant.
Recent nephropathy studies
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Blockade of angiotensin II has also been shown to have beneficial effects on the progression of diabetic nephropathy. The IRMA
2 (Irbesartan in patients with type 2 diabetes and microalbuminuria study group) showed that treatment with 150 mg or 300
mg irbesartan significantly reduced the rate of pro g ression from
microalbuminuria to diabetic nephropathy (defined by urinary
albumin excretion rate of > 200 µg/minute on three non-consecutive occasions) when compared to placebo, with minor differences in blood pressure noted between the two groups.16 The
MicroAlbuminuria Reduction with VALsartan in patients with
type 2 diabetes (MARVAL) study, also showed that treatment
with valsartan over a 24-week period significantly reduced urinary albumin excretion rate in patients with microalbuminuria at
baseline, while treatment with amlodipine had only minor effects
despite similar control of blood pressure in both treatment
groups.17
Definite benefits in terms of reductions in cardiovascular outcomes, separate from renal outcomes, have not been shown
using ARBs. Two studies have examined these drugs in patients
with type 2 diabetes and established diabetic nephropathy. In the
IDNT (Irbesartan Diabetic Nephropathy Trial) study, irbesart a n
was compared with amlodipine and placebo,18 and in the
RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin
II Antagonist Losartan) study losartan was compared with placebo.19 Both examined a composite end point of doubling of seru m
creatinine, development of end-stage renal disease, or cardiovascular death. In IDNT irbesartan but not amlodipine reduced
the composite end point, and in RENAAL losartan was better
than placebo. When the components of the end point were
examined, both irbesartan and losartan reduced the doubling of
creatinine and development of end-stage renal disease, but neither affected cardiovascular deaths, although numbers were
small and these were not primary end points (table 1). There was
no significant benefit in a secondary end point that comprised a
large number of cardiovascular outcomes. These studies, therefore, demonstrated a significant reduction in renal outcomes but
not cardiovascular outcomes in patients with diabetes and renal
disease.
DETAIL (Diabetics Exposed to Telmisartan and Enalapril) is the
first study to compare the effects of ACE inhibitors versus ARBs
on renal function in type 2 diabetes. This small study compared
the effects of telmisartan versus enalapril on the decline of renal
function in 250 patients with type 2 diabetes and hypertension.
There were no diff e rences in either the primary end point of
overall change in glomerular filtration rate (GFR), or secondary
end points of annual change in GFR, albumin excretion rate or
s e rum creatinine between the two groups.20 However, this study
was not large enough to make any comparisons between these
two groups in terms of their effects on vascular outcomes.
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DiseasE and diabetes) study is due to be published in the near
future and reports the results of the 1,502 subjects who had diabetes at time of entry into EUROPA.11 The relative risk reduction
with perindopril on primary and secondary end points was similar to that in the main EUROPA population but as there was a
higher event rate in diabetic patients, the absolute risk reduction
was greater.
The ‘number needed to treat’ (NNT) was more favourable for
diabetic patients. To prevent one cardiovascular death or nonfatal MI, 27 diabetic patients would need to be treated for four
years, as opposed to 40 patients in the main study cohort. In
addition, as in non-diabetic subjects, the protective effects of
perindopril were independent of blood pressure at baseline, and
independent of the blood pressure reduction achieved by the
drug, suggesting that perindopril may exert its protective effect
via other mechanisms e.g. accumulation of bradykinin, or
improvements in endothelial function.
The PEACE (Prevention of Events with Angiotensin
Converting Enzyme Inhibition) trial compared the effects of
placebo versus trandolapril on the prevention of cardiovascular
events in a cohort of 8,290 patients (17% of whom had diabetes) with established cardiovascular disease and normal or
only slightly reduced left ventricular function.12 Surprisingly,
there were no significant reductions in cardiovascular end
points, which contrasts to the HOPE and EUROPA studies.
There are several possible explanations for this. The PEACE
patients were at lower risk of cardiovascular events than
patients in previous studies; there were fewer events during the
trial from which to draw conclusions. Secondly, two years
before PEACE finished the steering committee advised the
investigators to substitute open-label ACE inhibitors for the
masked study treatment in patients with diabetes and either
overt proteinuria or hypertension and microalbuminuria. This
dilutes the treatment effect within the trial. Thirdly, patient
compliance and dose achievement was not as good in PEACE
as in EUROPA and HOPE. One positive finding in PEACE was a
reduction in the onset of new diabetes in the trandolapril
group, as has been seen in several other trials with ACE
inhibitors and ARBs.13
The LIFE (Losartan Intervention For Endpoint reduction in
hypertension) study compared the effects of losartan versus
atenolol-based treatment on cardiovascular morbidity and mortality. Losartan exerts potential beneficial effects not only via its
antihypertensive properties but also as a result of its blockade of
angiotensin II. For example, this should have a greater benefit on
re g ression of left ventricular hypert rophy.14 The LIFE study
demonstrated a 13% relative risk reduction in the composite prim a ry end point of cardiovascular death, MI and stroke. There
were no significant reductions in MI, but a highly significant re lative risk reduction of 24.9% in the incidence of stroke in the
losartan-treated group over the mean follow-up of 4.8 years. The
results from the LIFE diabetes subgroup of 1,195 individuals were
published separately15 and were even more dramatic. In subjects
with diabetes, treatment with losartan caused a 5% reduction in
the composite end point compared to atenolol, whereas a 2%
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THE BRITISH JOURNAL OF CARDIOLOGY
●
Evidence supports the use of ACE inhibitor therapy for
type 1 diabetic patients with nephropathy
(microalbuminuria or macroalbuminuria)
●
Evidence supports the use of ARB therapy for type 2
diabetic patients with nephropathy (microalbuminuria or
macroalbuminuria) in reducing renal outcomes, and for
patients with hypertension and left ventricular
hypertrophy (LVH) in reducing cardiovascular outcomes
●
HOPE and EUROPA/PERSUADE demonstrate the benefits
of reducing cardiovascular events in diabetic patients
with existing cardiovascular disease or microalbuminuria
●
We recommend the use of ACE inhibitors in all diabetic
patients with microalbuminuria, nephropathy,
h y p e rtension or previous cardiovascular disease; ARBs
should be used in patients who have LVH or who are
intolerant of ACE inhibitors
ARB
yes
no
Hypertension
yes
yes
CCF
yes
yes
Microalbuminuria
type 1
type 2
Macroalbuminuria
type 1
type 2
Cardioprotection
yes
no evidence
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ACE inhibitor
Key messages
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Evidence for use of angiotensin-converting enzyme (ACE)
inhibitors and angiotensin II receptor blockers (ARBs) in people
with diabetes. For patients with type 1 diabetes, evidence
favours use of ACE inhibitors in microalbuminuria and
macroalbuminuria. For patients with type 2 diabetes, evidence
favours use of ARBs in microalbuminuria and macroalbuminuria
for renal outcomes
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Table 2.
Discussion
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The Collaborative Study Group and other studies show there is
no doubt that manipulation of the renin-angiotensin system
slows the rate of decline of renal function in patients with type
1 diabetes and proteinuria (table 2). ACE inhibitors are widely
prescribed in type 1 diabetes and have been shown to be cost
effective given both the financial and human benefits of delaying the need for renal replacement therapy in patients.
M i c roalbuminuria is also a predictor of renal decline in
patients with type 2 diabetes, and the best evidence base for
delaying this decline lies with angiotensin receptor blockade as
shown by the IRMA and MARVAL studies, although there are
several smaller studies with ACE inhibitors in type 2 diabetic
patients that show similar renal effects. However, the best evidence for prevention of cardiovascular disease in this group of
patients with microalbuminuria currently lies with ACE inhibitors
rather than ARBs.21 Given that the risk of cardiovascular disease
is much higher than that of diabetic nephropathy in patients
with microalbuminuria, ACE inhibitors are probably the tre a tment of choice. This argument is given further weight by evidence from the DETAIL study, which suggests that ACE inhibitors
are equivalent to ARBs in delaying progression of nephropathy in
patients with type 2 diabetes. However, patients with hypert e nsion and documented left ventricular hypertrophy should pro b ably have losartan, based on the results of LIFE.
C
Combined blockade of RAS
Despite the controversy over which is the best agent to use in
blockade of the renin-angiotensin system (RAS), there is some
evidence to suggest that use of both together can act in synerg y
and have increased beneficial effects. Combined use of ACE inhibition and angiotensin receptor blockade has been shown to
have a number of beneficial effects in both experimental models
and clinical models. Short-term clinical studies have shown that
a combination of two agents at lower doses is superior in term s
of blood pressure lowering to single-site RAS blockade.22,23 In
h e a rt failure, the CHARM-Added study demonstrated that addi-
VOLUME 12 ISSUE 2 . MARCH/APRIL 2005
tion of candesartan to an ACE inhibitor in patients with heart
failure resulted in significant reductions in death due to cardiovascular disease and hospital admissions for heart failure.24 In
addition, the VALIANT (Va l s a rtan in Acute Myocardial Infarction)
trial, which studied the combined effect of valsartan and captopril on a number of cardiovascular outcomes in patients with
h e a rt failure, also showed a reduction in the rate of hospital
admissions for heart failure in the group receiving combination
therapy.25 Similarly, clinical studies have shown greater antihypertensive and antiproteinuric effects of combined RAS blockade
than either ACE inhibition or angiotensin receptor blockade
alone.26
Should all diabetic patients receive an ACE inhibitor?
For the small subset of patients of diabetes who do not have
hypertension, cardiovascular disease or microalbuminuria, is
there any case for treating these patients with ACE inhibitors
for the primary prevention of cardiovascular disease? A small
subset of the diabetic patients in the MICROHOPE study were
of this phenotype and ramipril was of benefit regardless of
whether or not patients were hypertensive, or had pre-existing
cardiovascular disease or microalbuminuria. The numbers in
each group, however, were small, with wide confidence intervals, and widespread treatment with ACE inhibition for the
primary prevention of cardiovascular disease in patients with
diabetes is not common practice. Controlling hypertension and
reducing risk using statin therapy have been shown to be more
effective strategies.27
In conclusion, ACE inhibitors should be given to all type 1
diabetic patients with microalbuminuria or nephropathy, and to
type 2 patients with hypertension, microalbuminuria, or existing
cardiovascular disease. All diabetic patients with hypertension
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and left ventricular hypertrophy should have an ARB such as
l o s a rtan as first-line therapy.
Conflict of interest
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P revalence of cardiovascular and renal complications in older adults with
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2. Lee WL, Cheung AM, Cape D, Zinman B. Impact of diabetes on coronary
a rt e ry disease in women and men: a meta-analysis of prospective studies. Diabetes Care 2000;23: 9 6 2 - 8 .
3. Trevisan R, Vi b e rti G. Diabetic Nephropathy. In: Turner HE, Wass JAH
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4. Lewis EJ, Hunsicker LG, Bain RP et al., for the Collaborative Study Group.
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5. St John Sutton M, Pfeffer MA, Moye L et al. Cardiovascular death and
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