Full text of DOI:10.2165/00003495-200262140-00001

Drugs 2002; 62 (14): 2007-2012
0012-6667/02/0014-2007/$30.00/0
LEADING ARTICLE
© Adis International Limited. All rights reserved.
The Role of Angiotensin Converting
Enzyme Inhibitors and Angiotensin II
Receptor Antagonists in the Management
of Diabetic Complications
Toomas Podar1 and Jaakko Tuomilehto2,3
1
2
3
Department of Endocrinology, Tartu University Clinics, Tartu, Estonia
Department of Public Health, University of Helsinki, Helsinki, Finland
Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion,
National Public Health Institute, Helsinki, Finland
Evidence suggests that ACE inhibitors can be advantageous for prevention
Abstract
and halting progression of both micro- and macrovascular complications in pa-
tients with diabetes mellitus. ACE inhibitors are useful antihypertensive agents
in both type 1 and type 2 diabetes; however, ACE inhibitor therapy often needs
to be supplemented with calcium channel antagonists, β-blockers or diuretics to
achieve good blood pressure control. ACE inhibitors are also indicated in non-
hypertensive patients with type 1 and type 2 diabetes who have micro- or
macroalbuminuria. The effect of ACE inhibitors in halting the development and
progression of retinopathy and, potentially, neuropathy needs further proof in
large-scale studies. More recently, angiotensin II receptor antagonists are emerg-
ing as drugs with the potential to be successfully included in the management of
diabetic complications, especially when ACE inhibitors are not suitable because
of adverse effects.
Angiotensin converting enzyme (ACE) inhibi-
hibitors may even prevent or ameliorate the course
of diabetes mellitus.
tors have been found to have multiple potential
uses in the management of diabetes mellitus. The
purpose of this review is to provide a trial-based
overview of the use of these drugs in the manage-
ment of macro- (usually cardiovascular death,
stroke or myocardial infarction) and microvascular
complications of diabetes. The focus is on the well-
studied prevention of macrovascular events and di-
abetic kidney complications, but data on the poten-
tial uses of these medications for diabetic eye and
nerve complications are also presented. Finally,
some intriguing data have suggested that ACE in-
Although blood pressure reduction is uniformly
recognised as preventive for the development of
renal damage and macrovascular disease in both
hypertensive and normotensive patients with dia-
betes, the target values to be achieved are still de-
bated. Seemingly, the lower the blood pressure the
better the protection against diabetic renal disease.
Some have suggested 130/85mm Hg in patients
with diabetes as a target.[1-3] The national Kidney
Foundation Hypertension and Diabetes Executive
Committees Working Group has recently sug-

2008
Podar & Tuomilehto
gested 130/80mm Hg as the target blood pres-
sure.[4] In patients with overt proteinuria values
even less than 120/80mm Hg might be advisable
but difficult to achieve. Thus far there is no evi-
dence for a particular threshold blood pressure
level that will provide a renoprotective effect in
patients with diabetes.
tion, the occurrence of cardiac events tended to be
lower with nitrendipine than with placebo but be-
cause of the small numbers this approximately
25% difference was not statistically significant.
Thus, both ACE inhibitors and calcium channel
antagonists seem to be equally effective in reduc-
ing macrovascular complications in hypertensive
patients with type 2 diabetes.
The Heart Outcomes Prevention Evaluation
(HOPE) study,[9] which was stopped prematurely
on the recommendation of the independent data
safety and monitoring board, convincingly showed
the benefit of ramipril versus placebo for the reduc-
tion of cardiovascular events and overt nephropa-
thy in patients with diabetes. Ramipril lowered the
risk of major cardiovascular outcomes by 25 to
30% in high-risk, middle-aged individuals with di-
abetes, many of whom but not all were hyperten-
sive. The cardiovascular benefit was greater than
that attributable to the decrease in blood pressure
since the reduction in diastolic blood pressure was
only 3mm Hg on average. Recently, this study
group reported a significant reduction of stroke in
patients with diabetes receiving ramipril compared
with placebo.[10]
The subgroup analysis of patients with diabetes
from the Captopril Prevention Project (CAPPP)
trial,[11] found a lower rate of fatal cardiovascular
events in the captopril than conventional (diuretic
and β-blocker) treatment group. The rate of myo-
cardial infarctions was 66% lower in the captopril
group than in the comparison group. The frequency
of all cardiac events and total mortality was also
lower in the captopril group, suggesting that ACE
inhibition is particularly appropriate for the treat-
ment of hypertension in patients with diabetes.[9]
In a newer analysis of the patients with diabetes,
the macrovascular endpoint occurred significantly
less frequently among those receiving captopril
than among those in the control group (relative risk
[RR] = 0.59; p = 0.02). The difference was attrib-
utable to fewer cardiac events among captopril-
treated patients, but there was no difference in
strokes. Blood pressure level was approximately
the same in both patient groups.[12]
1. Prevention of Macrovascular
Complications
In the United Kingdom Prospective Diabetes
Study (UKPDS) the effective reduction of arterial
blood pressure was shown to be beneficial in pa-
tients with type 2 diabetes in reducing the macro-
vascular outcomes,[5] but the ACE inhibitor used
(captopril) was not superior to other antihyperten-
sives.[6] Tight control of blood pressure signifi-
cantly reduced vascular complications in the
UKPDS study, but no firm conclusions can be
drawn as to whether ACE inhibition prevents
macrovascular complications in hypertensive pa-
tients with diabetes more efficiently than other
antihypertensive regimens.
The Swedish Trial in Old Patients with Hyper-
tension (STOP)-2 trial,[7] showed that among pa-
tients with diabetes lowering of blood pressure
with an ACE inhibitor to the same levels as with a
calcium channel antagonist, β-blocker or diuretic,
reduced the primary study end-points similarly.
However, a post-hoc analysis suggested that the
incidence of non-fatal myocardial infarction was
reduced more with ACE inhibitors than with cal-
cium antagonist treatment; on the other hand, there
was a tendency for a lesser reduction in strokes
during ACE inhibitor treatment. However, adjust-
ing for multiple comparisons when analysing sec-
ondary outcomes in subgroups would make these
small differences statistically non-significant and
clinically they are not significant either. The placebo-
controlled Systolic Hypertension in Europe (Syst-
Eur) trial[8] showed that patients with diabetes who
have isolated systolic hypertension treated with the
calcium channel antagonist nitrendipine had sig-
nificantly reduced total and cardiovascular mortal-
ity, stroke and all cardiovascular events. In addi-
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Drugs 2002; 62 (14)

ACE Inhibitors and Diabetic Complications
2009
It is evident from these studies that achievement
of low blood pressure is not easy to accomplish
with a single drug. Frequently three and more
drugs are needed to reach the blood pressure tar-
get.[6] The use of polypharmacy for the lowering
of blood pressure makes the judgement about
which drug or combination of drugs the beneficial
outcome can be mostly attributed, difficult. Al-
though ACE inhibitors are often cited as the first
line of therapy in hypertensive patients with dia-
betes, early prescription of a combination of anti-
hypertensive drugs is necessary. It is unclear at the
moment in which order calcium channel antago-
nists, β-blockers and diuretics should be added and
how the baseline clinical characteristics of the pa-
tient influence the choice of the physician.[13]
well as a 50% reduction in death and end-stage
renal disease over a 4-year follow-up.[17]
The Candesartan and Lisinopril Microalbum-
inuria (CALM) study,[18] comparing the ACE in-
hibitor and angiotensin II AT1 receptor antagonist
effects on blood pressure and albumin excretion,
and combination of these drugs, established that
lisinopril and candesartan cilexetil were as effec-
tive in reducing blood pressure and urinary albu-
min excretion in hypertensive patients with type 2
diabetes. Importantly, the combination of both
classes of drugs was more effective in reducing
blood pressure (about twice) and albuminuria, and
was well tolerated.
The Appropriate Blood pressure Control in Di-
abetes (ABCD) trial in patients with type 2 diabe-
tes found treatment of hypertension with enalapril
more efficient in preventing cardiovascular events
(especially myocardial infarction) than treatment
with nisoldipine.[19] But the study was not able to
show any difference in incidence of nephropathy
in hypertensive patients regardless of the intensity
of treatment or the agent used (ACE inhibitor or
calcium channel antagonist).[20] However, more
recently, the study group reported that a signifi-
cantly lower percentage of the 480 originally
normotensive patients with type 2 diabetes in the
intensively treated group (diastolic blood pressure
75mm Hg) progressed from normoalbuminuria to
microalbuminuria and from microalbuminuria to
albuminuria, experienced stroke or progression of
retinopathy than those in the moderately treated
group (diastolic pressure 80 to 89mm Hg).[21] The
choice of medication still made no difference.
A study from Israel investigated the effect of
enalapril versus placebo on the renal function and
albuminuria in normotensive-normoalbuminuric
patients with type 2 diabetes.[22] Enalapril treat-
ment was significantly superior to placebo during
the 6-year, double-blind, prospective study in pre-
serving renal function as judged both by the creat-
inine clearance and albumin excretion.
2. Development of
Diabetic Nephropathy
Diabetic nephropathy is the most common
cause of end-stage renal disease in the developed
world. High blood pressure is the main determi-
nant for diabetic nephropathy. While any lowering
of blood pressure reduces the risk of nephropa-
thy,[14] ACE inhibitors have been demonstrated to
be renoprotective in patients with type 1 diabetes
and are now the standard of care for both hyper-
tensive and non-hypertensive patients with type 1
diabetes used in everyday practice in patients ex-
hibiting any level of proteinuria. The benefit of
antihypertensive therapy with an ACE inhibitor in
patients with type 1 diabetes can be demonstrated
early in the course of the disease when micro-
albuminuria is the only clinical manifestation. In
one study, the administration of an ACE inhibitor
to normotensive patients with type 1 diabetes with
microalbuminuria decreased both albumin excre-
tion and progression to overt diabetic nephropathy
when compared with patients treated with pla-
cebo.[15] Lisinopril appears to slow the progression
of renal disease in normotensive patients with type
1 diabetes with little or even no albuminuria.[16] In
patients with type 1 diabetes with overt nephropa-
thy captopril was associated with a substantial re-
duction in the rate of decline in renal function as
Using a modelling approach, real data from
conducted trials and some assumptions, it has been
proposed that treating all persons with newly diag-
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Drugs 2002; 62 (14)

2010
Podar & Tuomilehto
nosed type 2 diabetes with an ACE inhibitor might
be the most cost-effective strategy for the preven-
tion of end-stage renal disease.[23]
in normotensive patients with type 1 diabetes and
retinopathy.[29] Retinopathy was evaluated using a
five-level scale. Retinopathy progressed by one
level in 13.2% of patients receiving lisinopril ver-
sus 23.4% of those receiving placebo. Lisinopril
also decreased progression by two or more levels
by 73% and the progression to proliferative retin-
opathy by 82% compared with placebo. Tight
blood pressure control in the UKPDS study signif-
icantly reduced the progression of diabetic retinop-
athy,[5] but treatment with captopril did not lead to
a superior outcome compared with atenolol.[6]
There is also evidence to contradict the efficacy of
ACE inhibitors compared to calcium channel an-
tagonists for slowing the development of retinop-
athy.[20]
The mechanism by which ACE inhibitors might
inhibit the progression of retinopathy beyond
blood pressure lowering is undefined. ACE is pro-
duced locally by vascular endothelial cells in ret-
ina,[30] which may have direct detrimental effects
on retinal blood flow and vessels, independent of
decrease in systemic arterial blood pressure. In-
creased intraocular generation of ACE could lead
to the increased production of vascular endothelial
growth factors that are involved in the angiogenic
process of proliferative retinopathy.[31] Large scale
randomised studies must be performed before
these drugs can be recommended as superior to
other antihypertensive agents for halting retin-
opathy.
Recent studies have shed light on the potential
mechanism of how ACE inhibitors exert their
renoprotective action.[24] This renoprotective ac-
tion appears to be in part independent of the effect
on systemic blood pressure which explains the ben-
efits also found in normotensive patients with dia-
betes. The intrarenal renin-angiotensin system is
activated in individuals with diabetes by a yet un-
known mechanism. The renoprotection is largely
attributable to their local renin-angiotensin system
inhibition in kidneys, by the dilation of renal effer-
ent arterioles, reducing the intraglomerular pres-
sure. However, angiotensin II is also produced in
the kidneys by non-ACE enzymes and thus angio-
tensin II AT1 receptor antagonists might provide
even greater benefit. The ultimate purpose of the
use of ACE inhibitors in microalbuminuric pa-
tients with diabetes is not just to reduce the albu-
min excretion rate or to prevent its progression per
se but also to prevent a future decline in glomerular
filtration rate, which would otherwise accelerate in
the majority of these patients. The Irbesartan Dia-
betic Nephropathy Trial (IDNT)[25] and Irbesartan
Microalbuminuria (IRMA)-2 study[26] both evalu-
ated the use of the AT1-receptor antagonist ir-
besartan and showed a significant preventive effect
on the progression of renal disease in patients with
type 2 diabetes. Another AT1-receptor antagonist
losartan may also be beneficial compared with β-
blockers for the reduction of cardiovascular mor-
bidity and mortality in patients with diabetes based
on the conclusion from the recent Losartan Inter-
vention For Endpoint reduction in hypertension
(LIFE) study.[27]
4. Diabetic Neuropathy
It has been demonstrated in animal diabetes
models that the ACE inhibitor lisinopril can have
an ameliorating effect on neuropathy. Lisinopril
was shown to normalise the motor conduction ve-
locity,[32] improve sensory conduction velocity
and normalise hypoxic resistance.[33] It was con-
cluded that the beneficial preventative effect of
lisinopril is likely to depend on a reduction of per-
ipheral vascular resistance and improvement of
tissue blood flow. However, there are few studies
in humans. A study involving 13 individuals re-
ported a significant improvement in nerve conduc-
3. Diabetic Retinopathy
It is unclear if ACE inhibitors have the same
benefit in diabetic retinopathy as they do in neph-
ropathy. A preliminary report in 20 normotensive
patients suggested that captopril might be as-
sociated with some benefit.[28] A more recent
randomised trial assessed the efficacy of lisinopril
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Drugs 2002; 62 (14)

ACE Inhibitors and Diabetic Complications
2011
tion velocity, temperature discrimination threshold,
and vibration perception threshold measurements
after 12 weeks lisinopril therapy.[34] A positive ef-
fect of ACE inhibition has also been documented on
autonomic neuropathy.[35] Quinapril significantly
increased parasympathetic activity in patients
with diabetes which might lead to the reduction
of the risk for malignant ventricular arrhyth-
mias. The effect of trandolapril on diabetic neu-
ropathy was assessed in 41 normotensive patients
with diabetes who were randomly assigned to
trandolapril or placebo. The patients receiving
trandolapril had modest but significant improve-
ment in several measures of peroneal and sural nerve
physiology, but no effect on vibration perception
threshold or autonomic function was seen.[36]
sion of both micro- and macrovascular complica-
tions in patients with diabetes mellitus. ACE inhib-
itors are useful antihypertensive agents in both
type 1 and type 2 diabetes; however, ACE inhibitor
therapy often needs to be supplemented with cal-
cium channel antagonists, β-blockers or diuretics
to achieve good blood pressure control. ACE in-
hibitors are also indicated in non-hypertensive pa-
tients with type 1 and type 2 diabetes who have
micro- or macroalbuminuria. The effect of ACE
inhibitors in halting the development and progres-
sion of retinopathy and, potentially, neuropathy
needs further proof in large-scale studies. More re-
cently, angiotensin II receptor blockers are emerg-
ing as drugs with the potential to be successfully
included in the management of diabetic complica-
tions, especially when ACE inhibitors are not suit-
able because of adverse effects.
5. Potential Prevention/Amelioration
of Diabetes
Acknowledgements
There are few data suggesting ACE inhibitors
may not only benefit patients with known diabetes
but also reduce the development of diabetes among
individuals free of diabetes at the start of treat-
ment.[11,37] However, in the former study[11] the
conventional treatment regimen included β-block-
ers and that may have contributed to the deteriora-
tion of asymptomatic glucose tolerance. There
have been hints that ramipril use may improve glu-
cose control in patients with diabetes compared
with placebo.[9] It appears that also AT1-receptor
antagonists may reduce the risk of developing di-
abetes in patients with hypertension compared
with β-blockers.[38] Again, these are findings from
post-hoc analyses and it will take several years be-
fore we will have more decisive data from new
trials addressing this issue as the primary question.
Two recently initiated studies, DREAM (Diabetes
Reduction with an ACE-Inhibitor and other Med-
ication) and ONTARGET (Ongoing Telmisartan
Alone and in Combination with Ramipril Global
Endpoint Trial) are currently evaluating this issue.
The authors received funding for the preparation of this
manuscript from the Academy of Finland (grant 46558). The
authors have no conflicts of interest that are directly relevant
to the content of this manuscript.
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Evidence suggests that ACE inhibitors can be
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© Adis International Limited. All rights reserved.
Drugs 2002; 62 (14)

2012
Podar & Tuomilehto
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Correspondence and offprints: Professor Jaakko Tuomilehto,
Diabetes and Genetic Epidemiology Unit, Department of
Epidemiology and Health Promotion, National Public
Health Institute, Mannerheimintie 166, Helsinki, FIN-
00920, Finland.
E-mail: jaakko.tuomilehto@ktl.fi
© Adis International Limited. All rights reserved.
Drugs 2002; 62 (14)