REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
10
VOLUME 7 NUMBER 1 • MARCH 2010
side effects in patients on combined dual renin–angiotensin
system blockade. However, the number of patients in the
CALM trial was only 199 and the side effects suffered by
patients in this study cannot necessarily be extrapolated to
a wider population. Patients undergoing dual blockade of
the renin–angiotensin system are at risk of potentially life-
threatening hyperkalaemia, which must be borne in mind by
prescribers and patients.
A newer class of drug has recently been licensed in the
United Kingdom with the advent of aliskiren, the first orally
available direct renin inhibitor. A recently published study
of aliskiren combined with losartan demonstrated a 20%
reduction in albumin:creatinine ratio compared with losartan
treatment alone when 599 hypertensive diabetic patients with
nephropathy were randomly assigned to the two treatment
groups and followed up for three months.
17
Several studies have used glomerular filtration rate
to define early diabetic nephropathy rather than simply
microalbuminuria. One such study, the DETAIL trial, enrolled
patients with type 2 diabetes, hypertension and early
nephropathy (glomerular filtration rate
<
70 ml/min/1.73 m
2
).
This study demonstrated that telmisartan was not inferior to
enalapril in the primary study outcome, which was the fall
in renal function over a five-year follow-up period.
18
A head-
to-head trial of the relative benefits of ACE inhibitors and
ARBs is unlikely and most physicians use these drug classes
interchangeably dependent on personal preferences and
according to patient side effects.
Macroalbuminuria and overt diabetic nephropathy
Once patients have reached the stage of overt diabetic
nephropathy, defined by proteinuria or abnormal renal
function, their annual death rate increases significantly.
Even at this stage the benefit of renin–angiotensin system
blocking agents has been demonstrated in studies designed
to demonstrate if renal function could be preserved. In type 1
diabetic patients (
n
=
409)withmacroalbuminuria (proteinuria)
and a serum creatinine
<
221
µ
mol/l, who were randomised
to receive captopril or placebo with a three-year follow-up,
the captopril group had a 50% reduction in the composite
end point of death, dialysis or transplantation which was
independentofthesmalldifferenceinachievedbloodpressure.
19
In the IDNT study of 1 715 hypertensive type 2 diabetic
patients with proteinuria patients were randomised to receive
placebo, 10 mg amlodipine or 300 mg irbesartan. With a
mean follow-up of 2.6 years there was a 20% reduction
against placebo and a 23% reduction against amlodipine for
the composite end point of doubling of serum creatinine,
end-stage renal disease and death in the irbesartan treated
group demonstrating the benefits of irbesartan even at this
stage of diabetic nephropathy.
20
The RENAAL trial randomised
1 513 similar patients to receive either losartan (50–100 mg)
or placebo with a 3.4-year follow-up. A 16% risk reduction
was observed for the losartan treated group in the primary
composite end point of doubling serum creatinine, end-stage
renal disease and death.
21
Disappointingly neither of these
trials could demonstrate a risk reduction in the secondary
end point of cardiovascular events.
The ACE gene itself has an important influence on
outcome in renal impairment. The homozygous deletion
(D/D) ACE gene polymorphism is a marker for increased risk
of atherosclerotic complications and nephropathy in diabetic
patients.
22
A recent analysis of ACE gene polymorphism in
the RENAAL trial showed that patients with the D allele in
the placebo group were more likely to reach the composite
end point of doubling of serum creatinine or reaching end-
stage renal disease. In the patients treated with losartan in
the RENAAL trial there was no correlation between ACE gene
polymorphism and renal outcome suggesting that losartan
may ameliorate the deleterious effect of the D allele of the ACE
gene.
23
Effects of ACE inhibitors have previously been shown
to be influenced by the insertion/deletion polymorphism of
the ACE gene in a study investigating progressive albuminuria;
in this study patients with the I/I polymorphism were found
to have the most benefit from lisinopril treatment.
24
Whilst
several studies and meta-analyses have demonstrated
the decreased risk of diabetic nephropathy in patients
with the II ACE gene polymorphism compared to the DD
polymorphism,
22,25
there are also studies which did not find
this association and the effects of the ACE gene polymorphism
on blood pressure itself are not clearly understood.
General measures to reduce cardiovascular risk
General measures to reduce cardiovascular risk are of
paramount importance in patients with diabetic nephropathy.
Smoking is a predictor of diabetic nephropathy
26
and
smokers must be given full assistance to give up as part of
the reduction of their cardiovascular risk profile. Aspirin, a
healthy diet, weight loss and regular exercise are all measures
which may be employed on an individual patient basis.
The role of lipid lowering is unproven in patients with
advanced diabetic nephropathy: in a trial of type 2 diabetic
patients on haemodialysis, atorvastatin did not lead to a
reduction in cardiovascular death, non-fatal myocardial
infarction or stroke.
27
However, this study may have been
confounded by the poor cardiac status of participating
patients and it seems counterintuitive to deny patients lipid-
lowering medications when their cardiovascular risks are so
high. Indeed some studies have shown a reduction in the
progression of diabetic nephropathy with statin therapy.
28
SHARP, a study of the effects of lowering cholesterol with
a combination of simvastatin and ezetimibe on the risk of
major vascular complications in patients with chronic kidney
disease, is currently underway. However, until this study
reports the evidence base for treating lipids in patients with
chronic kidney disease is weak.
The role of dietary protein restriction is uncertain in
patients with advanced renal impairment because of fears of
malnutrition.
However, there is some evidence that dietary protein
restriction to 0.8 g/kg/day may have a beneficial effect on
renal function and microalbuminuria in patients with diabetic
