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Nephropathy in type 2 diabetes: current therapeutic strategies
University of Melbourne Department of Medicine, St. Vincent’s Hospital, Victoria, Australia
Diabetic nephropathy is currently the commonest cause of end-stage renal failure in
most countries with a Western lifestyle. In addition to progressing to end-stage renal disease, patientswith type 2 diabetes and nephropathy are at especially high risk of cardiovascular death. A multi-faceted approach, aiming not only to slow the progression of renal dysfunction but also to reducethe risk of associated complications, particularly cardiovascular disease, is advocated. Current evidence-based guidelines serve a useful adjunctive role in providing target levels for therapeuticintervention.
nephropathy, type 2 diabetes, treatment.
type 2 diabetic patients is not only important for assess-ing risk of overt nephropathy, but also because of the
Diabetic nephropathy, currently the commonest cause of
close association between microalbuminuria and cardio-
end-stage renal failure in most countries with a Western
vascular disease,4 the leading cause of death in these
lifestyle, has reached catastrophic dimensions.1 In addi-
tion to progressing to end-stage renal disease, patients
Annual screening for microalbuminuria should com-
with type 2 diabetes and nephropathy are at an especially
mence at diagnosis in all patients with type 2 diabetes to
high risk of cardiovascular death. Strategies for the early
permit early intervention and to review associated
identification and treatment of diabetic nephropathy
conditions, in particular cardiovascular disease and
and its associated pathology have been developed and
retinopathy.8 In the Microvascular Outcomes in People
are constantly being updated in the light of new evidence
with Diabetes Mellitus Substudy: of the Heart Out-
comes Prevention Evaluation (MICRO-HOPE) Study,angiotensin-converting enzyme (ACE) inhibitor treat-ment provided protection from cardiovascular events
EARLY IDENTIFICATION AND
and also reduced progression to overt nephropathy in
patients with type 2 diabetes and microalbuminuria.9Current evidence-based options in patients with type 2
Diabetes is unique as a cause of renal dysfunction in that
diabetes would therefore include the use of an ACE
its development may be predicted a decade in advance
inhibitor in normotensive microalbuminuric patients
by the detection of small quantities of urinary albumin
to provide cardiovascular protection,9 and the use of
termed microalbuminuria.2 While approximately 80% of
either an ACE inhibitor or angiotensin receptor blocker
patients with type 1 diabetes and microalbuminuria will
(ARB) in hypertensive microalbuminuric patients to
progress to overt nephropathy over a 10-year period, in
slow the progression from microalbuminuria to overt
the type 2 diabetic patient only 20–50% of patients will
progress.3–7 However, detection of microalbuminuria in
Correspondence: Richard E. Gilbert, Associate Professor of Medi-
Control of blood pressure (BP) is of paramount impor-
cine, University of Melbourne Department of Medicine, St. Vincent’s
tance in slowing the progression of diabetic nephropa-
Hospital, 41 Victoria Parade, Fitzroy, Victoria, 3065, Australia. E-mail:firstname.lastname@example.org
thy. The US-based Joint National Committee (JNC)-VI
Accepted for publication 14 May 2001.
guidelines suggest a target blood pressure of < 130/85 in
patients with type 2 diabetes.12 However, in the presence
Appropriate adjunctive therapy should be guided by
of nephropathy with > 1 g/day proteinuria, a target BP of
patient considerations but could include b-blockers,
< 125/75 is advocated. Similarly, the US National
CCBs, diuretics and ARBs as these agents have been
Kidney Foundation, has suggested that on the basis of
shown to reduce proteinuria and/or cardiovascular
recent evidence, a target blood pressure of 130/80 is
A role for b-blockers in the diabetic patient, parti-
cularly those at high cardiovascular risk has emerged following the recent findings of the UK Prospective Diabetes Study (UKPDS) in which both ACE inhibitors
CHOICE OF ANTIHYPERTENSIVE DRUG
and b-blockers were shown to have cardioprotectiveeffects beyond that due to blood pressure reduction
Evidence from large, well conducted, double-blind,
placebo-controlled, clinical trials has repeatedly shown
While the use of CCBs in patients with diabetes, par-
the efficacy of blockade of the renin-angiotensin-aldos-
ticularly the dihydropyridines, has been the subject of
terone system as a key therapeutic strategy in reducing
controversy, several recent studies indicate that these
the progression of diabetic nephropathy. In patients with
agents reduce cardiovascular events in the hypertensive
nephropathy and type 1 diabetes, captopril treatment
diabetic patient.18–20 However, when compared directly
was associated with a 50% reduction in the risk of the
with ACE inhibitors, as in the Appropriate Blood Pres-
combined endpoints of death, dialysis and transplanta-
sure Control in Diabetes (ABCD) study21 and Fosinopril
tion that was independent of the small disparity in blood
vs. Amlodipine Cardiovascular Events Trial (FACET)
pressure between the groups.14 In type 2 diabetic patients
Trial,22 dihydropyridine CCBs provide less cardiovascu-
with nephropathy, two recent trials have shown that the
lar protection, although a post hoc
analysis of FACET
angiotensin II receptor blockers (ARBs) are also effec-
suggested a favourable response to a combination of ACE
tive as renoprotective agents. In the Irbesartan Diabetic
Nephropathy Trial (IDNT), 1715 patients were ran-
The combination of an ACE inhibitor with an ARB
domized to receive either the ARB, irbesartan, the
may also be useful in the diabetic patient as suggested in
calcium channel blocker (CCB), amlodipine, or placebo.
the Candesartan And Lisinopril in Microalbuminuria
All patients also received additional conventional anti-
(CALM) trial, showing an additive effect on blood pres-
hypertensive medication (non-ACE, non-ARB, non-
CCB) as required to control blood pressure. Patientsrandomized to receive irbesartan were 20% less likely(P
= 0.02) to reach a composite endpoint of progression
of renal disease or death when compared with placebo,and 23% (P
= 0.006) less likely when compared with
There is a clear relationship between glycaemic control
amlodipine.15 Similarly, in the Reduction of Endpoints
and both the development, and the progression of dia-
in Non-Insulin-Dependent Diabetes Mellitus with the
betic nephropathy in type 1 and type 2 diabetes.23 Gly-
Angiotensin II Antagonist Losartan (RENAAL) Study,
caemic control should be optimized, aiming for a target
1513 patients with type 2 diabetes and nephropathy were
haemoglobin A1c of 7.0% in most patients. In addition
randomized to receive either the ARB, losartan, or
to sulphonylureas, metformin and acarbose, new oral
placebo, with conventional blood pressure medication
hypoglycaemic agents have recently become available
(non-ACE, non-ARB) added as necessary to control
which should assist with attaining good glycaemic
hypertension. After an average of 3.4 years, patients
control. These agents include the insulin-sensitizing,
randomized to receive losartan were 16% less likely
PPARg agonist thiazolidendiones (rosiglitazone and
= 0.02) to reach a composite endpoint of doubling of
pioglitazone) as well as nonsulphonylurea, insulin secre-
serum creatinine, end-stage renal disease (ESRD) or
tagogues such as repaglinide and neteglinide.24 Further-
death.16 Neither IDNT nor RENAAL included an ACE
more, the development of insulin analogs with more
inhibitor treatment arm. Thus, the relative efficacy of
predictable profiles and the advent of inhaled insulin are
ACE inhibitors and ARBs in type 2 diabetic nephropa-
likely to make attaining target HbA1c levels easier with
Second-line antihypertensive agents
In clinical practice, achieving recommended blood pres-
Many patients with type 2 diabetes and nephropathy will
sure targets will frequently necessitate the use of multi-
have significant coronary artery disease, although this
ple antihypertensive drugs, with participants in clinical
will often be clinically silent. Indeed, most patients with
trials requiring an average of 3.2 different medications.13
type 2 diabetes and nephropathy will die from cardio-
vascular disease rather than from renal failure per se
reduce the risk of associated complications, particularly
Optimization of all cardiovascular risk factors such as
cardiovascular disease. Current evidence-based guide-
dyslipidaemia is therefore an important aspect in the
lines serve a useful adjunctive role in providing target
management of patients with diabetic nephropathy. As
levels for therapeutic intervention.
suggested by the recent consensus conference of theAmerican Heart Association, patients with diabetesshould be managed as a coronary disease equivalent with
regard to the treatment of risk factors.25 This is especiallythe case for patients with nephropathy, where an optimal
Richard Gilbert is the recipient of a Career Development
lipid profile should be sought including a suggested target
Award and Darren Kelly is the recipient of a Post Doc-
toral Fellowship, both from Juvenile Diabetes Founda-
Furthermore, some pilot experimental and clinical
studies have also suggested that the HMGCoA reductaseinhibitors may also have favourably influence the courseof diabetic nephropathy, independent of their effects oncirculating lipoproteins.26
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