Академический Документы
Профессиональный Документы
Культура Документы
& 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00
www.nature.com/jhh
ORIGINAL ARTICLE
ADVANCE: action in diabetes and vascular
disease
A Patel1, J Chalmers1 and N Poulter2
1
The George Institute for International Health, The University of Sydney and The Royal Prince Alfred
Hospital, Sydney, NSW, Australia; 2Department of Clinical Pharmacology, Cardiovascular Studies Unit,
St Marys Hospital Campus, Imperial College, London, UK
The burden of Type II diabetes is growing rapidly participants by March 2003, the study is currently half
worldwide, across high-, middle- and low-income coun- way through its planned follow-up of 4.5 years. Adher-
tries. This burden is associated primarily with increased ence to randomised study treatment is good; and loss to
risks of macrovascular and microvascular diseases, and follow-up is minimal. It is hoped that the study will
it is agreed that multifactorial treatment regimens are answer a number of unresolved issues. The blood
required to reduce it. ADVANCE (Action in Diabetes and pressure lowering arm will investigate the possible
Vascular disease: Preterax and Diamicron-MR Con- reduction in major vascular disease in patients with
trolled Evaluation) is a large-scale, 2 2 factorial, Type II diabetes whether or not they have hypertension,
randomised clinical trial. It will investigate the potential and the possible benefits of blood pressure lowering in
benefits of blood pressure lowering, using a fixed low- such patients already receiving background therapy
dose combination of perindopril and indapamide vs with the ACE inhibitor perindopril. The glucose control
placebo, and of tighter glucose control, using an arm will investigate the possible reduction in both
intensive gliclazide-MR-based glucose control regimen macrovascular and microvascular disease achieved
vs a standard guidelines-based regimen, separately and with tighter glucose control, targeting an HbA1c of
together. The two primary outcomes are a composite 6.5% and a fasting blood glucose of 6.0 mmol/l. Finally,
macrovascular end point of nonfatal stroke, nonfatal the factorial design will enable investigation of the
myocardial infarction and cardiovascular death; and a combined effects of more intensive glucose control and
composite microvascular end point of new or worsening tighter control of blood pressure.
nephropathy or microvascular eye disease. Following Journal of Human Hypertension (2005) 19, S27S32.
successful recruitment and randomisation of 11 140 doi:10.1038/sj.jhh.1001890
Keywords: blood pressure lowering; glycaemic control; perindopril; indapamide; Diamicron MR; fixed dose combination
Introduction: diabetes a global health and rising: total medical expenditure on patients
problem with diabetes in the USA in 1999 was four times
greater than expenditure in people without dia-
Diabetes is a major health problem afflicting mil- betes.4 The management of Type II diabetes and the
lions of people across high-, middle- and low- prevention of its complications is a high priority for
income countries.1 Individuals with Type II diabetes public health authorities in all nations.
have markedly increased risks of both macrovascu- Blood pressure and blood glucose levels are
lar disease (including coronary heart disease and among the main determinants of the risk of devel-
stroke) and microvascular disease (including ne- oping both macrovascular and microvascular com-
phropathy and retinopathy).2,3 Globally, coronary plications in patients with diabetes so that blood
disease is the commonest cause of death among pressure control and glycaemic control are para-
subjects with diabetes1 while in high-income coun- mount in this population.
tries diabetes is the leading cause of blindness and
end-stage renal disease.3 While the burden of
diabetes is increasing throughout the world, it is
doing so most rapidly in low- and middle-income Blood pressure glucose and vascular
countries.1,3 Furthermore, the medical costs of disease in Type II diabetes
managing diabetes and its consequences are high Blood pressure control and diabetes: current evidence
Observational data from the UK Prospective Dia-
Correspondence: Professor J Chalmers, The George Institute for
International Health, The University of Sydney, PO Box M201 betes Study (UKPDS)5 demonstrated that each
Missenden Road, Sydney NSW 2050, Australia. 10 mmHg decrement in systolic blood pressure was
E-mail: jchalmers@thegeorgeinstitute.org associated with around a 12% reduction in the risk
ADVANCE
A Patel et al
S28
of myocardial infarction in patients with diabetes. remains considerable uncertainty regarding the
The evidence from randomised trials such as the potential benefits in normotensive patients with
UKPDS and HOT studies6,7 and from meta-analyses diabetes.
such as that conducted by the INDANA group8 has 2. Are such benefits additional to those conferred
shown that blood pressure lowering in hypertensive by background ACE Inhibition? While the reduc-
patients with diabetes reduces the risk of major tions in vascular complications reported for patients
vascular disease, with greater benefits resulting from with Type II diabetes in the HOPE study were
more intensive treatment.68 More recent studies substantial,9 the degree to which these were due to
have shown reductions in the vascular complica- blood pressure lowering or to specific effects of ACE
tions of diabetes using an ACE inhibitor such as inhibition remains debated and uncertain. It is
ramipril (the HOPE Study9) perindopril (the EURO- therefore important to ascertain whether routine
PA trial10) or perindopril and indapamide (the blood pressure lowering patients with Type II
PROGRESS Trial11). The benefits of ACE inhibitor diabetes confers benefits that are additional to these
therapy in patients with diabetes and early mani- of background treatment with an ACE inhibitor,
festations of nephropathy have also been confirmed regardless of the level of blood pressure.
in recent studies and analyses comparing ACE 3. Will more intensive glucose control reduce the
inhibitors with a variety of blood pressure-lowering risk of macrovascular disease? While many diabe-
drugs.1214 The potential benefits of lowering blood tologists fervently believe that more intensive
pressure in nonhypertensive patients with diabetes glucose control, targeting lower levels of HbAlc, will
are less well documented. reduce the risk of major macrovascular disease, the
best available evidence, from the UKPDS trial,
remain inconclusive.20 There is a clear need for
Glycaemic control and diabetes: current evidence fresh evidence from trials of more intensive glucose-
lowering targeting lower levels of HbAlc and fasting
There is only limited evidence on the effects of good
glucose.
glycaemic control on the risk of vascular disease in
4. What are the combined benefits of better blood
Type II diabetes. Observational data from the
pressure control and more intensive glucose control?
UKPDS15 indicated that a reduction in the mean
Finally, while diabetes and hypertension are fre-
glycated haemoglobin Alc (HbAlc) concentration of
quent companions and indeed have been dubbed
1% was associated with a reduction in the risk of
The Bad Companions, there is no clear indication
myocardial infarction of 14% and of microvascular
whether the benefits of more intensive control of
complications of 37%. A recent meta-analysis of
blood pressure and of blood glucose will be
observational data in Type II diabetes, which
additive. Since these two therapeutic strategies are
included UKPDS, indicated that a 1% higher level
currently foremost in the management of patients
of HbA1c was associated with an 18% greater risk of
with Type II diabetes, it is clearly important to
cardiovascular disease.16 More recent evidence from
determine whether each has an independent benefit
the Asia Pacific Cohort Studies Collaboration in-
in reducing macrovascular and microvascular com-
dicates that a 1 mmol/l lower level of plasma glucose
plications.
concentration in patients with diabetes is associated
ADVANCE is a large-scale randomised factorial
with a 21% reduction in stroke and a 23% reduction
clinical trial designed to address these unresolved
in coronary events.17
issues.21
A number of randomised clinical trials have
reported that patients with Type II diabetes assigned
to more intensive glucose lowering exhibited greater ADVANCE: controlling blood pressure
reductions in the incidence of microvascular and blood glucose in Type II diabetes
events.1820 However, even in the largest of these
trials, the effects of glycaemic control on the risk of Study design
macrovascular disease remain inconclusive.20
ADVANCE is an investigator-initiated and -conducted
trial whose study design has been described
Unresolved issues fully elsewhere21 and is briefly presented here. The
study uses a factorial 2 2 design to address
ADVANCE (Action in Diabetes and Vascular disease: separately and together, the potential benefits of
Preterax and Diamicron-MR Controlled Evaluation) blood pressure lowering and of glucose control, in
was planned in 1999 in order to address a number of reducing the risk of macrovascular and microvas-
these issues in the management of patients with cular disease in patients with Type II diabetes.
Type II diabetes that were unresolved at the time
and that remain unanswered today.21 Study participants
1. Are there benefits of blood pressure lowering in Eligible subjects were over 55 years of age at entry,
normotensive patients? While the benefits of blood had a diagnosis of Type II diabetes mellitus first
pressure lowering in hypertensive patients with made at the age of 30 years or older and had an
Type II diabetes have been clearly established, there elevated risk of vascular disease.22 Both hypertensive