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Diabetes and Cardiovascular Risk
Cardiovascular Risk in Type 2 Diabetes – Reflecting on the ADVANCE Study
Sophia Zoungas,
1
John Chalmers
2
and Anushka Patel
3
1. Senior Research Fellow, Cardiovascular and Renal Divisions, The George Institute for International Health, University of Sydney, and
School of Public Health, Monash University, Melbourne; 2. Director, Professorial Unit, The George Institute for International Health, University of Sydney;
3. Director, Cardiovascular Division, The George Institute for International Health, University of Sydney
Abstract
The world is facing an unprecedented increase in type 2 diabetes. Most disability and premature mortality experienced by patients with
diabetes is related to vascular disease and, in particular, macrovascular disease (such as coronary heart disease and stroke) and
microvascular disease (such as retinopathy, nephropathy and neuropathy). Indeed, around 1.9 million cardiovascular deaths worldwide are
attributable to high blood glucose levels and diabetes, as well as to their associated dangerous companions of high blood pressure and
abnormal lipid levels. The global economic costs of diabetes, including foregone economic growth and increasing healthcare expenditure,
are substantial and are anticipated to grow. Therefore, strategies to reduce disease burden have continued to focus on reducing
cardiovascular risk. Recently, a number of large-scale clinical trials have evaluated approaches for managing cardiovascular risk in patients
with type 2 diabetes. Among them the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation
(ADVANCE) trial has reported the effects of blood pressure lowering and intensive glucose control on major vascular events in patients
with established type 2 diabetes. In this article we summarise the findings of the ADVANCE trial and discuss its relevance to the
management of cardiovascular risk in patients with type 2 diabetes worldwide.
Keywords
Type 2 diabetes, cardiovascular risk, mortality, complications, blood pressure treatment, glycaemic control, clinical trials
Disclosure: Sophia Zoungas, John Chalmers and Anushka Patel have received lecturing fees from Servier. John Chalmers holds a research grant from Servier as principal
investigator for ADVANCE. Sophia Zoungas is supported by a National Health and Medical Research Council of Australia Health Professional Research Fellowship. Anushka Patel
is supported by a National Heart Foundation of Australia Career Development award.
Received: 27 April 2009 Accepted: 16 July 2009
Correspondence: Sophia Zoungas, Cardiovascular Division, The George Institute for International Health, University of Sydney, PO Box M201, Missenden Road, Sydney,
NSW 2050, Australia. E: szoungas@george.org.au
Summary of the ADVANCE Trial Findings stroke and cardiovascular death) and major microvascular events
The ADVANCE trial was a factorial, randomised study of 11,140 (new or worsening nephropathy and microvascular eye disease),
individuals with type 2 diabetes from over 200 collaborating centres analysed jointly and separately. The average duration of follow-up
in 20 countries from Asia, Australasia, Europe and North America. was 4.3 years for the BP-lowering intervention and five years for
Participants with either a history of macrovascular or microvascular the glucose control intervention.
1,2
disease or at least one major risk factor for cardiovascular disease
and any initial level of blood pressure (BP) and blood glucose were In the BP-lowering arm of the study, the mean entry BP of
randomly assigned to the fixed combination of the angiotensin- participants was 145/81mmHg, with over 40% recording a BP below
converting enzyme (ACE) inhibitor perindopril and the thiazide 140/90mmHg.
1
Over the duration of active treatment, BP was
diuretic indapamide (4/1.25mg) or matching placebo and to reduced by a mean of 5.6/2.2mmHg compared with placebo. At the
intensive glucose control or standard guideline-based glucose end of follow-up the mean BP achieved was 134.7/74.8mmHg in the
control.
1,2
The glucose-lowering regimen for those randomised to active treatment group and 140.3/77.0mmHg in the placebo group
intensive glucose control was based on the modified-release (see Figure 1).
1
Active treatment reduced the risk of the combined
sulphonylurea gliclazide-MR 30–120mg daily. However, non- composite primary outcome of macrovascular and microvascular
pharmacological approaches, other oral agents and insulin were events by 9% (95% confidence interval [CI] 0–17; p=0.043). The
recommended to be added as required to achieve the target effects on major macrovascular events considered separately were
glycated haemoglobin (HbA
1c
) level of ≤6.5%.
2
The choice of of similar magnitude but not statistically significant (see Figure 2).
1
additional treatments was left to the discretion of the responsible Among those on active treatment, there was a 14% (95% CI 2–25;
physician. Participants randomised to standard guidelines-based p=0.025) reduction in all-cause mortality, driven by an 18% (95% CI
glucose control were permitted to use sulphonylureas (other than 2–32; p=0.027) reduction in cardiovascular mortality, as well as
gliclazide) and any other available glucose-lowering therapy, reductions in coronary events (14%; p=0.02) and renal events (21%;
including insulin. The primary outcomes were composites of major p=0.0001). No statistically significant reductions were observed in
macrovascular (non-fatal acute myocardial infarction, non-fatal cerebrovascular events or microvascular eye disease. There was no
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