Asian Cardiovasc Thorac Ann 2003;11:180-184
© 2003 Asia Publishing EXchange Ltd
Diabetes and Vascular Disease: a New International Trial
Anushka Patel, FRACP,
John Chalmers, MD,
Vivek Chaturvedi, MD,
Rochelle Currie, NZROT,
Helen Monaghan, BSc(Hons),
Bruce Neal, PhD
International Coordinating Centre for ADVANCE, Institute for International Health, University of Sydney, Sydney, New South Wales, Australia
For reprint information contact: Anushka Patel, FRACP Tel: 61 2 9351 0031 Fax: 61 2 9351 0008 email: apatel{at}iih.usyd.edu.au Institute for International Health, University of Sydney, P.O. Box 576, Newtown, NSW 2042, Australia.
 |
ABSTRACT
|
|---|
The prevalence of diabetes is increasing, particularly in developing regions of the world. The social and economic consequences of this disease and its complications are enormous. We discuss the scope and implications of the increasing burden of diabetes and describe the rationale and design of a new international study examining blood pressure lowering and glucose control interventions aimed at reducing the risk of vascular complications in people with type 2 diabetes. This study is the first large-scale randomized trial in diabetes to include participants from both lower- and higher-income regions of the world.
|
INTRODUCTION
|
|---|
Diabetes mellitus is a major worldwide public health problem of growing importance, particularly in developing countries. The Global Burden of Diabetes study1 estimates that the worldwide prevalence of adult diabetes was 4.0% in 1995 and projects that this will increase to 5.4% by 2025. In absolute terms, these figures equate to a 42% increase in the number of affected adults in high-income nations and a corresponding 170% increase in developing countries (Figure 1
). Given the estimates of population growth over this period, it is anticipated that there will be approximately 300 million adult diabetics worldwide by 2025, of whom 228 million will reside in developing countries.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 1. Projected percentage increase in the number of adults with diabetes, 1995–2025.1 EME = established market economies, FSE = former Socialist economies of Europe, LAC = Latin America and the Caribbean, MEC = Middle Eastern crescent, OAI = other Asia and islands, SSA = sub-Saharan Africa.
|
|
Much of the disease is and will continue to be observed in the heavily populated and increasingly urbanized low- and middle-income countries of Asia Pacific, the Middle East, and Latin America. India and China already have the largest number of adult diabetics in absolute terms, and proportionate increases over the next couple of decades will also be greatest in these 2 countries. In Asia, recent estimates of the prevalence of adult diabetes range from between 2.6% and 4.5% in rural and urban China;2 between 6.5% and 12.4% in urban India;3 more than 6.1% in certain urban regions of Indonesia;4 10.5% in the Kelantan state of Malaysia;5 about 9.0% in Singapore;6 13.9% in urban Thailand;7 to as much as 17.9% among certain Taiwanese ethnic groups.8 In addition, many studies also provide evidence of large numbers of individuals with impaired glucose tolerance.2,3,5,6
Another important feature of the ongoing epidemic of diabetes concerns the age structure of the adult diabetic populations in developing countries compared with that of higher-income nations. Currently, the prevalence of diabetes in developing countries peaks in the economically productive 45- to 64-year age group, compared with 65 years and above in developed regions (Figure 2). Future projections suggest that this difference will be accentuated.1
View larger version (16K):
[in this window]
[in a new window]
|
Figure 2. Projected age distribution of adults with diabetes in developed and developing countries, 2025.1
|
|
|
CONSEQUENCES OF DIABETES
|
|---|
Diabetes is associated with serious microvascular diseases (retinopathy, nephropathy, and neuropathy) as well as at least a two- to threefold increase in the risk of developing macrovascular diseases, such as myocardial infarction and stroke. These risks are well documented in Caucasian populations,9 and there is an increasing body of evidence that suggests similar associations in other populations. The Asia Pacific Cohort Studies Collaboration, an overview of prospective data including several tens of thousands of individuals from Australasia and East Asia, found that diabetes was associated with a relative risk of 2.19 (95% confidence interval, 1.81–2.66) of developing fatal coronary heart disease and 2.02 (95% confidence interval, 1.57–2.59) of fatal stroke.10 For both these outcomes, the relative risk of vascular disease associated with diabetes was greater in younger than in older individuals.
The socioeconomic consequences of diabetes and its associated complications are likely to be enormous, particularly for countries with limited resources and a persisting burden of communicable and maternal/perinatal diseases. It is estimated that in the world’s largest economy, the USA, the total medical expenditure on diabetics in 1997 was approximately quadruple that spent on nondiabetics on a per capita basis.11 Much of these costs relate to managing the vascular sequelae of the disease using sophisticated and expensive technologies, many of which poorer nations do not possess or cannot afford to use to a similar extent. While an important long-term goal is primary prevention of diabetes, there is an immediate and ongoing need to develop effective and relatively low-cost means of preventing diabetic complications.
|
MAJOR RISK FACTORS FOR VASCULAR COMPLICATIONS IN DIABETES
|
|---|
One of the most important determinants of vascular disease in diabetes is blood pressure. A large body of epidemiologic data suggests that the association between systolic blood pressure and the risks of both macro- and microvascular diseases is positive and continuous, with no definite lower level of blood pressure below which the vascular risks fail to decline further. This association is well illustrated in observational data from the United Kingdom Prospective Diabetes Study.12 This study found that each 10 mm Hg lower level of systolic blood pressure (between the range of below 120 mm Hg to above 160 mm Hg) was associated with an approximately 12% lower incidence of myocardial infarction. A similar observation is made when examining unpublished data from the Asia Pacific Cohort Studies Collaboration. These data collectively suggest that blood pressure lowering in diabetes may be extremely important in all populations, regardless of pretreatment levels of blood pressure.
Randomized clinical trials of blood pressure lowering among hypertensive individuals with type 2 diabetes have confirmed the benefits of treatment on both macro- and microvascular outcomes.13–17 There is some limited evidence from overviews of these trials that more intensive blood pressure lowering among hypertensive individuals results in greater benefits.16 Furthermore, the Heart Outcomes Prevention Evaluation study17 demonstrated that prolonged treatment with an angiotensin converting enzyme (ACE) inhibitor was associated with a significant reduction in the risk of vascular diseases in both hypertensive and nonhypertensive diabetic patients. The extent to which the observed effects are independent of blood pressure reduction remains unclear.
Another major determinant of vascular risk in diabetes is the level of glucose control. Epidemiologic data again show a continuous relationship between the degree of glucose control (as measured by the concentration of the glycosylated hemoglobin HbA1c) and the risk of vascular disease, with no clear "threshold" effect.18 The most reliable interventional data relating to glycemic control in type 2 diabetes currently available is from the United Kingdom Prospective Diabetes Study.19 The trial demonstrated that more intensive glucose lowering (achieving an average HbA1c level of 7.0% in the intervention group versus 7.9% in the control group) was associated with a significant reduction in microvascular disease (mostly retinopathy), but clear effects on the incidence of macrovascular disease were not observed.
A number of important issues relating to the management of both blood pressure and glucose levels in type 2 diabetes remain unresolved. First, is routine blood pressure lowering important in diabetes, even in those considered normotensive? Second, how important is blood pressure lowering on a background of ACE inhibitor therapy? Third, what is the balance between risks and benefits of intensive glucose lowering on the incidence of macrovascular disease? Fourth, will even more intensive glucose lowering than achieved in previous studies have even greater beneficial effects on the incidence of microvascular disease? Finally, what are the combined effects of intensive blood pressure lowering and glucose control on vascular risks in type 2 diabetes? The ADVANCE study20 (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) provides an opportunity to address these issues.
|
DESIGN OF THE ADVANCE STUDY
|
|---|
ADVANCE is a 2 x 2 factorial randomized controlled study examining the effects of blood pressure lowering and intensive glucose control on the incidence of macro- and microvascular diseases among 10,000 adults with type 2 diabetes. The overall design of the study is illustrated in Figure 3. The inclusion criteria for the study are broad: eligible participants include any individuals aged 55 years and above at study entry diagnosed with type 2 diabetes and at an increased risk of cardiovascular disease. The risk criterion can be fulfilled by the presence of at least one of a number of risk factors, including age of at least 65 years at study entry, diagnosis of diabetes for 10 years or more, history of macro- or microvascular disease, current cigarette smoking, high total cholesterol level, low level of high-density lipoprotein cholesterol, or microalbuminuria. There are no blood pressure criteria for study entry. In broad terms, participation is excluded by a definite indication for or contraindication to study treatment or by the need for long-term regular insulin therapy at study entry.
Following a 6-week run-in period of active blood pressure lowering therapy (perindopril 2 mg combined with indapamide 0.625 mg), eligible participants who tolerate and are adherent to therapy are randomized in a factorial design to 2 treatment comparisons. The first is a double-blind comparison of blood pressure lowering with a fixed-dose combination of perindopril 4 mg and indapamide 1.25 mg versus a matching placebo. The second is an open-label comparison of glucose control between an intensive regimen based on modified-release gliclazide with a target HbA1c level of 6.5% or less and a strategy based on standard local guidelines. The use of other concomitant therapies for both blood pressure and glucose control is largely unrestricted. Importantly, this includes the use of ACE inhibitors: if at any time (including at study entry) a participant has or develops an indication for ACE inhibitor therapy, this will be provided in the form of background perindopril 2 or 4 mg, to be taken in addition to the randomized blood pressure lowering treatment. Other blood pressure lowering therapies are also mostly unrestricted, except for the use of thiazide-like diuretics. Management of the glucose control strategy is essentially at the discretion of the responsible clinician, with the exception that if a sulfonylurea is used in the "standard strategy" group, it must not be gliclazide.
Participants in the study will be followed for an average of 4.5 years. There are 2 primary outcomes in the study for each of the treatment comparisons: a macrovascular composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death; and a microvascular composite outcome of new or worsening nephropathy or diabetic retinopathy. All primary events will be centrally adjudicated by an independent endpoint committee blinded to treatment allocation. The study is designed to provide at least 90% power to detect a 16% or greater reduction in the relative risk of each of the primary outcomes for each of the treatment comparisons (with 
= 0.05 and assuming a 3% or more annual event rate among participants in the control groups).
|
STUDY ORGANIZATION AND STATUS
|
|---|
This investigator-initiated and conducted study is centrally coordinated by the Institute for International Health in Sydney, Australia. Data management is provided by the Clinical Trials Research Unit in Auckland, New Zealand; and regional coordination is managed by centers located in Beijing, London, Melbourne, Montreal, and Utrecht. The regional participation in the study is summarized in Table 1. Pilot-phase recruitment commenced in Australia in June 2001, and recruitment was completed in March 2003 with 11,140 participants randomized from 216 clinical centers in 20 countries. Participant follow-up will continue until June 2006, with the reporting of preliminary results anticipated in 2007.
|
CONCLUSION
|
|---|
Diabetes is a major health problem worldwide. The social and economic consequences of this disease are enormous, thus efforts towards its prevention as well as developing cost-effective interventions to reduce the impact of its complications are vital. The ADVANCE study, the first large-scale randomized clinical trial in diabetes to include participants from low- to high-income countries, is designed to provide more reliable evidence regarding the use of blood pressure lowering and glucose control therapies in patients with type 2 diabetes. As a consequence of its pragmatic design and broad inclusion criteria, this study should provide results that have wide implications for the clinical management of high-risk individuals with diabetes.
|
Acknowledgments
|
|---|
The ADVANCE study is supported by grants from Institut de Recherches Internationales Servier and the National Health and Medical Research Council of Australia.
|
REFERENCES
|
|---|
- King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care
1998;21:1414–31.[Abstract]
- Wang ZZ, Huang XZ, Tang SB, Chen YM, Chen LG, Jin ZX, et al. The prevalence of NIDDM and IGT and related factors among residents in some areas of Hubei Province, China. Biomed Environ Sci
2000;13:148–53.[Medline]
- Mohan V, Shanthirani S, Deepa R, Premalatha G, Sastry NG, Saroja R. Intra-urban differences in the prevalence of the metabolic syndrome in southern India — the Chennai Urban Population Study (CUPS No. 4). Diabet Med
2001;18:280–7.[Medline]
- Sutanegara D, Budhiarta AA. The epidemiology and management of diabetes mellitus in Indonesia. Diabetes Res Clin Pract
2000;50(Suppl 2):9–16.
- Mafauzy M, Mokhtar N, Mohamad WB, Musalmah M. Diabetes mellitus and associated cardiovascular risk factors in north-east Malaysia. Asia Pac J Public Health
1999;11:16–9.[Medline]
- Lee WR. The changing demography of diabetes mellitus in Singapore. Diabetes Res Clin Pract
2000;50(Suppl 2):35–9.[Medline]
- Puavilai G, Kheesukapan P, Chanprasertyotin S, Chantraraprasert S, Suwanvilaikorn S, Nitiyanant W, et al. Random capillary plasma glucose measurement in the screening of diabetes mellitus in high-risk subjects in Thailand. Diabetes Res Clin Pract
2001;51:125–31.[Medline]
- Chen KT, Chen CJ, Gregg EW, Engelgau MM, Narayan KM. Prevalence of type 2 diabetes mellitus in Taiwan: ethnic variation and risk factors. Diabetes Res Clin Pract
2001;51:59–66.[Medline]
- Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care
1995;18:258–68.[Abstract]
- Asia Pacific Cohort Studies Collaboration. The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region. Diabetes Care
2003;26:360–66.[Abstract/Free Full Text]
- American Diabetes Association. Economic consequences of diabetes mellitus in the U.S. in 1997. Diabetes Care
1998;21:296–309.[Abstract]
- Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ
2000;321:412–9.[Abstract/Free Full Text]
- Lièvre M, Gueyffier F, Ekbom T, Fagard R, Cutler J, Schron E, et al.; INDANA Steering Committee. Efficacy of diuretics and beta-blockers in diabetic hypertensive patients. Results from a meta-analysis. Diabetes Care
2000;23(Suppl 2):B65–71.
- Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, et al.; Systolic Hypertension in Europe Trial Investigators. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med
1999;340:677–84.[Abstract/Free Full Text]
- UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ
1998;317:703–13.[Abstract/Free Full Text]
- Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet
2000;356:1955–64.[Medline]
- Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet
2000;355:253–9.[Medline]
- Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ
2000;321:405–12.[Abstract/Free Full Text]
- UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet
1998;352:837–53.[Medline]
- ADVANCE Management Committee. Study rationale and design of ADVANCE: Action in Diabetes and Vascular Disease — Preterax and Diamicron MR Controlled Evaluation. Diabetologia
2001;44:1118–20.[Medline]
TOP
ABSTRACT
INTRODUCTION
