Original ArticleIntensive Glucose Control and Cardiovascular Outcomes in Type 2 Diabetes
Introduction
The incidence of diabetes is increasing worldwide mainly though an increase in the prevalence of type 2 diabetes which accounts for >90% of all diagnosed cases. An Australian community based study estimated the prevalence of diabetes at 7.6% in 2000 with a predicted increase to 11.4% by 2025 if current trends continue [1]. In the United States, the prevalence of diabetes based on the 2005–2006 National Health and Nutrition Examination Survey (NHANES) was estimated at 12.9% [2].
The major causes of morbidity and mortality in subjects with diabetes are related to the development of cardiovascular (CV) disease, especially coronary heart disease (CHD). It is well established that subjects with type 2 diabetes are at a two- to four-fold increased risk of CV disease compared to people without diabetes. This risk persists even after accounting for traditional CV risk factors such as smoking, hypertension and dyslipidaemia. Indeed, in the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab), known diabetes (hazard ratio 2.6, 95% CI: 1.4–4.7) and even impaired fasting glucose (hazard ratio 2.5, 95% CI: 1.2–5.1) were independent predictors for CV mortality after adjustment for age, sex, and other traditional CV risk factors [3]. Such a finding suggests that this residual increased risk for vascular disease could be ascribed directly or indirectly to elevated glucose levels. Although cholesterol and blood pressure lowering trials have demonstrated a CV benefit in subjects with type 2 diabetes, the effects of intensive glucose control, aimed at achieving glucose levels close to those of euglycaemia, remain uncertain.
In this article we focus on the results of recent trials that have examined the relationship between intensive glucose control and CV outcomes in ambulatory subjects with type 2 diabetes.
Section snippets
Results from Observational Studies
Observational studies have generally shown a linear relationship between elevated glucose levels and increased CV mortality. However, for levels of glycaemia near or below the threshold for diabetes, the relationship has been described as continuous [4], a threshold [5] or “J-shaped” [6] depending on the measure of glycaemia used.
For approximately 10,000 individuals without diagnosed diabetes, the AusDiab Study reported a continuous increased risk for CV mortality with increasing two-hour
The United Kingdom Prospective Diabetes Study (UKPDS) Glucose Interventional Study
In the glucose interventional arm of the UKPDS, 3867 newly diagnosed subjects with type 2 diabetes were randomised to an intensive glucose control policy involving the use of sulfonylureas or insulin and a conventional policy based on lifestyle management. Over the 10-year period of the trial, intensively treated patients achieved a mean HbA1c of 7.0% compared with conventionally treated patients, who only achieved a mean HbA1c level of 7.9%. This degree of intensive glucose control was
Recent Intensive Glucose Control Trials
As most patients without diabetes have an HbA1c level below 6.5%, the question remained after the completion of the UKPDS in 1997 as to whether targeting HbA1c levels close to the non-diabetic range might still result in a significant reduction in CV events. Therefore, given the uncertainty as to whether intensive glucose control could reduce the risk of CV outcomes in subjects with type 2 diabetes, three large interventional trials were started to compare the effects of intensive versus
The ACCORD Study
In the ACCORD trial, 10,251 patients with established type 2 diabetes and at high risk of CV events were randomised to receive intensive glucose control (targeting an HbA1c < 6.0% and achieving a level of 6.4%) or standard therapy (targeting an HbA1c 7.0–7.9% and achieving a level of 7.5%). Numerous glucose-lowering therapies from a variety of drug classes were sequentially added in an attempt to achieve intensive glucose control. The unexpected finding of a higher CV mortality rate (hazard ratio
The ADVANCE Study
As opposed to the ACCORD trial, two other studies, the ADVANCE and VADT studies have found that intensive glucose control is not associated with higher CV or all-cause mortality rates. The ADVANCE trial, was designed to assess the effects of randomising 11,140 patients with established type 2 diabetes to intensive glucose control, achieving a mean HbA1c of 6.5%, or standard control, achieving an HbA1c of 7.3% [13]. Subjects in the intensive glycaemic arm all received modified-release gliclazide
The VADT Study
In the VADT study, 1791 North American veterans were randomised to intensive or standard glucose control. A variety of glucose-lowering medications, including metformin, glimepiride, rosiglitazone and insulin were used in an attempt to achieve a HbA1c target of <6.0% in the intensive control arm [14]. During the trial, intensive glucose control achieved a HbA1c of 6.9%, whereas standard control was associated with a HbA1c of 8.4%. After a median follow-up period of 5.6 years, the primary
The UKPDS Follow-up Study
After the UKPDS randomised intervention trials were completed in 1997, all surviving subjects entered into a post-trial monitoring program until 2007 [16]. At the end of the randomised trials all subjects were returned to usual physician care to continue the management of their diabetes. No attempts were made to keep the subjects in their randomised groups and the UKPDS investigators did not influence the management of subjects previously enrolled in the trial. Between 1997 and 2002, subjects
Results from Other Interventional Studies
Two other randomised trials warrant mention when considering the question as to whether intensive glucose control reduces CV events in type 2 diabetes. The first is the Kumamoto study that involved 110 subjects with type 2 diabetes who were randomised to receive intensive or less intensive insulin therapy [20]. Subjects enrolled in this trial had a duration of diabetes that ranged from 6 to 11 years and were followed over eight years mainly for the development and progression of microvascular
Results from Recent Meta-analyses
At least four meta-analyses that have included the results from the ACCORD, ADVANCE and VADT studies have been published since 2009. A summary of the main characteristics and findings of these analyses is presented in Table 2. The first study by Ray et al., combined the results of the UKPDS-33 (intensive glycaemic control with sulphonylurea and insulin versus conventional control) and the UKPDS-34 (intensive glycaemic control with metformin versus conventional control in overweight subjects)
The Pathological Effects of Hyperglycaemia on the CV System
Multiple indirect or direct pathways that result in accelerated atherosclerosis have been proposed to explain the deleterious effects of elevated glucose levels on the CV system. Indirect pathways promoted by hyperglycaemia include worsening of dyslipidaemia, especially the development of atherogenic dyslipidaemia (small dense low-density lipoproteins, reduced high density lipoproteins and increased triglyceride levels), sympathetic nervous system dysfunction and the development of chronic
Summary
In summary, the individual results from three recent trials have shown that, in the context of the current approach to reducing CV risk in subjects with established type 2 diabetes, involving blood pressure reduction, aggressive use of statins and anti-platelet therapies, a beneficial effect of glucose lowering alone cannot be shown. However, four meta-analyses that included results from these randomised trials have shown that intensive glucose control is associated with a significant reduction
References (27)
- et al.
Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study
Lancet
(2010) - et al.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
Lancet
(2005) - et al.
Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials
Lancet
(2009) - et al.
Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials
Nutr Metab Cardiovasc Dis
(2009) - et al.
Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies
Lancet
(2008) - et al.
Lifetime risk and projected population prevalence of diabetes
Diabetologia
(2008) - et al.
Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006
Diabetes Care
(2009) - et al.
Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab)
Circulation
(2007) - et al.
Blood glucose and risk of cardiovascular disease in the Asia Pacific region
Diabetes Care
(2004) - et al.
Glycemic control and coronary heart disease risk in persons with and without diabetes: the atherosclerosis risk in communities study
Arch Intern Med
(2005)
Low fasting plasma glucose level as a predictor of cardiovascular disease and all-cause mortality
Circulation
Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study
Diabetologia
Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study
BMJ
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