Original Article
Intensive Glucose Control and Cardiovascular Outcomes in Type 2 Diabetes

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Numerous observational studies have clearly shown a relationship between hyperglycaemia and cardiovascular (CV) disease. However, the United Kingdom Prospective Diabetes Study (UKPDS), which involved subjects with newly diagnosed type 2 diabetes, just failed to show that intensive glucose control significantly reduces CV events. The results of three subsequent large randomised controlled trials, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and the Veterans Administration Diabetes Trial (VADT), that involved approximately 25,000 subjects with established type 2 diabetes also failed to show that intensive glucose control, aiming for a glycated haemoglobin (HbA1c) level < 7%, significantly reduces CV events. The ACCORD trial even suggested that under certain circumstances, intensive glucose control is associated with an increased risk for CV and all-cause mortality. Although the exact mechanisms responsible for an increase in mortality in the ACCORD trial remain unknown, there was an association between increased rates of mortality with higher rates of severe hypoglycaemia in the intensive glucose control group. In contrast, a 10-year post-randomisation follow-up study of the tight glucose intervention arm of the UKPDS showed that intensive glucose control was associated with a significant reduction in the risk for myocardial infarction (MI), diabetes-related deaths and all-cause mortality. This suggests that early strict glucose control generates a legacy effect that is eventually translated into protection from CV events. Recent meta-analyses of the above randomised trails have also shown that intensive glucose control is associated with a reduced risk of MI, without a clear benefit on other CV diseases such as stroke. Furthermore, these analyses have also shown that intensive glucose control is associated with increased rates of severe hypoglycaemia but not increased rates of CV or all-cause mortality. Aiming for HbA1c levels of <7.0% still remains the general target for good glucose control. Under certain circumstances, aiming for lower HbA1c levels may be appropriate. This applies in the setting of newly diagnosed diabetes in relatively young individuals without significant co-morbidities and in patients treated with agents that minimise the risk of severe hypoglycaemia such as metformin. Whether this also applies to newer glucose-lowering agents that target the incretin system will depend on CV outcomes of long-term studies which are in progress.

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

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