Home > Education > Publications

		Literature Compendium

Current Concepts in Type 2 Diabetes

Volume 3
Special Considerations in the Management of Diabetes and Its Complications

Chapter 1
Global Cardiovascular Risk Factors in Type 2 Diabetes

Global cardiovascular risk, sometimes called cardiometabolic risk, is the probability of developing cardiovascular disease (CVD) within a defined period of time, taking into account several risk factors simultaneously. The concept of global cardiovascular risk is gaining wide acceptance today because the multifactorial and inter-related nature of diabetes, hypertension, atherosclerosis, and obesity is becoming better understood.

Global cardiovascular risk is characterized by the presence of abdominal obesity, atherogenic dyslipidaemia, hypertension, pre-diabetes (impaired glucose tolerance or impaired fasting glucose) or diabetes, a prothrombotic state, and a proinflammatory state. It delineates the cardiovascular risk commonly associated with obesity but not covered by traditional risk factors and describes the unanticipated clustering of cardiovascular risk factors associated with altered metabolism.

One of the most important health problems facing the world’s population today is the combined impact of obesity, diabetes, and CVD. Hence, it is critical that physicians and other health care providers understand the predictive relationship between metabolic risk factors and CVD and use aggressive intervention strategies to prevent or delay the progression of disease. Recent scientific and clinical findings have increased our understanding of the importance of diagnosing cardiometabolic risk factors and managing them with lifestyle and pharmacological approaches. In this chapter, Lorenzo and colleagues¹ discuss the relationship between derangements in cardiometabolic health and the risk of developing CVD.

Lorenzo and colleagues¹ evaluated the predictive value of metabolic syndrome with regard to CVD and diabetes risk. These investigators analyzed the risks associated with 3 different definitions of metabolic syndrome—those established by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the International Diabetes Federation (IDF), and the World Health Organization (WHO)—and compared them with NCEP ATP III multiple risk factor categories and 2-hour glucose values in the San Antonio Heart Study. They found that the NCEP ATP III definition of metabolic syndrome predicted incident CVD risk independently of age, sex, ethnicity, history of CVD and Type 2 diabetes, and family history of heart attack. All 3 definitions of metabolic syndrome had similar odds ratios, but the IDF definition had a greater sensitivity (except for the comparison with the NCEP ATP III definition in men) than the NCEP ATP III or WHO definition but also had a greater false-positive rate. Metabolic syndrome imparted a lower CVD risk than coronary heart disease (CHD) or CHD risk equivalents, which the investigators attributed to the lower false-positive rate of the latter. Metabolic syndrome did not predict new CVD events in individuals with CHD and/or CHD risk equivalents. In individuals who were free of CHD or CHD risk equivalents, all 3 definitions of metabolic syndrome had similar odds ratios. The investigators concluded that metabolic syndrome—whether established by the NCEP ATP III, IDF, or WHO definition—is associated with significant CVD risk, particularly in men ≥45 years of age and women ≥55 years of age, and increases CVD risk in individuals who are free of either CVD or diabetes. Based on the results of this study, clinicians can use metabolic syndrome to identify persons who are free of CHD and/or CHD risk equivalents but who are at increased risk for future CVD.

People with Type 2 diabetes are at increased risk for a number of vascular-related health problems, including CVD, early death, blindness, renal failure, and amputations. Current guidelines recommend lowering glycated haemoglobin to <7 % for most individuals with Type 2 diabetes to reduce microvascular and neuropathic complications and possibly macrovascular disease. These recommendations are based on epidemiological analysis and limited trials that have shown an association between degree of hyperglycaemia, as measured by plasma glucose or glycated haemoglobin, and serious health problems. The large-scale Action to Control Cardiovascular Risk in Diabetes (ACCORD)² and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)³ trials were specifically designed to directly assess the effect of intensive glucose control on major vascular outcomes in individuals with Type 2 diabetes. Eagerly awaited updates of these 2 trials were published in mid-2008 and reported contrasting findings. These updates are presented in this chapter and should generate continued discussion among those treating Type 2 diabetes.  

The National Heart, Lung, and Blood Institute of the National Institutes of Health stopped the intensive glycaemic control treatment arm of the ACCORD study² 17 months early because of safety concerns. This North American study randomized 10,251 individuals with Type 2 diabetes, an HbA_1c level ≥7.5 %, and established cardiovascular disease or multiple cardiovascular risk factors to intensive glucose control (target HbA_1c,
<6.0 %) or standard glucose control (target HbA_1c, 7.0 % to 7.9 %). The primary outcome was a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular-related death. Subsets of individuals were also randomized to blood pressure or lipid interventions. Baseline characteristics included a mean age of 62.2 years, a median HbA_1c of
8.1 %, and Type 2 diabetes for a median duration of 10 years. At a mean follow-up of 3.5 years, the use of intensive treatment, as compared with standard treatment, was associated with a higher number of deaths and no significant reduction in cardiovascular risk. Differences in mortality appeared 1 to 2 years following randomization. The intensive-therapy group had a significantly higher incidence of hypoglycaemia, weight gain, and fluid retention. The reason for the higher mortality rate was not determined, although the study concluded that neither hypoglycaemia nor any single drug therapy or combination of drug therapies played a role. Those individuals receiving intensive therapy were shifted to standard therapy, and the blood pressure and lipid interventions were continued.

In ADVANCE,³ carried out in 20 countries in Asia, Australasia, Europe, and North America, 11,140 individuals with Type 2 diabetes were randomized to intensive or standard glucose control and blood pressure lowering therapy irrespective of initial blood pressure level or placebo. Intensive control was defined as an HbA_1c level ≤6.5 % based on the use of the sulfonylurea gliclazide (modified release) and other drugs (except for other sulfonylureas) as needed. Primary outcomes were a composite of major macrovascular events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular-related death) and a composite of microvascular events (new or worsening nephropathy or retinopathy), analyzed both jointly and separately. A broad cross-section of individuals with Type 2 diabetes were included and at baseline had a mean age of 66 years, mean HbA_1c of 7.5 %, and mean 8-year duration of Type 2 diabetes. After a median follow-up of 5 years, intensive control, as compared with standard control, resulted in a significant reduction in the combined outcome of microvascular and macrovascular events and in major microvascular events but not in major macrovascular events. There was no significant difference between the 2 groups in the rate of cardiovascular-related death. The 21% relative reduction in the risk of new or worsening nephropathy was the main contributor to the 10% reduction in the combined primary outcome. The intensive group had a greater risk of severe hypoglycaemia and hospitalization.

ACCORD and ADVANCE are important contributions to the study of Type 2 diabetes because they were designed with adequate power to explicitly examine the effect of lowering HbA_1c to a tighter level than usual on major vascular outcomes. Release of more results from these 2 studies as well as analysis of their combined data may provide a clearer understanding of this relationship. 

References

1. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program-Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care. 2007;30:8-13.

2. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.

3. The Advance Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.

Click to proceed to Chapter 2.
Click to proceed to Chapter 3.
Click to proceed to Chapter 4.
Click to proceed to Programme Evaluation and Post-test.

Click to return to Opening Page.
Click to return to Table of Contents.
Click to return to Introduction.

The Literature Compendium is funded by an educational grant from Pfizer Inc.

Return to Education homepage