ReviewReducing cardiovascular risk in diabetes: Beyond glycemic and blood pressure control
Introduction
Type 2 diabetes, as an increasingly common chronic illness with an accompanying risk of cardiovascular complications, continues to be a global health priority. The number of adults with diabetes worldwide reached 171 million in 2000, and is expected to more than double by 2030 [1]. The data for parts of Asia and Africa are of even more concern; by 2025, the number of adults with diabetes in these regions is expected to rise by almost 200%. Approximately 80% of all diabetes-associated mortalities, as well as most hospitalizations, can be attributed to cardiovascular complications [2].
Patients with diabetes who have not had a myocardial infarction (MI) previously may have as high a risk for cardiovascular events as patients without diabetes who have experienced a prior MI [3]. Although other observational studies have not confirmed this ‘coronary risk equivalence’ of diabetes, some degree of acceleration of vascular risk is undisputed and once diabetes has become established, then this risk will approach that of existing coronary heart disease (CHD). Indeed, while CHD mortality rates in the United States have declined significantly in patients without diabetes (− 36% in males, − 27% in females), in the decade between National Health and Nutrition Examination Surveys I and II, patients with diabetes showed markedly less improvement (− 13% in males, + 23% in females), especially women [4]. This trend, coupled with the increasing prevalence of diabetes, represents an alarming prospect for patients with diabetes and calls for more active and effective management of cardiovascular disease (CVD) risk in this population.
Patients with type 2 diabetes are at this increased risk for CVD, and are more likely to experience severe or fatal CVD, because of a convergence of powerful risk factors. Risk factors frequently associated with diabetes include dyslipidemia, hypertension, insulin resistance, and obesity. In patients with diabetes, dyslipidemia is often particularly atherogenic, characterized by the combination of mild-to-moderate hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C) levels and low-density lipoprotein cholesterol (LDL-C) levels similar to those in patients without diabetes, but with a larger proportion of more atherogenic, small, dense low-density lipoprotein [5]. In 2001, the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines re-graded the elevated cardiovascular risk (a > 20% risk for developing CHD within 10 years) associated with type 2 diabetes and designated diabetes as a CHD risk equivalent [6]. This also was advocated in 2003 in the revised European Joint Task Force guidelines for CVD prevention [7]. In an update to the NCEP ATP III guidelines in 2004, [8] a new category of “very high risk” persons was introduced, which included patients with concomitant CHD and diabetes. In 2005, the American Diabetes Association (ADA) likewise categorized patients with diabetes and existing CVD as very high risk [9].
Data from the United Kingdom Prospective Diabetes Study (UKPDS) suggested that, in patients with diabetes, there would be a 30% reduction in risk of MI for each 1 mmol/l (39 mg/dl) decrease in LDL-C [10]. Mounting evidence indicates that lipid lowering substantially reduces CHD risk in patients with multiple risk factors whose cholesterol levels are at or near current guideline targets, [11], [12], [13] and evidence for this benefit in patients with diabetes was demonstrated by the results from the Collaborative Atorvastatin Diabetes Study (CARDS), which will be discussed in detail in Section 6, below [14]. Thus, guidelines recommend aggressive cholesterol-lowering therapy, not only for patients with CHD, but also for patients with diabetes.
In the NCEP ATP III guidelines, emphasis was also placed on the metabolic syndrome, a potential precursor to diabetes, as a secondary target of therapy after lowering LDL-C, and this syndrome has provoked much research interest. The NCEP ATP III guidelines define the metabolic syndrome as the presence of three or more of the stipulated risk factors, which include abdominal obesity, elevated triglycerides, hypertension, high levels of fasting glucose, and low levels of HDL-C. However, it is not yet determined whether cardiovascular risk in persons with the metabolic syndrome is independent of the associated risk factors [15], [16]. For this reason, the American Diabetes Association and the European Association for the Study of Diabetes recently released a statement advising that all CVD risk factors should be evaluated and treated regardless of whether the patient can be diagnosed with the metabolic syndrome, and expressed doubt about the value of the metabolic syndrome as a marker for cardiovascular risk [17]. This review therefore focuses on the known cardiovascular risks in patients with diabetes, whilst highlighting the potential future importance of metabolic syndrome in further categorizing risk.
Section snippets
Lipid abnormalities and atherosclerosis in type 2 diabetes
Obesity is a major risk factor for diabetes and dyslipidemia. Insulin resistance of fat cells and impaired insulin-mediated skeletal muscle uptake of free fatty acids underlie diabetic dyslipidemia. Insulin resistance causes fat cells to undergo greater breakdown of their stored triglycerides and a greater release of free fatty acids into the circulation. Increased availability of fatty acids to the liver results in synthesis of triglycerides, cholesteryl esters, and very low-density
Reducing cardiovascular risk in patients with type 2 diabetes
The first priority in the treatment of diabetes is glycemic control. As the UKPDS demonstrated, intensive glycemic control in patients with type 2 diabetes was associated with a significant reduction in diabetes-related end points [21]. The reduction was mainly in microvascular disease (i.e., damage to the smallest blood vessels as occurs in retinopathy). The impact on macrovascular disease (i.e., damage to large blood vessels as occurs in CVD) was of borderline statistical significance.
Altering the lipid profile in patients with type 2 diabetes
Interventions to improve glycemic control usually lower triglyceride and LDL-C levels only modestly (up to 10–15%), necessitating further efforts to bring lipids to target levels [5], [37]. Several classes of drugs targeted specifically at lipid lowering (statins, fibrates, niacin, and cholesterol absorption inhibitors) have shown efficacy in diabetic dyslipidemia. Efficacy of these agents appears to be comparable in patients with and without diabetes, but differs both across and within drug
Guidelines for reducing CVD risk in patients with type 2 diabetes
Guidelines for lipid management in diabetic patients have been developed, based primarily on data from analyses of the diabetic populations in major primary and secondary prevention trials. The current treatment guidelines suggest intervention through diet, exercise, lifestyle modifications, glycemic control and, when required, lipid-lowering pharmacological therapy. The NCEP ATP III, ADA, and the Third Joint European Task Force suggest that a minimal LDL-C goal of < 2.6 mmol/l (100 mg/dl) is
Role of intensive lipid lowering in patients with type 2 diabetes
In the primary and secondary prevention trials using statins, the efficacy of statins was demonstrated across varied populations (men and women, young and older patients, patients with diabetes, and patients with varying risk for developing CHD). Recent trials have presented evidence for more aggressive LDL-C-lowering intervention in selected populations. A significant reduction in risk for the primary end point was observed with intensive atorvastatin 80 mg vs. moderate pravastatin 40 mg
Summary
The focus in diabetes has tended to be on control of blood glucose alone, and only recently on the control of blood pressure. However, because of the high risk and more serious consequences of CVD in this population–and because of the empirical evidence that this risk can be safely and effectively reduced by available therapies–emphasis increasingly is placed on CVD prevention in patients with diabetes. Post hoc analysis of landmark primary and secondary prevention trials and the recent data
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