The interplay of cardiovascular risk factors in the metabolic syndrome and type 2 diabetes

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1 European Heart Journal Supplements (2004) 6 (Supplement G), G3 G7 The interplay of cardiovascular risk factors in the metabolic syndrome and type 2 diabetes D.J. Betteridge* Department of Medicine, University College London Medical School, London, UK KEYWORDS Cardiovascular disease; Diabetes; Dyslipidaemia; Metabolic syndrome Cardiovascular disease (CVD) is the major cause of morbidity and mortality in the western world, and patients with diabetes have a 2- to 3-fold greater risk of CVD death than those without. This suggests an interaction between diabetes and other CVD risk factors such as hypertension and dyslipidaemia. The treatment of CVD risk factors in patients with diabetes reduces the incidence of CVD death but macrovascular damage is present in patients prior to the onset of overt diabetes, so the early identification and treatment of patients at risk of diabetes is essential for the primary prevention of CVD. Risk factors for diabetes and CVD are more likely to occur simultaneously than would be expected by chance, and this cluster of disorders is collectively called the metabolic syndrome. Individuals with the metabolic syndrome have an increased risk of CVD prior to the development of impaired glucose tolerance and diabetes, and patients with both the metabolic syndrome and diabetes are at greater risk of coronary heart disease death than patients with either diabetes or the metabolic syndrome alone. Although reducing glucose levels significantly reduces the risk of microvascular disease in patients with diabetes and/or the metabolic syndrome, it is not sufficient to significantly reduce the incidence of macrovascular disease. Additional risk factors, including hypertension and dyslipidaemia, must also be targeted in patients with these disorders. c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology. Introduction Cardiovascular disease (CVD) is the major cause of morbidity and mortality in the western world. The identification and early treatment of patients at risk of CVD is essential for the prevention of a first or recurrent cardiovascular (CV) event. Patients with type 2 diabetes and/ or the metabolic syndrome are 2 4 times more likely to develop CVD than patients without. Patients with diabetes have traditionally been treated for hyperglycaemia but it is now recognized that other CVD risk factors, such as dyslipidaemia, hypertension and obesity, must also be treated. Furthermore, since patients with the metabolic * Correspondence: D.J. Betteridge, Department of Medicine, University College London Medical School, London, UK. Tel.: ; fax: / address: j.betteridge@ucl.ac.uk (D.J. Betteridge). syndrome have an increased risk of CVD prior to the development of impaired glucose tolerance (IGT) and diabetes, the syndrome has become the focus for the primary prevention of macrovascular disease. This paper reviews some of the recent trials examining the interplay of risk factors for CVD in patients with the metabolic syndrome and/or type 2 diabetes, and the importance of treating the risk factors in these high-risk patient groups. Patients with type 2 diabetes are at high risk of CVD Type 2 diabetes has become a worldwide epidemic and the number of cases is predicted to increase rapidly over the next 10 years. Patients with type 2 diabetes are at X/$ - see front matter c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology. doi: /j.ehjsup

2 G4 greater risk of stroke and peripheral vascular disease, and are 2 4 times more likely to develop CVD than patients without diabetes. The largest cause of morbidity and mortality in this patient group is macrovascular disease. Patients with type 2 diabetes have reduced survival rates following a myocardial infarction (MI), and have a poorer prognosis following coronary artery bypass graft and percutaneous transluminal coronary angioplasty procedures than patients without diabetes. The emphasis for treating CV risk in this patient group must, therefore, be on primary prevention, which depends on the early identification and treatment of patients at increased CV risk. CVD risk factors in patients with type 2 diabetes Edwin Bierman identified the risk factors for CVD, which underlie diabetes, in These so-called black box factors include hyperglycaemia, which causes macrovascular damage via advanced glycation end-point proteins; oxidative stress and insulin resistance/hyperinsulinaemia; dyslipidaemia; hypertension and haemostatic abnormalities. Hyperglycaemia is an important marker for long-term mortality in patients with acute MI. In a prospective study of 181 patients (mean age 63.5 years with acute MI) Norhammer et al. 2 found that 35% of patients had previously undiagnosed IGT and a further 31% had undiagnosed diabetes at both admission and 3 months later. Since these abnormalities can be detected early in the post-mi period, fasting and post-challenge hyperglycaemia in the early phase of an acute MI can be used to identify high-risk individuals. In the Multiple Risk Factor Intervention Trial (MRFIT), the risk of CVD mortality in men with (n = 5163) and without (n = 342,815) diabetes was increased with raised serum cholesterol levels, systolic blood pressure (SBP) and cigarette smoking. 3 The effects of multiple risk factors on CVD death rates were additive and, in some cases, multiplicative. For each risk factor and combination of risk factors men with diabetes had a 2- to 3-fold greater risk of CVD death than men without diabetes. Although treating risk factors for CVD in patients with diabetes reduces the risk of CVD death, the Nurses Health Study has shown that macrovascular damage occurs prior to the onset of diabetes. 4 In this study, 117,629 female nurses, aged years with normal glucose tolerance at baseline, were screened for CVD risk. Of the 5894 women who developed type 2 diabetes during the 20 years of follow-up, the relative risk (RR) of CVD was 2.82 for the period before the diagnosis and 3.71 for the period after the diagnosis, compared with women who did not develop diabetes. Women with diabetes at baseline had a 5.02 RR of developing CVD. These data indicate that CVD risk reduction is likely to be more effective if patients are treated prior to the onset of diabetes, rather than post-diagnosis. D.J. Betteridge Metabolic syndrome: criteria and prevalence Clustering analysis has shown that risk factors for diabetes and CVD are more likely to occur simultaneously than would be expected by chance, suggesting that they underlie the same metabolic disorders. 5 This cluster of disorders is collectively called the metabolic syndrome a term synonymous with syndrome X, insulin-resistance syndrome, plurimetabolic syndrome and Reaven s syndrome. Since patients with the metabolic syndrome have increased risk of CVD prior to the development of IGT and diabetes, it has become the focus for the primary prevention of macrovascular disease. Until recently, however, there were no unifying criteria for the definition of the metabolic syndrome and so its prevalence and characteristics are not clearly understood. In 1998, the World Health Organization (WHO) defined the syndrome as IGT or type 2 diabetes plus two of the following criteria: hypertension (>160/90 mmhg or on therapy); dyslipidaemia (plasma triglycerides [TGs]>150 mg dl 1, and/or high-density lipoprotein [HDL]-cholesterol <35 mg dl 1 for men and <39 mg dl 1 for women); obesity (body mass index [BMI] >30 kg m 2 and/or waist:hip ratio >0.9 for men and >0.85 for women); microalbuminurea (urinary albumin excretion rate >20 lg/min). 6 For patients without IGT, insulin resistance (defined as the highest quartile of the homeostasis model assessment [HOMA] IC index) is required in addition to two of the criteria. 6 Based on these criteria, the metabolic syndrome was identified in 10% of women and 15% of men with normal glucose tolerance, 42% of women and 64% of men with IGT, and 78% of women and 84% of men with type 2 diabetes. 7 The risk of CVD mortality was significantly increased in individuals with the metabolic syndrome (P < 0.001). 7 More recently, the Third Report of the National Cholesterol Education Program s Adult Treatment Panel (NCEP ATP III), 8 redefined the criteria for the metabolic syndrome as three or more of the following risk determinants: abdominal obesity (waist circumference 120 cm for men and 88 cm for women); raised TGs (>150 mg dl 1 ); low HDL-cholesterol (<40 mg dl 1 for men and <50 mg dl 1 for women); hypertension (>130/85 mmhg) and raised fasting blood glucose (FBG) (>110 mg dl 1 ). It should be noted, however, that the definition of central obesity used in these guidelines is not appropriate for every country. The metabolic syndrome, as defined by the NCEP ATP III criteria, 8 is more common than previously thought, with approximately 44% of Americans over the age of 50 years who participated in the Third National Health And Nutrition Examination Survey (NHANES III) meeting the criteria. 9 Of the NHANES III participants, the lowest prevalence of coronary heart disease (CHD) was observed in patients without the metabolic syndrome, regardless of whether they had diabetes (8.7% prevalence) or not (7.5% prevalence). The metabolic syndrome without diabetes was present in 28.7% of NHANES III participants and the prevalence of CHD in this patient group was 13.9%.

3 Cardiovascular risk factors in metabolic syndrome and type 2 diabetes G5 However, the highest prevalence of CHD (19.2%) occurred in the 14.8% of patients with both the metabolic syndrome and diabetes. Effects of treating risk factors in patients with the metabolic syndrome and/or diabetes It is well established that the treatment of CVD risk factors in patients without the metabolic syndrome and diabetes significantly reduces the incidence of micro- and macrovascular events. A number of studies have been carried out to establish whether the management of CVD risk factors in patients with diabetes reduces risk in a similar way. Hyperglycaemia In the 10-year UK Prospective Diabetes Study (UKPDS), intensive blood glucose control significantly decreased the risk of microvascular complications (predominantly retinal photocoagulation) in patients with newly diagnosed type 2 diabetes. 10 However, the effect on macrovascular disease, in particular MI, was less significant. In UKPDS 3867 patients, median age 54 years, with FBG >6.1 mmol l 1 and <15.0 mmol l 1 and no symptoms of hyperglycaemia, were randomly assigned either conventional dietary treatment or intensive sulphonylurea or insulin treatment. Mean glycated haemoglobin A 1c (HbA 1c ) was reduced to 7.0% in the intensive treatment group compared with 7.9% in the conventional group a reduction of 11%. Intensive treatment significantly reduced microvascular risk by 25% (P = ) compared with conventional treatment, whereas the reduction in MI risk (16%) was only of borderline significance (P = 0.052). In a UKPDS substudy (n = 3642), a 1% reduction in mean HbA 1c, adjusted for possible confounders at diagnosis of diabetes, was associated with a 37% reduction in microvascular complications (P < ) and a 14% reduction in MI (P < ). 11 No threshold of risk was observed for any end-point but the lowest risk was observed in patients with HbA 1c values in the normal range (<6.0%). In both studies, the relationship between glycaemic control and macrovascular disease was less pronounced than that between glycaemic control and microvascular disease. Therefore, although good glycaemic control is important for the reduction of both types of vascular disease, alone it does not have a major impact on reducing the risk of macrovascular disease, and as a result additional risk factors must be treated. Hypertension The risk of diabetic complications is strongly associated with raised SBP. In a study of 3642 UKPDS patients, a 10 mmhg decrease in mean SBP was associated with statistically significant risk reductions of 13% for microvascular disease (P < ) and 11% for MI (P < ). 12 Again, no threshold of risk was observed for any endpoint but the lowest risk was observed in those with SBP <120 mmhg, demonstrating that lowering SBP has a major impact in decreasing macrovascular disease risk in patients with diabetes. Similarly, results from the multi-centre, randomized Hypertension Optimal Treatment (HOT) study suggest a relationship between lowering diastolic blood pressure (DBP) and major CV events. 13 In this study, 1501 patients with diabetes, aged years with mean DBP 105 mmhg, were treated with a calcium channel blocker to target DBPs of 680 mmhg, 685 mmhg or 690 mmhg. A 2-fold reduction in relative CV risk was observed in the 680 mmhg group compared with the 690 mmhg group. Further evidence for the positive relationship between tight blood pressure (BP) control and the reduction of CV risk derives from the UKPDS 38 study. Here, 1148 hypertensive UKPDS patients (mean age 56 years, mean BP 160/94 mmhg) were randomized to either tight BP control (<150/85 mmhg) or less-tight control (<180/ 105 mmhg), using captopril or atenolol. 14 Following a median follow-up of 8.4 years, mean BPs were 144/82 mmhg versus 154/87 mmhg (P < ), respectively. This difference was associated with a 24% reduction in diabetes-related end-points (P = ), a 32% reduction in deaths related to diabetes (P = 0.019), a 44% reduction in strokes (P = 0.013), and a 37% reduction in microvascular risk (P = ). Dyslipidaemia Insulin resistance in adipocytes leads to decreased suppression of lipolysis by insulin. In obese subjects, this is associated with increased levels of fatty acids that damage the arterial wall and promote atherosclerosis. The lipid profiles of insulin-resistant subjects are often characterized by raised TGs, small, dense low-density lipoprotein (LDL), cholesterol-rich remnants and low HDL. Although many of these features are related to insulin resistance, diabetic dyslipidaemia persists despite efforts to control glucose. Analyses of CHD risk reduction in the major statins trials, however, suggest that reducing lipid levels is as effective for the prevention of CHD in patients with diabetes as in those without (Table 1). Furthermore, the Heart Protection Study (HPS) showed that the reduction in first CV event incidence associated with lipid lowering was independent of initial lipid levels. 15 This is important for patients with insulin resistance since baseline lipid levels in this group are often higher than normal. In the past, many clinical trials excluded people with diabetes and so, until recently, it was not known whether lipid lowering in this patient group had a greater, lesser or neutral effect on CV risk than in the non-diabetic population. The GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) study 16 was an open trial of 1600 CHD patients, including 313 with type 2 diabetes, randomized to either usual care or atorvastatin for an average of 3 years. The dosage of atorvastatin was

4 G6 D.J. Betteridge Table 1 CHD prevention trials with statins: diabetic patients subgroup analyses CHD% risk reduction Overall Diabetes Primary prevention AFCAPS/ Lovastatin (NS) TexCAPS HPS Simvastatin (P < ) ASCOT-LLA Atorvastatin (NS) Secondary prevention CARE Pravastatin (P = 0.05) 4S Simvastatin (P = 0.002) LIPID Pravastatin (NS) 4S reanalysis Simvastatin (P = 0.001) HPS Simvastatin (P < ) Primary and secondary ALLHAT Pravastatin (NS) titrated from 10 to 80 mg day 1 (mean dose 24 mg day 1 ) until the NCEP ATP III target LDL-cholesterol level was achieved (<100 mg dl 1 ). Compared with the usual care group, mean lipid levels were significantly reduced in the atorvastatin group total cholesterol by 36%, LDLcholesterol by 46%, TGs by 31% and non-hdl-cholesterol by 44% while HDL-cholesterol was increased by 7%. This was associated with a 51% reduction (P < ) in primary end-points (death, non-fatal MI, unstable angina, congestive heart failure, revascularization and stroke) compared with the usual care group. In patients with type 2 diabetes, risk reduction increased to 58% (P < ). 16 The first lipid-lowering trial to be completed specifically in patients with diabetes is the Collaborative AtoRvastatin Diabetes Study (CARDS). 17 In this multi-centre, placebo-controlled trial, 2838 patients with type 2 diabetes (serum LDL-cholesterol 6160 mg dl 1, TGs 6600 mg dl 1, without established CV or cerebrovascular disease) were randomized to atorvastatin (10 mg day 1 )or placebo for a minimum of 4 years. Atorvastatin was estimated to produce a net reduction in LDL-cholesterol of about 40%, and a reduction in TGs of 13 27%. The primary objective was to investigate whether treatment with atorvastatin reduced the incidence of major coronary events, revascularization procedures, unstable angina, resuscitated cardiac arrest or stroke. The study was originally scheduled to complete in 2004/2005. However, due to a substantial and significant benefit in favour of the atorvastatin-treated group (one-sided P < , Cox regression), the study was terminated almost 2 years early, in June Treatment goals for patients with the metabolic syndrome and/or diabetes Although blood glucose reduction significantly reduces the risk of microvascular disease in patients with the Table 2 AHA prevention conference VI: diabetes and vascular disease goals of therapy Glycaemia HbA 1c <7% (ADA) BP <130/85 (JNC VI) <130/80 (ADA) LDL-cholesterol <100 mg dl 1 (2.6) (NCEP) HDL-cholesterol <40 mg dl 1 Raise HDL (no goal) TGs ( mg dl 1 ) Non-HDL-cholesterol <130 mg dl 1 (3.4) BMI >25 kg m 2 Lose 10% body weight (OEI) Physical activity Exercise (ADA) Cigarettes Stop Pro-thrombotic state Low-dose aspirin (ADA) Used with permission from Grundy SM, et al. Prevention Conference VI. Diabetes and Cardiovascular Disease. Executive Summary. Conference Proceedings for Healthcare Professionals from a Special Waiting Group of the American Heart Association Circulation 2002;1153: metabolic syndrome and/or diabetes, glucose control alone is not sufficient to significantly reduce macrovascular disease. Additional risk factors, such as hypertension, dyslipidaemia, smoking and obesity, must also be treated in patients with these disorders. The target levels for CVD risk factors in these high-risk patient groups are summarized in Table 2. Conclusion Patients with diabetes have a 2- to 3-fold greater risk of CVD death than those without. This suggests an interaction between diabetes and other CVD risk factors such as smoking, hypertension, IGT and obesity. While the treatment of CVD risk factors in patients with diabetes reduces the incidence of CVD death, macrovascular damage, however, is present in patients prior to the onset of overt diabetes, and so the early identification and treatment of patients at risk of diabetes is essential for the primary prevention of CVD in this patient group. Since patients with the metabolic syndrome have an increased risk of CVD prior to the development of IGT and diabetes, it has become the focus for the primary prevention of macrovascular disease. The metabolic syndrome is defined as three or more of the following risk determinants: abdominal obesity, raised TGs, low HDLcholesterol, hypertension or raised FBG. Since the components of the metabolic syndrome are associated with insulin resistance, many of these risk factors are also present in patients with diabetes. Patients with both the metabolic syndrome and diabetes are at greater risk of CHD death than patients with either diabetes or the metabolic syndrome alone. Although reducing glucose levels significantly reduces the risk of microvascular disease in patients with diabetes and/or the metabolic syndrome, it is not sufficient to significantly reduce the incidence of macrovascular disease. Additional risk factors, such as hypertension, dyslipidaemia, smoking and obesity, must also be treated in patients with these disorders.

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