The European Society of Cardiology
Managing dyslipidaemia – multiple patients and multiple approaches: metabolic syndrome, familial hypercholesterolaemia and hypertension
Emory University, Atlanta, GA, USA
* W. Virgil Brown, MD, Charles Howard Chandler Professor of Internal Medicine, Director of the Division of Arteriosclerosis and Lipid Metabolism, Emory University School of Medicine, Woodruff Memorial Building, Bldg. A, 1365 Clifton Road, NE, Atlanta, GA 30322, USA. Tel.: +1-404-235-3001
w.virgil.brown{at}med.va.gov
Abstract
High risk of coronary heart disease (CHD) events is present in a number of patient populations in addition to those with pre-existing CHD, other atherosclerotic disease or diabetes. Patients with the metabolic syndrome are at increased CHD risk and require attention to low-density lipoprotein cholesterol (LDL-C) lowering in addition to management of hypertriglyceridaemia, low high-density lipoprotein cholesterol and non-lipid risk factors. Patients with hypertension in addition to other cardiovascular risk factors are at increased risk of CHD and have recently been shown to derive marked benefit from statin treatment. Patients with heterozygous familial hypercholesterolaemia, characterised by dramatically raised LDL-C and high risk for early CHD, require large reductions in LDL-C to meet recommended target levels, and newer statins possess the LDL-C-lowering efficacy to bring many of these patients to such goals. Identification of high-risk patients and prompt institution of appropriate management strategies can serve to reduce the overall burden of cardiovascular disease.
Key Words: Dyslipidaemia • Metabolic syndrome • Familial hypercholesterolaemia • Statins • Coronary heart disease • LDL cholesterol
Introduction
Apart from existing coronary heart disease (CHD), other atherosclerotic disease or overt diabetes, a number of other conditions pose high risk for CHD and warrant aggressive treatment and management. These include the metabolic syndrome, heterozygous familial hypercholesterolaemia (HeFH) and hypertension.1 In HeFH, which is characterised by dramatically increased low-density lipoprotein cholesterol (LDL-C) levels, LDL-C reduction is imperative to reduce risk of early CHD.2 In CHD risk reduction, however, decreasing LDL-C is important, not just when elevated levels are present but also in the context of elevated coronary risk associated with a variety of additional risk factors. Reduction of LDL-C is an important component of treatment in the metabolic syndrome and in hypertensive patients.
Metabolic syndrome
The metabolic syndrome is a constellation of risk factors associated with insulin resistance that poses high risk for diabetes and increases risk for CHD at every level of LDL-C (see the article on metabolic syndrome by Andrew Tonkin in this issue).3 In addition to elevated blood glucose, clinical features include central adiposity, hypertension and elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) levels. LDL-C levels may be normal or moderately elevated, but a preponderance of atherogenic small, dense LDL is characteristic of the dyslipidaemia in the metabolic syndrome; thus, LDL-C reduction to target levels based on overall risk assessment is recommended in patients with metabolic syndrome.
The following constitutes a reasonable approach to lipoprotein treatment in metabolic syndrome. Fasting plasma cholesterol, triglycerides, LDL-C and HDL-C should be measured. Dietary control using the step II American Heart Association diet should be instituted, and recommendations regarding exercise should be made, since exercise and weight loss address both glucose and lipid disorders. Hypoglycaemic treatment should be instituted or adjusted to optimise glycaemic control. In patients with the metabolic syndrome who are at high risk for CHD based on overall risk assessment, the primary lipid treatment goal is to treat elevated LDL-C, indicated by a level of 
3.4 mmol/l (130 mg/dl), to a target of 
2.6 mmol/l (100 mg/dl). Statin treatment should be initiated at a low dose and subsequently titrated to achieve the LDL-C goal; in patients with very high LDL-C, adjunctive treatment with a resin or ezetimibe may be added if statin treatment is insufficient. A fibrate or niacin can be added to statin treatment when triglyceride levels are 2.3 mmol/l (200 mg/dl) or HDL-C 1.0 mmol/l (40 mg/dl).1 Statin treatment can be titrated if necessary to achieve the non-HDL-C goal.
The second lipoprotein goal is to reduce triglycerides in patients with dyslipidaemia predominantly consisting of hypertriglyceridaemia (i.e. triglycerides 2.3 mmol/l [200 mg/dl] and LDL-C 3.4 mmol/l [130 mg/dl]). In this case, the objective may be to reduce triglycerides using a non-HDL-C goal level of 3.4 mmol/l (130 mg/dl). To that end, treatment may be initiated with a fibrate or niacin; a statin should then be added at a low dose and titrated to achievement of the non-HDL-C goal. A third lipoprotein goal is to increase HDL-C, with this being best achieved with weight loss through diet and exercise.
Information on the effectiveness of pharmacotherapy in reducing CHD risk associated with the insulin resistance state comes largely from diabetic subpopulations of treatment trials. A post hoc analysis of outcome in 202 CHD patients with diabetes defined as blood glucose 7.8 mmol/l (140 mg/dl) in the Scandinavian Simvastatin Survival Study population showed that simvastatin treatment reduced cardiovascular events by 55% vs placebo (23% vs 45%).4 In the Heart Protection Study,5 which included nearly 6000 patients with diabetes with or without prior CHD, simvastatin treatment resulted in a relative risk reduction for first major vascular event in diabetic patients (20.2% vs 25.1%) similar to the 24% reduction observed in the overall study population of more than 20,000 high-risk patients (19.8% vs 25.2%) (Fig. 1). 6 In the Veterans Affairs HDL Intervention Trial7 (VA-HIT) in men with CHD, gemfibrozil therapy produced a 24% reduction in CHD death, myocardial infarction (MI) or stroke (28% vs 36%) among 627 patients with diabetes.
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Treatment with newer statins such as rosuvastatin offers the potential for very pronounced effects in lowering LDL-C as well as marked beneficial effects on other aspects of dyslipidaemia in metabolic syndrome. For example, in studies in hypercholesterolaemic patients, rosuvastatin has been reported to reduce LDL-C by up to 63%, reduce triglycerides by up to 28% and increase HDL-C by up to 14%.8
Heterozygous familial hypercholesterolaemia
HeFH is difficult to diagnose at the genetic level, but this syndrome of very high LDL-C inherited as an autosomal dominant disorder is relatively common, with about 500,000 affected US individuals.9 Patients with HeFH have dramatically increased levels of LDL-C (present from infancy) and thus an extremely high risk of early-onset coronary disease. In a family screening study excluding probands with HeFH and CHD, Stone et al.10 found coronary disease in 16% of men by age 40 and in 52% and 33% of men and women, respectively, by age 60. Slack11 found coronary disease in 5%, 51% and 85% of men by age 30, 50 and 60, respectively, and in 68% of women by age 60.
Newer statins offer the potential to bring a sizable proportion of HeFH patients to currently recommended LDL-C goals through marked LDL-C reductions. In a recently published force-titration study in 623 patients with HeFH, atorvastatin 20, 40 and 80 mg 
over 18 weeks brought 44% of patients to National Cholesterol Program Adult Treatment Panel (ATP) III LDL-C goals. It is impressive that rosuvastatin 20–40 mg (the highest marketed dose) resulted in goal attainment in 49% of rosuvastatin patients, compared with 33% of atorvastatin patients 
.12
If statin therapy is insufficient to achieve LDL-C goals, combination treatment with a resin (cholestyramine, colestipol, colesevelam), cholesterol absorption inhibitor (ezetimibe, phytosterol and phytostanol esters) or niacin should be considered.
Ezetimibe has recently been approved for treatment of primary (familial and non-familial) hypercholesterolaemia and as combination therapy for homozygous familial hypercholesterolaemia. In a randomised, placebo-controlled study of patients with primary hypercholesterolaemia who had not achieved ATP II goals with dietary changes and statin monotherapy, the addition of ezetimibe to statin therapy led to a further 25% reduction in LDL-C levels.13 Pitavastatin, a new statin available in Japan, has shown efficacy in HeFH. In one study, total cholesterol and LDL-C were reduced by 37% and 48%, respectively, in 30 HeFH patients taking pitavastatin 4 mg/day for 8 weeks.14
High blood pressure
Given the benefits observed with statin therapy in patients with hypertension who are at risk for CHD and the finding that hypertension augments risk when present with other risk factors, LDL-C reduction must be a focus of treatment in such patients. Hypertension should be treated appropriately. The Heart Protection Study included more than 8000 patients with treated hypertension, with simvastatin treatment reducing relative risk of first major vascular event among these patients (22.4% vs 28.1% with placebo) to a similar degree as the 24% risk reduction (19.8% vs 25.2%) seen in the overall study population (Fig. 2).5 As can be seen from comparing rates in the placebo subgroups with and without, overall risk was higher in patients with hypertension.
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The recently reported results of the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm15 indicate marked benefits with cholesterol reduction in hypertensive high-risk patients. The trial involved approximately 10,000 hypertensive patients with three or more additional cardiovascular risk factors who received randomised antihypertensive treatment; this was a subgroup of more than 19,000 of these patients with non-fasting total cholesterol of
6.5 mmol/l (250 mg/dl). Those with higher cholesterol were given usual care management for the lipid abnormalities. The lipid-lowering arm of the study involved use of atorvastatin 10 mg or placebo. LDL-C was lowered with atorvastatin by 1.3 mmol/l (50 mg/dl) at 1 year and by 1.0 mmol/l (40 mg/dl) at 3 years. The trial was stopped early because of a significant effect of atorvastatin in reducing the frequency of non-fatal MI or CHD death (Fig. 3). The hazard ratio for this primary outcome measure with atorvastatin treatment was 0.64 [95% confidence interval (CI), 0.50–0.83], reflecting a 36% reduction in this primary end point. Atorvastatin treatment was also associated with significant reductions in risk for fatal and non-fatal stroke (hazard ratio, 0.73; 95% CI, 0.56–0.96), total cardiovascular events (hazard ratio, 0.79; 95% CI, 0.69–0.90) and total coronary events (hazard ratio, 0.71; 95% CI, 0.59–0.86), although no significant reduction in overall mortality was observed (hazard ratio, 0.87; 95% CI, 0.71–1.06).
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Conclusion
There are multiple types of patients who need more aggressive therapy to reduce CHD risk, including those with metabolic syndrome, HeFH and hypertension. New drugs and novel combinations can provide the efficacy in modifying lipid profiles that are necessary to achieve the recommended lipid goals in such patients. Identifying the high-risk patient and establishing a plan for lifelong management are necessary to provide the benefit in cardiovascular disease risk reduction that is now available.
References
- Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97
[Free Full Text] - Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt SC. Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia. Am. J. Cardiol. 2001;87:547–553[CrossRef][Web of Science][Medline]
- Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709–2716
[Abstract/Free Full Text] - Pyörälä K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20:614–620[Abstract]
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22[CrossRef][Web of Science][Medline]
- Collins R, Armitage J, Parish S, Sleigh P, Peto R. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–2016[CrossRef][Web of Science][Medline]
- Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N. Engl. J. Med. 1999;341:410–418
[Abstract/Free Full Text] - Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc. Drug Rev. 2002;20:303–328[Web of Science][Medline]
- Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. Scriver CR, Beaudet AL, Sly WS, Valle D. Metabolic and Molecular Basis of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995. p. 1831–2030
- Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation. 1974;49:476–488
[Abstract/Free Full Text] - Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet. 1969;27(2):1380–1382
- Stein EA, Strutt K, Southworth H, Diggle PJ, Miller E. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Am. J. Cardiol. 2003;92:1287–1293[CrossRef][Web of Science][Medline]
- Gagne C, Bays HE, Weiss SR, et al. Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am. J. Cardiol. 2002;90:1084–1091[CrossRef][Web of Science][Medline]
- Kajinami K, Koizumi J, Ueda K, Miyamoto S, Takegoshi T, Mabuchi H. Effects of NK-104, a new hydroxymethylglutaryl-coenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia. Hokuriku NK-104 Study Group. Am. J. Cardiol. 2000;85:178–183[CrossRef][Web of Science][Medline]
- Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-then-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicenter randomized controlled trial. Lancet. 2003;361:1149–1158[CrossRef][Web of Science][Medline]
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