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HYPERCHOLESTEROLEMIA AND CVD
Summary of the state of affairs
Hypercholesterolemia is one of the major modifiable risk factors for cardiovascular disease, which is the leading cause of death in the United States and the world. Strong evidence indicates that the risk of atherosclerotic vascular disease is related to plasma cholesterol levels (ie, the higher the level of cholesterol, the higher the burden of disease).1 Although certain drugs and diseases are associated with hypercholesterolemia, the most likely contributor to this condition in most patients appears to be the Western lifestyle, which includes a high-fat diet, superimposed on a patient’s genetic susceptibility for hypercholesterolemia. In the United States, one third of the adult population is noted to have elevated levels of total cholesterol. Only a minority of these individuals take pharmacologic therapy to reduce their cholesterol levels, which could, in turn, reduce their risk of cardiovascular disease.
Recent guidelines
The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III) is due to update its recommendations in 2007 with minor modifications for low-density lipoprotein (LDL) cholesterol (LDL-C) goal levels for the highest risk categories. Its current recommendations provide an evidence-based and practical approach to risk assessment that, when combined with appropriate therapy, likely improves overall survival. These recommendations include suggested LDL-C levels at which to initiate therapeutic life changes (TLC) and consider drug therapy for patients in each risk category.2
Lipid-Lowering Therapy Recommendations from NCEP ATP III3
|
Risk Category |
LDL-C Goal |
Initiate TLC |
Consider Drug Therapy |
| High risk |
<100 mg/dL
(Optional goal is <70
mg/dL.) |
≥100 mg/dL |
≥100 mg/dL
(At <100 mg/dL,
consider drug options.) |
| Moderate high risk |
<130 mg/dL |
≥130 mg/dL |
≥130 mg/dL
(At 100-129 mg/dL,
consider drug options.) |
| Moderate risk |
<130 mg/dL |
≥130 mg/dL |
≥160 mg/dL |
| Lower risk |
160 mg/dL |
≥160 mg/dL |
≥190 mg/dL
(At 160-189 mg/dL,
LDL-lowering is optional.) |
Role of the expanded lipid profile and emerging risk factors
Multiple robust studies that date as long ago as the Framingham heart studies have revealed age, family history of premature coronary heart disease (CHD), diabetes, elevated levels of total cholesterol or LDL-C, low levels of high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, physical inactivity, and smoking as the traditional risk factors that contribute to cardiovascular disease prognosis. Additional lipids, including triglycerides (TG), lipoprotein (a), small LDL particles, and HDL subspecies, are emerging as independent risk factors for CVD, but data on these risk factors are still accumulating. The outcome of treating emerging dyslipidemia risk factors is not as clearly established as is the outcome of targeting the level of LDL-C, which is a modifiable condition.
Metabolic syndrome comprises a group of risk factors that includes dyslipidemia, hypertension, abnormal glycemic metabolism due to insulin resistance, and abdominal obesity.3 Metabolic syndrome has become recognized as a harbinger of excess morbidity and mortality that results predominantly from cardiovascular disease. Increasing prevalence of obesity has contributed to increasing prevalence of metabolic syndrome.4
Metabolic syndrome is diagnosed when more than 3 of the following characteristics are present:
-
Abdominal obesity (waist circumference >40 in for men and >35 in for women)
-
Elevated TG levels (≥150 mg/dL)
-
Low HDL levels (<40 mg/dL in men and <50 mg/dL in women)
-
Elevated blood pressure (≥130/85 mm Hg)
-
Impaired fasting glucose level (≥100 mg/dL)
Treatment guidelines for dyslipidemia in cardiovascular disease
The treatment of hypercholesterolemia focuses on both general lifestyle modification (weight loss, diet, exercise) and targeted treatment of the cholesterol to lower its level with selective agents. The best available treatment for each individual should be considered. For example, if a patient has elevated LDL levels, low HDL levels, and elevated TG levels, combining a statin with niacin would decrease LDL levels and help increase HDL levels. Combination drug therapy in individuals who do not reach target lipid level goals is becoming more common. However, the risk of adverse drug reactions should also be addressed. Agents used to treat dyslipidemia include the following:
-
Antilipemic agents (eg, niacin)
-
Bile acid resins (eg, cholestyramine, colesevelam, colestipol)
-
Cholesterol absorption inhibitors (eg, ezetimibe)
-
Fibric acid derivatives (eg, fenofibrate, gemfibrozil)
-
HMG-CoA reductase inhibitors (eg, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin)
-
Herbal or nutritional supplements and dietary approaches (eg, garlic, guggulipid, red yeast rice, policosanol, fiber, soybeans, phytosterols)
HMG-CoA reductase inhibitors (also known as statins) are the most potent of available agents to lower the levels of total cholesterol and LDL. In multiple randomized placebo-controlled trials, statins have been shown to reduce coronary morbidity and mortality and, in some cases, total mortality.5 These agents may have benefits beyond their cholesterol-lowering abilities, such as pleiotropic actions on atheromatous plaques and atherogenesis.6 At recommended dose range, the potencies of statins from highest to lowest are as follows: rosuvastatin, atorvastatin, simvastatin, lovastatin, fluvastatin. Their mean LDL level reductions are as follows: rosuvastatin, 45-63%; atorvastatin, 39-60%; simvastatin, 35-50%; lovastatin, 25-48%; and fluvastatin, 20-30%. With newer combination therapy, the improvement in cholesterol and LDL levels in patients with dyslipidemia is more significant.
The two most common adverse effects of statins and fibrates are myositis (including, rarely, rhabdomyolysis) and elevation in transaminase enzymes, causing hepatotoxicity. The incidence of myositis increases in patients who receive combination therapy that consists of statins and high-dose niacin and fibrates.7 Outcome data are available for statins, niacin, fibric acid derivatives, and bile acid resins. Fibrates can lower serum triglyceride levels by 25-50%, decrease LDL levels by 10-25%, and raise serum HDL levels by 15-25% in hypertriglyceridemia. At high doses, the less costly vitamin niacin can increase HDL levels up to 26%, decrease LDL levels up to 17%, decrease triglyceride levels up to 35%, and decrease lipoprotein(a) levels up to 27%. Flushing is a major adverse effect of niacin; it can be lessened by taking aspirin prior to taking niacin.
Prevention
Lifestyle modification and pharmacologic therapy are currently available means of lowering cholesterol. Evaluation begins with risk factor analysis and quantification of risk. For example, a Framingham risk score can be calculated and LDL level goals set. Healthy lifestyle changes include aerobic and cardiovascular exercise and a low-fat diet, which help decrease the prevalence of obesity and the incidence of hypercholesterolemia. Increased consumption of dietary fiber like oat bran, soy foods, and plant compounds (plant stanols and sterols) can reduce LDL levels.8 In epidemiological studies that focused on lifestyle changes, regression of metabolic syndrome has been observed. However, halting the progression of disease requires starting these modifications early in life.9 The NCEP provides the following dietary guidelines:
-
Total fat should be less than 30% of energy intake.
-
Saturated fat should be less than 7% of energy intake.
-
Polyunsaturated fat should be less than or equal to 10% of energy intake.
-
Monounsaturated fat should be 10-15% of energy intake.
-
Cholesterol should be less than 200 mg/dL per day.
-
Carbohydrates should make up 50-60% of energy intake.
For patients who have risk factors and are not achieving lipid level goals, pharmacologic treatment should be selected based on overall risk versus benefits, tolerability, and cost to the patient. Clinicians should keep in mind that patients with very high risk factors or refractory hyperlipidemia may require more than one pharmacotherapeutic agent.
A major pitfall in the management of patients with hyperlipidemia is failure to achieve the desired LDL cholesterol target goal. When using the strategies discussed above, clinicians should recall that some interventions (eg, statins) have significant potency in addition to clinical, evidence-based, patient-centered outcomes data, while other interventions (eg, herbs) lack that degree of proven validity.
References
1. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials.
JAMA. 1997;278:313-21.
2. 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).
Circulation. 2002;106:3143-421.
3. Grundy SM, Cleeman JI, Merz NB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
Circulation. 2004;110:227-39.
4. Hu G, Qiao Q, Tuomilehto J, et al. Metabolic syndrome predicts higher cardiovascular and all-cause mortality.
Arch Intern Med. 2004;164:1066-76.
5. Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit: Impact of statin trials.
Circulation. 1998;97:946-52.
6. Girona J, La Ville AE, Plana N, et al. Simvastatin decreases aldehyde production derived from lipoprotein oxidation.
Am J Cardiol. 1999;83:846-51.
7. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients.
Arch Intern Med. 2003;163:553-64.
8. Key TJ, Thorogood M, Appleby PN, Burr ML. Dietary habits and mortality in 11,000 vegetarians and health conscious people: results of a 17 year follow up.
BMJ. 1996;313:775-9.
9. Chen W, Srinivasan SR, Li S, et al. Metabolic syndrome variables at low levels in childhood are beneficially associated with adulthood cardiovascular risk: the Bogalusa Heart Study. Diabetes Care. 2005;28(1):126-31.
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