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THE ROLE OF HYPERTRIGLYCERIDEMIA IN THE DEVELOPMENT OF CARDIOVASCULAR DISEASE
CURRENT STATE OF AFFAIRS
Cardiovascular disease (CVD) is the leading cause of death in the developed world. Well-established risk factors that contribute to CVD include family history, hypertension, smoking, diabetes, dyslipidemia, age, and lifestyle, in addition to other factors that are less clearly elucidated. Elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol are well recognized as the lipid parameters with the highest correlation to CVD. Other contributing lipid parameters include suboptimal levels of high-density lipoprotein (HDL) cholesterol and elevated levels of triglycerides. Epidemiologic evidence suggests that triglyceride levels are an independent risk factor for CVD. Chronic elevation of serum triglyceride levels is associated with endothelial dysfunction.1
BACKGROUND
Meta-analyses of prospective studies indicate that hypertriglyceridemia is an independent risk factor for coronary heart disease (CHD).2 Such studies include the Helsinki Heart Study,3 the Atherosclerosis Risk in Communities (ARIC) study,4 the Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial (VA-HIT),5 and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.6
The Helsinki Heart Study was a randomized, 5-year, double-blind, placebo-controlled primary prevention trial that studied 4081 middle-aged men with dyslipidemia who were treated with gemfibrozil. A 34% reduction in the incidence of CHD was observed, with reductions of 10% in serum total cholesterol levels, 11% in LDL cholesterol levels, 14% in non-HDL cholesterol levels, and 35% in triglyceride levels.3 The original treatment group experienced a 23% relative risk reduction in CHD mortality (P = .05) after 18 years.
In the ARIC study, over 12,000 middle-aged individuals without CHD were observed for 10 years. Hypertriglyceridemia was associated with development of CHD in women in this study. This association was not statistically significant in men in this study.4
The FIELD trial and VA-HIT are discussed in more detail below.
RISK FACTORS AND PATHOGENESIS
Several factors, including obesity, physical inactivity, cigarette smoking, excessive alcohol intake, and high-carbohydrate diets, are associated with hypertriglyceridemia. Some chronic diseases, such as type 2 diabetes, chronic renal failure, and nephrotic syndrome, contribute to hypertriglyceridemia. Certain drugs, such as corticosteroids, estrogens, retinoids, and beta-blockers (in high doses), also contribute to hypertriglyceridemia. Inherited disorders, including familial combined hyperlipidemia, familial hypertriglyceridemia, and familial dysbetalipoproteinemia, are well-recognized predisposing genetic conditions.
The role of triglycerides in CVD is mediated via atherogenic
triglyceride-rich lipoproteins. Very low-density lipoprotein (VLDL)
cholesterol is a measure of the atherogenic remnant lipoproteins.
Patients with diabetes, insulin resistance, and metabolic syndrome often
have lipid profiles characterized by hypertriglyceridemia, low HDL
cholesterol levels, and small, dense LDL cholesterol particles. When LDL
cholesterol particles are small and dense, they are more easily oxidized
and less easily cleared; this situation increases atherogenesis.7
In the VA-HIT, 2531 men with CHD, an HDL cholesterol level of 40 mg/dL or less, and an LDL cholesterol level of 140 mg/dL or less received either gemfibrozil (1200 mg/d) or placebo. The VA-HIT researchers followed up with these subjects for 5 years. The reduction in death due to CHD among subjects with diabetes was 41% (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39-0.91;
P = .02). Among the individuals without diabetes, gemfibrozil was most efficacious for those in the highest quartile for fasting plasma insulin level (risk reduction, 35%;
P = .04).5 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 [ATP III]) incorporated hypertriglyceridemia into the defining characteristics of the metabolic syndrome. Metabolic syndrome also includes low HDL cholesterol levels, hypertension, abnormal glucose levels, and obesity.2
CURRENT GUIDELINES
The American Heart Association (AHA) and the NCEP ATP III have released recommendations based on risk stratification. The NCEP ATP III suggests categorizing triglyceride levels as follows:
-
Normal triglyceride level is less than 150 mg/dL.
-
Borderline high triglyceride level is 150-199 mg/dL.
-
High triglyceride level is 200-499 mg/dL.
-
Very high triglyceride level is greater than or equal to 500 mg/dL.
The treatment target is serum triglyceride levels below 150 mg/dL.
NCEP ATP III identifies non-HDL cholesterol level as a secondary target of therapy in individuals whose serum triglyceride level exceeds 200 mg/dL. Non-HDL cholesterol levels can be estimated as the difference between total cholesterol levels and HDL cholesterol levels or as the sum of LDL cholesterol levels and VLDL cholesterol levels. The goal level of non-HDL cholesterol for individuals with high serum triglyceride levels can be set 30 mg/dL higher than the goal identified for LDL cholesterol levels.2
TREATMENT
Treatment depends on the cause and degree of hypertriglyceridemia and involves both lifestyle strategies and pharmacotherapeutic interventions. For borderline high or high hypertriglyceridemia, the primary aim of therapy is to achieve target LDL cholesterol goals; the first approach is usually lifestyle changes. The lifestyle changes recommended by NCEP ATP III include the following:
-
Reduced intake of saturated fats and dietary cholesterol
-
Intake of dietary options to enhance lowering of LDL cholesterol
-
Weight control
-
Increased physical activity
Pharmacotherapy should be added if lifestyle changes do not achieve target goals. Initially, non-HDL cholesterol level goals can be achieved by intensifying therapy with a drug that lowers LDL levels (often HMG-CoA reductase inhibitors [statins]). In patients receiving statins, a reduction in triglyceride levels of up to 35% frequently accompanies the reduction in LDL cholesterol levels.
If target goals are not achieved with statin use, addition of a second agent can be considered with appropriate caution. Such agents may include fibric acid derivatives (fibrates), nicotinic acid derivatives, fish oils (omega-3 fatty acids), ezetimibe, and therapies that target insulin resistance. Because different agents have different mechanisms of action, combining different agents is effective if they are applied judiciously to avoid drug interactions.
In the unusual cases of very high serum triglyceride levels (>500 mg/dL), prevention of acute pancreatitis through the lowering of triglyceride levels takes precedence. This approach requires very low-fat diets (<15% of energy intake), avoidance of alcohol, weight reduction, increased physical activity, and, usually, a drug that lowers triglyceride levels, such as a fibrate or nicotinic acid. Only after triglyceride levels have been lowered to less than 500 mg/dL should attention turn to lowering LDL cholesterol levels to reduce risk for CHD.2
Fibrates are the most potent agents for lowering triglyceride levels. Fibrates include fenofibrate, bezafibrate, and gemfibrozil. Through peroxisome proliferator-activated alpha receptors, fibrates significantly impact the synthesis of several apolipoproteins (apo) and enzymes of lipoprotein metabolism as well as the expression of several genes involved in fibrinolysis and inflammation. Fibrate therapy has been reported to decrease levels of apo C3 (a powerful inhibitor of lipoprotein lipase) and increase levels of apo A1 and lipoprotein lipase activity. Such changes contribute to improved catabolism of triglyceride-rich lipoproteins, which leads to a substantial increase in HDL cholesterol levels accompanied by a shift in the size and density of LDL particles from small, dense LDL particles to larger, more buoyant cholesteryl ester–rich LDL particles.8
In a 1-year study involving patients with CHD and combined hyperlipidemia whose triglyceride levels remained elevated despite treatment with simvastatin, omega-3 fatty acids lowered triglyceride levels by 20-30%.9
The FIELD study involved 9795 individuals who had type 2 diabetes and untreated (not receiving statin therapy) hypercholesterolemia or hypertriglyceridemia. These subjects were randomized to a placebo arm and a fenofibrate arm. Statins were added to the treatment if LDL cholesterol level goals were not achieved. Total cardiovascular events were reduced from 13.9% to 12.5% in the fenofibrate group. Total mortality was not significantly different; it was reported at 6.6% in the placebo group and 7.3% in the fenofibrate group (P = .18).6
CONCLUSION
Triglycerides play a significant role in the development and progression of CVD and must be maintained at optimum levels. Hypertriglyceridemia should be treated in conjunction with other cardiovascular risk factors and is a secondary target after target levels of LDL cholesterol and total cholesterol have been addressed.
REFERENCES
1. Lundman P, Eriksson MJ, Stuhlinger M, et al. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine.
J Am Coll Cardiol. 2001;38(1):111-6.
2. 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.
3. Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study.
JAMA. 1988 Aug 5;260(5):641-51.
4. Sharrett AR, Ballantyne CM, Coady SA. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study.
Circulation. 2001 Sep 4;104(10):1108-13.
5. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT).
Arch Intern Med. 2002 Dec 9-23;162(22):2597-604.
6. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
Lancet. 2005 Nov 26;366(9500):1849-61.
7. Nesto R. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome.
Am J Cardiovasc Drugs. 2005;5(6):379-87.
8. Despres JP, Lemieux I, Robins SJ. Role of fibric acid derivatives in the management of risk factors for coronary heart disease.
Drugs. 2004;64(19):2177-98.
9. Durrington PN, Bhatnager D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
Heart. 2001;85(5):544-8.
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