OVERVIEW

Hypertriglyceridemia correlates with an increased risk of cardiovascular disease (CVD), particularly in the context of low HDL-C levels, elevated LDL-C levels, or both. Some studies have demonstrated that, when low HDL-C levels are controlled for, elevated triglyceride levels do not correlate with CVD risk; however, other studies have suggested that triglycerides are an independent risk factor. Because metabolism of triglyceride-rich lipoproteins (eg, chylomicrons, VLDL) and metabolism of HDL-C are interdependent and because of the lability of triglyceride levels, the independent impact of elevated triglyceride levels on CVD risk is difficult to confirm. However, randomized clinical trials using triglyceride-lowering medications have demonstrated fewer coronary events in both primary and secondary coronary prevention populations.

Persons with type 1 or type 2 diabetes mellitus, particularly if the disease is poorly controlled, are especially prone to develop hypertriglyceridemia. The risk of CVD in those with elevated triglyceride levels and diabetes mellitus is substantial. People who are obese and/or sedentary frequently have elevated triglyceride levels and are at significantly increased risk of both fatal and nonfatal cardiac and vascular events. Furthermore, users of any type of tobacco are commonly found to have elevated triglyceride levels and, accordingly, are at significantly increased risk for coronary artery disease (CAD). Tobacco users who have elevated triglyceride levels with low HDL-C and high LDL-C levels are at particularly high risk for fatal and nonfatal cardiovascular events; aggressive modification has been shown to reduce the risk of these events.

CLINICAL GUIDELINES

The latest guidelines from the Third Report of the National Cholesterol Educational Program (NCEP-III) and the Adult Treatment Panel (ATP-III) reclassified serum triglyceride levels as follows:

Classification of Triglycerides

While the rare inherited disorders of severe hypertriglyceridemia require severe restrictions in dietary fat intake, most elevated triglyceride concentrations can be at least partially controlled by a program of diet, exercise, and weight loss. Therefore, prevention entails pursuing an active lifestyle with regular aerobic and toning exercise; eating a diet low in fat, simple carbohydrates, and alcohol; and maintaining a lean body. These beneficial habits reduce the probability of developing hypertension and type 2 diabetes mellitus, thereby lowering the risk of CVD.

ATP-III and the World Health Organization have identified the following general features of the metabolic syndrome that substantially increases the risk of both fatal and nonfatal cardiovascular and peripheral vascular events: (1) abdominal obesity, (2) a triglyceride level greater than 150 mg/dL, (3) an HDL-C level less than 40 mg/dL for men and less than 50 mg/dL for women, (4) a blood pressure value greater than 130/85 mm Hg, and (5) a fasting glucose level greater than 110 mg/dL.

In a retrospective analysis of the Scandinavian Simvastatin Survival Study (4S) carried out with simvastatin, investigators found the same results that had earlier been demonstrated in a retrospective analysis of the Helsinki Heart Study, a primary prevention study with gemfibrozil. This retrospective analysis found that subjects with the metabolic syndrome (in this case defined by the lipid triad of low HDL-C, high triglyceride, and elevated LDL-C levels) received more benefit from simvastatin therapy than those with elevated LDL-C levels alone. A very similar post hoc analysis of the Helsinki Heart Study showed that subjects with the lipid triad benefited the most from gemfibrozil therapy. In 1990, on the basis of that finding, the US Food and Drug Administration (FDA) approved gemfibrozil for primary prevention in patients with the lipid triad. In summary, the findings of the 4S study using simvastatin were similar to those of the Helsinki Heart Study using gemfibrozil.

ASSOCIATION WITH CORONARY ARTERY DISEASE

Hypertriglyceridemia is now an accepted independent risk factor for CAD. Early epidemiologic data from the Framingham Heart Study suggested a strong correlation between increased triglyceride levels and CAD risk, although the correlation was statistically significant only for women. The association between triglyceride levels and CAD risk in men was demonstrated by the Prospective Cardiovascular Münster (PROCAM) study, which reported a linear relationship between low-to-moderate triglyceride elevations and increased cardiovascular event rates. An additional important finding of the PROCAM study was that the CAD risk associated with hypertriglyceridemia occurred regardless of LDL-C or HDL-C levels.

The relationship between elevated triglyceride levels and CAD risk was further substantiated in a meta-analysis of 17 population-based prospective studies, which found 32% and 76% increases in CAD risk for men and women, respectively, for every 1 mmol/L (88 mg/dL) increase in triglyceride levels. Although adjustment for HDL-C attenuated this increased risk (to 14% in men and 37% in women), triglyceride levels still remained a statistically significant independent risk factor for CAD.

More recently, the Copenhagen Male Study found that the risk of ischemic heart disease was 120% greater for men with triglyceride levels in the upper third (141-1984 mg/dL) and 50% greater for those in the middle third (97-140 mg/dL), compared with the risk for men in the lowest third (38-96 mg/dL); this observation confirmed hypertriglyceridemia as a strong, independent risk factor for ischemic heart disease. In addition, the Bezafibrate Infarction Prevention (BIP) study demonstrated that, for persons with established coronary heart disease (CHD), triglyceride levels are independently correlated with the risk of stroke or transient ischemic attack.

THERAPEUTIC EFFECTS OF LOWERING TRIGLYCERIDES

The Helsinki Heart Study (HHS) and the Benzafibrate Infarction Prevention (BIP) study have provided evidence for the benefits of triglyceride lowering in prevention of cardiovascular events. In the 5-year HHS, a primary prevention study, gemfibrozil treatment decreased the number of CHD events by 34%, with a 43% reduction in triglyceride levels. The greatest benefit was observed in subjects with baseline triglyceride levels of more than 200 mg/dL. In the BIP study, which was conducted with 3122 middle-aged men and women with preexisting CAD, bezafibrate therapy was associated with a 21% reduction in triglyceride values. Although there was a nonsignificant reduction (9%) in the primary end point of nonfatal myocardial infarction and cardiovascular death, post hoc analysis revealed a significant reduction (40%) in the primary end point in subjects whose baseline triglyceride levels were more than 200 mg/dL (P = .03).

In the 5 major placebo-controlled trials of HMG-CoA reductase inhibitors (statins) that studied both primary and secondary prevention patients, statin therapy lowered CHD events by 24-37% in those with elevated LDL-C levels (mean range at baseline, 139-192 mg/dL). Mean baseline triglyceride levels were borderline high in these trials, ranging from 132-162 mg/dL and were reduced by 10-15% with statin therapy. In general, study participants with higher baseline triglyceride levels had a higher probability of coronary events.

More recently, in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, reductions in LDL-C and triglyceride levels, which were considerably greater than those in the landmark statin trials, resulted in significant reductions in total mortality and coronary morbidity and mortality, as well as in stroke. The GREACE study was a randomized 3-year study of 1600 CHD patients who received either structured care with atorvastatin or usual care from their physicians. As with the major statin trials, the mean baseline triglyceride level was borderline high at 184 mg/dL. Atorvastatin treatment (mean dose, 24 mg/d) reduced triglyceride and LDL-C values by 31% and 46%, respectively (compared to 3% and 5% with usual care), and was associated with a 43% decrease in overall mortality (P = .0021) and a 47% decrease in coronary mortality (P = .0017).

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