Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy

I t has long been recognized that elevated triglyceride levels are associated with increased risk for coronary heart disease (CHD). However, it has not been determined whether elevated triglycerides are an independent risk factor for CHD. Thus, the predictive power of triglyceride levels are often reduced or lost when other risk factors, particularly high-density lipoprotein (HDL) cholesterol or diabetes mellitus, are taken into account.1,2 A number of recent findings, however, have provided compelling evidence of the independent association of elevated triglycerides and major coronary events, including a meta-analysis documenting an independent incremental risk of such events with triglyceride elevation.3,4 A persistent caveat is, however, the lack of clear identification of diabetic subjects in these studies. In the large, population-based Munster Heart Study (Prospective Cardiovascular Munster Study [PROCAM]),5 an 8-year follow-up of nearly 5,000 men aged 40 to 65 years without evidence of myocardial infarction (MI) at entry showed that the risk for MI or sudden cardiac death increased markedly as triglyceride levels increased from ,2.26 mmol/L (,200 mg/ dl) to 9.02 mmol/L (799 mg/dl) (Figure 1). (There were too few subjects with triglycerides .9.02 mmol/L to analyze this group.) The association of triglyceride levels with major coronary events remained significant after adjustment for low-density lipoprotein (LDL) and HDL cholesterol levels, and other important coronary risk factors. The association of elevated triglyceride levels (.2.26 mmol/L) with risk of CHD was particularly strong when the LDL/ HDL ratio was .5. This finding corroborated an earlier result from the Helsinki Heart Study,6 a randomized, placebo-controlled primary prevention trial involving .4,000 middle-aged men. Placebo recipients with an LDL/HDL cholesterol ratio .5 and triglyceride level .2.30 mmol/L had a relative risk [RR] for CHD of 3.8. They had the greatest protection with hypolipidemic therapy (gemfibrozil); there was a 71% decrease in CHD events compared with the corresponding placebo subgroup. Similar findings have been reported in the Physicians’s Health Study, a prospective nested case-control study of the effect of nonfasting triglyceride levels and LDL particle diameter on the risk for MI.7 The men who experienced a MI had significantly smaller LDL particle diameter and significantly higher triglyceride levels than control subjects. After adjustment for lipid levels and other coronary risk factors, the significant association of LDL size disappeared, whereas the association with elevated triglycerides remained (RR 1.40 per 1.13 mmol/L [100 mg/dl] increase).7 As in PROCAM,5 the triglyceride/total cholesterol interaction in the Physicians’ Health Study was significant, with the highest risk for MI observed in patients with triglyceride levels and total/HDL cholesterol ratios in the highest tertiles (Figure 2).7 Other recent studies have shown associations between LDL particle size and CHD risk (with some data showing it to be an independent risk factor),8–10 and there is a clear physiologic basis for a link between triglyceride elevation and reduced LDL particle size. The Copenhagen Male Study11 reported 8-year follow-up data showing that elevated fasting triglycerides are a strong and independent risk factor for incident CHD. In 2,906 white men initially free of overt cardiovascular disease, increasing triglycerides were significantly associated with CHD; incidence rates of disease were 4.6% in the lowest triglyceride tertile From the Division of Preventive Medicine and Nutrition, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York. This work was supported in part by an unrestricted educational grant from Parke-Davis, Ann Arbor, Michigan. Manuscript received September 4, 2000; revised manuscript received and accepted December 21, 2000. Address for reprints: Henry N. Ginsberg, MD, Irving Center for Clinical Research, 630 West 168th Street, New York, New York 10032. E-mail: hng1@columbia.edu. FIGURE 1. Incidence of major coronary events per 1000 men according to triglyceride level during 8-year follow-up in the Munster Heart Study (n 5 4,639 men aged 40 to 65 years; 258 events). Reprinted with permission from Assmann et al.5