Diagnosis and Management of Abnormal Plasma Lipids

Four classes of lipoproteins transport the lipids found in human plasma during the fasting state: very low density (VLDL), intermediate density (IDL), low density (LDL), and high density lipoprotein (HDL). These lipoproteins all undergo extensive modifications as they circulate. Consequently, there is considerable heterogeneity among the particles within each lipoprotein class. Triglycerides comprise 50 to 65% of the mass of VLDL which is synthesized primarily in the liver and metabolized in the circulation first to IDL and finally to form LDL. LDL is the major carrier of cholesterol and cholesteryl esters, which together account for about half of its mass. HDL, originating as a nascent particle in both liver and intestine, contains about 50% protein in its mature form. Chylomicrons transport dietary fat from the intestine and are cleared so rapidly that they are never present in normal individuals after an overnight fast. The major protein components in the lipoproteins are apolipoprotein B48 in chylomicrons, Bioo in VLDL, IDL, and LDL, and Al in HDL (1). Numerous epidemiologic studies and animal experiments have clearly shown that LDL is an atherogenic lipoprotein and that increased levels of cholesterol and LDL cholesterol (LDLCh) are associated with an increased risk of coronary artery disease (CAD). Small dense LDL particles are especially atherogenic. Epidemiologic data have also shown an association between low levels of HDL and excessive CAD. In most studies, elevated triglycerides were an independent risk factor for CAD only in women. However, hypertriglyceridemia can contribute indirectly to CAD because it is almost always accompanied by low levels of HDL cholesterol (HDLch) and increased amounts of small dense LDL. Extremely high triglyceride levels (>1000 mg/dl) can trigger attacks of acute pancreatitis. Before the mid 1980s, aggressive treatment of plasma lipid abnormalities was limited by the lack of proven benefits from lowering LDL or raising HDL levels. Two intervention studies, the Coronary Primary Prevention Trial (CPPT) and the Helsinki Heart Study, have now demonstrated that improving the levels of these lipoproteins significantly reduced the number of coronary events. Another clinical trial used repeat coronary angiography to show that lowering LDL and raising HDL slowed the progression of lesions in coronary arteries and bypass grafts. Treatment did not decrease overall mortality in these trials, a result predictable from their relatively small size and the short periods of follow-up. However, men treated 15 yr earlier with nicotinic acid for 6 yr in the Coronary Heart Project had an 11% lower overall mortality than the control group. Taken together with the serious consequences of CAD, these findings dictate aggressive efforts to identify and treat abnormalities of plasma lipids and lipoproteins. Because the fall in LDLCn was considerably greater than the rise in HDLCh in the CPPT, the benefits were attributed primarily to the reduced LDLch levels. The drugs used in the other studies decreased triglycerides and increased HDLCh significantly, but LDLch also fell by 10% or more. Thus, no study has unequivocally proven the benefits of raising HDLch alone. However, sophisticated statistical analyses of the data from the Helsinki Heart Study suggested that the 10% increase in HDLch levels was the major contributor to the smaller number of coronary events in the treatment group. These trials were all done in men between the ages of 35 and 59, and there is no direct evidence that improving LDL or HDL levels will decrease coronary events in women or men who are younger or older than those studied. Since complications of CAD are the major cause of death in women, albeit at an older age than in men, it is likely that women will also benefit from improved levels of LDL and HDL. Control of abnormal levels should be especially protective in younger individuals who have less atherosclerosis at the outset and a longer period of potential treatment to slow its progression. Guidelines for detection and treatment of elevated LDL levels