Many experts are convinced that it's time to move beyond lowering of LDL cholesterol for preventing coronary events, since considerable risk remains even after LDL cholesterol is lowered to target levels. There is, for example, a large at-risk population with the metabolic syndrome marked by a normal-range LDL cholesterol but low HDL cholesterol and high triglycerides.
A host of secondary lipid targets have been proposed—small dense LDL particles, lipoprotein(a)1 and other HDL subspecies, apolipoprotein B-100, triglycerides, and triglyceride remnants such as apo-E2—and each has its champions in the research community. But only non-HDL cholesterol is ready for use in routine clinical practice, said Dr. Hunninghake, professor of medicine and pharmacology at the University of Minnesota, Minneapolis, and a panelist on the board of the National Cholesterol Education Program.
Assays for the other proposed secondary lipid targets are unstandardized, expensive, not widely available, or hard to interpret. And most of these candidate targets are supported only by epidemiologic evidence, not clinical trial data showing that intervention to achieve the target does reduce clinical events. Such tests are suitable for use in research and in sophisticated lipid clinics but not in everyday practice, he said.
LDL cholesterol will continue to be the primary lipid target, Dr. Hunninghake predicted. Non-HDL cholesterol will come into play mainly in individuals with high triglycerides and/or low HDL.
Non-HDL cholesterol—total cholesterol minus HDL cholesterol—can be measured via the classic lipid profile and does not require fasting measurements. The number combines the levels of highly atherogenic very-low-density lipoprotein and intermediate-density lipoprotein, as well as LDL.
"It's a pretty simple approach. It's not very sexy, but it's probably reasonably practical," he observed.
Non-HDL cholesterol values should not exceed LDL levels by more than 30 mg/dL, Dr. Hunninghake said. Thus, if a patient's LDL is at the goal of 100 mg/dL but non-HDL cholesterol is more than 130 mg/dL, it's time to add a fibrate or niacin.
Reaching consensus on recommendations for cholesterol measures is made difficult by the accelerated pace at which key trials in preventive cardiology come out and lead to shifts in opinion. The last guidelines from the National Cholesterol Education Program were published in 1994, prior to release of numerous landmark clinical trials in coronary prevention. New NCEP guidelines are expected later this year.
One point of continued contention is how to redefine "low" HDL cholesterol. Everyone agrees that the current cutoff of 35 mg/dL is too low. But even raising it modestly to 40 mg/dL would label one-third of U.S. men and one-fifth of women as having low HDL. And the proportion of people with coronary disease who would fall into this category is far larger.
The clinical benefit of boosting HDL remains controversial. The chief support comes from the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), but there is disagreement about whether the observed benefit was due to HDL raising. Some argue that the HDL increase was incidental to gemfibrozil's effects on the peroxisome proliferator-activated receptor (PPAR), which regulates gene expression related to the atherosclerotic process, he noted.
Hypertriglyceridemia has attracted attention as an independent risk factor for coronary heart disease. There is probably considerable room for improved risk reduction through greater attention to triglycerides, but target levels for triglycerides haven't been defined in clinical trials. Also, reduction of triglycerides has not been proven to afford further benefit after aggressive LDL lowering in a hypertriglyceridemic patient. Large trials designed to answer the question are underway.
In addition to tackling the issue of secondary lipid targets, Dr. Hunninghake also predicted these developments:
Acceptance of an LDL cholesterol
level below 100 mg/dL as a valid target.The importance of putting nearly
everyone with cardiovascular disease on a statin.Routine hospital discharge on a
statin following a coronary event.Health Plan Employer Data and Information Set (HEDIS) guidelines still suggest that an LDL cholesterol target of 130 mg/dL is acceptable. But evidence from large randomized trials points to clinical benefit for secondary prevention with an LDL target of 100 mg/dL, he said.
Dr. Hunninghake said that he counts himself among the many experts who believe that an LDL cholesterol target of 60-80 mg/dL is more appropriate, but he admitted that there is no definitive evidence to support this stance. The ongoing 10,000-patient Treating to New Targets (TNT) trial should eventually provide the answer.
He also noted that the recent Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) trial showed in 3,086 patients that statin therapy should start while patients are hospitalized for a coronary event, rather than waiting to see what several months of dietary therapy accomplish.