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For many years, clinical guidelines on the treatment of dyslipidemias have focused on reducing low-density lipoprotein (LDL) cholesterol. However, emerging science, when combined with earlier epidemiological research, is beginning to show that a low level of high-density lipoprotein (HDL) cholesterol is another, independent risk factor for developing coronary heart disease (CHD).
"At every level of LDL, epidemiological studies have shown that the level of HDL makes a difference in the rate of cardiac events," says Om Ganda, MD, director of the lipid clinic at Joslin Diabetes Center in Boston. "The problem is that epidemiological studies do not prove cause-and-effect."
The epidemiological support for increasing HDL can be traced from the original Framingham Heart Study.1 Other Framingham studies showed the incidence of myocardial infarction (MI) increased twofold for men with HDL levels <52 mg/dl and fourfold for women.2 However, the lack of large, randomized controlled trials studying the long-term benefits associated with raising HDL have impeded the development of evidence-based clinical guidelines.
"With the publication in 2001 of the newest National Cholesterol Education Program (NCEP) guidelines, there is beginning to be a grudging recognition that HDL is an important risk factor in the development of CHD," says William Boden, MD, director of cardiology at Hartford Hospital and professor of medicine at the University of Connecticut School of Medicine. "Now people have begun to appreciate that there is more risk associated with dyslipidemia than can be explained solely by LDL."
This has led to the inclusion of HDL classification levels in NCEP's Adult
Treatment Panel III (ATP III) guidelines. Serum levels <40 mg/dl are said
to be low and those 
60 mg/dl are high. However, at this time, ATP III is
silent on what to do about low levels.
"The problem is that the current guidelines leave clinicians hanging, and NCEP sends out mixed signals to physicians in practice," Boden says. "They admit that HDL is an important risk factor, but then say they aren't sure there are data that support efforts to raise it."
WAITING FOR DATA
Thus far, only the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) has looked directly at how raising HDL affects CHD in patients with low levels of the lipoprotein. The study found that raising HDL significantly reduced the rate of cardiac events at 1 year—at least among the studied population of men with low HDL but with LDL and triglyceride levels below those suggested for initiation of gemfibrozil (Lopid, Parke-Davis) therapy.4
"Another problem we run into is that LDL metabolism is more straightforward and easier to treat with statins," says Mark Deeg, MD, PhD, associate professor of medicine and biochemistry at the Indiana University School of Medicine in Indianapolis. "HDL metabolism is intertwined with triglyceride metabolism, which results in a clinical ambiguity."
A recent meta-analysis by Rakesh S. Birjmohun, MD, and colleagues suggested that both niacin and fibrates can have an important impact on HDL levels.5 Fibrates reduced the risk for major coronary events by 25%, whereas current available data for niacin indicate a 27% reduction. For fibrates and niacin, respectively, their random-effects model showed 11% versus 10% reduction in total cholesterol, 36% versus 20% reduction in triglycerides, 8% versus 14% reduction in LDL, and 10% versus 16% increase in HDL. However, the researchers did not attempt to link these results to changes in CHD end points.
There also is a paucity of information on how to combine medications if one alone does not sufficiently lower HDL. However, some clinicians suggest that more than one medication may be needed in many cases.
"Polytherapy may be especially important in those with very low HDL," Deeg says. "After all, it is unusual to have monotherapy in hypertension. It would not surprise me at all if this was true in this case as well."
Control of diabetes is another factor, as poor control increases triglyceride levels, Ganda says. "As [glycated] hemoglobin (A1C) levels decline from 9% to 7%, you get a 30–40% reduction in triglycerides and highly significant increases in HDL."
IN THE MEANTIME
All three doctors interviewed agree it is important for primary care clinicians to know the complete lipid profile for their patients. The risk assessment should include total cholesterol, LDL, HDL, and triglycerides. When needed, they suggest first treating patients for high levels of LDL with statins, as the science behind that recommendation is the most robust.
When triglycerides are elevated and HDL is low, the situation is not as
clear. Use of niacin and fibrates, such as gemfibrozil, appears promising and
should be considered. However, evidence-based knowledge about which medication
to use first, when to add other medications, and the long-term impact on CHD
end points awaits the results of several large-scale trials currently under
way. 
References
2. Abbott RD, Wilson PW, Kannel WB, et al.: High density lipoprotein
cholesterol, total cholesterol screening, and myocardial infarction: The
Framingham Study. Arteriosclerosis 8: 207–211, 1988.
3. 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 285:2486–2497, 2001.
4. Rubins HB, Robins SJ, Collins D, et al.: Gemfibrozil for the
secondary prevention of coronary heart disease in men with low levels of
high-density lipoprotein cholesterol: Veterans Affairs High-Density
Lipoprotein Cholesterol Intervention Trial Study Group. New Engl J
Med 341:410–418, 1999.
5. Birjmohun RS, Hutten BA, Kastelein JJ, et al.: Efficacy and safety
of high-density lipoprotein cholesterol-increasing compounds: A meta-analysis
of randomized controlled trials. J Am Coll Cardiol 45: 185–197, 2005.
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