Monday, January 09, 2006

Raising HDL

Drugs that lower cholesterol and other blood fats are the world's biggest sellers, with nearly $27 billion in sales in 2004, up 12% from the year before. Yet Lipitor and other statins, the blockbuster drugs that dramatically lower blood levels of bad cholesterol (LDL), cut heart attacks and strokes by just 30% to 40%. Even in high doses, statins alone can't undo artery disease.

"That's the hard, cold reality of the last 15 years of research," says the Cleveland Clinic Foundation's Steven Nissen. "We need more."

The new drugs either raise "good" cholesterol (HDL) or try to improve its effectiveness. That's because HDL is a kind of blood-borne barge that hauls fat from the artery wall to the liver for excretion. Studies show that people with high levels of HDL have cleaner arteries and less risk of heart attack.

In the pipeline:

  • Torceptrapib to raise HDL (Pfizer)
  • JTT-705 to raise HDL (Roche)
  • apoA-1: component of HDL used to remove plaque from artery walls (various companies)
  • MK-0254 to raise HDL without flushing side effect of currently available niacin(Merck)
Why raise HDL?

In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), which involved 2531 men with coronary artery disease (CAD) and low HDL-C (mean = 32 mg/dL), treatment with gemfibrozil 1200 mg/day raised HDL-C by 6% compared with placebo, with no differences in LDL-C observed. Results: reduced coronary events, including nonfatal heart attack, fatal heart attack, and sudden cardiac death, by 34% compared with placebo when examined 5 years later.

Clinical Strategies to Elevate HDL

Nondrug Therapy
  1. Diet. High-carbohydrate, low-fat diets may be associated with low HDL.
  2. Obesity. HDL may also decline with obesity, while decreases in body mass index have been associated with increases in HDL.
  3. Regular aerobic exercise can raise HDL modestly (studies in women have demonstrated almost a 25% rise from baseline following 12 weeks of moderate-to-high aerobic exercise [target heart rate 60% to 80% of maximum]).
  4. Smoking has been associated with low HDL as well as increased oxidative stress, endothelial injury, and a range of vascular and other adverse sequelae. Conversely, smoking cessation has been associated with significant increases in HDL.
  5. Moderate alcohol use is associated with increased HDL in a dose-dependent fashion (where "moderate" is defined as 2-3 drinks a day for men, 1-2 drinks a day for women).
  6. Fish Oils. Dietary modification to increase the consumption of cold-water fish (eg, salmon) rich in omega-3 polyunsaturated fats may help to raise HDL.

Drug Therapy

  1. Statins. HMG-CoA reductase inhibitors modestly raise HDL levels.
  2. Fibrates. Binding agents modestly raise HDL levels.
  3. Niacin. Vitamin moderately raises HDL levels.

HDL is instrumental in mediating reverse cholesterol transport (clearing out clogged atreries), has antioxidant properties, and exerts other potentially vasculoprotective effects. The risk of CAD increases as circulating HDL levels decrease. Even modest increases of HDL on the order of 6% have been associated with significant reductions in coronary morbidity and mortality, particularly in patients starting out with low HDL levels. Statins, fibrates, niacin, and/or certain combinations of these agents according to labeling are currently available. A number of promising HDL raising therapies are on the horizon.

While we wait for the new and better drugs, we can drop heart disease risk quite significantly by adopting some of these strategies.


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