Does raising HDL (good cholesterol) improve health? New study says ‘no’

High levels of LDL (bad cholesterol) increase the risk of cardiovascular (CV) adverse events such as myocardial infarction (aka heart attack) and stroke. Statins (such as Lipitor, which recently went generic) lower LDL, cut the risk of stroke and heart attacks, and are fantastic drugs.

Conversely, high levels of HDL (good cholesterol) are associated with low rates of adverse CV events. Niacin is a drug known to increase HDL. On Thursday, Merck announced the results of one of the largest cardiovascular studies to date. Called the “Heart Protection Study-2” (aka HPS-2 THRIVE), this study enrolled 25,673 patients. Not only did niacin fail to improve outcomes, there was some suggestion that patients taking niacin did worse than patients taking placebo. This is all Merck has disclosed thus far. Full results will be presented for further scrutiny at medical meetings in the future.

There are several caveats to interpreting the HPS-2 THRIVE data. One is that Merck combined niacin with a novel agent to prevent flushing, a side effect commonly caused by niacin. It is possible that this agent was harmful. A second caveat is that some smaller prior studies (such as ARBITER-2 and ARBITER-6) suggested hints of benefit for niacin users. Notwithstanding these caveats, given the totality of medical evidence, it appears questionable as to whether drugs that raise HDL actually do any good. Even if they do, the benefits are likely much smaller the positive effects produced by statins and blood pressure medicines.

This is not the first time that raising HDL failed to help improve health. Until recently, scientists had high hopes for a new class of drugs known as CETP inhibitors, which raise HDL by 50-100%. The first drug in this class, torcetrapib (developed by Pfizer), showed evidence of harming patients. The second drug, dalcetrapib (from Roche), showed no benefit (though it did not appear to cause harm).

Discovering drugs is not only challenging, it’s expensive. The cost of the torcetrapib development program was estimated to be approximately $800 million. That’s a lot of money, even for Pfizer, especially in light of the failed trial results.

Despite promising epidemiological rationales, several other drugs have also failed to prevent CV disease. These include:

Folate: elevated blood levels of homocysteine are another marker of increased CV risk. Folate (aka vitamin B9) lowers homocysteine levels. Unfortunately, clinical trials investigating folate in heart disease failed to show any benefit.

Fish oil: Fish oil lowers triglycerides (another lipid associated with heart disease). Despite this, the majority of evidence suggests that taking fish oil does not have any medical benefit. I have written previously about fish oil here and here).

Antibiotics: At one point, it was postulated that, since markers of inflammation are associated with adverse CV outcomes, perhaps chronic antibiotic use would reduce CV risks. Accordingly, Pfizer studied daily doses of the antibiotic azithromycin (Zithromax) in the WIZARD study. Alas, this too yielded no benefit.

Vioxx: Vioxx (aka rofecoxib, an anti-inflammatory drug similar to Celebrex and ibuprofen) was developed for pain. Blood levels of certain chemicals associated with inflammation are also associated with higher risks of bad CV events. One such chemical is called C-reactive protein, or CRP. Vioxx lowers both inflammation and  CRP levels. Despite reducing CRP levels, Vioxx was pulled off the market in 2004 after the VIGOR and APPROVE studies suggested that chronic Vioxx use increased the risks of suffering a heart attack.

sources: Merck announces results of HPS-2 THRIVE study (Merck), HPS-2 THRIVE misses primary end point: No benefit of niacin/laropiprant (TheHeart.org)

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