Print Eric Van De Graaff, M.D.

There’s good news coming out of the world of cardiology drug research.

In Chicago this last week at the annual meeting of the American Heart Association, Dr. Christopher Cannon of Brigham and Women’s Hospital in Boston announced the findings of the DEFINE trial, a study meant to assess the effect of a new drug called anacetrapib on lipid levels, most particularly the level of HDL cholesterol.  To put these findings into perspective I’ll bore you with a little history.

We look at cholesterol as the composite of three general subtypes: triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL).  This sort of breakdown is clinically useful despite being an oversimplification of a family of complex molecules.  LDL is the dangerous lipid and the one we follow most as we treat patients to decrease risk of heart attack and stroke.  The optimal LDL level is debatable, but for most people lower generally means better (we shoot for under a hundred in most higher-risk patients).  Triglycerides are small bundles of fat floating in the blood stream and are elevated in people with fatty diets, poorly-controlled diabetes, and persons with a relatively common genetic predisposition.  The impact of triglyceride level on one’s cardiovascular health is not quite as clear-cut as that of LDL, but it is also generally viewed as a molecule you’ll want to own only in limited quantities.

HDL is the protective form of cholesterol and you want as much as you can get.  Long ago we discovered that people lucky enough to be born with elevated levels of this particle are far less likely to develop coronary artery disease.  What remains to be seen is if we can lower the risk of heart attack in a person with low HDL by artificially raising HDL to comparable levels.

For some time now we’ve had good medication to bring down LDL and triglyceride levels but we’ve never really had anything that dramatically raises the level of the protective HDL.  When I was in medical school we were taught that moderate alcohol intake and exercise could raise HDL to a degree—for best effect our instructor recommended that we strap on our Nikes and “run from bar to bar.”  Niacin, a vitamin, has been used with limited effect.  A high dose of this drug (2 to 3 grams) can bump the HDL level by 10-30% but at a cost of significant side effects.  Consumers of high-dose niacin can expect facial flushing shortly after ingesting their daily dose, often to the point of intolerability.  If you ever want to experience what your grandmother went through with menopause, just pop a couple niacin tablets and you’ll have a better appreciation for hot flashes.

For years we’ve been awaiting the magic pill that can raise HDL and confer the theoretic protection on the millions of people born with sparse HDL levels.  We thought that the drug torcetrapib was the answer.  This is a compound that was the subject of gleeful speculation a couple of years ago while it was undergoing study.  Unfortunately, torcetrapib ended up as a disappointment when it was found to actually increase the rate of cardiac death among the study participants.  It is estimated that the pharmaceutical giant Pfizer spent more than $800 million in an attempt to bring this drug to market.  When the results were announced the company’s market value dropped $21 billion overnight.  This ultimately led to the decision by Pfizer to terminate its efforts at developing new drugs to combat heart disease.

Now we have anacetrapib.  In this recent study the level of HDL in the drug-treated volunteers rose a whopping 138% when compared with the placebo group.  To put this in perspective, a patient with an HDL of 30 mg/dL will bump their level to 40 mg/dL on a glow-in-the-dark dose of niacin, but will end up at over 70 mg/dL on anacetrapib—a level that should pretty much nuclear-proof the coronary arteries.

That is, if an artificial bump in HDL ends up being protective.  The current trial was designed to assess anacetrapib’s ability to alter lipid profile and (more importantly) prove the safety of the drug.  Much to the relief of its manufacturers, it appears that the new drug has none of the deleterious effect of the previously studied torcetrapib.

We won’t know if anacetrapib actually saves lives until 2015 or later.  That’s the projected date that Merck hopes to have completed a trial involving 30,000 volunteers.  Until then, I guess the best we can do is keep planning our daily runs around the locations of the town’s watering holes.

In somewhat related news, another important new medicine has just been approved for sale in the United States.  Pradaxa (generic: dabigatran) is the first drug in a half century to serve as a safe and effective replacement for warfarin (Coumadin) in patients with atrial fibrillation.  As many of you know, warfarin was originally developed and marketed years ago as rat poison.  These days, closely monitored use of warfarin is safe but cumbersome and its use is hampered by numerous drug and diet interactions.  Pradaxa is poised to change all that (no adjusting dose, no dietary restrictions).  Those of us in the business of treating atrial fibrillation are excited to see something new come along that is safe, easy to use, and doesn’t have a history as a rodenticide.



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7 Responses to New Cholesterol Drug Might Be Good News

  1. Monte K says:

    Good stuff, buddy. Thanks for the read. Hope things are well this holiday season.

  2. Michael Aaronson MD says:

    is apo A1 milano going to come out?

  3. Dr. Van De Graaff says:

    Dr. Aaronson,

    I don’t think we’ll see this therapy anytime soon. You are referring to a synthetically-derived version of the HDL-like protein found naturally in a small population of Italy. These people were found to have less CAD than predicted. The original research on this was published in 2003 and showed plaque regression among a small cohort of volunteers with established coronary disease. The molecule is apparently quite complex and has yet to be developed and tested to an adequate degree. For now I think raising our intrinsic HDL is still our best bet.

    I’ll use this opportunity to plug Dr. Aaronson’s very informative medical blog: http://www.michaelaaronsonmd.com/

    He is a frequent contributer to the Alegent General Health Blog and one of the smartest guys I know.

  4. Brett Hiller says:

    I have decided to celebrate this medical breakthrough over a basket of deep fried cheese. Mmmhhhh…

  5. Kelli T says:

    You are such a good writer, despite how boring the content may be (not that this was) you always make it a good read. Thanks for your contributions, happy holidays!

  6. Bill Estey says:

    I would imagine the government will be watching the clinical trials with extreme interest. If in fact anacetrapib demonstrates protective properties to the 30,000 volunteers, it could be speculated that the insurance companies would have to give a real close look at coverage of this new med, with cost savings associated to co-morbidities and interventions for CAD. Looking forward to seeing more as this develops.

  7. Bob G says:

    Dr. Van De Graaf,

    I, too, am intrigued by the possibilities of theis drug class and specifically the outcome studies for this drug. It seems that although we have made significant strides in reducing cardiovascular mortality there is still plenty to learn about a very complex set of variables. Thanks for the great blog. You certainly have a skill for writing and are obviuosly a top notch clinician as well.
    Thanks again!

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