Liquid plumber, Pacman and Heart disease…The Anacetrapib story

It beats 100,000 times per day. It pumps liters of blood per minute. If it stops, you stop, in about six seconds. For the human heart to contract this reliably, without hiccups, it requires a steady stream of nutrients. A healthy heart has clean pipes.

There are two ways to keep pipes clear of blockage.

Option A: Not put stuff in them that would block them off. For most, in this land of plenty, this isn’t really a viable strategy.

Option B: Periodically clean the debris out.

Presently, in cardiology, pipe cleaning is the territory of the “squishers.’ Mechanically, they squish blockages, suck debris out, and prop the pipe open with metal cages called stents.

But in the future, perhaps as early as 2015, pipe-cleaning may be the province of spectacled biochemists, rather than quarterback-like interventional cardiologists.

Such chemical unclogging, call it the “liquid plumber” method, was the big story from this week’s AHA meeting.

The magic pill’s name is anacetrapib. It is an experimental HDL (good) cholesterol-increasing drug, developed by Merck. I use the term magic, because the impact on HDL levels is like magic. Exercise, previously known as the best way to increase HDL, can raise levels 5-20%. Anacetrapib resulted in a 138% rise in HDL. As icing on the cake, it also lowered LDL (bad) cholesterol by 40%.

Why is this so exciting? It isn’t squishing, burning, or shocking; it’s a pill. How could a pill be that cool?

Here’s why.

HDL is thought to be good cholesterol because it acts as a scavenger—like in Pacman.  HDL removes plaque-building bad cholesterol from the artery wall and transports it to the liver, for processing. More HDL particles is like having more Pacman. (Is it a coincidence that Pacman turns thirty this year?)

Science is funny though. Just because high HDL levels are good, doesn’t mean that raising their levels with a chemical will also be good. In 2006, Pfizer found this out the hard way, when their HDL-raising drug (torcetrapib) flopped. Yes, Pfizer’s pill increased HDL, like it was supposed to, but it also increased the risk of heart attack and death (ouch). It was an 800 million dollar debacle.

Although in the same chemical class, Merck’s drug, anacetrapib, is felt to be different than Pfizer’s, torcetrapib.  Opposite to its predecessor, in the preliminary (1600 patient) DEFINE trial, anacetrapib did not increase blood pressure or the risk of heart attack.  In fact, as a secondary endpoint there were fewer cardiac procedures in the ‘liquid-plumber’ (anacetrapib) group.

Ironically, I was on my trainer, exercising, raising my HDL, when my interventional cardiology colleague called me back.  I had called him for his take.

He was serious, when he bemoaned that if this pans out like some predict, Merck’s version of liquid plumber may put him out of work.

Looks like we will find out in a few years.  A 30,000 patient randomized controlled trial of adding anacetrapib versus placebo to atorvastatin is set to begin enrolling patients.

It is exciting news, but for advocates of exercise, the message is worrisome.  A pill is better than exercise.  That one will be hard to swallow.

JMM

Good journalistic pieces on the DEFINE trial are at:
Ron Winslow’s WSJ story.
Larry Husten’s Cardiobrief blog
h/t to Will and William for the Pacman and Liquid plumber reference.

Comments

  1. Sherri says

    sometimes I think we just shouldn't mess with Mother Nature like we do

    Take a pill to fix everything mentality. :(

  2. Anonymous says

    Maybe this is simplistic, but many of us try to do all the right things and still have family histories that "doom" us to high cholesterol, high blood pressure and other problems. I'm glad the experts keep working on pills etc. for everyone. Sometimes Mother Nature isn't enough to protect all of us. I'm sure I could improve on my healthy living but even after I lost 20 lbs. to try to avoid going on high blood pressure medicine, I still had to go on two meds a year ago (at 45 yrs.) just as my mom did and her mom did. Bad genes, I guess.

  3. DrJohnM says

    Anony,

    Agree. Innovation in medical therapeutics is a great thing. As a society, we should continue to incentivize ingenuity. AF could not be ablated if not for JNJ, and others. Look no farther than our American cycling champion, Lance. No matter what you think of Lance, that he is here is directly related to pharmaceutical innovation (and Indiana doctors–I might add.)

    HDL-increasers are exciting. We will see whether their favorable biomarker modifications lead to real improvements in outcomes.

    It is fun being in this game.

    JMM

  4. Anonymous says

    John,

    I'm a little skeptical about this… I went to some links you recommended to learn more about this trial, why did they pick subjects that were already at goal and on statins? Would you think the results would have been different if patients had not been on statins or at goals? Just wondering whether I miss something.

    Thanks,

    Tim

  5. Anonymous says

    Hi, what is the role of Apo-A1? How does it help lower cholesterol? Can anyone tell me how it works. Is it available for purchase? Thanks.

  6. DrJohnM says

    Tim,

    Why did they pick there study group? Here is a cut from the 'Intro' section of the NEJM paper: "In many patients, however, a high residual risk of cardiovascular events persists despite aggressive statin therapy to lower LDL cholesterol, especially when other lipid abnormalities, such as low HDL cholesterol, persist after statin therapy… Accordingly, targeting additional lipid risk factors is an approach that is currently recommended to further reduce the risk of cardiovascular disease."

    Statins have a proven track-recortd for reducing cardiac events in 'high-risk' individuals. WHo knows what the future holds, but my guess is that the HDL-enhancers primary role will be as add-ons to statins. At least initially, until the HDL drugs are proven effective in hard outcomes–rather than just biomarker reductions–it would seem unethical to withhold statin therapy in a high risk patient cohort.

    JMM

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