Heartfelt with Dr Melissa Walton-ShirleyView all posts »
The HDL ceiling: Cracked today by DEFINE and the CETP inhibitor anacetrapibNov 17, 2010 12:33 EST
Because lifestyle modification is the ever-elusive holy grail of plaque stabilization, and because those of us who've been ravaged by years of self-imposed endothelial battering need help in a hurry, we continue our quest to find the perfect solution to the prevention and treatment of coronary artery disease. Today's presentation by Dr Chris Cannon was elating to say the least. The HDL levels went out the roof with the oral selective CETP inhibitor anacetrapib. As a matter of fact, those patients had so much HDL, they were swimming in it, achieving a level of over 100 with a simultaneous reduction in LDL levels. It was every cardiologist's fantasy, but it was also a little unnerving. It was kind of like, after finally being taken to the zoo you found yourself behind the glass, standing right in the middle of a legion of quiet gentle gorillas but with a dangerous and aggressive potential. We all remember the torcetrapib outcome; flying high with its HDL-raising capabilities but shot down by elevated blood pressure, mortality, and cardiac events, the outcome of which for some was devastating. This compound was different, though, and it didn't just scoot by with marginal data, it soared! And with no safety concerns as well. I don't think in my seven years of being with theheart.org that I've come out of any meeting so optimistic. Well, except maybe one other time. That was in 2003.
I attended a small abstract presentation somewhere in the world that reported on the infusion of recombinant DNA with the same gene sequence as HDL. The study had 47 patients suffering from unstable angina who were then evaluated by intravascular ultrasound (IVUS), and "voilà!" the first "Drano effect" ever with any compound in history, effectively unplugging vessels to a statistically significant "p-value" degree. I left thinking we were now on a Star Trek–like course with key in hand to the universe of MI prevention. It is now 2010, and I'm still waiting, at least I was until this morning.
I did ask the question why it was that we veered off course with the IV preparation that produced IVUS-proven plaque burden reduction and therefore presumed stabilization. The answer was that the compound, ApoA1 Milano, was difficult to manufacture, and apparently there were some hypersensitivity concerns and then problems with delivery. Who wants to infuse anything when you could take it PO? However, I had fantasized that perhaps we could infuse it during unstable-angina admissions or PCI procedures or at least until we learned how to reproduce the same effect with an oral preparation.
That's the hope for today's anacetrapib, the new CETP inhibitor. It's a whole new drug class, and instead of cracking its head on the HDL ceiling, it smashed through it and kept on flying. An upcoming trial in the not-too-distant future is planned to look at event rates. For my birthday present next year, I hope they plan an invasive IVUS arm to actually look at what's happening to plaque volume and power the trial to look at hard primary end points like death and MI. I quipped that a safe HDL-raising compound could be "the gift that keeps on giving," to which someone who is a rather tall, articulate gentleman who wears wire-rimmed glasses, works at a well-known center in Baltimore, MD, and whose initials are RB, quipped, "Yeah . . . like venereal disease," meaning we hope that it's proven to be an effective compound that will infiltrate, like wildfire, every echelon of lipidology.
Well said, my friend who shall remain nameless, well said. And remember, you did say I could quote you! :-)