Tuesday, December 4, 2012

The Cholesterol Hypothesis on the Beam: Dalcetrapib, PCSK9 inhibitors, and "off-target" effects of statins

The last month has witnessed the publication of three lines of research that could tip the balance of the evidence for the cholesterol hypothesis depending how things play out.  Followers of this blog know that I have a healthy degree of skepticism for the cholesterol hypothesis which was emboldened by studies of torcetrapib (blogged here and here) and anacetrapib that have come to light along with the failures of vytorin (ezetimibe; blogged here and here and hereand the addition of niacin to statins to improve cardiovascular outcomes in parallel with improvements in cholesterol numbers.

I think it's finally time to bury the CETP inhibitors. The November 29th NEJM (published online on November 5th) reports the results of the dal-OUTCOMES trial of dalcetrapib in patients with a recent acute coronary syndrome. Almost 16,000 patients were enrolled in this study of high risk patients, providing the study with ample power to detect meaningful improvements in cardiovascular outcomes - but alas, none were detected. The target is HDL, so the LDL hypothesis is not debunked by these data, but I think it is challenged nonetheless.

Another new class of drugs is the PCSK9 inhibitors, which are monoclonal antibodies directed against the protein PCSK9 which binds to LDL receptors on the liver. Prevention of binding of PCSK9 to the LDL receptor by the antibody allows the LDL receptor to be recycled to the surface after endocytosis, thereby effectively up-regulating the removal of LDL from the bloodstream by the liver. These drugs are administered by subcutaneous injection weekly and in early trials have been shown to demonstrably lower LDL levels. One such monoclonal antibody, AMG145, manufactured by Amgen, was evaluated in a dose-ranging trial of 160 statin-intolerant patients (see JAMA published early online November 5th) and it led to marked LDL reductions of between 41%-63% compared to a 15% reduction with placebo/ezetimibe.  (Here's another article from the November 15th NEJM.) So here we have another agent which has the desired effect on its target, LDL, a surrogate endpoint.  And, in addition to the possibility of a novel therapeutic agent, we have yet another opoprtunity, as we did with CETP inhibitors, to test the cholesterol hypothesis, but this time with LDL as the target.  In my mind, the results of trials of these powerful PCSK9 inhibitors with clinical endpoints (now planned or underway) will provide the best evidence to date in support of or against the cholesterol hypothesis.  If I were a betting man, I would wager no greater than 1:1 odds that these trials will be successful, and I can't wait to see the results.  OK, I am a betting man - so I'm going to bet that the PCSK9 inhibitors do not improve clinical outcomes.  And that won't mean that the cholesterol hypothesis is bust, but it will be strong evidence against it, especially when combined with the ezetimibe data and all the other data on agents that lower HDL.

So, if the cholesterol hypothesis is wrong, why do statins work?  Indeed it may be an accident of history that the statins are both powerful reducers of LDL and robust agents for the treatment and prevention of cardiovascular disease.  And it may be that other effects of statins are responsible for the latter.  Another recent study in the November 8th NEJM, for all its shortcomings and limitations as detailed by the editorialist, suggests the possibility that statins affect health and pathophysiology in ways separate from their effects on cholesterol metabolism. In this retrospective observational study, the progression of cancer appeared to be attenuated in cancer patients who were using statins.  This provides at least a small appetizer for a full course meal of thought on the subject.

(Niacin is having a rough time of late too.  See:  Merck says Niacin Drug Has Failed Large Trial.)
Only time will tell if the cholesterol hypothesis pans out, and whether other purported health benefits of statins are confirmed. Certainly these are exciting times in this field of research, as well as for the gamblers and bookies among us.  Perhaps I should call it the "Fantasy Research League."


  1. One reader asked:

    Interesting. It does seem like the cholesterol lowering and cardiovascular benefit may be separate. Do you think it is their effect (stabilizing?) on the endothelium that is beneficial?

  2. I'm no vascular biologist, so I can't speculate on mechanisms. But this naivate affords a broader, more far-sighted perspective allows me to see certain trends without distraction by the details and the "party line". And I think these data are startling and should rattle the "true believers." Indeed, there was great enthusiasm for the CETP inhibitors. We can thusly infer that the vascular biologists (and Big Pharma) thought the entire paradigm was consistent with what was "known" - and BEHOLD - they were wrong. And now that we have those unexpected but robust data, I think we CANNOT ignore them in terms of their relevance to the overarching paradigms. We have to reconsider our cherished beliefs. And that's why it's so interesting to an aspiring iconoclast.

  3. Dr. Aberegg, when will the house of cards we call all surrogate markers fall?

    We continually fall into allowing surrogate markers to become dogma way too early in research. If it looks right on a chalk board and has a great MOA, then it must be right... Avandia, Vioxx, etc...

    When we actually look at the evidence, as doctors as yourself have, it is clear to see that we know statins save lives, and the others, as you mention do not. We also, IMHO, have no data to suggest what a specific LDL goal should be in anyone. We waste so much money and time titrating lipids rather than just getting folks on statins and then based on TNT using the highest dose statin a patient could tolerate, if they so chose.

    My money is that the PCSK9 drugs will do an awesome job of changing LDL, but will not affect CV outcomes/mortality as you state, BUT, there will be a HUGE outcry by researchers, lay people, and cardiologists that we are missing something! There must be some explanation for those results... subgroups will be studied, excuses will be made, but the lipid hypothesis will go on, maybe even more strongly after being handily rejected by those kind of results. Dogma is nearly impossible to change.

    I think copernicus died at the hands of his revelations that the earth wasn't the center of the universe.

  4. Hi Dr. Abberg

    When we say statins "work" this pertains to secondary prevention in middel aged males who have had heart attacks and severe coronary artery disease. It's not for the elderly or women generally. For primary prevention they are next to useless.

    They work under these circumstance , but there is a huge caveat:

    It is not nearly as great as numbers in the medical journals claim.It is dramatically exaggerated.

    The drug companies have manipulated these numbers and used relative risk to make it sound impressive. You will hear numbers like reduced cardiovascular deaths by 50%. The actual absolute numbers show the real figures. The documentary "Statin Nation" does into detail about this toward the end . It's avilable on YouTube. JUPITER was a trial where this shady fraud occured.

    Doctors who are very busy do not dig into it deeper and see the 50 % quote and wet their pants in delight.

    It's is extremely unethical to manipulate numbers like this.

    The reason statins work under the said conditions is likely due to their 12 other effects they have- their pleotropic effects. All NON- statin cholesterol lowering trials are failures- drug or diet for reducing CAD and total mortality. This is very telling.

    Another telling things is that atherosclerosis ONLY happens at areas of damage to the endothelium. It does not occur "just anywhere." What ever is causing the intial damage to the endothelium is ultimatley causing coronary herat disease.

    Possible causes? Viruses, microbes, toxins, poor diet, immune system etc. Dr. Uffe Ravnskov and Kilmer McCully have a great hypothesis set forth. LDL lipoprotein is strongly involved in the immune system defense. It binds to and attacks invaders. Interesting fact: Rats injected with human LDL lipoprotein before given injections of bacteria or viruses - MOST live compared to the control rats who do not get injections of human LDL .

    As Isaac Newton said - it is about the WEIGHT of the evidence, not the numbers of experiemtns.

    You have a nice blog.

    Take care,