This is discussion forum for physicians, researchers, and other healthcare professionals interested in the epistemology of medical knowledge, the limitations of the evidence, how clinical trials evidence is generated, disseminated, and incorporated into clinical practice, how the evidence should optimally be incorporated into practice, and what the value of the evidence is to science, individual patients, and society.
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 anacetrapibthat have come to light along with the failures of vytorin (ezetimibe; blogged here and here and here) and 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.
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."