The Cardiologist Giveth, then the Cardiologist Taketh Away: Revision of the Cholesterol Guidelines

There has been quite a stir this week with the publication of the newest revision of the ACC/AHA guidelines for the treatment of cholesterol.  The New York Times is awash with articles summarizing or opining on the changes and many of the authors are perspicacious observers:

• 3 Things to Know About the New Cholesterol Guidelines by Harlan Krumholz of Yale
• Don’t Give More Patients Statins by authors from Harvard and UCSF
• Experts Reshape Treatment Guide for Cholesterol
• New Cholesterol Advice Startles Even Some Doctors
• Questions For A New Class of Cholesterol Drugs

As the old Spanish proverb states, "rio revuelto, ganancia de pescadores" - when the river is stirred up, the fishermen benefit.  I will admit that I'm gloating a bit since I consider the new guidelines to be a tacit affirmative nod to several posts on the topic of the cholesterol hypothesis (CH).  (More posts here and here and here, among several others - search for "cholesterol" or "causal pathways" on the Medical Evidence Blog search bar.)

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 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.

MRK and SGP: Ye shall know the truth, and the truth shall send thy stock spiralling

Apparently, the editors of the NEJM read my blog (even though they stop short of calling for a BOYCOTT):

"...it seems prudent to encourage patients whose LDL cholesterol levels remain elevated despite treatment with an optimal dose of a statin to redouble their efforts at dietary control and regular exercise. Niacin, fibrates, and resins should be considered when diet, exercise, and a statin have failed to achieve the target, with ezetimibe reserved for patients who cannot tolerate these agents."

Sound familiar?

The full editorial can be seen here: http://content.nejm.org/cgi/content/full/NEJMe0801842
along with a number of other early-release articles on the subject.

The ENHANCE data are also published online (http://content.nejm.org/cgi/content/full/NEJMoa0800742
and there's really nothing new to report. We have known the results for several months now. What is new is doctors' nascent realization that they have been misled and bamboozled by the drug reps, Big Pharma, and their own long-standing, almost religious faith in surrogate endpoints (see post below). It's like you have to go through the stages of grief (Kubler-Ross) before you give up on your long-cherished notions of reality (denial, anger, bargaining, then, finally, acceptance). Amazingly, the ACC, whose statement just months ago appeared to be intended to allay patients' and doctors' concerns about Zetia, has done a apparent 180 on the drug: "Go back to Statins" is now their sanctimonious advice: http://acc08.acc.org/SSN/Documents/ACC%20D3LR.pdf

I was briefly at the ACC meeting yesterday (although I did not pay the $900 fee to attend the sessions). The Big Pharma marketing presence was nauseating. A Lipitor-emblazoned bag was given to each attendee. A Lipitor laynard was used to hold your $900 ID badge. Busses throughout the city were emblazoned with Vytorin and Lipitor advertisements among others. Banners covered numerous floors of the facades of city buildings. The "exhibition hall," a veritable orgy of marketing madness, was jam-packed with the most aesthetically pleasing and best-dressed salespersons with their catchy displays and gimmicks. (Did you know that abnormal "vascular reactivity" is a heretofore unknown "risk factor"? And that with a little $20,000 device that they can sell you (which you can probably bill for), you can detect said abnormal vascular reactivity.) The distinction between science, reality, and marketing is blurred imperceptibly if it exists at all. Physicians from all over the world greedily scramble for free pens, bags, and umbrellas (as if they cannot afford such trinkets on their own - or was it the $900 entrance fee that squeezed their pocketbooks?) They can be seen throughout the convention center with armloads of Big Pharma propaganda packages: flashlights, laser pointers, free orange juice and the like.

I just wonder: How much money does the ACC receive from these companies (for this Big Pharma Bonanza and for other "activities")? If my guess is in the right ballpark, I don't have to wonder why the ACC hedged in its statement when the ENHANCE data were released in January. I think I might have an idea.

Torcetrapib, Ezetimibe, and Surrogate Endpoints: A Cautionary Tale

In today's JAMA, (http://jama.ama-assn.org/cgi/content/extract/299/12/1474 ), Drs. Psaty and Lumley echo many of the points on this blog over the last six months about ezetimibe and torcetrapib (see posts below.) While they stop short of calling for a boycott of ezetimibe, and their perspective on torcetrapib is tempered by Pfizer's early conduct of a trial with hard outcomes as endpoints, their commentary underscores the dangers inherent in the long-standing practice of almost unquestioningly accepting the validy of "established" surrogate endpoints. The time to re-examine the validity of surrogate endpoints such as glycemic control, LDL, HDL, and blood pressure is now. Agents to treat these maladies are abundant and widely accessible, so potential delays in discovery and approval of new agents is no longer a suitable argument for a "fast track" approval process for new agents. We have seen time and again that such "fast tracks" are nothing more than expressways to profit for Big Pharma.

Psaty and Lumley's chronology of the studies of ezitimibe and their timing are themselves timely and should refocus needed scrutiny on the role of pharmaceutical companies as the stewards of scientific data and discovery.