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Cardiovascular Disease

The Torcetrapib Catastrophe

This is a complete clinical disaster: the world’s largest drug company just ditched their potential biggest drug. And this comes two days after a press conference where they talked about how they were planning to submit it for approval within months. Development of torcetrapib, the cholesteryl-ester transfer protein inhibitor designed to raise HDL levels, has been halted. Last week, that sentence would have been the subject of nightmares at Pfizer, but now it’s the top of the news. No alarm clock buzz will make it go away. If you’re looking for an example of just how difficult drug development is, look no more.
The story broke on Saturday: the 15,000-patient trial that was underway (half on Lipitor, half on Lipitor plus torcetrapib) showed excess deaths in the combination group (82 versus 51). That figure’s impossible to ignore or explain away, and now the problem will be to explain what caused it. There are other CETP inhibitors in development, such as JTT-705 (from Japan Tobacco and Roche) and one from Merck as well. Both these companies have just had a tremendous shock, since we don’t know (yet) if the patient deaths were due to CETP inhibition itself, the combination of it with the HMG CoA reductase inhibition of the statin, an off-target effect of torcetrapib with the statin, or just an off-target effect of the drug on its own. I’m sure that intense reviews of all the clinical data are going on. Things just got much more complicated.
As for Pfizer, they now have a monstrous hole in their near-term pipeline. Looking back, they’ve had a terrible run the last couple of years, with a number of promising drugs dropping on them, but nothing compared to this. I don’t think anyone’s had one to compare with this, at least in terms of the expectations for a drug. I was just talking with some people from the company last week (along with many of my colleagues), looking into employment possibilities. After this, I think we may have to keep moving. I don’t think that Pfizer’s going to be in the mood for hiring.

48 comments on “The Torcetrapib Catastrophe”

  1. BCP says:

    This was a huge shock — if it turns out that this is related in any way to the blood pressure effects that have be known for a few years now, things could get even more interesting.
    I wonder if we’ll get a peak at the IVUS data any sooner.

  2. Derek Lowe says:

    It’s going to be interesting to see the trading in Pfizer’s stock tomorrow. Good thing it has such a huge float, because otherwise it probably wouldn’t open until noon. As it is, the NYSE specialists will have quite a time matching up all those sell orders.

  3. Garmon says:

    Have you seen it reported whether there was any attempt to screen out patients whose blood pressure increased subsequent to beginning participation?
    I’ve seen that Pfizer was confident that any increase in risk due to increased blood pressure would be swamped by the beneficial effects of the drug, but why take the risk? It seems to me that they could have knocked out anyone whose SBP rose more than 4-5mm Hg in either group (they noted a 2.7 mm mean Hg rise in Phase II). Did they decide to throw caution to the wind?

  4. Daniel Newby says:

    I don’t understand the experimental design. What Pfizer needed to know was what effect torcetrapib had on the human body. So why did they do a post-marketing drug-drug interaction study? They have only themselves to blame.

  5. carola bairos says:

    Daniel, I sincerely hope you’re not in the research business. Do you see how flawed your thinking is? Is it a good thing–for potential patients–that Pfizer structured its studies the way they did? Sure, they’re interested in delivering the world’s next mega-blockbuster, but they don’t want to kill people in the process. Sheesh.
    The sad part of all of this is Pfizer is now talking about doing more mergers and acquisitions to get them out of trouble–when it’s exactly those actions that got them into this mess. Just what we need–more researchers and labs to integrate…
    CNNMONEY/FORTUNE has a good piece on this…

  6. Chrispy says:

    Word seems to be that the solution for Pfizer is to buy, buy, buy: I’ve heard Amgen floated as a potential purchase candidate. How big could Pfizer possibly get?

  7. milkshake says:

    Bigger than Enron.

  8. Matt says:

    So, would this be a good time to pick up some Pfizer on the cheap, expecting a rebound in the coming months/years? Or is this blow so painful that they may not recover for some time?

  9. Daniel Newby says:

    “Daniel, I sincerely hope you’re not in the research business.”

    I’m in defense and security R&D. We try to keep jetliners from being blown up, spies from becoming radioactive, and more subtle sorts of mayhem. It’s a pain in the butt. How do you quantify the risk that a city will be killed by an obscure wickedness, let alone measure whether your fancy gadgets make any improvement.

    From where I stand, drug evaluation looks like a pretty cut and dried business. You get to actually change variables (OMG one at a time!), and you get more than zero events during the measurement period (a luxury to wallow in). And Pfizer went and threw it away. They were cocksure that torcetrapib would miraculously be both good and pharmacologically trivial. I know you have to force yourselves to be optimistic in the Wonder Drug Business, but come on!

    “Sure, they’re interested in delivering the world’s next mega-blockbuster, but they don’t want to kill people in the process.”

    Alas, the only way to learn how something affects mortality is to measure how many people it saves or kills. The duty of the investigators is to ensure that the outcome teaches something about the new treatment. If you’re not going to learn whether there is any point to the treatment, the whole thing is just an empty exercise.

    Thanks to the study design, Pfizer has learned very little so far. They may never learn anything, meaning the deaths were in vain. There is also a chance that the deaths were a fluke interaction with Lipitor, that torceptrapib alone is actually superior at saving lives, which means that thousands of people are being needlessly killed by inferior statins. We really don’t know, and it will take a minor miracle to learn it from the “data”.

  10. MW says:

    I believe that in earlier trial phases, they do exactly that: make sure the drug itself doesn’t kill anyone. The problem is that there is probably less of a benefit from taking torcetrapib alone versus a statin alone. Therefore, to get FDA approval as well as to make $$$, you have to show that the combination is better than either drug alone. This is why Roche’s trial is taking the same approach (Derek’s next post).

  11. Kay says:

    I infer from above that some sort of drug-drug interaction was involved in the blow-up. If this is the case, I missed the evidence. Can anyone post a link?

  12. Derek Lowe says:

    Kay, that’s still up the air, I’d say. The excess mortality was in the group getting both statin and CETP inhibitor, which is what has everyone worried. But whether it’s drug/drug, mechanism/mechanism, or some other combination of the two is (as far as I know) an open question.

  13. Judy Shapiro says:

    Daniel, the thing is, the target population that Pfizer is marketing the drug to is ALREADY taking statins, at least if their doctors are doing their job. The chance that patients would be willing to drop a well-tested drug (statins) just to go with a newer drug is slight. So, how would Pfizer have been able to recruit 15,000 people willing to go off their statins to participate in the study, especially since 7,500 of them would have to go on a placebo and be taking NOTHING for their heart problem, when a known effective drug (a statin) was available? Would YOU give up a drug that was known to reduce your chance of death by 33%, just to have a 50% chance of getting a drug that might not do anything?
    At any rate, torcetrapib was intended to be used along with a statin (Lipitor), so it made sense to test it that way.

  14. dave says:

    “If you’re not going to learn whether there is any point to the treatment, the whole thing is just an empty exercise.”
    I believe the point is to save peoples lives? You do the best and quickest route to determine if the drug can be of use to patients.
    If it is not you bin it.
    If it is you sell it.

  15. sciwriter says:

    True, trial recruitment would have been difficult had there been a torcetrapib-only arm, but I think what’s being overlooked here is that Pfizer wanted to package the two together–The idea was to save Lipitor when its patent expired in 2010. It’s never been completely about torcetrapib’s potential on its own…
    In fact, the company was intially only looking to sell it in combination with Lipitor (keeping it out of reach for all those patients who are now taking generic Zocor). After facing a ton of criticism, earlier this year they agreed to back away from that strategy.
    Either way, what a mess…

  16. Dogmeat says:

    Interesting. The question which Pfizer should have the answer from previous studies, is the rate of death seen on lipitor alone per patient year of exposure. Is this rate greater or less than 51 per 7500 enrolled patients over the duration of this currently halted study (i.e. the torcetrapib alone death rate)? Of course this is infered data since it was not conducted at the same time and under the same cohort, but still does give an indication of the relative safety of torcetrapib alone. This should be sufficient for hypotheses generation.
    Next question of importance is the mechanism(s) of enhanced death. Is this related to dislodgement of plaque with downstream embolization or secdondary to hypertension, hypertriglyceridemaia or other unknown side effects? Could this be a drug that works too well at the tested dosage? Plaque takes years to develope and maybe it is best to remove it slowly. Should Pfizer be halting all study on this drug or only rethinking it clinical dosing. This is an interesting drug that may still have great utility if its mechanisms of action are fully understood.

  17. Judy Shapiro says:

    Dogmeat said: Is this rate greater or less than 51 per 7500 enrolled patients over the duration of this currently halted study (i.e. the torcetrapib alone death rate)?
    There was *no* torcetrapib alone group in Pfizer’s study. The two groups were Lipitor (a statin) alone, and Lipitor plus torcetrapib. That’s what Daniel was criticizing.
    Sciwriter, I agree that Pfizer was extremely motivated trying to package the two drugs together. However, statins are so common now for heart patients that I’m not sure you could get an ethics committee to approve a control group that got just a placebo, instead of a statin. I know that the UK’s National Health Service is thinking of providing drugs that prevent heart attacks to all British citizins over the age of 50, whether they have heart disease or not. That makes it kind of hard to say heart patients should take no drug at all, just to test the latest of many lipid-altering drugs.
    As for refusing to sell patients torcetrapib unless they also bought Lipitor, that would have been unconciable.

  18. clinical trialist says:

    There is no way Pfizer could’ve gotten the answer from previous studies–phase 2 lipid studies tend to involve only a few hundred patients each, and to run for much shorter periods of time–thus the number of cases in each arm would’ve been too low to determine whether there was a difference or not. If you do the math, 80 deaths/7500 subjects over several years = ~0.33 deaths/100 subjects over 1 year = ~0.08 deaths/100 subjects/3 months (the usual duration of lipid studies). The ONLY way to determine if there is a difference in death rates is to do a morbidity and mortality study, which involves ~15000 subjects and runs ~4-5 years (and costs hundreds of millions of $$), which is what Pfizer had to do.

  19. Daniel Newby says:

    “Daniel, the thing is, the target population that Pfizer is marketing the drug to is ALREADY taking statins, at least if their doctors are doing their job. The chance that patients would be willing to drop a well-tested drug (statins) just to go with a newer drug is slight.”
    Perhaps not. IIRC, for low- and moderate-risk people, the statins require one patient-century of dosing to prevent one cardiovascular event. Given the adverse effects of statins, and the plausibility that a CETP inhibitor might be therapeutic, many people would find the risk acceptable. (In fact, I expect that honestly describing statin costs-versus-benefits would make many potential subjects skip the trial AND drop their statin. “I have to put up with a century of sore muscles to avoid one stinking heart attack? Forget that!”)

  20. Hap says:

    If you take statins, you don’t have “a century of sore muscles” – if you are unlucky enough to see this side effect, you might not have to worry about even a month of sore muscles, let alone a hundred years of them.

  21. Daniel Newby says:

    Hap: Apparently statins give quite a few people muscle pain and/or weakness without causing serious rhabdomyolysis. It’s a real conundrum for people with high carodiovascular risk: put up with pain and minor muscle damage, or invite Mr. Heart Attack over for dinner.

  22. Hap says:

    DN: Sorry; I knew about the muscle breakdown but I hadn’t heard (or read too shallowly, more likely) about the muscle soreness. I take Zocor, and haven’t seen it, fortunately.
    Would raising HDL help lower heart attack risks if LDL isn’t lowered?

  23. Judy Shapiro says:

    IIRC, for low- and moderate-risk people, the statins require one patient-century of dosing to prevent one cardiovascular event.
    But was the Pfizer study done on low and moderate risk subjects? I’d think they’d want subjects at high risk of heart attacks, who are the ones who would benefit most from a statin.

  24. RADmanZulu says:

    The BP elevating problems of torcetrapib surfaced in early Phase 2. The current wisdom of the time is that one of the metabolites inhibited mono amine oxidase. The Groton team felt that it could be managed by lowering the dose and hoped that atorvastatin would also lower BP. Pfizer was running a big study called RESPOND which was evaluating BP lowering effects of atorvastatin at the time.
    All the studies are done on top of atorvastatin for two reasons. 1. It is impossible to ethically study patients at risk today without allowing statins. 2. All the financial modeling showed that Pfizer made more money if torcetrapib was not available as a single entity because the real gain was through recapturing the Lipitor business before the 2011 patent extension.
    Torcetrapib failed because inhibiting CETP is a flawed strategy. It raises HDL by interfering with its functionality. The majority of cholesterol return to the liver is via ApoB particles and this requires functional transfer from HDL to LDL via CETP. All the RCT studies done by Pfizer, in animals and humans, either failed to show an increase or showed a trend towards worsening RCT and the best they could claim out of them was that “RCT was not worsened”. Not too promising for an HDL elevating drug! When that fact came out, the discussion morphed to the other effects of HDL (anti-oxidant, anti-inflammatory, anti-coagulant) but this data was totally lacking for torcetrapib. Early in the program, people like Brian Brewer and Michael Brown warned Pfizer that blocking CETP was likely to accelerate atherosclerosis. Over time, everyone drank the Cool Aid but now the truth is out. It’s not the BP, it’s the mechanism. While BP is a potent risk factor, the BP elevation with torcetrapib does not explain the magnitude of the disaster. Particularly if you feel that there is a balancing benefit from CETPi.
    Future HDL approaches will have to focus on functionality rather than levels of HDL. The next successful drug will likely lower HDL while improving it’s functionality and will work via SRB1!

  25. Derek Lowe says:

    An excellent comment. I agree that the blood pressure elevation doesn’t seem to explain what happened in the clinic, in either the magnitude or the variety of effects.
    Has Roche said anything about the effects of the JTT compound on reverse cholesterol transport, I wonder?

  26. BCP says:

    Radman – a very interesting post. You raise a couple of questions that I’ve been wrestling with. First I was under the impression that Torcetrapib produced HDL2 was in fact effluxed via SRB1 and that RCT was not a major issue here — obviously this could well have been “window dressing” as you describe, but I’m still interested to think this through a little more. Is there a limit to how much HDL2 you want coursing through your veins? Is too much a bad thing? If so, then I suppose that this could explain the positive outcomes with Niacin – although Niacin operates through a multiplicity of mechanisms.
    Secondly, you elude to a better drug profile at the end of your message including “lowering HDL” (correct?) and presumably elevating SRB1 efflux. If this were to happen, what happens to the functionality of the HDL? I’m not sure I understand how lower levels of circulating HDL could give rise to a better outcome.

  27. JudyShapiro says:

    RADmanZulu, thank you for a very enlightening post!
    I have a question for you, and for anyone else here who might have an answer.
    Fibrates such as gemfibrozil also raise HDL values, but have been real failures so far when it comes to improving clinical outcomes. Do you think there may be a problem similar to that with torcetrapib — maybe HDL was raised, but it’s functionality was not, and so Reverse Cholesterol Transport isn’t improved by fibrates?
    My interest in fibrates isn’t academic. My husband (who had a heart attack at age 39) is on a fibrate, but I’m thinking that he might be better off dropping the fibrate so that he could tolerate a higher dose of statins.

  28. RADmanZulu says:

    Fibrates haven’t been a complete failure. The Helsinki Heart Study was positive and so was the VA-HIT Study. In fact the VA-HIT study was widely quoted as evidence that HDL elevation works. Prior to this, there really wasn’t any conclusive evidence that elevating HDL was of benefit. Certainly the HDL changes in all the statin studies such as 4S, WOSCOP etc did not correlate with improvements in outcomes. I think people are fundamentally mistaken when they think about Fibrates as HDL elevating drugs. They have very modest effects on HDL and I believe the positive effects seen in the VA-HIT study were due to the changes in the LDL profile rather than HDL changes. Fibrates lower triglycerides and promote a change in LDL from small and dense to large and bouyant.
    In discussing your husband’s case, it would be necessary to understand more about his lipid profile and what he is already on. What is his HDL, LDL and triglycerides. Is he overweight, have the metabolic syndrome or have Diabetes? Does he have a family history of Diabetes?
    He may well be better off on Lipitor 80 mg and forget the fibrate but it’s hard to say without more information. Certainly he would probably benefit by being on a large dose of Fish Oil regardless.

  29. Judy Shapiro says:

    Thanks very much, RADmanZulu, for your insights.
    My husband has a severe case of Type 2 Diabetes — his hemoglobin AIC values are OK now (6.6) but to get them there, he has to take 4 different diabetes drugs (insulin, Byetta, Actos, and metformin), plus he exercises a ton and he follows a pretty strict diet. (It really ticks me off when people claim that all Type 2 Diabetics could control their blood sugar with proper lifestyle — I’d bet that most people who say that have a far worse lifestyle than my husband does.)
    His LDL levels are very good, and were good even before he started taking lipid-modifying drugs — he wasn’t on any lipid-modifying drugs before he had his heart attack, and his total cholesterol then was about 120. His HDL, though, is quite low — only about 30 even now that he takes the maximum dose of a fibrate (145 mg daily of Tricor). His triglycerides are normal right now, but that might be because of the Tricor — I don’t remember exactly what they were back before his heart attack, but they were somewhat high.
    Before taking Tricor, he was on niacin for a while, but it raised his glucose levels unacceptably high.
    My concern about Tricor is that although it seems to really improve people’s lipid values, it never seems to cause any reduction in overall mortality. The FIELD study actually showed a non-significant increase in mortality in people on a fibrate.
    Right now, my husband is on only 10 mg of Zocor because of the concern that taking a fibrate plus a statin will increase the risk of rhabdomyolosis. But statins seem a lot better at decreasing mortality than fibrates, so I’m not sure foregoing a higher level of statins is a good trade-off.
    I’m interested in anyone’s thoughts on this, thanks.

  30. RADmanZulu says:

    I understand your frustration with people’s comments about how easy it is to manage Diabetes with diet. Another question, if you don’t mind. Your husband’s LDL is “quite good” but what are the numbers. Acceptable for a Diabetic with coronary artery disease is below 70 mg/dL. The recent change to the NCEP guidelines based on the TNT Study, REVERSAL and PROVE-IT clearly stated that these types of patients should consider getting their LDL down below 70.
    Simvastatin 10 mg is a very low dose. There are no data for this dose showing that it can reduce events. The 4S study used 20-40 and other endpoint studies used higher doses. Of course, I believe that 10 mg has a benefit but it is very likely the benefit seen with Fibrates – in the 15 to 20 percent range. Also Simvastatin is not necessarily a good choice. It has a higher incidence of muscle problems than atorvastatin and at it’s higher doses this becomes quite noticeable – look at the label. Atorvastatin is safer and is safe at it’s highest dose of 80 mg. Atorvastatin at 10 mg is as effective as simvastatin at 20, Atorva 80 is clearly more effective than simva 80 and safer for muscle, the main problem with combined fibrates and statins.
    My advice is to maintain strict glucose (HbA1c) control, this has the biggest impact on cardiovascular events (MDRD Study). It sounds like he is doing that and this is very hopeful. Secondly, get the LDL below 70, at least, and lower if possible. Thirdly add a fibrate, dosing at the opposite end of the day to the statin dose and stop immediately if bilateral muscle pain starts. Fourthly take 4 large fish oil capsules and 81 mg of aspirin a day.
    A good word about Fibrates. The FIELD Study showed a benefit in terms of CV events for those events it was powered for. Don’t concern yourself about the mortality events, its not uncommon for statin studies that weren’t powered for mortality to show small adverse trends on moratlity due to chance.
    The way I interpret FIELD is that there was a small (19%) but significant (p=0.003) reduction in total CV events. For the primary endpoint, which had fewer events, there was a small (11%) difference which wasn’t quite significant (p=0.16). This data is supported by significant benefits in the renal vasculature and the eye. FIELD had a significant design defect which allowed twice as many placebo patients to get additional statins as patients in the fenofibrate arm. The benefit would almost certainly have been bigger and more convincing if the investigators had used one of several possible mechanisms to avoid this.
    A last word, blood pressure control is also vital to avoid future cardiovascular events. Diabetics with heart disease need particularly control. A systolic BP below 120 is essential.

  31. Judy Shapiro says:

    RADmanZulu, I want to say a belated thanks for your comments! (I became extremely busy at the end of last term, and then was away.)
    I very much appreciate your suggestions. I agree that a simvastatin dose of 10 mg is quite low. I’ve tried asking my husband’s cardiologists to increase the dose, and have been repeatedly told that it isn’t necessary. We’ve tried changing cardiologists, but have gotten the same answer. I’m tempted just to buy a statin (maybe atorvatstain, based on your suggestion) from somewhere that doesn’t require a prescription, such as Mexico.
    I’m impressed by your knowledge — may I ask what your background is? If you are willing to email me, I can be reached using as an email address the word pipeline followed by an at sign, followed by my full name and then .com (with no spaces).

  32. Israel Bryson, MD says:

    Two years ago I made a significant discovery in cholesterol metabolism that caused rapid reversal of vascular disease in 1 to 2 months (6 months max in smokers). I contacted Pfizer and other statin producers, and asked for help (since it would possibly extend any statin patent, i.e. worth billions). All denied my request based on no previous trials ever done. However my event rate is zero ( 2 years ) in a post MI / CVA / DM / PVD population that averages initially close to LDL 200 and still smokes. The patent is being processed now. Also the AAFP research network has shown interest and hopefully soon our pilot study will take off. Anyone who knows someone in “vascular dire straits” ( half of my population ), send them on, and I will treat them.
    By the way the side effects are: LFTs lower, Osteoarthritis in some reduces, angina reduces/resolves, erectile dysfunction improves, pulses normalize and DOE reduces/resolves.
    Thanks for your time,
    Israel Bryson,MD
    Johnson County Community Center for Health
    508 W. Elm Street
    Wrightsville, GA 31096
    478 864-2600

  33. Judy Shapiro says:

    Wow, Israel Bryson, that sounds amazing! I will be giving you a call.

  34. clinical trialist says:

    “extend any statin patent”–actually when you add a new drug to an existing drug (say, a statin), the existing drug’s patent still ends when it ends, and people can still buy the existing drug as a generic. It’s just that if you patent the combination then that (the combo itself) is a new patent. A case in point is Vytorin which is an ezetimibe and simvastatin combination. You can still get generic simvastatin despite the creation of the combo–the simvastatin patent expired last year, just as it was scheduled to. When ezetimibe’s patent expires, then people can buy generic ezetimibe AND generic simvastatin as separate pills, or they can choose to take Vytorin which has both drugs combined in one pill. When the Vytorin patent expires, then generic companies can make the combo too.

  35. clinical trialist says:

    Israel–I don’t know if your discovery is a drug or what–if it is, well torcetrapib worked great to decrease atherosclerosis in numerous rabbits and then also increased HDL by ~50% in early human clinical trials. It then cost the pharmaceutical company nearly a billion dollars to do the right trials that finally showed that it didn’t work. So…don’t take the rejection personally, big pharma needs to be conservative. Again, if your discovery is a drug, as you may have figured out by now, the right people for you to approach is the venture capitalists. Then you do early trials (as it sounds like you are doing), and if it looks promising enough then big pharma will buy it from you for a billion.
    Finally–just a word of caution–many a fortune has been wasted on drug projects fueled more by enthusiasm than by good solid double-blinded data.

  36. anon says:

    It would seem that even if Torcetrapib had successfully gotten through its trials it would have made no difference to people with CHD. When the results of the trials were presented at the American College of Cardiology’s 56th Annual Scientific session in April, they showed no difference in the rate of plaque progression when compared to the group taking Atorvastatin by itself.

  37. mikef says:

    One very important aspect of this entire discussion has to do with the actual chemical structure of the torcetrapib molecule. This drug contains 9 flourine atoms in each molecule. Lipitor, the drug administered concurrently with torcetrapib in the trials, is also fluorinated.
    In my opinion, the deaths seen in this trial are very likely due to the cardiotoxic effects of excessive fluorine exposure. Moreover, no information as to other fluorinated drugs these patients may have been taking seems to be available for review. For example, if Zetia were also being taken, then another tri-fluorinated molecule is in the mix.
    If one reviews the effects of fluoride overdose (in excess of 1-2 mgs/day from all sources) in the literature, it is easy to make the case that fluorinated drugs contribute to the daily load.
    At issue is whether or not free fluoride ion is liberated from these drugs. If so, then one need only look at the known toxic effects of this highly bioactive material that would include elevated BP, fatal cardiac arrythmias, thyroiditis and so on. These effects are dose dependant and it is not surprising to me in the least that deaths were seen in the treatment arm of the study.
    Another example of the possible link to fluoride exposure, please consider two fluorinated drugs, Provacid and Protonics. Both of these drugs have been linked to increased hip fracture which is a well known effect of fluoride overdose.
    Please do not take lightly what I am saying here. I currently am an FDA Advisory Panel member and the potential problems associated with fluorinated drugs will surely be a critical issue in the coming years.

  38. TNC says:

    If you are who you say you are, you are intensely stupid for posting anonymously on blogs. Stay out of the comments and get back to work.

  39. milkshake says:

    The post # 37 confirms that being on the FDA advisory board does not preclude one from being a self-important imbecile. Polyfluorinated drugs are problematic from the PK point of view but Dr. Mike F probably got much higher fluoride load as a child, from being repeatedly banged over his head with a non-stick pan.

  40. weirdo says:


  41. It is much too simplistic to consider blood levels of cholesterol as the “be all”, and “end all” of heart disease prevention. Blood pressure and sugar, obesity, genetics and smoking are also important, as are other types of fat in the diet. In fact, unless the reduction in dietary fat is extreme (such as the Pritikin or Ornish diets which few people will follow) diet change alone may not have a large effect on cholesterol levels. That’s why most doctors reach for their prescription pads when they see a cholesterol level over 200 on the lab test results.
    However, if you are 40 or 50 or even 60 and your only risk factor for heart attacks is high cholesterol it is hard to prove that lowering it with pills will make you healthier or live longer. In my 40’s I quit smoking and dropped my own cholesterol from 240 to 140 by a very low fat diet. I started jogging and ended up running marathons in my 50s. That total program probably saved my life. But few people will go to those extremes. I am now 73, in great shape and plan to live another 20+ years. (Hey, I better, my fiancé is only 41!)
    Healthy diets help prevent heart disease through various means, not just cholesterol levels. We have gotten fixated on cholesterol because of the constant ads for drugs to lower the levels. Even most doctors have been fooled into thinking (and prescribing) this way. I have an essay at my website, entitled “Bad Cholesterol is Good Marketing”. Big Pharma want us all the hate and fear cholesterol so they can sell more Lipitor, Crestor and the like. In fact cholesterol is a vital substance used to build every cell in the body and many hormones such as testosterone and progesterone. No “bad” cholesterol means no sex life. Is that bad or good? One large organ up there between your ears is made of cholesterol. There are many reports over the years about central nervous system dysfunction in patients taking statins. There are now calls to ban Crestor, the newest and strongest statin because of CNS and other scary side effects.
    If you need a statin, you probably need blood pressure pills too (usually 2, sometimes 3). Did your doctor tell you that as long as you live and eat unhealthfully you will have to take these pills every day for the rest of your life?!! If your cholesterol and blood pressure are high and your waist is bigger than your hips, you have or will get type 2 diabetes. That combination is called the metabolic syndrome. This syndrome is deadly. People with the metabolic syndrome, beside having more heart attacks and strokes, become diabetic and end up with senile dementia and kidney failure on dialysis in a nursing home. Oh yes, and likely blind with one leg amputated too. This is every senior citizen’s worst nightmare. And 23% of adults have the metabolic syndrome right now. That’s almost one in four Americans. Many of them don’t even know they have it. It is even more common in blacks, native Americans, native Hawaiians and Hispanics from south of the border. The 5 or 6 or 7 or 8 different drugs taken for this syndrome only delay but do not prevent these sad and terrible outcomes.
    Bottom line: an unhealthy diet and lifestyle causes so many problems that to try to deal with all of them by taking multiple pills for a lifetime is about as effective as chasing a flock of chickens on a motorcycle. (Hey, I just made up that bizarre analogy. How do you like that?)

  42. Hank Feretz says:

    It’s probably the Lipitor (atorvastatin) component. This is not as safe as it’s purported to be.

  43. Hank Feretz says:

    Dr. Bennett omits from his post that the vast majority of cholesterol problems stem from genetics (75%) versus 25% from diet. If he’s a studied doctor then he should know this cold. A person with a terrific low-fat, low cholesterol diet who has a genetic predisposition for high cholesterol can still be outside their goal range due to genetics.
    He also states that, “if you are 40 or 50 or even 60 and your only risk factor for heart attacks is high cholesterol it is hard to prove that lowering it with pills will make you healthier or live longer.” This is complete BS.

  44. James McHale says:

    I was part of the drug study. This drug put me into heart failure. I have been on Lipotor since 1995 no Problem. I have not recovered from the damage it caused.

  45. Glendon Norris says:

    I as an Irish citizen have seen the effects of the failure of this drug in the commercial and econmoic aspect. Pfizer is a major employer in Cork (Ireland), since this drug has failed Pfizer has decided to close 2 of its Cork plants. (Lipitor and Viagra were manufactured in Cork).

  46. Gordon Ashworth says:

    The torcetrapib molecule has nine fluorine atoms. Does the chemical nature conferred by this extreme halide substitution affect the redox chemistry of cholesterol? Why is this not a central theme to the discussion of this drug? I can see such a molecue having a devastating impact on the anti-oxidant effect of cholesterol on muscle tissue in the heart and arteries, leading to angina.

  47. JOHN S says:


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