Well, we've met the three stooges LDL delivery truck. LDL levels are a critical risk factor for CV disease and the lower it goes (the more we get those idiots off the road) the lower CV risk goes. Little children have LDL levels in the 20-30 range. So far so good. Rising HDL levels are associated with decreasing risk... go get 'em Dudly Do-Right!BUT! back to Framingham and those poor poor pin-cushion people. Over 1/3 of all heart attacks and strokes occur in apparently healthy folks with completely normal cholesterol levels. Enter rust! oxidation!... come hither inflammation. You see, when the little giblet of cholesterol gets dropped (so to speak) remember it tries to bury itself in the wall of the blood vessel. That process creates inflammation. It's the combination of cholesterol AND inflammation that cause trouble.There are a number of molecular markers of inflammation that sit at the critical interface between the blood flow and the vascular endothelial cells. Those endothelial cells are a very active organ, intensely involved in the management of the disease. They're involved in the transmission of the cell adhesion molecules across that border. They're critically involved in the tethering and adhesion of the monocytes and the macrophages; attachment through the variety of adhesion molecules (E-selectin, P-selectin, vascular cell adhesion molecule [VCAM] and the like); migration of these cells into the intimal space; and inside that milieu with oxidized LDL, the conversion of these into lipid-laden macrophages and the development of the atherosclerotic plaque.HA! just kidding, sort of... I just wanted to let everyone know I can say those big words too! Ok OK enough showing off, back to the story...The process of inflammation and oxidation result in something similar to rust... it's a sort of wearing out process. Lo and behold, there appears to be a marker for this rust process... a blood test called HIGH SENSITIVITY C-REACTIVE PROTEIN (HS-CRP). Back in 1997, it doesn't seem like that long ago, a study was published of doctors and their health. In the Physician's Health Study, they were trying to understand why individuals were having heart attacks in the absence of major clusters of risk factors. They were able to demonstrate that as levels of the high-sensitivity CRP went from low to high, the risk of having a heart attack (MI) went up quite dramatically over the next 8 years of these men's lives. And... in this case "these men" was me!If we fast-forward to 2003, there are now 16 large-scale, prospective epidemiologic studies. These studies derive from large-scale cohorts around the world. And this phenomenon has been true in every study evaluated. Your CRP level, when you are healthy, predicts very dramatically the risk of future hear attacks and strokes. This was true for heart attack, stroke, peripheral arterial disease, and fatal stroke. It's true in the Framingham Heart Study. It's true in Europe. It's true in Japan. Every group studied has been highly consistent. The really weird thing is this... HS-CRP, the marker for inflammation, predicts heart attacks and strokes but not cancer or the risk for other inflammatory diseases like rheumatoid arthritis, lupus, etc. BUT! HS-CRP also does a great job of predicting the risk of developing one other disorder... the next paragraph can be safely skipped, well... actually... truth be known, the whole post can be safely skipped... but I digress, back to writingWith funding from the National Heart, Lung, and Blood Institute (NHLBI), a study was done that simply asked the question, "How well does a series of markers predict risk in blood samples stored at study entry among individuals who were followed into the future to have hard cardiovascular end points (that would be heart attacks and strokes)?" They discovered the markers that many were interested in -- lipoprotein(a) [Lp(a)] and homocysteine -- were rather weak predictors. There's interleukin-6, total cholesterol, and our gold standard for LDL cholesterol screening, highly significant but a modest predictor in the overall scheme of things. There is intercellular adhesion molecule (ICAM)-1 and adhesion molecules, and serum amyloid A, an alternative acute-phase reactant. For apolipoprotein (apo) B, there is the evidence it's a very good marker. The total cholesterol-to-high-density lipoprotein (HDL) cholesterol ratio is another way of getting at the issues of total and HDL combined.The big surprise was this... the single best predictor of future trouble had nothing to do with cholesterol... it was HS-CRP! BUT the super best marker of trouble was to look at HS-CRP plus the total cholesterol to HDL ratio...in udder words... with lots and lots of Dudly Do-Rights out on patrol and little or no inflammation... you are good to go. It doesn't matter what your three stooges LDL are fumbling and dropping... if everything that gets dropped gets picked up... well it just stands to reason.Back to that HS-CRP and the next blockbuster... it turns out that HS-CRP is a super predictor of who's gonna get diabetes! Ah, diabetes... specifically adult onset diabetes is just like water poured on iron increasing the rusting-inflammatory processes in the body.Now... finally... where to make some money... Of course the best way to make a bit of money would be to not have to buy any of the drugs we'll discuss. How to do that? First... a bit of daily exercise. Second, fruits and veggies and a lean meat diet. Third, a glass of red wine looks better and better. Forth, and most important, choose your parents wisely.on to the companies...first is Pfizer. Pfizer has made a huge bet on Dudly Do-Right... HDL. Now remember, HDL stands for high density lipo-protein. Let's break that down again... high density stands for "heavy" and lipo-protein stands for cholesterol (the lipo part) and protein. It's the protein that does the critical work. It's the protein... remember apo-1-milano. Remember above... the two great determinants of cardio-vascular risk are HDL and inflammation (marked by HD-CRP). One is a molecule (the HDL protein) and the other is a process (inflammation and the inflammatory response). Pfizer made the brilliant decision to focus on the molecule and not the process. Many of the biotech's have focused on the process, an infinitely more difficult trick.Pfizer has defined the game with the development of torcetrapib, which is currently in massive Phase III trials, and the purchase of Esperion and its little Italian protein. Now let me tell you about phase three trials. I doubt they're what you think they are. Here's how Pfizer does it. They target influential and "high prescribing" cardiologists and enlists them into the phase three study. This gets Pfizer lots of patients into the study but more importantly it introduces influential physicians to the drug and gets them used to seeing the results. Further, when you're involved in a critical look at a drug, you develop a "feel" for the drug and are much more likely to incorporate it into your practice. Last, the targeted physicians are able to influence the prescribing habits of legions of other doctors who listen to these key cardiologists for prescribing advice. I've talked with three other cardiologist groups who are in the phase three trails and they are getting astounding results with the combination of torcetrapib and lipitor. We're talking about LDL's down in the 30's and HDL's rising into the 60's and 70's... wow! Everything I hear tells me torcetrapib combined with a statin will be a huge blockbuster. Right now, Cholesterol-lowering statins are the largest-selling class of drugs in the world, generating roughly $20 billion in annual sales. Pfizer is ready to take this game to the next level. AND, after they finish with torcetrapib comes apo-1-milano (remember, apo-1-milano is the hella-mega Dudly Do-Right scavenger protein) which can be injected directly into veins and start shrinking cholesterol plaques right away. Along with their other molecules, Pfizer in the low 20's will make a super investment over the next 10 years.Pfizer is trying to define the treatment of cardiovascular disease in terms of HDL. SMART! It's a molecule and not a process... but somebody is going to take the other stance and go toe to toe with Pfizer....Remember the scene in the Godfather when Don Corleone (Brando) keeps telling Michael (Pacino) how "they" are going to come after him... well I can just see Pfizer's CEO, Don Hank McKinnell, telling his CFO that they'll be able to tell which big pharma is going to be the one... who's gonna come after Pfizer... by which company strikes a deal with....yup, you guessed it.... a run through the contenders and a prediction...next couple posts :)e ps: quick hint... Kit will "get it" if she reads this... the big lunkhead dummy is sadder but gets wiser and I'm buying as we speak
emiller8988.........outstanding series of posts on the cholesterol "problem". Are you telling us the truth that you are, in fact, a practicing cardiologist? As a retired oncologist, I am amazed at the time you must have to spend to present your thoughts in the very interesting manner that you use......I would like to make one comment and ask one question. When I was in training I think I learned that CRP was a non-specific indicator of inflammation;it would become elevated if there was an inflammatory process anywhere in the body. Another such non-specific indicator was the ESR( erythrocyte sedimentation rate). My question: has any research been reported on the relationship, if any, of an elevated ESR and atherosclerosis???? Are the CRP and ESR related or correlated in this regard? As you know, the ESR is about as simple and simple minded a test as there is. Again, thanks for your remarkable contributions; you make a difficult subject enjoyable and easier to understand.
Missash, the "play one on TV" line is too obivous and silly. I fear the little play is rife with inaccuracies. The notes are not exactly referenced. The HS-CRP and ESR question is good... and has an interesting answer. I believe your thinking a step behind the HS-CRP question. Recall that ESR goes up WHEN you have an infection, cancer, myeloma, etc... HS-CRP goes up (or "is" up) BEFORE the heart attack or stroke. Isn't that interesting? HS-CRP is a predictor, not a consequent indicator. It's not like these plaques are actively inflammed... to the point that it would raise non-specific indicators of inflammation. Nope, it looks like somehow HS-CRP is a relatively specific indicator of CV risk. The predictor effect for diabetes is a real eye opener isn't it? All of this will somehow tie into insulin resistance, the pleiotropic effect of statins, and all sorts of mysteries of medicine.It really was a genius move for Pfizer to focus on a molecule and not the inflammatory process wasn't it? I've not read one word about why or how Pfizer decided to do that and it seems a point that not a single analyst has latched on to (nothing I've read anyway). Boy! would I love to know if they did it by assiduous effort and conscious decision or did they just sort of get sucked that direction by momentum... was it sedulity or serendipity?e
e ps: quick hint... Kit will "get it" if she reads this... the big lunkhead dummy is sadder but gets wiser and I'm buying as we speakHmm....I think I have an inkling of the inflammatory contender but must confess ignorance of their ally. Are you buying PFE? Now down to $24.48. I would hold off on AGIX. I am also waiting for PFE to sink more. It most likely will. I have never seen so much negative press in the face of absolutely no news. Everyone seems to hate PFE and they have done nothing different to warrant the scorn. We all knew the patent expirations were coming--no news there. So far Celebrex and Bextra are still in place(final word in February). Maybe a few more lawsuits. They came out with a new drug a couple of weeks ago for macular degeneration--appears to be largely ignored by investors. They just purchased another biotech. They are repatriating billions of dollars. They have inhaled insulin in Phase III trials, they are doing well with torcetrapib in Phase III trials and they have a weight loss/smoking cessation treatment in the works. Such a terrible company :(If they lose in Feb, look for a big price drop and PFE shares will definitely be on sale.One lonely voice in support of big pharma>^..^<
Another such non-specific indicator was the ESR( erythrocyte sedimentation rate). My question: has any research been reported on the relationship, if any, of an elevated ESR and atherosclerosis???? Are the CRP and ESR related or correlated in this regard? As you know, the ESR is about as simple and simple minded a test as there is. If I may butt in, ESR and CRP are not correlated, and in particular not for vascular disease. CRP, as emiller noted, is highly correlated with heart disease and more broadly, vascular disease, of which diabetes should be considered a part of (as elevated glucose and insulin levels have endothelial inflammation and damage as their primary destructive effects). As an interesting aside, many patients with an active lupus flare (SLE) have both elevated ESR and elevated CRP as a reflection of both connective tissue inflammation and specific vascular inflammation (talk about a terrible disease). I had a patient this week with an ESR of 116 and a CRP >50 (and this was on Imuran and Plaquenil)! I DRip PFE and am adding cash by the bucketload.ab
I had a patient this week with an ESR of 116 and a CRP >50 (and this was on Imuran and Plaquenil)! Curious if you have tried any of the new biologics(Remicade, Enbrel, Raptiva, Humira) for SLE?And if so, any success? I get the occasional lupus patient and control is a problem. I have one elderly woman that I can't ethically put on prednisone and she claimed Plaquenil worsened her dry eye and macular degeneration. Looking for another avenue.I remember a year or so ago, JNJ was on the skids for very little reason. Picked some up at $49 and I missed the bottom at $44. The market is often irratonal>^..^<
eb,these posts of your's have been a lot of fun, but....I use niacin every day...and exercise a few times a week. There are three types of niacin. I use the initol whatever it is? sp?It is non-toxic......and non-flush.....It is the main thing other than exercise that ups the HDL. db
Curious if you have tried any of the new biologics(Remicade, Enbrel, Raptiva, Humira) for SLE?I just diagnosed this lady a couple of months ago and I initially started the Plaquenil with a prednisone taper. Her manifestations were pretty severe so I sent her to our visiting rheumatologist (who's an academic from the university teaching hospital) and he started Imuran. Personally, I hate the stuff, but it did help. As for Enbrel, etc., I've not used it in SLE, but have used it in RA several times. Sometimes it works and sometimes it doesn't and I have had several incidences of increased infections, particularly the longer they've been on it. I have a lady with RA and a serious needle phobia on leflunomide (Arava) which helps a lot but has worsened her diabetic control and is probably causing a neuropathy to appear. I think the take home message is that when you seriously disrupt immunomodulatory homeostasis you can expect undesired consequences, so I'm really careful who I use those drugs with. On the investing front, Sanofi-Aventis (SNY) is another favorite drug stock that I own in addition to PFE as I feel pretty sure that the hype for Accomplia will push the stock to near 50. While we're on the subject of antiobesity drugs, first mover status, such as SNY will enjoy, will be important, because...fearless prediction coming...they will be a huge disappointment to the vast majority of users. What you'll see is an inability to produce more than 10-15% bodyweight loss, which although measurably helpful in reducing risk, will not be anywhere near the affect that most patients will be looking for. For example, a woman 66" tall who weighs 280# (BMI of 45) loses 15% to 238 (BMI of 38) but her personal goal is 150#. She's helped herself from a risk standpoint but only marginally from a psychological standpoint so she quits buying the drug. These drugs aren't going to turn Oprah into Halle Berry.ab
TMFKitKat, You type as if you regret buying JNJ at $49 and not waiting until $45 or at least imply that you should have waitied until closer to the bottom. I think you are too hard with your self-analysis - with JNJ now at almost $62 and the latest high over $64 you did pretty well (and are hopefully still in it). I'm a member of FoolAdvisor and David's most recent intro contains a tenet from Pathagorus' school that I'll quote (at risk of him sending lawyers after me): "One must not eat from a whole loaf": Don't get greedy. Don't always think you should pick the exact bottom of a stock when you buy, and don't always expect to pick the top when you sell. That's the "whole loaf," and you don't have to eat the whole loaf to be a good investor. In fact, you'll be a better investor if you don't try to eat the whole loaf. So according to David you are probably a pretty good investor. JR
ab posted, in pertinent part:I DRip PFE and am adding cash by the bucketload.PFE is one of my favorites at these prices. I have been adding to my existing holdings weekly via PFE's DRIP. And PFE is now sporting a 3.0% dividend. And it has increased its dividend every year for some 30+ years. What's not to like now as a good value stock candidate? The $18+ billion in cash it holds? All the recent bad news will pass. Meanwhile the potential of its well-stocked pipeline is enormous. And I dispute the notion that a negative decision at the FDA meeting in February on the Cox-2 drugs will cause further declines in the stock price--it's already there.BTW and FWIW, PFE is also a BMW Method underpriced favorite: http://invest.kleinnet.com/bmw1/stats20/index.htmlDavid
Forth, and most important, choose your parents wisely.Uhmmm....do they give redo's?Buffy (who's dad's side of the family is lousy with blood pressure and heart issues...)
Back to that HS-CRP and the next blockbuster... it turns out that HS-CRP is a super predictor of who's gonna get diabetes! Ah, diabetes... specifically adult onset diabetes is just like water poured on iron increasing the rusting-inflammatory processes in the body.Now... finally... where to make some money... HEY!!!!!!!!! That's my money!eag (early Type II diabetic)
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