
Subject: cholesterol act two Date: 1/21/2005 11:58 AM
Recommendations: 72
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 writing

With 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 :)


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
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