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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« The Breslow Chirality Paper Mess, Resolved | Main | Strangely Good Results in Diabetes and Cardiovascular Disease »

May 17, 2012

Is HDL Always "Good Cholesterol"?

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Posted by Derek

The failure of Roche's dalcetrapib has a lot of people wondering just what's going on with HDL as a cardiovascular drug target. And this isn't the first time - there have been a number of puzzling findings in the lipoprotein field that point out to us that we don't know nearly as much about this area as we might think. Many promising therapeutic ideas in it have turned out disastrously.

Now there's a new paper in The Lance that underscores this, and how. The authors have done large genome-wide association studies looking for polymorphisms that affect lipoproteins, and they're following those up with clinical data on cardiovascular outcomes. Untangling the effects of HDL, LDL, triglycerides and other factors isn't easy, but they did find one mutation that appears to raise HDL alone. Looking at the people carrying that one, they find that there's no amelioration of risk in them at all. That's as opposed to the mutations that lowered LDL levels, which were consistently associated with lower risks.

This doesn't (necessarily) mean that HDL is useless as a predictor of cardiovascular risk, but it definitely means that it isn't as simple as "HDL = Good Cholesterol!". What this means for things like CETP inhibition is anyone's guess.

Comments (13) + TrackBacks (0) | Category: Cardiovascular Disease


COMMENTS

1. NoDrugsNoJobs on May 17, 2012 11:40 AM writes...

Yes, yes, yes - There are so many variables. Particle size, co-occurrence with other lipid abnormalities, etc - so many things are there, so complicated. Thats why we need huge phase 3 studies, unfortunately. I wonder whether Pfizer/Bayer will be able to parse their data in a post-mortem and may find their drugs actually worked well in one or more lipid sub-types. The problem is that those sub-types would still need to be highly populated for the event driven data to make any statistical sense.

Permalink to Comment

2. bradpalm1 on May 17, 2012 1:44 PM writes...

Since inhibition of the HMG-CoA reductase pathway (which statins do by inhibiting HMG-CoA reductase early in the cascade) appears the best way to lower cholesterol and reduce cardiovascular events, why doesn't pharma look to develop long-acting bisphosphonates which also lower cholesterol by their inhibition of farnesyl pyrophosphate synthase further down the same pathway? Has anyone ever looked at the lipid profiles of patients dosed with yearly administration of zoledronic acid (Reclast) for osteoporosis?

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3. SomeGuy on May 17, 2012 4:15 PM writes...

Sekar Kathiresan gave a talk about a month ago where he related exactly this - HDL as a target for CVD is useless. Lowering LDL is the single most important thing you can do - raising HDL does nothing.

Since CETP seems to do both it might have some benefit, but all of that benefit comes from lowering LDL. That's why PCSK9 looks so promising too.

Permalink to Comment

4. Not Me on May 17, 2012 7:12 PM writes...

Begging your pardon, but do you perhaps mean "The Lancet"? Please accept my apologies if I am mistaken. Thank you.

Permalink to Comment

5. Not Me on May 17, 2012 7:12 PM writes...

Begging your pardon, but do you perhaps mean "The Lancet"? Please accept my apologies if I am mistaken. Thank you.

Permalink to Comment

6. Anonymous BMS Researcher on May 17, 2012 7:14 PM writes...

As m.xkcd.com/552 says in the alt-text, "correlation does not imply causation, but it does waggle its eyebrows suggestively and gestures furtively while mouthing 'look over there.'"

Correlation generates hypotheses, but even the strongest correlations do not prove mechanism. Biomarkers and surrogate endpoints are no substitute for hard endpoints.

Interestingly, the same issue of The Lancet has another interesting paper, this one about LDL for which we already know interventions save lives. This paper suggests statins may even be worth prescribing to people whose predicted five-year risk of heart disease is less than 10% and who therefore would not be considered candidates for statins under current guidelines. Basically it seems even at what are generally considered low LDL levels, lower is still better.

It certainly is a mystery, if raising HDL doesn't seem to prevent heart attacks, then how come high HDL has such a strong negative association with cardiovascular diseases? Maybe HDL just happens to be raised by other factors that do prevent heart disease? I dunno and I doubt anybody else does either. Correlation can lead one astray. In Biostatistics class the professor mentioned a classic example of spurious association: there is a positive relationship between alcohol consumption and lung cancer. Nobody thinks alcohol has much effect on lung cancer, the most likely explanation is that people who drink a lot are also more likely to be smokers.

Permalink to Comment

7. Anonymous BMS Researcher on May 17, 2012 7:15 PM writes...

As m.xkcd.com/552 says in the alt-text, "correlation does not imply causation, but it does waggle its eyebrows suggestively and gestures furtively while mouthing 'look over there.'"

Correlation generates hypotheses, but even the strongest correlations do not prove mechanism. Biomarkers and surrogate endpoints are no substitute for hard endpoints.

Interestingly, the same issue of The Lancet has another interesting paper, this one about LDL for which we already know interventions save lives. This paper suggests statins may even be worth prescribing to people whose predicted five-year risk of heart disease is less than 10% and who therefore would not be considered candidates for statins under current guidelines. Basically it seems even at what are generally considered low LDL levels, lower is still better.

It certainly is a mystery, if raising HDL doesn't seem to prevent heart attacks, then how come high HDL has such a strong negative association with cardiovascular diseases? Maybe HDL just happens to be raised by other factors that do prevent heart disease? I dunno and I doubt anybody else does either. Correlation can lead one astray. In Biostatistics class the professor mentioned a classic example of spurious association: there is a positive relationship between alcohol consumption and lung cancer. Nobody thinks alcohol has much effect on lung cancer, the most likely explanation is that people who drink a lot are also more likely to be smokers.

Permalink to Comment

8. Susurrus on May 17, 2012 8:43 PM writes...

@7:

Researcher 1: "I used to think that correlation implied causation, but then I took a statistics course and learned that it does not."

Researcher 2: "It sounds like the course helped."

Researcher 1: "Maybe... I don't know."

Permalink to Comment

9. Xmedchemist on May 17, 2012 9:07 PM writes...

@6:"This paper suggests statins may even be worth prescribing to people whose predicted five-year risk of heart disease is less than 10% and who therefore would not be considered candidates for statins under current guidelines."

Does the drugification of life have any limits?

Permalink to Comment

10. John F. on May 17, 2012 10:33 PM writes...

Published earlier this month:

http://www.hsph.harvard.edu/news/press-releases/2012-releases/hdl-cholesterol-heart-disease.html

'Some HDL, or "Good" Cholesterol, May Not Protect Against Heart Disease'

HDL that contains apoC-III is not so good. Subjects in the study with the highest levels of that form of HDL were 60% more likely to develop CVD.

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11. mike on May 18, 2012 4:56 AM writes...

How long do you want to live?

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12. Rock on May 18, 2012 10:14 AM writes...

Simply measuring total HDL cholesterol is a poor means of predicting outcome. Raising the number of HDL particles, by exercise or niacin for example, is clearly beneficial. But taking the HDL particles you have and jamming them full of cholesterol because they can't off-load it to VLDL (the very reason HDL is called "good") by blocking CETP does not, to me, seem like a viable strategy.

Permalink to Comment

13. Matthew Herper on May 18, 2012 6:13 PM writes...

Just to emphasize how complicated things are: the paper did show a small but significant benefit with the CETP gene.

That shouldn't make anyone comfortable (yes, CETP lowers LDL) but I really think if this doesn't make your head spin you're not looking hard enough.

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