Sunday, December 09, 2007

Clofibrate and PUFA

It's a bit difficult not to post about the cholesterol hypothesis. I'm sheepish to admit that it is in a large part because it is such an easy target. But mostly because it also encapsulates herd stupidity beautifully. And it's wrong, yet keeps giving tricky suggestion that it might be right.

So today I want to look at clofibrate. This drug is a killer on a par with torcetrapib but does, like the statins, reduce cardiac "incidents". So the obvious conclusion is that, deep down, somewhere, anywhere, LDL cholesterol is the cause for heart disease. That's wrong.

Clofibrate is a stimulator of PPAR alpha receptors. It increases the production and activity of peroxisomes, which are cell organelles with many functions, one of which is the burning of lipids. Lowering intracellular lipids lowers insulin resistance. This is generally considered to be a Good Thing. I doubt this, if it is drug induced. Forcing your body to burn fatty acids while overloading it with glucose from your diet seems a bit odd to me. And very much in to the territory of the Law of Unintended Consequences.

Clofibrate also lowers cholesterol. So the cardiologists used to love it (until the body count got too high). But is there causality between the reduced cholesterol and reduced cardiac episodes?

Look what clofibrate does to the PUFA in the myocardium of rats.

It goes some way to correcting the appalling omega 3 to omega 6 ratio produced by the junk described as laboratory rodent "chow". I don't think anyone would object to correcting the omega 3 deficiency which is so ubiquitous in bodies of both lab rats or Food Pyramid munchers. Personally, doing this by eating 5 pence worth of fish oil capsules a day allows me to eat cheap UK beef rather than the seriously nice but expensive grass fed stuff. The latter is a weekend treat only.

No, there is a world of difference between taking a few grams of fish oil per day and putting a large spanner in your metabolic works called clofibrate. Correcting PUFA ratios would be expected to reduce cardiac incidents. Dropping your cholesterol level is probably the cause of the increased all cause mortality.

For statins the effects are about even, for clofibrate the increased mortality effect predominates.

But the message I get from both of these drug classes is that, while they were developed to reduce chloesterol, they do other things. A cholesterol lowering drug only gets out of the lab and in to clinical practice if its unknown, unsought and accidental benefits outweigh the cholesterol lowering problem it causes. It is these accidental benefits which determine whether any cholesterol lowering drug stands the test of time.

Who would have imagined clofibrate had its cardiovascular effects through going some way to correcting the fatty acid balance of the myocardium? That's not why it was developed.

BTW both Actos (pioglitazone) and Avandia (rosiglitazone) also work on PPAR receptors (PPAR gamma this time, rather than alpha) but they do similar things. They are used for their insulin resistance lowering effect. They are much less useful that putting your bagel in the bin and represent a VERY big spanner in your metabolic works. I notice that they don't seem to be too good for you, now they are in general use. Any more than clofibrate is.

Peter

2 comments:

Stan said...

It's probably hard to describe this cholesterol failure better than presented by Kendrick (see below, after THINCS website):

Part 1: Cholesterol http://uk.youtube.com/watch?v=XPPYaVcXo1I

Part 2: Familial Hypercholesterolaemia http://uk.youtube.com/watch?v=-Xrr8MjDJ78

Part 3: About Statins http://uk.youtube.com/watch?v=jE_RIQY53ys

Part 4: Stress and the HPA axis (Bjorntorp) http://uk.youtube.com/watch?v=fHIA8usGxEM

Part 5: CVD Populations and Stress http://uk.youtube.com/watch?v=Na_Ear8OdJM

Enjoy watching 8-:)

Stan

Peter said...

Hi Stan,

Yes, Kendick is the most enjoyable read of the published cholesterol skeptics! I need to make time to listen to his youtube lectures. So much to do...

Thanks

Peter