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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: Twitter: Dereklowe

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November 3, 2002

Cholesterol Lowering, One Way or Another

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Posted by Derek

Schering-Plough and Merck have won FDA approval for Zetia, their cholesterol absorption inhibitor that I've spoken about from time to time. That's a big step for them, although approval was pretty much assumed. The drug won't reach its real potential, though, until they can get their combination Zocor/Zetia formulation approved, which is the next big push. (I can highly recommend this article from Forbes, which presents a very accurate portrait of how the drug was developed.)

The two drugs have complementary mechanisms. Zocor is a statin, an inhibitor of an enzyme with the melodious name of hydroxymethylglutarate coenzyme A reductase. It's responsible for a key step in the cascade that synthesizes cholesterol from scratch. Merck was the first company to get one of these inhibitors on the market, and they've done extremely well with them over the years, although their current compound, Zocor, has slipped behind Pfizer's juggernaut Lipitor.

There are a number of statins out there, but one (Bayer's Baycol) was recently pulled from the market. That highlights some of the small (but real) differences between the different compounds: Bayer's compound ran into a similar toxicity problem that has affected the other statins (a rare inflammation of muscle tissue,) but seemingly showed more of it. To the best of my knowledge, no one knows what influences patient susceptibility to this effect, and it's something that hangs a bit over the entire field. Sounds like a good candidate for toxicogenomics, although it's hard to know where to start looking.

Zetia, on the other hand, has nothing to do with HMG-CoA reductase - rather, it inhibits the other source of cholesterol, absorption from the diet. Combine the two, and there really shouldn't be much excess cholesterol left. (I've always wondered what would happen if you really loaded up on both, though, because cholesterol, despite its bad reputation, is essential. Would some endogenous synthetic pathway that we don't even know about suddenly kick in? What would cholesterol deficiency look like, anyway?)

By itself, Zetia doesn't do any better job of lowering cholesterol than a statin does. But in combination with one, you can take the statin at lower doses than you would need it in a monotherapy. This would presumably lead to lower incidence of side effects, so it could be that events have conspired to bring the drug in at just the right time.

One wild card is that HMG-CoA reductase inhibitors may be good for more than lowering cholesterol - for example, there may be a protective effect for Alzheimer's. There's been a cholesterol handling/Alzheimer's link known for some time (a long and knotty subject that I'll take up in some future post.) So here's a question - are the possible side benefits of the statins due to lowered cholesterol only? Or are they due to something else that comes out of inhibiting HMG-CoA reductase? Or is it door number three - some other target entirely that statin-like structures also hit?

There's also the question of how much good lowering cholesterol really does. That's not something that's going to affect Zetia (or Lipitor, or anything else) for a long while. But the dietary fat controversy that Gary Taubes and others have been stirring up makes a person wonder how much good all this cholesterocentricism (new word! you saw it here first!) really does. That's a topic for another day, too!

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