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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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In the Pipeline

« Funding People, Not Projects? | Main | Avandia Goes Out »

May 18, 2011

Fenofibrate: Good For Much?

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Posted by Derek

Abbott has some difficult times ahead with their fenofibrate franchise. That's TriCor, and its newer formulation, TriLipix. Fenofibrate, as I've mentioned here before, is an oddity among drugs. It was discovered way before anyone had a mechanism of action, and even now, while it's supposed to be a PPAR-alpha ligand, no one's completely happy with that explanation. (For one thing, it's not very potent at that nuclear receptor, while other PPAR-alpha compounds have crashed in clinical trials for various reasons). But it can lower triglycerides and raise HDL, which should both (in theory) be beneficial effects, and it's been a big seller over the years.

But how much good does it do? That's always the big, important, slow question in the cardiovascular field. The data for fenofibrate have always been somewhat messy (although probably positive overall), but a new study has muddied things up. As the FDA puts it, in the documents for an advisory committee meeting tomorrow (PDF):

Over the last 40 years laboratory and clinical data have suggested the potential of fibrates to reduce cardiovascular risk. However, data from large clinical outcomes trials have produced mixed results. The inconsistent outcomes may be a result of differences in pharmacodynamic properties among individual fibrates or study populations or both.

The new data, from a trial called ACCORD-Lipid, is another one looking at fenofibrate plus a statin, which is the usual combination (that way, at least in theory, you go after triglycerides, low HDL, and high LDL simultaneously). But this trial, in a large population of diabetic patients, showed that overall, the rate of major adverse cardiovascular events (MACE) was statistically identical between the statin/fenofibrate and statin/placebo groups. No advantage! It gets trickier with a bit of subgroup analysis: women showed some evidence of worse outcomes with fenofibrate as opposed to statin alone. The group that seemed to benefit, on the other hand, were the patients who started out with the highest triglycerides and the lowest HDL. (See that FDA file above for all the numbers and more).

That's disconcerting. Is fenofibrate only helping the worst-off patients, and doing nothing (or worse) for the others? That a question worth wrestling with for a drug that sold well over a billion dollars last year. And beyond that is the same sort of question that came up when all the ezetimibe data hit: how much do we really know about blood markers versus real cardiovascular outcomes? Can you hit the various numbers by different routes, some of which are beneficial and some of which aren't? What is it that we're not understanding?

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs


COMMENTS

1. Ed Terry on May 19, 2011 5:45 AM writes...

The clinical results from Accord and Enhance studies are confusing only in the framework of the lipid hypothesis.

These studies may provide evidence that the lipid hypothesis is flawed. If lipid biomarkers indicate a disturbance in the metabolic condition, perhaps the focus should not be on HDL, LDL, and triglycerides levels, but should instead be on the parameters that lead to "undesirable" lipid levels.

For example, several studies have shown that the degree of lipid-lowering by statins is unrelated to the clinical benefits. A low dose of simvastatin is as effective as much higher doses. Yet, the treatment guidelines focus on reaching arbitrarily-established lower levels.

Unfortunately, there's a very substantial investment in the lipid hypothesis which discourages examining other approaches to finding the underlying causes of heart disease and CVE.

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2. Nate on May 19, 2011 9:00 AM writes...

I pretty much agree with Ed that cholesterol is really just a biomarker of cardiovascular health and what I see coming out supports this theory.

The failure of zetia and other "pure" cholesterol lowering agents to reduce CV events points to this.

What I think is that cardiovascular vascular oxidization stress is really what we want to lower if we want to see improved outcomes and it just happens that statins do this to some extent.

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3. renee kellman on May 15, 2013 10:58 AM writes...

after taking fenofibrate........ended up after a few weeks to approx a month with horrific joint pain and stiffness in my knees. When I got off after a few months 3-4 I now still have symptoms.............They had a class action suit in 2009 settled why still selling.? Md also responsible.
You have to be your own doctor or just stay away from the statins and triglyceride lowering drugs. Will pain and stiffness ever stop or is it permanent?? If anyone knows please e mail me at NYCrk6@Yahoo.com
Thanks

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