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March 15, 2010
It's easy to lose sight of what a drug is supposed to do. Many conditions come on so slowly that we have to use blood chemistry or other markers to see the progress of therapy in a realistic time. And over time, that blood marker can get confused with the disease itself.
To pick one famous example, try cholesterol. Everyone you stop on the street will know that "high cholesterol is bad for you". But the first thing you have to do is distinguish between LDL and HDL cholesterol - if the latter is a large enough fraction of the total, the aggregate number doesn't matter as much. And fundamentally, there's not a disease called "high cholesterol" - that's a symptom of some other cluster of metabolic processes that have gone subtly off. And the endpoint of any therapy in that field isn't really to lower the number in a blood test: it's to prevent heart attacks and to extend healthy lifetimes, mortality and morbidity. As we're seeing with Vytorin, it may be possible to drop the numbers in a blood test but not see the benefit that's supposed to be there.
Another example of this came up over the weekend. The fibrates are a class of drugs that change lipid levels, although the way they work is still rather obscure. They're supposed to be ligands for the PPAR-alpha nuclear receptor, but they're not very potent against it when you study that closely. At any rate, they do lower triglycerides and have some other effects, which should be beneficial in patients whose lipids are off and are at risk for cardiac problems.
But are they? Type II diabetics tend to be people who fit that last category well, and that's where a lot of fenofibrate is prescribed (as Abbott's Tricor in the US, and under a number of other names around the world). A five-year study in over five thousand diabetic patients, though, has just shown no difference versus placebo. Again, there's no doubt that the drug lowers triglycerides and changes the HDL/LDL/VLDL ratios. It's just that, for reasons unknown, doing so with fenofibrate doesn't seem to actually help diabetic patients avoid cardiac trouble.
Mortality and morbidity: lowering them is a very tough test for any drug, but if you can't, then what's the point of taking something in the first place? This is something to keep in mind as the push for biomarkers delivers more surrogate endpoints. Some of them will, inevitably, turn out not to mean as much as they're supposed to mean.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Drug Assays
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