Lowering Cholesterol a Lot

Recent issues of both The New England Journal of Medicine (May 8) and JAMA (May 14) included clinical trials of the same investigational drug for lowering serum cholesterol levels. Both trials were funded by Amgen. The drug is evolocumab, a fully human monoclonal antibody that reduces serum concentrations of LDL-C by preventing degradation of LDL-C receptors. Many non-statin drugs can reduce LDL-C levels, but doubts about whether LDL-C lowering per se lowers the risk of cardiovascular disease have limited their use. The January, 2014 issue of Treatment Guidelines from The Medical Letter on Drugs for Lipids summarized the situation as follows:

“New guidelines from the American College of Cardiology and American Heart Association no longer recommend using specific cholesterol targets in the treatment of hyperlipidemia. HMG-CoA reductase inhibitors (statins) are the lipid-lowering drugs of first choice for treatment of most patients with atherosclerotic cardiovascular disease. They can decrease the incidence of major coronary events and death in such patients. Taken as an adjunct to diet, exercise, and smoking cessation, statins can also reduce the risk of first cardiovascular events and death in patients with risk factors such as elevated levels of low-density lipoprotein cholesterol (LDL-C) and diabetes. Their benefits in these patients clearly outweigh their adverse effects. Combining a statin with another LDL-C lowering drug, such as colesevelam, niacin, or ezetimibe, can reduce LDL-C levels further than a statin alone, but studies demonstrating that such combinations improve clinical outcomes are lacking.”

All of which, you would think, would discourage pharmaceutical manufacturers from developing any more non-statin lipid-lowering drugs. Studies that attempt to demonstrate improvements in clinical outcomes are difficult and expensive gambles at best. And evolocumab is not a convenient once-a-day pill. It is given subcutaneously every 2-4 weeks. But it lowers LDL-C a ton. In the New England Journal trial, mean reductions in LDL-C after a year of treatment with the antibody varied from 48.5% to 61.6%. In the JAMA study, after only 10 weeks, it reduced LDL-C levels by up to 66%. In one group of patients, mean LDL-C went from about 125 mg/dL to about 45 mg/dL. And all this with <2% side effects, none of them serious. If lowering LDL-C by itself can ever prevent cardiovascular disease, this drug would seem to have about as good a chance of demonstrating that as we are likely to come across.

When the FDA approves it, we will review it in The Medical Letter.


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Comments

  1. William DeMedio MD says:

    If we had outcomes data for this medication, it would certainly very strongly suggest that it is the actual lowering of LDL-C, and not another effect of 3-HMG CoA reductase inhibitors that causes decreased premature cardiovascular mortality rates with their use. Unfortunately our FDA seems biased in that they are more interested in surrogate effects rather than actual clinical outcomes when it comes to evaluating new medications for approval. The taxpayers deserve more, as although the FDA is funded by their fees from manufacturers, it is the taxpayers who ultimately end up bearing the high expense of new medications that are potentially no better than lower cost, existing ones. It is this inherent conflict of interest within the FDA which really needs to be resolved.

  2. Yes – this new drug has potential to “lower Cholesterol a lot” – but demonstrating that Cholesterol lowering will translate into improve outcome are 2 very different things. Without such demonstration – the jury should be “out” regarding Amgen (which isn’t cheap and isn’t convenient to take). We’ve had enough of surrogate outcome data. Real patient outcome improvement data without causation of significant side effects over time should be required before recommending this agent.

  3. Ben Reiter says:

    I wonder why the FDA would even approve such a drug without outcome studies

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