Both mainstream and medical press outlets are cautiously touting a new treatment currently in clinical trials for hyperlipidemia, or high cholesterol. Data on this drug are extremely limited -- the most recent report concerns the first of twelve trials run by Sanofi and Regeneron; the trial involved just over 100 participants -- but as far as managing numbers, the experimental treatment appears to lower LDL (so-called "bad cholesterol") levels to a greater degree than Zetia, an existing anti-cholesterol drug made by Merck. What is this new treatment? How excited should people with high cholesterol be about it?
The experimental treatment currently in clinical trials is a monoclonal antibody known as alirocumab. Monoclonal antibodies are immune cells that are clones of a parent cell, typically made by fusing human cells with cells from the spleen of a mouse that has been injected with an antigen. Transgenic mice are used to make the monoclonal antibodies "humanized." The tipoff that a biological agent is a monoclonal antibody is a name ending in "mab." The alirocumab trials have involved biweekly injections in order to deliver the drug -- definitely different from existing drugs like Zetia and statins, which are generally delivered in pill form. (Monoclonal antibodies were initially developed as cancer therapies.)
The aim of giving people with high cholesterol alirocumab is to inhibit proprotein convertase subtilisin kexin 9 (PCSK9), which regulates LDL receptor levels. Trial aims include measuring the effect of alirocumab on lipid metabolism in adults with levels of LDL between 100 and 190 mg per dL (compared to placebo), determining whether alirocumab affects circulating lipid levels in individuals with gain-of-function mutations in their PCSK9 gene (combined with statins, with a control group receiving a placebo plus statins), and measuring the effect of alirocumab on LDL levels in adults with LDL levels between 100 and 190 mg per dL (compared to ezetimibe, a.k.a. Zetia). For the purposes of clinical trials, alirocumab is also known as SAR236553 and as REGN727.
There are a few items of interest with respect to the alirocumab clinical trials. One is the choice of Zetia as a comparator. Zetia, or ezetimibe (as it is generically known), was designed to lower cholesterol levels by decreasing cholesterol absorption in the small intestine. However, Zetia has been controversial in that it has been shown to lower cholesterol, but not to reduce cardiovascular events, in individuals taking it. In fact, in the trial known as ENHANCE, "fatty plaques in arteries that can cause heart problems [...] grew almost twice as fast in patients taking Zetia along with Zocor [a statin] than in those taking Zocor alone." In another trial, ezetimibe along with simvastatin "did not affect the primary endpoint of aortic valve and cardiovascular events."
Another item to note is that even statins have a tenuous connection with a reduced risk of death from cardiovascular events, and have troubling side effects. As noted by cardiologist Eric Topol of the Scripps Clinic, "We're overdosing on cholesterol-lowering statins, and the consequence could be a sharp increase in the incidence of type II diabetes." Dr. Topol asserts, "Let's just round this off and say that one in every 200 patients treated with any of the three most potent statins will get the side effect of diabetes." Dr. Topol further comments that statins have limited effectiveness in a wide swath of individuals taking them: "In patients who have never had heart disease and who are taking statins to lower their risk, [...] the reduction of heart attacks and other major events is only 2 per 100."
Finally, it is interesting to note that alirocumab has been tested in some patients with not-very-high (or even clinically "near-ideal") LDL levels. For example, NCT01644474, the trial profiled in today's New York Times article, involved patients with LDL levels between 100 and 190 mg per dL. According to the Mayo Clinic, LDL levels between 100 and 129 mg/dL are considered "nearly ideal," and LDL levels from 130-159 mg/dL are only "borderline high." The NYT does not tell us how many of the 103 trial participants were in the "high" cholesterol range of 160-190, nor does it report the LDL level breakdown between the Zetia group and the alirocumab group. Additionally, the NYT reports, "Of the 52 patients taking alirocumab, 14 had to increase their dose midway through the trial because their cholesterol level had not dropped enough." It almost goes without saying that this trial has not been published in a peer-reviewed journal.
Amid all the talk about "familial hypercholesterolemia" and "genetic factors," it is interesting to note that the average woman has an LDL level of 118 mg/dL -- a figure that could have landed her in the alirocumab trials. It's hard to imagine a hereditary disease with which the average American could be diagnosed. Where did it come from, one wonders, this genetic epidemic?
Therefore, one must temper one's enthusiasm for a new cholesterol drug with the knowledge that it is a biological agent delivered via biweekly injection, the most recent trial announcement involves a comparison with a drug of debatable efficacy, and trials to date have involved individuals with relatively low cholesterol. Do the benefits of this new drug exist? Will they outweigh the risks? Only time (and a lot more data) will tell.