Thanks to a tip from “Jack Friday” of the Pharmagossip blog, I’ve read this paper which appeared in Atherosclerosis this past summer. A large multi-center team put a lot of work into studying the Vytorin combination (ezetimibe and simvastain, the cholesterol absorption inhibitor and a classic HMG CoA reductase inhibitor) in 72 healthy male subjects. I was initially excited about it, because reading the abstract it seems as if they’ve found a real difference between taking the combination versus taking the drugs by themselves, which is rather a hot topic these days. But read on.
The subjects were divided into three groups, receiving 10 mg/day ezetimibe (basically Zetia monotherapy), 40 mg/day simvastatin (Zocor monotherapy) or the combination (Vytorin). The results? Well, LDL cholesterol went down in all groups, as expected – this much was known already. (Total cholesterol was down as well, but this was basically all due to LDL reduction). Ezetimibe alone lowered LDL by 22%, simvastatin by 41%, and the combination lowered it by 60%: so far, so good. Those are just the kinds of numbers that convinced people to go on Vytorin in the first place.
Cholesterol synthesis showed an interesting pattern, but one that makes sense. Simvastain lowered it, as well it should – that’s the whole rationale for a statin in the first place. But ezetimibe actually increased it, which could be interpreted as the body’s attempt to get back to previous cholesterol levels after the dietary supply was cut off. The combination was a wash, as you’d expect – the two canceled each other out. These results have been found in other studies as well.
Meanwhile, cholesterol absorption was the flip side of endogenous synthesis. Ezetimibe lowered it (again, as well it should!), and simvastatin had essentially no effect. The combination, then, showed an overall lowering of cholesterol absorption – no surprises, and this, too, has been seen in other work.
The gene for the surface LDL receptor showed a different pattern. Ezetimibe by itself didn’t do much to its expression levels, but simvatatin sent it up (and thus the combination sent it up, too). When they looked at the actual LDL-receptor protein, though, none of the three regimens had an effect. The abstract for the paper makes more out of this than the paper itself does, to my eyes. The abstract singles out the combination therapy as upregulating the gene but not protein expression, as if that were some new effect, but simvastatin alone does the exact same thing. I didn’t see anything particularly surprising here, and the bottom line is that none of the three treatments did anything to LDL receptor protein levels, which is how real clinical effects would be expected show up.
The differences these investigators found with Vytorin as compared to its two components seem to me to be either already known, completely reasonable and expected, or so small that it’s uncertain if they exist. I have a feeling that that’s why this work was published in Atherosclerosis - a perfectly good journal, mind you, but if something dramatic had shown up, I’ll bet they could have made New England Journal of Medicine, JAMA, The Lancet, Nature Medicine or the like.
Overall, this study just seems to be confirmation of why Merck and Schering-Plough felt safe in making a big marketing play for Vytorin. If lowering LDL is good, and if lowering LDL is the reason that people take statins, then Vytorin does it even more. If you were shown these results without knowing that they were for Vytorin, you'd think that someone had discovered a real blockbuster of a new cholesterol-lowering drug. So we’re right back to asking why ENHANCE didn’t show a benefit in artery wall thickness. And that, no one knows.