Ezetimibe, Statins, and Heart Disease

Ezetimibe, Statins, and Heart Disease

Headlines are filled today with news that a popular combination of drugs for lowering cholesterol levels is no better than the older of the two drugs alone (c.f. “Trial: Popular cholesterol drug fails to improve heart disease” CNN, http://www.cnn.com/2008/HEALTH/03/30/cholesterol.drug.ap/index.html). Cholesterol and the mechanisms for lowering it are subjects with which I am not unfamiliar.

This conclusion comes from the so-called ENHANCE trial of vytorin vs simvastatin

[An aside, in clinical trials, especially those related to cardiovascular disease, there is a tradition of clever names from tortured acronyms and this one is one of the more tortured: Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression – you figure out how this is an acronym]

suggests that the combination therapy is no better than the statin alone. So, if one is taking the combination (sold as Vytorin), as I am doing, should one quit and switch to a statin alone? Not so fast.

I am a firm believer in evidence-based therapy. Prior to the ENHANCE study, all evidence suggested that ‘lower is better’ and ezetimibe in combination with a statin lowers cholesterol more than a statin alone. This current study contradicts the 'lower-is-better' dictum.

I wonder why this might be so. After all, my intimate familiarity with the mechanisms by which cells regulate production of cholesterol and LDL suggests that lower should be better, as do previous clinical studies. Cells, however, are not bodies, and knowing how a drug works doesn’t necessarily mean that we know _everything_ that it does. Thus, clinical studies can trump laboratory science. Notwithstanding the foregoing, the current results provide little basis for a clear conclusion that can be used in developing therapeutic guidelines for the general populace.

One potentially crucial issue is the choice of patients with familial hypercholesterolemia as the study group. People with FH have mutations in the gene encoding the LDL receptor, the protein that pulls most of the LDL from the blood stream. These mutations partially or completely disable the receptor so that it cannot remove LDL cholesterol from the blood. As a result, FH patients have very high levels of cholesterol in their blood, chiefly as LDL (the bad cholesterol). Cholesterol-lowering therapy aims to lower cholesterol levels in the blood. This in turn stimulates production of the LDL receptor that clears cholesterol from the blood, leading to lower cholesterol in the blood in a ‘virtuous’ cycle.

At the same time, lower cholesterol levels also cause the cells of your liver to make more of the enzymes needed for you to make your own cholesterol. As you make more cholesterol on your own, excess cholesterol is exported to the bloodstream as LDL, raising levels. This vicious cycle can be broken by the statin drugs. These block the ability of your liver to make its own cholesterol but don’t keep it from making more LDL receptor. Thus, you pull more cholesterol out of the blood and don’t make more to replace it.

Ezetimibe (the other drug in Vytorin, also sold by itself as ‘Zetia’) works in a completely different way. It keeps your gut from absorbing the cholesterol in the foods that you eat. It does this by blocking the function of a protein of the lining of your gut that is needed to grab cholesterol from the food passing by and carry it into your cells and, eventually, to your blood stream. If this protein cannot do its job, the cholesterol that you eat passes out with the rest of the dietary waste (Yechhh!).

When cholesterol levels are lowered (by statins, ezetimibe, or both), you make more LDL receptor and you keep LDL levels low. Bear in mind that the subjects of the ENHANCE study lack fully-functional LDL receptors. It may well be that they show no benefit, at least in part, because they lack the mechanisms needed for the benefit to work. The present data do not address this issue.

In the Enhance study, moreover, the subjects had been on various cholesterol-lowering regimens for some years prior to this test and may already have been at or near the maximal therapeutic benefit before the trial began. If so, they then would be unlikely to show further benefit.

Another point to note is that the endpoint of this widely-trumpeted study is not heart disease per se (despite the attention-grabbing headlines), but rather a surrogate of heart disease, carotid intima-media thickness . The intima is the lining of arteries and the carotid arteries carry blood from the heart to the brain – the intima-media is where arterial cholesterol plaques form. Thickening of the carotid arteries is easily and quickly measured non-invasively. Thus the choice of this measure is pragmatic – we cannot go around slicing up patient’s heart vessels to measure plaques and no one wanted to wait until they died to get a clue).

The evidence that carotid intimal-medial thickness is a good surrogate endpoint for predicting heart disease risk is modest in 34 studies that have been done. Further, when the period of study is only two years, as in the case of the ENHANCE study, any beneficial effect on ultimate disease outcomes is likely to be negligible. This is because it probably takes about two years for lower levels of circulating lipid to have an effect on existing arterial plaques. All the same, it seems unlikely that long-term heart disease risk reduction would happen _without_ reducing plaque accumulation.

The bottom line is, looking behind the headlines, I don’t think these results are especially informative of much of anything beyond therapy for FH patients. Extrapolating from this select and extreme subset to the general population is problematic. For now, I’ll keep taking my Vytorin and wait for better data.