Uptake blockers do not improve on statins

It has not been a very good couple of weeks for big pharma in the public eye. They’ve been taking a pounding in the political arena since the primary season finally got into full swing. Last week, we learned that today’s medicines, rather than funding tomorrow’s miracles, mostly finance power lunches with your cardiologist. And this week, Merck and Schering-Plough, after much delay, finally announced the results of a major study, called ENHANCE, that did not demonstrate any benefit to using the highly-touted drugs Vytorin and Zetia rather than a generic statin.

Because almost everyone who owns a TV knows that Vytorin blocks both sources of cholesterol, and that “Zetia works differently“, the results seem particularly damning. The companies involved did not help this appearance by holding back the results so long, and indeed doing so may have exposed them to lawsuits from shareholders and customers. The study was primarily performed by imaging the carotid artery, and in this regard no statistically significant difference was observed between patients treated with Vytorin (statin + Zetia) and statin alone. Also, there was no statistically significant difference in the number of patients who died from cardiac events or strokes, or suffered non-fatal infarctions in the study. While vytorin lowered cholesterol levels by 56% after 24 months vs. the 41% lowering seen in the statin group, this did not translate into improved outcomes by any measure.

So, is this a case of evil pharmaceutical companies trying to gouge consumers over worthless medications? Not exactly. Like every campaign promoting prescription drugs, commercials for Zetia and Vytorin oversold the benefits and did not sufficiently emphasize the risks of these medications. Their failure to improve outcomes in this study is troubling, but because adverse outcomes were so rare overall, it would be difficult to establish an effect one way or another. Also, this study was not geared towards measuring plaques and clots directly; rather it (indirectly) measured the effect of these drugs on atherosclerosis. The effect of uptake blockers on infarction rates was an incidental measurement.

One important consideration when interpreting these results is that the study group was not constructed to resemble the general population. Rather, the study was performed on individuals who had familial hypercholesteremia, a genetic condition that causes greatly elevated levels of LDL in the bloodstream. Without the data in hand I of course cannot make a solid judgment, but one possibility that immediately suggests itself is that in this population even a significant diminution of LDL levels is not sufficient to improve outcomes. There’s just too much cholesterol for these uptake blockers to affect the outcome. In a normal individual with significantly lower levels of LDL Zetia and Vytorin might have a much greater effect.

Moreover, all the individuals in this study were already taking statins—which contributed to the low rate of adverse outcomes. It may be that the marginal improvement from adding an LDL blocker on top of a statin simply isn’t that great. However, for individuals who cannot take a statin due to side effects, taking an uptake blocker might be a significant improvement over doing nothing. The study does not, as far as I can tell, speak to this possibility.

There is always the possibility that this study points to completely unsuspected aspects of arterial disease. For instance, these results might indicate that once lesions form they attract cholesterol very strongly, and therefore only extreme reductions in circulating LDL can affect their growth. Alternately, this outcome may indicate that mechanisms unrelated to circulating lipids play a more significant role in determining plaque thickness than previously suspected. In light of the highly unusual population used as study subjects, any grand pronouncements in this regard are premature. If these findings are replicated in upcoming studies of greater duration on more representative samples, however, a substantial re-examination may be in order.

The findings of the ENHANCE study don’t really indicate that you should burn your Vytorin prescription and go back to just a generic statin, but it does create doubt as to whether this approach will prove efficacious in the general population. Further study, promptly published, is called for, and it would be wise for Merck and Schering-Plough to pull their advertising campaigns for the time being. Doctors should also be less eager to prescribe Vytorin for patients who are responding well to statins alone, but for patients who are not improving greatly with statins (or cannot take them at all), then a prescription for Vytorin (or Zetia) would still seem to be justified. As always, the best approach is to exercise and eat healthy foods, though that’s much easier said than done.