Doc Gumshoe’s News: Some Good, Some Not So Good

By Michael Jorrin, "Doc Gumshoe", January 5, 2015

[ed note: Michael Jorrin, who we like to call “Doc Gumshoe”, is a longtime medical writer (not a doctor) who writes non-investment articles about medicine and health topics for us once or twice a month. As with all of our guest contributors and columnists, he chooses his own topics and his words are his alone]

In a recent New Yorker, a rapturous write-up of an Indian restaurant on the upper West Side of Manhattan (Awadh, on Broadway at 98th Street) concluded with these words: “At the end of such an extravagant meal, it’s hard not to feel as if one has imbibed a pound of melted butter and a quart of cream. But, as you may have heard, the medical establishment now says that butter is good for you, or, at least, not bad for you. We concur.”

Doc Gumshoe can’t possibly know what Shauna Lyon, the writer of the New Yorker piece, had in mind with that assertion, but here are some possibilities:

  • One, she’s aware of the now widely-accepted premise that only about 15% to 20% of the cholesterol in our bodies entered as cholesterol. We synthesize most of it from a variety of things we eat, and synthesize it we must, because cholesterol is essential for life.
  • Two, she has paid attention to the increasing emphasis on the effects of total diet on heart disease risk, with special attention to transfats, salt, and sugar as menaces, and less emphasis on the old bugaboos such as butter, eggs, and cream.
  • Three, she has noticed that, according to the recent guidelines promoted by a couple of influential medical societies, people are recommended to start taking statins mostly on the basis of risk factors, and once they’re on statins, their cholesterol levels are no longer monitored. So, if cholesterol isn’t being monitored, why worry about trifles like an extra pound of butter and a quart of cream?

No matter. Underlying this speculation is an uncertain state of affairs when it comes to the overall management of cardiovascular risk factors. The definitive formula has yet to be derived, even though guidelines and recommendations keep being issued. Doc Gumshoe readers may remember my comments on the new statin guidelines, which were promulgated by the American College of Cardiology and the American Heart Association (ACC/AHA) about a year ago. (If you missed it, you can check it out here.) Here’s a quick summary of those guidelines:

  • They attempt to quantify total cardiovascular risk by arriving at a percentage figure for a ten-year risk of cardiovascular events (heart attack or stroke), based on an algorithm. Individuals aged 40 – 75 whose ten-year risk is 7.5% or higher are recommended to take statins.
  • They recommend that persons whose LDL-cholesterol levels are 190 mg/dL or higher should take statins.
  • They also recommend that all persons with existing heart disease or Type 2 diabetes should take statins.
  • However, specific LDL-cholesterol goals are not part of the new guidelines. According to the guidelines, regular monitoring of blood cholesterol levels is not necessary, and the effects of treatment should not be based on how much cholesterol-lowering takes place.

It was estimated that implementing these guidelines would result in 70 million people in the US being on statins.

The ACC/AHA guidelines were immediately criticized, on a number of grounds, by some of the most eminent cardiologists in the land. I do not know how widely they have been put into practice.

So, keep those guidelines in mind while we quickly review a new study that sheds interesting light on the whole question of managing cardiovascular risk.

IMPROVE-IT: Not huge news, but definitely provocative…

This was a large, long study of a drug that a lot of practitioners didn’t have much confidence in. The drug was ezetimibe (Zetia), given in a combined formulation with simvastatin, and marketed by Merck as Vytorin. The study, whose results were made public at the American Heart Association 2014 Scientific Meetings this past November, enrolled 18,144 high-risk patients within 10 days after they had sustained an acute coronary event such as a heart attack (myocardial infarction or MI) or a stroke. Baseline LDL-cholesterol levels in all patients in the study were quite low, in most cases 100 mg/dL or even lower.

Patients were assigned either to a statin alone or to the ezetimibe-simvastatin combination, and followed for six years, until there had been 5,250 primary endpoint events in the trial, those being cardiovascular death, MI, stroke, or hospitalization for acute coronary events. The results of the study were by no means a huge home run for the Vytorin combo, but they were significant in more ways than one.

Patients on the combined ezetimibe-simvastatin combination had 13% fewer MIs, 14% fewer strokes, and 21% fewer ischemic strokes than patients who were on a statin alone. (Note: these were relative risk reductions, not reductions in the absolute risk.) Differences in other endpoints were minor, and there was no difference in cardiovascular deaths.

In the context of our discussion about guidelines, however, one of the most interesting results was that at the conclusion of the study, the mean LDL-cholesterol level in the statin alone group was 69.9 mg/dL, while in the ezetimibe-simvastatin group the mean LDL-C level was 53.2 mg/dL.

This suggests (but does not prove!) that a reduction in LDL-C of about 15 mg/dL from an already quite low level resulted in real and significant clinical benefit in terms of lowering the rate of acute coronary events.

A hole in the ACC/AHA guidelines

The ACC/AHA guidelines explicitly state that continued monitoring of cholesterol levels is not needed once a patient is put on a statin regimen. Yet here we have a study in patients, all of whom are on statins, where a difference in LDL-cholesterol results in important clinical benefit. How can that difference in LDL-C be attained without cholesterol monitoring? How can the clinicians track what’s going on with patients if they don’t measure the cholesterol levels?

And, just as important, what keeps patients adherent to treatment if there aren’t markers to let them know how they’re doing?

The thrust of the ACC/AHA guidelines is to reduce the focus on the lipid levels and pay increased attention to the other risk factors. Clearly, those other risk factors are important. But the IMPROVE-IT study actually told us something we really didn’t know before, specifically that lowering LDL-C to levels considerably below those previously thought to be optimal, even in high-risk patients, delivers real benefits.

How is ezetimibe different from statins?

In a nutshell, ezetimibe takes aim at that pound of melted butter and quart of cream that you ingest at that Indian restaurant. What it does, with moderate effectiveness, is prevent the cholesterol in that butter and cream (and also in the filet mignon and foie gras that you wolf down at the French restaurant) from passing through the walls of your small intestine and making its way into your bloodstream. Statins, in contrast, inhibit cholesterol synthesis, so teaming up the inhibitor of cholesterol transport with the inhibitor of cholesterol synthesis would seem to make good intuitive sense.

The flaw in this proposition is that, in most people, under most circumstances, most of the time, dietary cholesterol contributes to at most 15% to 20% of our total circulatory cholesterol. Therefore, ezetimibe isn’t ever going to result in big cholesterol reductions.

I suspect that when ezetimibe was in the very earliest stages of investigation as a potential cholesterol-lowering drug, the general assumption in the medical community was that our circulating cholesterol entered our bodies in the obvious for