More thoughts on cholesterol and eztemibe (Zetia)

The target of LDL might not be wrong but how we get there likely is. Agressively lowering cholesterol with high dose STATINS seems to work in several trials.

What people fail to realize is that there was no add on drugs in these studies. You either got there with diet and statin or you didnt. The researchers didnt add Zetia.

Thus, doctors shouldnt assume that just getting to a number matters (see the glitazone story for HGA1C). But how you get there.

“Agressively lowering cholesterol with high dose STATINS seems to work in several trials. ”
But was it because they lowered cholesterol or because of anti-inflammatory action?

Additionally, most studies looked at secondary prevention or at least at people in very high risk group. Especially males. Then the guidelines somehow extrapolated the results to primary prevention that seemed to include people with relatively low 10-year heart desease risk. Case in point – my 10-year risk is slightly under 1%. Yes, when one year my LDL went about 4 points above the number in the guidelines for my number of risk factors, my doctor was too quick to prescribe. Oh and I know a healthy, slim, athletic female who is a head of a local hiking club is on statins too. I also read a post from an otherwise healthy ballet teacher whose doctor put her on statins and who was worried about muscle side effects (since her muscles were kind of important given her job). Now this woman was risking her ability to do this job just to get the numbers down thinking that he is in the imminent risk of heart attack. Doctors usually “forget” to mention one’s absolute risk. After all “this will reduce your risk by 30%” or “this will prevent a heart attack” sounds so much more convincing than “this will reduce your risk from 1% to .7%”.

Pray, show me a single study which demonstrated heart attack and mortality benefit for primary prevention in low-to-average risk females. If statins work not because they reduce LDL but by some other mechanism, would the same mechanism apply to all otherwise healthy people who are currently on statins?

Talking about P4P. There was a story recently about a company’s (Clarian health, I believe) plan to penalize employees for not meeting a number of health metrics. Guess what – LDL over 130 was on their list, but not other risk factors. So according to this company a person whose LDL is over 130 shall pay more for health insurance even if this person has a low heart attack risk. Assuming that a perticular employee is already OK on lifestyle changes (slim, etc.), they are essentially forcing their employees to take drugs. Including Zetia. Regardless if it’d benefit them. Now this is smart, especially from a company that is supposedly involved in health care and should know better.

The results of ENHANCE are not entirely surprising in that it has previously been shown that ezetimibe does not improve endothelial function. Landmesser et al., Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans, Circulation. 2005;111:2356-2363.
My 14-year-old daughter has heterozygous familial hypercholesterolemia. She is on lovastatin 40 mg. Her cardiologist wanted to add ezetimibe as her LDL is still very high, but I said no. We obviously don’t have all the answers here. It seems likely that some of the effects of statins are due to LDL-lowering since other LDL-lowering drugs have reduced cardiovascular events (e.g., bile acid sequestrants), but clearly there is more going on. I think it is time to rethink our approach to development of these drugs. No drug should be approved based solely on lowering LDL. At a minimum, demonstration of an effect on atherosclerosis should be required, with clinical outcomes studies required to follow within a set period of time. In addition, promotion of plant sterols and stanols based on LDL-lowering is seriously suspect.

I would caution Judy B on her suggestion of lowering LDL increases plaque. This might be a spurious finding of this study. No, I repeat, no study of statins has ever shown plaque increase on a statin. Remember this study was simvastatin/ezetimibe compared to simvastatin alone. We need more info from this study to better understand it. I cant fathom a mechanism by which the statin would work in one group of patients and not the other arm of the trial. Ezetimibe is not really absorbed and works locally to reduce fat absorption/transport (simple description). Unless it somehow interferes with statin absorption I dont know what else it would do to explain the findings. I interpret this trial to show a lack of benefit (beyond lowering LDL)of adding ezetimibe to high dose statin. I dont interpret it as harming folks.

What I wish we had a trial of is ezetimibe vs dose of statin that led to a similar LDL reduction. Then we could put this LDL hypothesis to bed once and for all. I suspect the statin would reduce outcomes and ezeimibe wouldnt despite lowering LDL 10-15%.

Also would be nice to have a trial of statin at high dose without monitoring LDL compared to targeted LDL reduction with a statin to see if outcomes differed. WOuld be intersting if they didnt.

Statins do more than just lower cholesterol. They are known to have significant pleiotropic effects. One of them being as an anti-inflammatory. So to state that studies have shown an ever decreasing mortality rate as statin dosage increases, therefore ever decreasing LDL is the reason for this, is misguided. None of these studies bothered to measure any of the other effects of Statins. How do we know that the reason for the statin performance is not due to an increased anti inflammatory effect? In fact, I would say from the results of this Zetia trial that this might be the case? I would also add that doctors and scientists need to revisit the cholesterol theory of heart disease and start sifting through the data. This has not been the first time that some trial or meta analysis results have contradicted the theory, but no one seems to care or be bothered. Maybe now someone ought to care!

The ENHANCE trial just continues to demonstrate how sceptical we must be of the information the drug reps feed us. As a concierge family doc who makes house-calls all day, I haven’t seen a drug rep up close for over 2 years. Instead I’m forced to read the Prescriber’s letter, Medical Letter, refer to Up TO Date often, etc… How glad I am.

Andrew Oakes-Lottridge, MD
Personalized Health Care, Inc.
(239)694-6246
http://www.DrAndy.us