Friday, January 18, 2008

Zetia, are things getting better?

I like zetia.

It had a lot going for it. No bungling in the advertising department this time. They must have learned their lesson from the crash and burn of torcetrapib, the standard fate of drugs without an X, Y or Z in their name. So it was the big Z for Zetia. Even the drug name, ezetimbe, has that cool z... It has overtones of relaxing, good times, not in the least difficult, eze in fact.

And it's turned to be one of the best cholesterol lowering drugs ever. I don't have the full study (does anyone?) I'm just looking at the press reports and Dr Nissen's squirming featured on Dr Eades' blog. But the best thing is:

I don't think they killed anyone with Zetia.

This is a big improvement on both torcetrapib and clofibrate. I've no idea about the actual fatalities, and I doubt the Zetia study was powered to detect changes in overall death rate anyway. Total mortality always seems something of a gamble in cholesterol lowering trials. Mind you, just thinking aloud, there seems to be no talk of "a trend towards improved survival", so perhaps there was an non significant increase in fatalities, I hope not. As I say, I don't have the numbers. But it seems impossible to spin this study to be pro Zetia. Tragic.

Apart from the bankruptcy of the lipid hypothesis, why did Zetia fail?

That's pretty obvious. Have a look at this paper. Those poor hyper responders to dietary cholesterol were fed eggs. Their cholesterol went up. Oh no. Except it was the "good" lipoproteins which increased.

"These findings suggest that the increases in LDL-C and HDL-C due to increased egg consumption in hyper-responders are not related to an increased number of LDL or HDL particles but, to an increase in the less atherogenic lipoprotein subfractions."

Similarly in this study they found

" the LDL peak diameter was increased during the EGG period for all subjects."

I believe increased LDL particle diameter is considered to be a Good Thing.

Now if Zetia stops you absorbing your breakfast eggs, you don't have to be a genius to predict what it will to the "atherogenicity" of your lipids.... Oh, but your calculated LDL goes down with Zetia. Yawn again.

Anyway, Zetia is less frankly toxic than some the previous non statin cholesterol lowering agents, for what that's worth.

Still useless. How did a drug with such a cool name fail?



Stan Bleszynski said...

Perhaps a cholesterol-heart disease connection or correlation is real after all?

Strong negative correlation in the low total cholesterol or low LDL range is also a correlation!

What makes me think so is that the latest Merck study seems to be consistent with the J-LIT study!

Both used simvastatin and both studies have shown worsening of cardiovascular risk, by a large factor (2 and 6 respectively) for those patients who have lowered their cholesterol the most!

Perhaps it's not just that unlike the statin, Ms "Easy Timbie" may have blocked some essential fat absorption but perhaps the lack of serum cholesterol itself, below certain threshold, might have contributed to the disease, for example through the shutdown of self regeneration and healing?

Stan (Heretic)

Peter said...

Hi Stan,

Yes, I fully agree that we should expect a very low LDL-C to be associated with vascular catastrophes. From my basic viewpoint, arterial damage is repaired using LDL-C using the apoB 100 receptor. Low LDL-C is produced by the statins because each liver cell is so desperate for cholesterol it puts out every LDL-C receptor on its surface it can manage. I guess initially the endothelial cells do the same, so modest LDL-C reductions are tolerated relatively well and the pleiotrophic effects predominate. If there are any pleiotrophic effects from your drug that is. As LDL-C gets below some magic number the endotheial cells can put out as many receptors as they like, they can't have what isn't there. My guess is that the LDL-C level at which problems become apparent is determined by the anti inflammatory and antioxidant effects of the hypocholesterolaemic agent. For torcetrapib and clofibrate these were woefully inadequate. Now ezetimbe too. The statins hang on in there as no one reads the J-litt paper. And now ANOTHER gem from Dr Davis, calcium supplements raise HDL-C, drop LDC and kill people. I have never, ever, ever, ever found a better source of information disproving the lipid hypothesis than Dr D!!!!! Yet still he believes.....


Peter said...


No overall mortality figures for the calcium trial, let's just leave it at increase cardiovascular problems as we have no body count. Or, more likely, a non significant increase in all cause mortality but the study wasn't powered to... We'll never know


Psipsina said...

You might find this amusing:

Mark's comment (in the comment section) is priceless: "So you're saying it doesn't work?"

You especially have to watch their marketing video:

"Unlike some statins, ZETIA has not been shown to prevent heart disease or heart attacks."


Peter said...

Nauseating video!!!!!! Enjoyed the list of world's worst drugs though, some new ones there. A few giggles had in the reading...


cavenewt said...

Peter Attia sent this link to his email list today, with a promise to blog about it soon. He describes it as "interesting." I don't know if he means that in a good way or a bad way.

"Extremely low LDL-C concentrations cause no clinically relevant side effects."

Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels—The zero-LDL hypothesis