Sunday, November 18, 2007

Best ever statin study?

I missed this landmark paper last year, full text here. Possibly because, as it continues the demolition of the cholesterol hypothesis, it received absolutely zero publicity. I posted about the J-Litt study here, but this one is even better.

The paper is from the Essen group (in Germany) and describes their study comparing normal dose atrovastatin (10mg/d) with high dose atrovastatin (80mg/d).

Same drug, different dose rates, different cholesterol levels. Follow your patients for a year and have the coronary artery calcification progress tracked by electron-beam computed tomography. This is a reasonably well designed study, except see the "phew" comment below.

How much difference does it make if you drop your LDL-cholesterol to 87mg/dl as compared to 109mg/dl?

I think the answer is technically known as "diddly squat". Or zero, zilch, nuthin, nowt.

The answer as to why is pretty clear from table 3 shown here.

Look at the falls in hsCRP and fibrinogen on low vs high dose atrovastatin. They're the same between groups. Ie the anti inflammatory effect and anti thrombotic effects are maxed out at 10mg, so no further benefit is seen at 80mg. From my point of view this is fortunate. Had these pleiotropic effects not maxed out the study might have suggested lowering cholesterol was beneficial. But 80mg of atrovastatin is no better an anti inflammatory agent than 10mg is. Phew.

The paper discussion is an amusing catalogue of excuses and references to studies "better" designed to show the benefits of aggressive statin use. The trick is to use different drugs and give the best anti inflammatory statin at the highest dose rate. Then the lowest cholesterol correlates with, but is not responsible for, the least CV problems. It is also sensible NOT to measure CRP or fibrinogen, otherwise you end up with a study like this one, where people can see what's going on.

This group strike me as genuine medics who believe in the lipid hypothesis and are genuinely surprised that they have trashed the cholesterol hypothesis by accident. Still, I'll leave them with the best line from their conclusions, ignoring the squirming in the discussion and the plea for more time to get an effect. Here it is:

"we did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis"

Peter

Thank you to Dr Davis of Track Your Plaque for citing this unheard of paper

and to

Drs Axel Schmermund, MD; Stephan Achenbach, MD; Thomas Budde, MD; Yuri Buziashvili, MD; Andreas Förster, MD; Guy Friedrich, MD; Michael Henein, MD; Gert Kerkhoff, MD; Friedrich Knollmann, MD; Valery Kukharchuk, MD; Avijit Lahiri, MD; Roman Leischik, MD; Werner Moshage, MD; Michael Schartl, MD; Winfried Siffert, MD; Elisabeth Steinhagen-Thiessen, MD; Valentin Sinitsyn, MD; Anja Vogt, MD; Burkhard Wiedeking, MD; Raimund Erbel, MD

for this excellent study, published in a full-text-for-free journal.

10 comments:

Brian said...

Peter

You’ve just got it all wrong!

Anyone who is deliberately (and really) on a diet of 80% of calories from animal fat is either being provocative to see what reaction they get, or just plain foolish. I don’t know which PubMed studies have given you support, but clearly you’ve not studied the totality of heart disease – from starting point with fatty streaks through to all the stages of development, ending with a heart attack. All of this pathology is amply demonstrated to be heavily and negatively influenced by things such as animal fat, and LDL level.....amongst others. Even the guy you seem to like – Dr William Davis of Track Your Plaque fame, has lowering LDL as a key plank of his treatment regime. It seems from your comments about exploding cholesterol myths that you are one of the ‘cholesterol doesn’t matter’ brigade, and have found a few studies, well one at least, which seem not to support lowering of cholesterol (LDL). as beneficial.

I don’t have the time or inclination to fill in all the gaps in your education, but here are a few titbits to get you on a better track and maybe save your life. I’m also enclosing a list of some 80 references which support the facts that lowering cholesterol – particularly LDL (whether by statins or naturally), and practising a low fat diet is beneficial in cardiovascular disease – both helping to prevent it and regressing it.

At 51 you still have chance to clear out all that plaque that may be growing there, as yet undetected by calcium scans.(Newly forming soft plaque often isn’t). If you are one of Nature’s wonders who can eat as much animal fat as you can, and still not have heart disease, I urge you to make yourself available for a clinical study so that your genetic make up can be published and science can learn the secrets of the few people like you. Maybe you have that elusive combination of genes that keeps your HDL high, and turns off the bad effects of your fatty diet. If so, think yourself lucky, but please don’t put it about that this diet is good for anyone else!

You seem pretty cynical when you talk about the amusing catalogue of excuses given by the researchers in the study you gleefully cite for lack of evidence of regression of calcium during the study. You award them the status of genuine academic researchers – afford them some respect therefore in canvassing the possible reasons why their study showed this effect. After all, that’s part of the normal process in a study – look at the reasons the results are what they are. These aren’t excuses, they are ideas. One other possible reason they don’t mention is that just maybe serial calcium scoring is too inaccurate to determine progression/regression. I have recently attempted to get a response on this on Dr Davis’ website but I fear he won’t publish it because it raises severe doubts about calcium scanning as a methodolgy for follow up. I have quoted to him studies which show that regression can actually generate a higher calcium score. So, be careful what weight you put on this study, because without IVUS, I don’t believe they could reasonably assume progression or regression using calcium scans.

Your comments do not begin to do justice to the topic of whether lowering cholesterol is of any use – importantly, can it induce regression. The study you mention is but one of many which showed the opposite effect. You do not mention the others, you seem to have been waiting in the shadows to leap out when you found this one. Come on, be professional.

The other regression studies I refer to are too many to discuss in detail, but I will touch on some and give you a list of these so you can study more breadth of evidence.

Firstly, you ignored the studies quoted by the authors of the study you cite which showed the opposite of their results. These were (their references 4 and 25), Nissen et al JAMA 2004 291 1071-1080 and Achenbach et al Ciculation 2002 106 1077-1082. Both these showed substantial benefits of cholesterol reduction. These benefits included halting the progress of CAD as determined by IVUS and reducing progression to 9% in a group of patients who had been progressing by 25%.

There is something very peculiar about the study you cite in that an 80mg dose of Atorvastatin usually would reduce LDL by something like 40-50% whereas the patients on this study only achieved an 18% reduction – unheard of in most of the studies I have seen.(106 down to 87) Even then, their LDL was still 87 – about 2.2 – again not low enough to expect regression according to many studies where this occurs at levels much below – eg 1.8 or less. The researchers themselves make the comment that perhaps the lack of results is because cholesterol was not reduced enough. Based on many studies I have read this is perfect sense to me, obviously not to you because I think your just want to prove a point that lowering cholesterol is of little use, rather than learn.

Apart from the two studies above, here are more which show regression. I will run out of time to comment on them all.

1. Nicholls et all JAMA 2007 297 499-508

Regression of CAD demonstrated when LDL was substantially reduced and HDL increased by at least 7.5%. Regression shown via IVUS. This was an analysis of 4 previous randomised trials.

2. Reversing Coronary Artery Stenosis

This is a textbook by Lance Gould an eminent doctor in which various studies of his are shown on regression over 20 years. His studies as published in the book and in journals have LDL lowering as a vital factor, He has taken patients left as incurable with normal therapy and reversed their heart disease. Check him out.

3. von Birgelen et al Circulation 2003 108 2757-2762

This study showed no annual plaque increase when LDL went below 75(1.9). Method was IVUS

4. Lima et al Circulation 2004 110 2336-2341

This study demonstrated regression started (measured by MRI ) after only 6 months of statin treatment, and that regression was closely linked to amount of LDL reduction.

5. Schuler et al Circulation 1992 86 1-11

In this study of exercise and a low fat diet, progression was less in the exercise/diet group than a control group. In the intervention group, regression occurred in 30%, no change in 50% and progression in 20%. No drugs were involved.

6. Niebauer et al American Journal of Cardiology 1995 76 771 – 775

This was another exercise/low fat diet study. In those exercising most(>5 hrs/wk), regression occurred. Progression was slowed on the whole in the intervention group.Both progression and regression was associated with cholesterol levels.

7. Small Donald M Arteriosclerosis 1988 8 103-129

This fellow was a major expert in the cardiovascular research field. He reviews the evidence supporting the association between lipids and CHD. He states that when cholesterol is lowered below 150, lipids are mobilized from lesions and regression starts. After long periods of this, the lesions are purged of lipids and true regression occurs.



8. Corti et al Circulation 2002 106 2884-2887

This study looked at the effect of a statin on existing plaques in asymptomatic patients. Plaque was measured in the carotid arteries. During two years, plaque regressed .The researchers said that the effect was due to the lipid lowering effect of the statin

9. Edward D Frohlich - Preventive Aspects of Coronary Heart Disease Textbook

Chapter 7 of this is abput the reversibility of CHD. It says that where cholesterol is reduced, lesions improve and that reversal is feasible in these conditions.

10 . Wissler R and Vesselinovitch D Annals of New York Academy of Sciences 1976 275 363-377

Even in 1976 these two experts were saying that CHD is almost completely preventable and substantially reversible – if cholesterol is reduced below 150. At this level, lipid deposits disappears from plaques and regression of CHD occurs.

11. Nissen et al JAMA 2006 295 1556-1565(ASTEROID trial)

This trial treated patients with a statin and achieved LDL averaging at 60.8(1.5) and increased HDL by 14.7%. Regression occurred in 78% of patients with progression in 22% . They point to the linear relationship between LDL reduction and amount of regression. They also mentioned that there does not appear to be a lower limit of LDL below which benefits of reduced CHD cease.

12. Ornish et al JAMA 1998 280 2001-2007(Lifestyle Trial)

This famous study demostrated regression after one year with more after 5 years for the group which followed an extreme low fat vegetarian diet plus exercise.

I have run out of time to note any more regression evidence – coupled with lowering cholesterol, but there are more studies showing the same things as above.

What follows now is a reference list from a paper I wrote in 2004. Some of the references duplicate those above. The areas covered are the benefits of low fat diets, benefits of lowering cholesterol. regression, and how low cholesterol is not harmful.

Once you’ve got through this lot, you might change your views.

I also recommend you check out Esseltyn who has been conducting a reversal study for some 20 years, published at various stages. He has taken people who have been told they are dying from CHD – failed by-passes etc, and cured them. The message is getting boring, but as usual he does it with a low fat diet, statins where necessary, lost of fibre....etc, with lowering of LDL as a key component. Those same dying people are still living twenty years later.

Are all these experts wrong, as well as the expert advisory panels on cardiovascular disease? I very much doubt it. Is the body of evidence all pointing in the same direction for 50 years all wrong? Again I doubt it.

References

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Peter said...

Hi Brian,

I put a short post up at the current top of the blog to direct any current readers to your comment. I wouldn't want anyone to miss it.

Peter

Bruce said...

Brian: "All of this pathology is amply demonstrated to be heavily and negatively influenced by things such as animal fat, and LDL level.....amongst others."

This is nonsense. You can't isolate all the other factors in the modern diet, such as refined carbs, PUFAs, processed trans fats, deficiencies, etc. Show me a study feeding humans or animals 80% fat (or higher), and 20% protein (or less), with none of hte above things included. Then, we can talk. Until then, I think you'd do well to stop believing guys like Dean Ornish and T. Colin Campbell, neither of which has any integrity.

Here is an article debunking many of your claims about animal fats. I look forward to your response.
http://www.cholesterol-and-health.com/China-Study.html
http://www.cholesterol-and-health.com/Campbell-Masterjohn.html

Willow said...

Reducing salt/sodium intake reduces high cholesterol safely and easily, without recourse to drugs, and of course benefits health in many other ways too.

O Primitivo said...

A possible explanation why primitive people have lower/lowered cholesterol levels when compared to industrialised societies:

Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists
http://www.anth.ucsb.edu/faculty/gurven/papers/gurvenetal2009plosone.pdf

Blood lipids, infection and inflammatory markers in the Tsimane of Bolivia. American Journal of Human Biology
http://www.anth.ucsb.edu/faculty/gurven/papers/fahetal2010.pdf

Ed Terry said...

Thanks for posting Brian's comments Peter. I really feel for him.

I got into a heated discussion with a cardiologist who wanted to put me on a statin because my LFL was elevated....at 80! I pointed out to him there's never been a study showing that is the LDL-lowering effects of statins that produce any benefit. He reluctantly admitted that any benefit were from statin's pleiotropic effects. Of course, no one has proved that either. Of course, other drugs have been used to lower LDL but they actually increased mortality from CVD...oops.

It's simply amazing for what passes as critical thinking today. Years ago, as a pharmacist, I simply accepted everything that was in the medical literature. It took a degree in chemical engineering to provide me with the ability to critically analyze data to see what claims the data supported.

Too bad Brian didn't provide the location of his blog. I would love to read it when I get bored.

Christopher Davis said...

If Brian's evidence-based response offends your bone-deep dogmas about the treatment of hyperlipedemia, maybe you should retort with meaningful, equally evidence-based responses instead of "feeling bad for him".

AlexB said...

Christopher

I rarely take anycurrent interest in the Hyperlipid blog as, often, the proponents of this regime, particularly Peter are so dismissive and closed-minded, as well as arrogant in their handling of a non-believer. Despite the fact it is some years since I gave them 80 references which lend support to my views, no one has bothered to look at these and make any rational comment. Unfortunately Peter and Co. do not want to open their minds to change and prefer books by non medical scientists, journalists etc. From the date I gave them all this material there have been other important studies showing the benefits of lowering LDL to further support my arguments. Additionally, and I doubt you will find this on the Hyperlipd blog, studies have been published highlighting the dangers of a high-meat diet - with which they seem happy;with increased fibre, fruit and vegetables - which they seem to denigrate. The bottom line for me is they failed miserably to address my challenge - what does a high saturated fat diet do to help someone like me who has proven heart disease whereas my evidence showed that lowering LDL was a cornerstone to survival in this context. Silence. Now years on, and still on my super-low fat diet high in veggies, fruit and fish and nuts, and with the help of statins aspirin and lots of exercise, I am maintaining very low LDL and TriG, very high HDL, low body weight, and OK glucose/insulin. At 73 I can still run up hills and am asymptomatic even though I have a CT angiogram proving I had three blockages at around 50% in 2008. Thanks for appealing to reason, but I doubt the Hyperlipds are going to change.

AlexB said...

Christopher

I rarely take anycurrent interest in the Hyperlipid blog as, often, the proponents of this regime, particularly Peter are so dismissive and closed-minded, as well as arrogant in their handling of a non-believer. Despite the fact it is some years since I gave them 80 references which lend support to my views, no one has bothered to look at these and make any rational comment. Unfortunately Peter and Co. do not want to open their minds to change and prefer books by non medical scientists, journalists etc. From the date I gave them all this material there have been other important studies showing the benefits of lowering LDL to further support my arguments. Additionally, and I doubt you will find this on the Hyperlipd blog, studies have been published highlighting the dangers of a high-meat diet - with which they seem happy;with increased fibre, fruit and vegetables - which they seem to denigrate. The bottom line for me is they failed miserably to address my challenge - what does a high saturated fat diet do to help someone like me who has proven heart disease whereas my evidence showed that lowering LDL was a cornerstone to survival in this context. Silence. Now years on, and still on my super-low fat diet high in veggies, fruit and fish and nuts, and with the help of statins aspirin and lots of exercise, I am maintaining very low LDL and TriG, very high HDL, low body weight, and OK glucose/insulin. At 73 I can still run up hills and am asymptomatic even though I have a CT angiogram proving I had three blockages at around 50% in 2008. Thanks for appealing to reason, but I doubt the Hyperlipds are going to change.

shrimpgoup said...

Holy mother, if those last few comments aren't a result of Peter finally authorising a few straggling comments then, boys - take a bow, this is spectacular.

Christopher issues a challenge to people on a nigh-on 6 year old post, and then within 24 hours, like some goddamn Bat Signal has gone off, Brian (who is apparently now AlexB) reappears to assure us he's totally not bothered. Twice!