Monday, December 22, 2008

Cholesterol and Son of J-LIT

The 10 year follow on to the J-LIT study is out. My view and update of the original J-LIT study was that it was one of the better statin studies and provided more information on the effects of pharmacologically lowered cholesterol levels, on a background of the known pleiotropic effects of the statin drugs, than most other studies. At a fixed dose of simvastatin (mostly 5mg per person per day) there is a relative beneficial effect if your statin induced hypocholesterolaemia is mild, with a significant increase in cardiovascular, cancer and all cause mortality if your TC drops below 160mg/dl and/or your LDL-C drops below 80mg/dl.

Well now the 10 year follow up is published.

What happens at the 10 year mark? Well, you are as welcome to try and find out as me, but I've failed.

There is a tabulated display of cardiac "events" vs on-study cholesterol levels in the results section. That's it. They have mortality data, including cardiac deaths and cancer deaths, for each cholesterol grouping, but these are not mentioned (they were there in J-LIT). Perhaps they have decided that we will be so preoccupied with the reduction in cardiac "events" that the risk of dying becomes so unimportant that we won't want to know about it.

Well I'd like to know.

This is the total of the information about all cause mortality by cholesterol level:

"The relative risk of all-cause mortality was also analyzed in relation to the average serum lipid levels during the 10-year treatment period in the primary prevention cohort study (data not shown comment: You bet it's not shown!). The results were the same as those in the previous report.2"

Now of course all studious cardiologists will naturally want to know exactly how lethal low cholesterol levels are, so will look up reference 2. You think not? Well, just to help out, here are the all cause mortality data from the 6 year report cited as ref 2 and plotted by TC intervals. The LDL-C vs all cause mortality curve is the same shape but a bit flatter. Look at the left hand end.



The left hand end is where these cardiologists want you to be. There is no difference between the data at 6 years vs those at 10 years is what they say. Seriously low TC or LDL-C will significantly increase you risk of being dead. Obviously, if you are a cardiologist, that is far better than having a cardiac "event"!

This 10 year report MUST also have the relative risk data for cardiac death in the low cholesterol group but they have forgotten to even mention it. I'd just remind you that in the original J-LIT study cardiac mortality was 6.23 time higher in the group with TC below 160mg/dl vs the reference group with TC of 200-219mg/dl. Again, perhaps having someone dead is less tiresome than having to manage a pesky survival heart attack. I dunno. BTW the LDL-C concentration in the group with TC <160mg/dl and 6.23 times relative risk of cardiac death was <80mg/dl, ie cardiological Nirvana.

Is that it? Not quite.

All cause mortality (irrespective of lipid levels) did get a brief mention:

"However, the overall mortality rate of the primary prevention cohort was higher during the 10-year period (4.47 deaths per 1,000 patient-years) than for the 6-year J-LIT period (3.69 deaths per 1,000 patient-years). The main factor contributing to the increase of mortality in the present study was probably aging, because the mean age had increased by 6 years for this extension study compared with that for the original J-LIT study"

Reading carefully here it seems they were comparing death rate in the first 6 years with death rate in the total 10 years, which included the first 6 years. That is, the all cause mortality in the last 4 years of the study must have been quite a bit higher per year than the overall quoted 10 year value as it is diluted down by the inclusion of the first six year value. Reverse engineering the numbers ties my brain in a knot. But that's how it has to be. What was to stop them adjusting the figures for age? Maybe the result!

They scared themselves with their honesty about mortality in the original J-LIT study and so they have been a lot more cautious with data release this time around.

So how do you sum up Son of J-LIT?

Dead bodies are less worrisome than cardiac "events".

Peter

PS I think I have commented that the original J-LIT study could be repeated on any cohort of people on a fixed dose of a given statin and that this has never been done, for obvious reasons. I think we can add that the exercise is so scary to a statinator that even the original J-LIT investigators have refused to repeat the exercise, even though they are the developers of the methodology and have the same cohort available. Wow.

18 comments:

mark said...

Thanks for the update, Peter. I have gone through the first J-Litt paper in depth and have it in front of me to pull up some data.

The first study had 42,360 patients for whom results were analyzed in the primary cohort, and 5127 in a secondary cohort, for whom results were omitted.

In the updated study, only 19,905 individuals opted to continue sumvastatin treatment. This means that 22,455 individuals stopped treatment willingly. A little less, given that some died and stopped treatment unwittingly lol. Only about 47% of the original participants continued the simvastatin treatment.

Why did over half of the original participants quit treatment? And what does this say about the results from the follow-up study? Likely, those who experienced the least side effects from biofeedback, who were less sensitive to simvastatin, continued. So those who responded most favourably to simvastatin continued.

From the Sr. abstract: "Incidence of adverse drug reactions during the 4-year extension period was lower than previously." This fits well with what I suggested, that those who experienced greater sensitivity and side effects due to simvastatin treatment discontinued the study. Those who had the most favourable response.

Here's some really disturbing stuff from the abstract:

"All 51,321 patients (including 19,905 who agreed to continue the study) were analyzed."

Recall that J-Litt looked at 42,360 patients. According to these numbers, they rewrote the results of J-Litt Jr. to include the secondary prevention cohort that was omitted. The secondary cohort included: (from the original) "the remaining 5,127 patients who had a history of CHD were enrolled in the secondary prevention cohort, and the clinical characteristics of which are reported elsewhere."

They also included another group that the original excluded: (from the Jr.) "4,934 patients were excluded for the following reasons: lack of follow-up data (932 patients), violation of inclusion/exclusion criteria (63 patients), unwillingness to participate (6 patients), and incomplete covariance (3,933 patients)."

Sort of. I'm really not sure how they got the 51,321 number. Jr. began with 52,421 original. That is really really weird.

And yeah, the abstract makes no mention of all-cause mortality, and on the cardiac front, refers to cardiac events vs. major cardiac events.

In summary: the results of the original were rewritten to include the secondary cohort with a history of CHD and those who were excluded for various reasons. In addition, they used any kind of cardiac event vs. Significant ones. The second half of the study used patients who responded most favourably to simvastatin and more than half discontinued treatment.

One question I have is do the 19,905 in the final four years include that secondary prevention cohort? Or was it selectively included in the reanalysis of the Jr. And kept out of the Sr.?


Mark.

Sue said...

"Patients with an LDL-C level>or=140 mg/dl had a far higher risk of coronary events than those with a level<100 mg/dl. CONCLUSIONS: Long-term, low-dose simvastatin therapy was safe and effective in Japanese patients with hypercholesterolemia. Serum LDL-C levels should be <140 mg/dl to decrease coronary risk and a low cholesterol level should be maintained for as long as possible."

How can they get away with saying that? As you wrote <160mg/dl increases cardiac mortality. Are they just saying at <140mg/dl you won't have a cardiac event (they don't mention that you might die at this level)?

Peter said...

Mark, It looks like they lumped together the primary and secondary prevention cohorts as the patient characteristics mention about 9% with previous CHD. The all cause mortality with time comment excludes patients with previous CHD. The data are so selective and badly described that the re written study has cognitive dissonance stamped all over it. What goes on in the heads of these people?

Perhaps they are all on statins.

Sue, the 140mg/dl LDL cut off simply chops off the patients who had the highest LDL pre study and failed to respond to statin therapy. You just have to ask what disease process was going on in these patients, but we're not going to find out from the J-LIT study or its follow on. And yes, the group which wrote this offering knows all about the all cause mortality effects of LDL <80mg/dl...

Peter

pooti said...

Man, Peter! Thanks so much for continuing to educate me about all the science. You make understanding these studies soooo much easier. :D

Bryan - oz4caster said...

Peter, thanks for a great laugh to start off the holidays!

"Perhaps they are all on statins."

What are the authors trying to hide anyway? Being so secretive about the data really makes me wonder.

I was on statins for about 10 years, until I quit about 3 years ago. I can't honestly say I noticed any side effects while I was on pravacor 20mg and then lipitor 10mg per day. I quit because on the lipitor my TC was around 130! Not good! But no doctor ever told me that :)

And I really wish they'd come up with a new name for "cholesterol", when they're really talking about certain size ranges of lipoproteins that just happen to have some cholesterol in them. Especially since it appears to be the oxidized fats and glycated proteins transported in these lipoproteins that are problematic, not the true cholesterol. Very misleading.

Dr. B G said...

Peter,

Never thought there'd be a 'son' of J-Lit! I appreciate your brain for reviewing this.

They're all descendants of SEAS and SHARP trials too...

THANKS!!
-G

Dr. B G said...

Ooops... btw IMPROVE-IT as well *ha*

Chris said...

Happy Christmas Peter. Thanks for all the excellent work you do on this blog - it is much appreciated.

mark said...

Indeed. Merry Christmas, and thanks for the blog. You got me started or catalysted my start into researching cholesterol, HBa1c, diet, vegetables at a deeper level.

Mark.

marco said...

Merry Christmas, Peter, and thanks for your wonderful Blog.

Marco

elizabeth said...

Hi Peter,

I am brand-new as finally managed to get a password etc on Google that is working.

I have three major questions I wish to raise.

I am still completely uncertain as to why PUFAs are quite so terrible for me .

I eat a mix of pure butter, some olive oil and some other oils occasionally. Am trying to get caloreis in right now and do add in margarine also sometimes. I just cannot find the time to plough through all the literature on PUFAS and late at night - it does not make sense. Are some PUFAS in the day horrensous for me ?Please tell me how to simply work out a 4% ratio of PUFAs. I cannot just eat butter and goose fat all the time, is too calorific for me and too rich. I do eat them and the coconut also but is not always nice on the old digestion... I am having 120g a day of fat. How do I work out the 4% that can be allowed PUFAs in that - sorry to appear quite so dim. Can't get to grips with the percentages. I checke the margrine yesterday and if I have that then 100g has 8g saturatged fat, 13 mono and 5 PUFA - is that such an appalling ratio?

I have horrendous back pain at the minute - how can i get rid of this. I have less 20g carbs, lots of fat and 40g protein a day - back pain is no better after 90 days. Why? How come yours is so amazing and mine so appalling?

Also, ketsosis and uric acid? I am prettty sure I am highly acidic as full on ketosis and when eating the foie gras we live on here in France, I got inflammed ear cartlidge and fingers - high purine food, like all offal etc.

It is so hard to cure these ailments.. how come it works for you but not me - cannot tolerate the cream as suffer horrendously from dairy and latose - runny nose and sore eyes every time as with the butter - hence the margarine preference for me.

Have a bit of soy full fat cream in my coffee - could this be the uric acid, back pain problem.. really?

Please advise and reply so I know this post is finally working for me.

Thanks, Elizabeth

elizabeth said...

I wonder if any one can respond to me would welcome all advice...was anorexic and am now 4 months into full on recovery with three full meals a day etc. I am not some anorexic air-head who is all screwed up, but, am screwed up physically right now and any advise would be welcome. I am 40 years old and now weigh 40kg. I have two children and manage the house and a job and the whole "getting better" thing into the bargain. I have been following this site for 2 months now, came to it via the Michael Eades site as was focusing on high protein initially.

My issues/questions are as follows:

-It is very hard to get the carbs in and stay out of ketosis. I do not wish to be in Ketosis as I believe it is one extra load on the poor old body- however, when I eat any carbs, whatsoever, the result is truly horrendous.

Rye bread - one tiny piece, sends me sky high and hot and cold and hypo and hyper.
Veggies are killing me because they will not digest.

-I can manage 99% chocolate and am living on that at the moment for the carbs.

-Was managing lots of foie gras -( do live in France after all!) but, now have tophi, can you believe, on my ear cartilidge which must be the uric acid load.... shit, shit and so have dropped that. Am living on masses of fat in all forms (Oil, butter and yes, margarine also as is lactose free, the lactose in cream and buuter and cheese is killing my eyes and stomach) limited protein and masses of 100% chocolate.

Is all a bit of a mess but am basically trying to get in the 1600calories a day as required on the minimum amount of intake so as to lessen my stomach issues.

Please adivse, has anyone been through this on this site?

I would love to be eating more carbs to keep out of ketosis, I think am on about 15g a day right now. Not enough by a long shot. I am aiming for 40g protein a day and 120g fat.Do manage this on and off, protein tends to be salmon and tuna and pork and beef and lots of kidneys and liver. That bit is good, but even then, cana only be 50g piece at a time and really sends my insulin high. I know this because I go very cold and tired, then very hot and hyper.

I wake up around 3 am feeling very sick often, especially after the fat intake at night or if I eat too late.

Please, help anyone... am a little desperate. Live in Geneva and France and have very little access to English speaking stuff apart form sites such as this from the UK.

Thank you to all at Hyperlipid - Genevois Elizabeth

Chris said...

Elizabeth, reading those comments I really feel for you, but I don't this is not really a discussion forum. It is Peter's blog where he posts a variety of stuff about diet.

You say you are a recovering anorexic which gives me the impression that you have had "issues" with food and diet. Please just concentrate on getting yourself well and do not obsess about percentages and grams. Meat, offal, eggs, more eggs, potato... etc. Back pain can have lots of causes too - not least stress - it isn't just diet.


all the best

gunther gatherer said...

Elizabeth,

I agree with Chris, but would also suggest that you simply concentrate on taking gluten out of your diet for several months and not pressure yourself with any other aspects of this regimen right now.

If you read Peter's other entries and their associated study links, gluten is known to have strong associations with eating disorders, depression and addictive behaviour in general.

Chris said...

Gunter Gatherer is right. Go gluten free. And stop stressing about things.

Connie said...

Elizabeth, come on over to Eades' forum. Other people have had these issues, some of us do OD, and it IS a discussion forum.

http://www.proteinpower.com/forum/

Peter said...

Hi Elizabeth,

Your question requires a little time. Soon.

Peter

Peter said...

Hi Elizabeth,

Anyone who has gone from anorexia to 1600kcal/d is doing something right.

The PUFA toxicity is a complex story and as such is spread over both Hyperlipid and Stephan's blog amongst many other places. Vegetable derived fats (omega 6) are unstable and their breakdown products are highly biologically active, probably most of those actions are bad for you (though this may depend on circumstances). Very long chain omega three fats are protected by the body and do not seem to cause the same problems. Eating some is probably good.

The easy answer to the correct amount of omega 6 is simply to avoid them all together. There is enough in any real food to meet your needs so aiming for zero added PUFA is reasonable. To make sure you get enough omega 3 fats as little as 5ml of good quality fish oil per day is plenty.

I'm not aware of any convincing evidence that a low or high purine diet has any effect on tophi or uric acid levels in general. These are controlled by fructose and genetics and will normally sort out if you get on to a sustainable LC real food diet.

I would suggest that 40g/d of protein is too little for weight gain. As a recovering anorexic you probably need more. Six egg yolks is 20g of protein. This for breakfast is a low volume and eating the same for lunch would get you to up to 40g/d of protein with a seriously useful amount of vitamins and minerals. That just leaves another 20g from meat or offal as an early evening meal and you are at much more useful level of protein intake. Using beef fat for cooking the eggs is less ketogenic than butter because the medium chain fats in butter convert very easily to ketones, the longer saturates in beef fat are used as they are without the ketosis step. Use lots and use a spoon to eat the eggs and fat.

If you have digestive problems with vegetables don't forget that chocolate is a vegetable and contains fibre and starch in amounts that might be contributing to gut and spine problems. Stearic acid (the fat in chocolate) is plentiful in beef fat, it just doesn't taste as good.

You might consider clarifying butter to make ghee as a method of increasing fat intake, there would be some medium chain triglycerides but this is preferable to the trans fats and omega 6 fats in margarine. Ghee has no lactose, tastes excellent and is very calorie dense.

If you really cannot tolerate vegetables on a gut function basis you should look at the SCD site at

http://www.breakingtheviciouscycle.info/beginners_guide/beginners.htm

In the short term you could even consider glucose powder, about 10g at a time, added to clarified butter (for the fat and calories), taken in the aftermath of each meal. That's 30g/d of glucose and the fat load from the previous meal should blunt the glucose spike. As a recovering anorexic you should be insulin sensitive and handle this ok. About 100mg/d of vitamin C might be worth taking at this level of complete vegetable exclusion. As your gut recovers getting the small amount of vit C you need on a on a LC diet becomes easy.

I would fully agree with Chris and Gunther that anyone with any sort of gut or eating disorder should 100% stop all gluten, probably all grains. You have no way of knowing exactly why you feel so ill after rye bread, just listen to the message and avoid doing it again...

There is more on starch and spine problems at

http://www.kickas.org/

If you can get sorted short term like this you can start choosing vegetables from either the SCD lists or the KickAS preferred sources and get a little variety in to your diet.

But that 1600kcal is an achievement. Stay with it.

Peter