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Mar 31

Several weeks ago I wrote a piece that reported on a paper (Shalev et al., 2009) that indicated that those patients that adhered to their prescribed statins had a decreased mortality rate compared to those that did not adhere.

However, I would be doing a disservice if I didn’t report the excellent critique of this paper by Michael R. Eades on his blog.

The problem with the statin study, as Dr. Eades points out, is the separation of those that self-adhered to taking the drug and those that didn’t adhere. Because maybe the type of people that don’t adhere to their prescription are fundamentally different that those that do adhere. One possibility is that those adhere to their medication care more about their health.

Dr Eades talks about a near 30 year old New England Journal of Medicine study and points out these interesting results of this pre-statin drug used to lower cholesterol:

Subjects were randomized into two groups - those in one group got the drug, those in the other got the placebo.  After the subjects were on either the drug or the placebo for five years, researchers calculated the mortality from the number of deaths in each group.  Turned out that the five-year mortality of those on clofibrate was 20.0 percent whereas the five-year mortality of those on the placebo was 20.9 percent, or essentially the same.  Taking the drug was no different than taking the placebo, i.e., the drug was worthless. Had one of the researchers not looked a little closer, that would have been the end of the story.

When the data were looked at from the perspective of how many people actually took the drug as prescribed, the researcher discovered that those subjects who took at least 80 percent or more of their clofibrate had a five year mortality of only 15.0 percent, substantially less than the overall five-year mortality.  Those who took their clofibrate sporadically had a five-year mortality of 24.6 percent, significantly higher than those who took it as directed, a piece of data that would seem to confirm the efficacy of clofibrate.  Right?  Not necessarily.  Let’s look at compliance with the placebo.

Turns out that those subjects on the placebo who regularly took their placebo had a five-year mortality of 15.1 percent while those who took their placebo sporadically had a five-year mortality of 28.3 percent.  What this study really showed was that there is something intrinsic to people who religiously take their medicine that makes them live longer.

You should read his complete piece, but I think you get the general story. The bottom line is it didn’t matter if you were taking the medication or the placebo you lived longer if you were the type of person that would adhere to taking your ‘medication’. And among those that regularly took their medication there were no difference between those that received the cholesterol lowering drug or the placebo.

Dr. Eades goes on to point out another paper published in Lancet that found very similar results (Granger et al., 2005). In this case they were looking at congestive heart failure comparing a drug and placebo.

Those taking the drug (Candesartan) showed no difference in mortality compared to those taking placebo.  But when compliance was evaluated, those taking either the drug or the placebo as directed had much lower mortality than those taking either one sporadically.

Going back to the 2009 cholesterol lowering statin drug study the reported decrease in mortality is in the group that regularly took their medication compared to those that didn’t bother to take their medication regularly. And now you know from the 30 year old study this type of measurement (study) is not very valid.

Dr. Eades piece goes on to dive into further details such as all the actual randomized double blind clinical studies while reducing cardiovascular death in those with increased LDL levels, do not show any reduction in overall mortality (he argues there is an actual increase in cancer and other causes of death that balances out the gains in the cardiovascular system).

He concludes (but read the whole piece):

Don’t fall for the false promise of this or any other version of an observational study.  These kinds of studies do not prove causality.  Nor do they prove that a drug regimen works.  The patients in this study who religiously took their statins had better all-cause mortality than those who didn’t.  But, as we saw above, adherers always have better all-cause mortality than non-adherers.  In this case, was it that the adherers lived longer or was it that statins conferred some sort of benefit.  We can’t tell.  But we do know that in the real studies, the randomized control trials, statins didn’t do squat, so my vote would be that what we’re seeing here is an adherer effect and not a statin effect.

I am not saying I agree with all the views and opinions of Dr. Eades, but I think his argument regarding the above discussion is valid.

see also:

statins bad for myelination?

long term statin use bad for your long term health?

(Dr. Eades also correctly points out how it is impossible (or nearly impossible) to run a correct randomized double blind studies with many lifestyle interventions - such as the exercise study I discussed yesterday - and hence you can not ‘prove’ anything with these type of interventions).

Jul 24

Low levels of the good cholesterol, high-density lipoprotein (HDL), is linked with worse memory performance. So here is another example of what is traditionally considered a heart health measurement that also give us important information about our brain health (see here).

The nice thing about the various cholesterol measurements is that many of you will know your measurements so then you can see where you fall when I provide the details below. If you don’t know your measurements I would suggest you find out - for both your heart and brain health.

You have all heard about cholesterol, but in overly simplistic terms it can be broken down to bad cholesterol, low-density lipoprotein (LDL) and good cholesterol, high-density lipoprotein (HDL) - see wiki entry.

In a recent study by Singh-Manoux et al., 2008 they studied 3,673 subjects at both age 55 and 61 and measured their total cholesterol, HDL, triglycerides (all were measured after an overnight fast), and short term verbal memory. After controlling for all the various variables (e.g. education) they found that subjects with HDL levels <= 40 mg/dL had worse memory than those with high HDL levels (>= 60 mg/dL). Additionally, those subjects that had a drop of HDL from age 55 to 61 also had a drop in memory ability. The authors giving us these results suggest that having HDL levels between the two extremes (41 - 59 mg/dL) does not produce significant differences it is only at the two far ends of the spectrum that differences are found. But these are not extreme values for I know a triathlete that has HDL level is at 96 mg/dL. Additionally, you must remember that subjects that showed a drop in HDL levels over the 6 years between the tests showed a decline in memory - suggesting small changes of HDL are meaningful.

Now if you are in your twenties you might think that this whole cholesterol thing only concerns ‘older’ people. But I can tell you I have a friend in her twenties that HDL was in the 30s, meaning it would fall into the bad memory group (for the record she has a good memory - but what is going to happen when she gets older?). And I know another friend that while he eats very healthy falls into the low category. Therefore, you can not assume that because of your age, eating and exercise habits, body type that you must have a good high level of HDL. So no matter what your age it would not hurt to know your cholesterol and its various sub components.

But more importantly once you find out your measurements to do something about them. We can choose various lifestyles and/or drugs to change our levels to hopefully improve both our body and brain health.

Very quick list of things to do to increase your HDL levels: quit smoking, lose weight, exercise, mild levels of alcohol, increase consumption of good fats (e.g. fish, olive oil, nuts). However, things are never quite this simple. In a future piece I will give you more details that might shock you a bit - it surprised me.

For now find out your various cholesterol measurements when you can, and with or without this knowledge make appropriate lifestyle choices (which we all already know at various levels) that is know to increase your HDL levels - and improve most other health measurements.

(via FuturePundit)

Jul 10

Does early long term use of statins decrease progenitors cells and result in dementia at an earlier age than normal?

Earlier I had written a post about how cholesterol lowering drugs may be prescribed to kids as young as 8 year olds as suggested by recent guidelines released by the American Academy of Pediatrics.

Statins are the most widely prescribed drug to lower cholesterol - are there potentially any long term side effects on the brain in kids taking them for all or most of their lives? Interestingly, statins are also being studied for their potentially positive effects on the brain including Parkinson’s disease and dementia. In general the researchers find positive effects of statins on these two brain diseases (though not conclusive), so why then would we be worried about their long term negative effects on brain health?

A new in vitro paper (Sim et al., 2008) studying statins found that in a dose dependent manner this drug at equivalent doses used by humans increased the differentiation of glia progenitor cells into oligodendrocytes (via Rochester University). What does that really mean? Progenitor cells (in this case glial) are similar to stem cells, but just a little further down the commitment line and in general have less potential to form all types of cells. Glial progenitor cells can become astroyctes and oligodendrocytes. Throughout our lifetime there is an overturn of these cells and we get the new cells to replace the old ones from these glial progenitor cells (there is still a limited supply of these cells). Oligodendrocytes myelinate our axons and a decrease of oligodendrocytes is involved in diseases such as multiple sclerosis (MS an autoimmune disorder). Interestingly, researchers are exploring the potential use of statins to treat MS.

Sim et al., found that statins resulted in 5 times more oligodendrocytes in culture of human brain tissue compared to samples not treated with statins. Conversely, the statin treated brain tissue had 1/6 the number of glial progenitor cells. Therefore, it appears that statins increase the differentiation of glial progenitor cells into oligodendrocytes. The end result being statins results in more oligodendrycytes, which can be good when treating condition when there has been a loss of these cells(MS, brain injury, spinal cord injury, or other condition which cause damage to oligodendrocytes). However, what about the long term use of statins?

Early I pointed out that researchers have found some positive results of statin treatment on reducing dementia. But in a more recent paper the authors pointed out that in randomized controlled trails that statins prescribed later in life (older people) there is no effect on dementia. I wonder if does the age related decrease in glial progenitor cells play a role in the lack of effect of statins in older people. Statins can not significantly increase the number of oligodendrocytes cells if there are too few glial progenitor cells.

There is growing research (reviewed here) that suggest that the loss of white matter (oligodendrocytes) possibly plays a larger role in age related dementia than gray matter loss (neurons). Part of the reason there would be a loss of oligodendrocytes would be the age related loss of the glial progenitor cells. Therefore, is it possible that statins used in middle age individuals protects them from dementia because they increase the differentiation of glial progenitors cells into oligodendrocytes, which protects these individuals from the natural age related loss of these cells. However, this same treatment may have no effect on older individuals (as reported above) because the number of glial progenitor cells are too low for statins to have its biological effect?

So what do you would think would happen if an individual starts taking statin treatment at a young age? Is it possible that the higher rate of differentiation of glial progenitor cells into oligodendrocytes could deplete these important cells. Would kids taking statins from a young age end up with very early dementia because of the depletion of glial progenitor cells which would result in an eventual depletion of oligodendrocytes? I do not know the answer, but with the recent results by Sims et al., if confirmed in vivo we might need to rethink the long term use of statins (possibly including 20 and 30 years olds that start taking these drugs). Of course one needs to balance the danger of cardiovascular disease (CVD) from high cholesterol (and the other various cholesterol measurements) and future dementia.

One potential solution might be using non-drug treatments that lower bad cholesterol and increases good cholesterol (exercise and appropriate nutrition).

Update: I wrote about some new research which suggest that statin use may inhibit myelination, which may be detrimental for your long term brain health.

Update II: Though we have to be cautious about the possible long term effects of statins on brain health - specifically myelin - new research points to postive effects on statins reducing the risk of dying from all causes of death

Update III: Reanalysis of the paper in update II suggest that maybe statins do not decrease mortality rate.

Jul 7
These children, playing in a public space, var...Image via Wikipedia

American Academy of Pediatrics released new guidelines, as reported here, that are suggesting that anti-cholesterol drugs be prescribed for kids as young as 8 year old if they have high levels of LDL (bad cholesterol, see below) and other risky conditions (e.g. obesity, high blood pressure). What do you think of this example of their new guide lines?

A bit of background.

In an earlier overview article I mentioned that cholesterol measurement as an indicator of your health. Within reason low cholesterol (less than 200 mg/dL, though other suggest lower than 150 mg/dL) is better than high cholesterol, but there are some negatives if your cholesterol is too low, though most of us do not have to worry about that situation.

The next level of measurements are looking at high density lipoprotein (HDL: good cholesterol) and low density lipoprotein (LDL: bad cholesterol) components of cholesterol (interestingly, that are further level of assessment, but I will not cover that today). For optimum health you want low LDL (less than 100 mg/dl, others suggest less than 70 mg/dL). On the other hand you want high levels of HDL. More recent research concentrate more on the ratio of total cholesterol/HDL, or LDL/HDL ratio among additional measurements (I will cover these in detail at another time).

But all that aside, does developed countries have something to be concerned about if the medical establishment are taking the dramatic steps of promoting anti-cholesterol drugs for kids?

From the article on the CNN site:

“With one-third of U.S. children overweight and about 17 percent obese, the new recommendations are important, said Dr. Jennifer Li, a Duke University children’s heart specialist.

“We need to do something to stem the tide of childhood obesity,” Li said.”

But what does doing something about the tide of childhood obesity have to do with high cholesterol and high LDL? These blood measurements are the product of the obesity - so why not treat the cause (overeating, obesity) rather than the symptoms? What about increased play (or exercise) and eating healthy food instead of taking more drugs?

What do you think? If you have kids (or imagine if you had kids) would you put them on (under the guidelines of your family doctor) anti-cholesterol drugs if they fall into this category as described in the guidelines - or would you choose lifestyle changes?