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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).

Feb 13

Update I: maybe statins do not decrease mortality

Today, I will briefly discuss two papers that report reduced mortality by either following the Mediterranean diet, or taking statins.

I wrote a piece early this week about how a Mediterranean diet decreases the chances of the elderly developing mild dementia and Alzheimer’s disease (and an earlier post on how dietary restriction improves memory performance in the elderly). Now I will give the summary of a paper that examine the effects of the Mediterranean diet on all causes of mortality.

Mediterranean diet:

Sofi et. al., 2008 (complete paper freely available here) did a meta-analysis of 12 paper that covered over 500,000 people and found that a two point difference (scores ranged from 0 to 7-9) in adherence to the diet was associated with reduced risk of mortality. They also found that those having that more strictly followed the diet had lower risk of mortality from cardiovascular disease, cancer along with reduced incidences of Alzheimer’s and Parkinson’s disease.

Conclusions Greater adherence to a Mediterranean diet is
associated with a significant improvement in health
status, as seen by a significant reduction in overall
mortality (9%), mortality from cardiovascular diseases
(9%), incidence of or mortality from cancer (6%), and
incidence of Parkinson’s disease and Alzheimer’s disease
(13%). These results seem to be clinically relevant for
public health, in particular for encouraging a
Mediterranean-like dietary pattern for primary prevention
of major chronic diseases.

But you might ask yourself the pertient question - what the heck is a two point difference in adherence scale mean?

Adherence to a Mediterranean diet was defined
through scores that estimated the conformity of the
dietary pattern of the studied population with the
traditional Mediterranean dietary pattern. Values of
zero or one were assigned to each dietary component
by using as cut offs the overall sex specific medians
among the study participants. Specifically, people
whose consumption of components considered to be
part of a Mediterranean diet (vegetables, fruits,
legumes, cereals, fish, and a moderate intake of red
wine during meals) was above the median consumption
of the population were assigned a value of one,
whereas a value of zero was given to those with
consumptions below the median. By contrast, people
whose consumption of components presumed not to
form part of a Mediterranean diet (red and processed
meats, dairy products) was above the median consumption
of the population had a value of zero
assigned, and the others had a value of one.

Okay, does that make sense? Are you above or below the median for these categories and who are we comparing ourselves against?


Shalev et. al., 2009 examined over 200,000 patients taking statins that included one group that had coronary heart disease, but a second group that had no indication of cardiovascular disease. Those subjects that had > 90% adherence to taking their statin medication had a 45% reduction in risk of death compared to those with < 10 % adherence. And this result held up for both groups - meaning that taking statins also reduced or risk of dying even if you didn’t have any indications of cardiovascular disease.

A stronger risk reduction was calculated among patients with high baseline low-density lipoprotein cholesterol level and patients initially treated with high-efficacy statins. CONCLUSIONS: Better continuity of statin treatment provided an ongoing reduction in mortality among patients with and without a known history of CHD. The observed benefits from statins were greater than expected from randomized clinical trials.

Like the Mediterranean diet reported meta-analysis the statin results do not come from a randomized clinical trial - however they are both interesting. I haven’t yet acquired the full statin paper but would like to see the further breakdown of the data - are the patients that are less likely to adhere to taking their medication just less interested in their health in general - but maybe the same could be said about those that do not adhere to the Mediterranean diet.

And the futurepunduit sums it up well:

If you have high cholesterol do something to lower it. Take statins if you can’t be bothered to radically change your diet. Or take statins and radically change your diet. Or at least change your diet. On the other hand, if you have a death wish I don’t have any arguments to offer for why to take statins. But maybe if you changed your diet for the better you might feel better and less inclined to die.

But I would wonder if we should diet or consider taking statins even if you don’t have high cholesterol since these two paper suggest they both will lower your risk of dying  - though I would do more research before deciding to take statins - there is still ongoing controversy regarding the long term safety of statin use - see my articles here, and here).

Update: maybe statins do not decrease mortality.

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.