Simvastatin and the ApoE4 Allele

[JimBG]

This is probably old news for many but I thought this article in Circulation was quite interesting. it's conclusion was:

" —Myocardial infarction survivors with the e 4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin."

http://circ.ahajournals.org/content/cir ... 6.full.pdf

Don't know if there have been any follow-up studies, but this is probably why Craig Venter started taking SV when he learned he was a 3/4.

[Fiver]

Thanks for sharing. I know there is much debate about the statins and AD. But this type of study and a few others showing statin use is associated with a delay in onset of AD was convincing to me. I also think that if statins really led to AD we'd be seeing a big spike in cases, given the popularity of statins. Just my thinking. Could be wrong. Nice to think the ticker will keep ticking too. So I'm with Venter on this one.

[Julie G]

Here's a really thoughtful paper examining the pros and cons of statins with regards to cognition. IMHO, we need more unbiased work like this. It's a free access paper.

The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830056/

Abstract
Nearly 30% of adults 40 years and older in the United States are on a statin. Their widespread use heightens the importance of careful consideration of their varied effects on the body. Although randomized controlled trials have not confirmed cognitive impairing effects with statins, continuing evidence suggests statins have the ability to cause reversible cognitive impairment in some patients. Paradoxically, statins have also been shown to decrease the risk of dementia, Alzheimer’s disease, and improve cognitive impairment in some cases. However, randomized controlled trials have similarly failed to find the beneficial effect. Supporting evidence for both claims is compelling whereas known limitations of the clinical trials may explain the lack of findings. This narrative review aims to explain why there is still controversy and how both effects can, and may, be possible. The mechanisms that have been hypothesized for each effect are seemingly independent from one another and may explain the contradicting results. Being mindful of the complex effects of statins, health care providers need to be able to identify patients who are at risk for or already experiencing cognitive impairment from statin use while also identifying those who could potentially decrease their risk of dementia with statins.

[Verax]

Over 32 million people in the United States (10% of Americans) are currently on a statin with an estimated 56 million people (24% of Americans) eligible to consider a statin. Fourty-1 % of patients on statins are 75 years and older, 42 % are between 65 and 74 years, and 17 % are between 45 and 64 years [5]. The widespread use of statins heightens the importance of careful consideration of their effects on the body.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830056/ (Background section)

More recent studies have suggested that only ~50% of patients who receive a prescription for a lipid-lowering drug continue to take the medication 6 months later.[10] This proportion falls to ~40% after 12 months[11] and to ~15%-30% after 5 years.[12]

https://www.medscape.org/viewarticle/496144_3 "The Forgotten Cardiac Risk Factor: Noncompliance With Lipid-Lowering Therapy: Why We Should Strive to Improve Compliance".

It's not clear to me from the first quote that they take noncompliance into account. Drug manufacturers have persuaded physicians to prescribe immensely profitable drugs and patients to buy for a bit but "widespread prescribing" does not necessarily translate into "widespread use." The second paper goes into this a bit.

Added together, it puzzles me that statins could have much of an effect to prevent AD when incidence of AD increases in spite of such widespread practices. For example, 41% of users are >75, but the first paper observes the major effect would likely be from midlife use with hyperlipidemia. But "more study is needed"--hope it includes the E3/E4 phenotype.

I'll do what my doc orders and she put me on pravastatin for primary prevention 3 months ago after years on atorvastatin and will likely switch me to rosuvastatin to try to raise HDL. Thanks, Julie, for this very useful paper, it makes me consider CoQ10; I see that it is part of the Bredesen protocol.

[Fiver]

Thanks Julie. More reading.

That's A LOT of people prescribed a statin!

Hi Verax. I was curious to know if the low compliance was specific to statins. I went right to the source (Wikipedia, wink) and, at first look, it seems compliance is about equally poor with other drugs. See: https://en.wikipedia.org/wiki/Adherence_(medicine) In short, compliance is a problem across the board.

Regarding effectiveness and compliance: as drugs go, statins seem to work surprisingly well even when taken less than prescribed. Alternating days seems to provide about 75% of the benefit of daily use, for example. And the newer statins are more powerful, so that rouvastatin taken occasionally might be as effective as strict use of an earlier statin. Not saying it is recommended, but here it might protect the studies experimental design, so that the data are less likely to be skewed by over-reporting of compliance.

Here are two studies I thought were interesting and useful, especially the first. Both show at least some benefit to statin use, but again there are other studies and other viewpoints.

Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316146/
Figure 4 might be my favorite figure of all

Cholesterol, Statins, and Dementia: What the Cardiologist Should Know
https://onlinelibrary.wiley.com/doi/ful ... ZAQY.email
Figure 1 was very interesting

[Verax]

Thanks, Fiver, yes, what you write is reassuring. My doc said she would write "Rx as directed" so I could buy a bunch and then split them, as they are Tier 2 and a co-pay.

[JimBG]

Thanks to all for the references. This is certainly a complicated topic with much to digest. I found the "What the Cardiologist Should" piece particularly interesting arguing that statins could help prevent AD if introduced early enough but are ineffective in treating it. Also that the evidence to prevent ASCVD is much stronger. I know though that some challenge that saying the absolute risk reduction is "miniscule" (1-2%) in large studies like JUPITER, and the public is misled when relative risk reductions of 33% or more are quoted; and that there are other side effects/risks which are not factored in. That said it seems hard for me to believe that all these researchers, doctors and medical associations in the US, Europe and across the world are all wrong in recommending statins for prevention and treatment of ASCVD.

[cwicker]

I think the research is pretty robust as to the cardiovascular benefits of statins. But, these are population studies and we don't know what individuals do benefit. The ASCVD calculator helps, but I don't feel it is robust enough. I think looking at genetics to determine such things, like the APOE allele is useful. My healthy brother (APOE3/4), who died from a cardiac arrest, could have benefited from a statin. But, if he's like me, the side-effects from muscle aches, are intolerable (17xs increased risk of myopathy according to Prometheus) and I've tried multiple kinds with CoQ10.

[Fiver]

I think the research is pretty robust as to the cardiovascular benefits of statins. But, these are population studies and we don't know what individuals do benefit. The ASCVD calculator helps, but I don't feel it is robust enough. I think looking at genetics to determine such things, like the APOE allele is useful.

Hi. I had the same question. I was happy to see E4s analyzed as a separate population in these studies. Since they are meta-analyses/review they have larger overall populations and enough E4s to make conclusions the individual studies could not (not enough E4s in each individual study to have statistical power). Nice that they concluded that the beneficial effect was actually stronger for E4s. I guess that's not surprising that a statin would help E4s more, given the elevated risk of CVD. I know statins for AD is debatable. I decided that the benefits outweigh the side effects for those at mid-life and hope I wont be wrong! I have family members who had heart attacks in their early 40s, which really got my attention.

[cwicker]

For me, I think the benefits outweigh the risks too. But, I just can't tolerate the muscle pain. I do get some benefit with micro doses. I take 5 mg Atorvastatin twice a week but need to take about every 4th week off as the muscle pain becomes intolerable enough that I am reluctant to exercise. But, I think those side-effects are genetically determined.