2020 Deep Dive into Statins with Roberta Brinton et al

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circular
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2020 Deep Dive into Statins with Roberta Brinton et al

Post by circular »

Sadly, this paper doesn't mention ApoE4, despite that Roberta Brinton has done work on our genotype before. Most likely that's because the data used in this retrospective study didn't include that information. Nevertheless, since the question of whether to take a statin, and if so what kind, comes up often, this seems like an important work to include here.

It appears to rely on the same large dataset used in the this paper Susan posted last July wherein Roberta Brinton et al report encouraging findings that HR in women helps forestall neurodegenerative diseases.

Statin therapy and risk of Alzheimer's and age-related neurodegenerative diseases (2020, retrospective cohort study, n=288,515 participants among US Humana claims, potential COI, some will recognize one of the authors: Roberta Brinton)
Results

Exposure to statins was associated with a lower incidence of Alzheimer's disease (1.10% vs 2.37%; relative risk [RR], 0.4643; 95% confidence interval [CI], 0.44-0.49; P < .001), dementia 3.03% vs 5.39%; RR, 0.56; 95% CI, 0.54-0.58; P < .001), multiple sclerosis (0.08% vs 0.15%; RR, 0.52; 95% CI, 0.41-0.66; P < .001), Parkinson's disease (0.48% vs 0.92%; RR, 0.53; 95% CI, 0.48-0.58; P < .001), and amyotrophic lateral sclerosis (0.02% vs 0.05%; RR, 0.46; 95% CI, 0.30-0.69; P < .001). All NDD incidence for all statins, except for fluvastatin (RR, 0.91; 95% CI, 0.65-1.30; P = 0.71), was reduced with variances in individual risk profiles. Pathway analysis indicated unique and common profiles associated with risk reduction efficacy.

HIGHLIGHTS
∙ Statins are associated with decreased incidence of Alzheimer’s disease, dementia, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.
∙ Each statin lowered the incidence of neurodegenerative diseases (NDD) with the exception of fluvastatin.
∙ Pitavastatin and atorvastatin exerted greatest reduction of NDDdiagnosis.
∙ Unique and common pathways of statins were associated with risk reduction profile.
∙ Unique statin targets could advance a precision medicine approach

[Emphasis added]
I'm not (yet?) educated on interpreting the statistics, so I welcome feedback on that and anything else.

As always, it's good to review the section about the limitations of the study:
As this study is a retrospective analysis of a claims database, there are several limitations. Importantly, patients included may have obtained services beyond those included in this dataset, such as lifestyle modifications, which are recommended as first-line treatment in addition to the cholesterol-lowering therapies.18 This study used a claims dataset, which relies on the physician’s diagnosis and the ICD code assigned to each patient presentation. Because the diagnosis is clinical, there may be overlap between AD and dementia codes given similar presen- tations despite different underlying pathophysiologies. Furthermore, there could be biases in the prescribing trends for statins that cannot be controlled in the model. Additionally, two statins (pitavastatin and fluvastatin) had fewer than 1000 claims; and select patient demographics (eg, socioeconomic status) are not commonly included in insurance claims and thus were not assessed. Finally, there could be factors, known and unknown, that may not be adequately addressed in this analysis despite propensity-score matching.
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SusanJ
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

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circular wrote:I'm not (yet?) educated on interpreting the statistics, so I welcome feedback on that and anything else.
Very interesting paper. I'm certainly not an expert in statistics, but what I found interesting was their protein/gene pathway analysis for statins in which 4 clusters emerged based on mechanisms of action.
To better understand the differences in the risk reduction efficacy profile for each statin, we used a systems biology approach to identify protein/gene pathways associated with each statin therapy (Figure 4). This analysis determined common versus unique biological mechanisms of action for each statin therapy...

Pathway analysis using GO‐BP enrichment identified unique and common gene networks for each cluster (Figure 4B). For the purposes of this report, we focused on neurological pathways. Pitavastatin and rosuvastatin, the first cluster, included angiogenesis, cellular response to oxidative stress, cellular response to amyloid beta, and regulation of action potential. Fluvastatin and pravastatin, the second cluster, included positive regulation of retinoic acid receptor signaling as a relevant neurological pathway. Lovastatin and simvastatin, the third cluster, involved negative regulation of lipid storage, long‐term synaptic potentiation, cellular response to L‐glutamine, and auditory receptor cell fate commitment pathways. Last, atorvastatin, the fourth cluster, comprised response to estradiol, positive regulation of tau‐protein kinase activity, cellular response to thyroglobulin triiodothyronine, regulation of vitamin D receptor signaling, aging, hippocampus development, and embryonic hemopoiesis.

The common GO‐BP pathways for the four clusters are mainly involved in metabolic processes, such as fatty acid biosynthetic process and cellular response to glucose starvation (Figure 4B). Additionally, those statins that target ITGAL (first and third clusters) are involved in immunological pathways as regulation of immune response, inflammatory response, and antigen processing of exogenous peptide antigen via major histocompatibility complex class I (Figure S1 in supporting information). Statins that target HDAC2 gene (second, third, and fourth clusters) share pathways including Notch signaling; oligodendrocyte differentiation; positive regulation of gluconeogenesis; cellular response to hydrogen peroxide; transforming growth factor beta receptor signaling; and neurological pathways including layer formation in cerebral cortex, neuron maturation, neuron apoptotic process, cerebral cortex neuron differentiation, and smoothened signaling pathway involved in spinal cord motor neuron cell fate specification (Figure S1).
It's fascinating that the statins have potential impact on more than just inflammation, as has been touted in the past. Actions like cell response to oxidative stress and amyloid beta, or regulation of lipid storage and tau-protein kinase activity, and that all statins are involved in fatty acid biosynthesis and response to glucose starvation responses seems important with regard to brain health.

I've been reluctant to take statins for all the reasons we've discussed on this forum, but everything I've done to improve my health has not brought my lipid numbers down, even though my doctor thought it should. I've constantly struggled with a high-fat diet (low in saturated) increasing my lipid numbers, while a moderate-fat diet brings lipids back down, but whacks my A1c. And with a family history of heart attacks, diabetes, not to mention the results of my last heart scan, well, maybe I'll have a long talk with my doctor about this paper.

Thanks for posting!
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

Post by NewRon »

I've also struggled with lipids.

I'm not able to decipher the technical language, would anybody be able to simply describe the relative advantages/disadvantages of each of the four clusters of statins?
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

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NewRon wrote:...would anybody be able to simply describe the relative advantages/disadvantages of each of the four clusters of statins?
I don't know if it's that simple, but if we look at it through the lens of precision medicine, this research might suggest that certain statins work better for us based on our specific genetics and challenges.

So for example, pitavastatin and rosuvastatin, the first cluster, might help if your lab results suggest high oxidative stress (suggested by myeloperoxidase or lipid peroxidation tests), or imaging suggests amyloid beta accumulation.

Fluvastatin and pravastatin, the second cluster, might help boost retinoic acid receptor signaling (impacted by beta-carotene to Vitamin A conversion among other things), which is related to many diseases including cancer, fat deposition and insulin resistance.

I think we need to remember that just because they might be related to a pathway, it's all speculation until more research shows exactly how they impact each of these pathways in adults. And I'd love to see if ApoE4 status has any added impacts.

But generally, Brinton et al are seeing the signals that statins, overall, can decrease one's risk of NDDs. Many here depend on diet, exercise, supplements, etc to target these same pathways. For me, that might not be enough, and hence my plan to discuss if putting low-dose statin therapy in my arsenal makes sense.
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

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SusanJ wrote: Thanks for posting!
You're welcome! I'm so glad you found it helpful and also interesting as I did.

Maybe we just need a little statin cocktail pill that uses some from each cluster :D I agree, all this needs further work, but I'm bringing this paper to my doctor as well.

There's also the question of statin relevancy to people like me who have normal lipids but high CRP or hsCRP, especially in the context of ApoE4.

Elsewhere I posted Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers which shows that CRP > 8 in people with ApoE4 is associated with AD. Since my hsCRP has always been elevated, I had my CRP tested. It came back normal. Then I found Cumulative Exposure to High‐Sensitivity C‐Reactive Protein Predicts the Risk of Cardiovascular Disease, and of course we know that vascular disease is incahoots with other pathologies involved in AD. So while my CRP isn't yet elevated, and my doctor appeared to think that meant I don't need a statin in the context of ApoE4 and CRP, I now need to go back to her with two papers suggesting that maybe I still need to consider a statin. First I need to really focus in on the details before I take up more of her time with it.

Another important thing to mention is there are genetic variants that raise the risk of statin myopathy. Several showed up for me in Rhonda Patrick's Cholesterol report:
SLCO1B1
Increased Risk For Myopathy With Statin Use
Noteworthy
SNPs Involved
rs4363657(C;T)

This genotype, rs4363657(C;T), has been associated with a 4.5-fold increased risk for developing myopathy from statin use according to a genome-wide association study involving 12,000 participants who were taking 80 mg of simvastatin (a type of statin) and 20,000 participants taking 40 mg of simvastatin daily.

Statin-related myopathy following administration of simvastatin or atorvastatin appears to be dose-dependent. Increased risk of myopathy has not been observed with osuvastatin, however.

Bilirubin is a byproduct of the normal breakdown process of red blood cells. Abnormal bilirubin levels are associated with altered cardiovascular disease risk and drug metabolism. Variants of the rs4363657 SNP on SLCO1B1 may influence bilirubin levels.
SLCO1B1
Increased Risk For Myopathy With Statin Use
Noteworthy
SNPs Involved
rs4149056(C;T)

This genotype, rs4149056(C;T), has been associated in a study of more than 500 men and women taking atorvastatin, simvastatin, or pravastatin with a greater likelihood of experiencing muscle-related drug complications.
COQ2
Increased Risk For Myopathy With Statin Use
Noteworthy
SNPs Involved
rs4693596(C;C)

This genotype, rs4693596(C;C), has been associated twice the risk of developing statin-related myopathy in a study of nearly 300 people of European ancestry who were taking statins…

Blood levels of CoQ10 can drop by more than half with statin treatment, and some research suggests that in the setting of CoQ10 deficiency, a concurrent ATP deficiency might induce painful myopathy. In addition, a decrease in CoQ10 levels tends to be accompanied by a higher lactate to pyruvate ratio in the blood, which is commonly seen in myopathy – an indication that the mitochondrial respiratory system is not functioning properly.

Some research suggests that taking CoQ10 supplements may reduce symptoms of myopathy; however, larger randomized controlled trials need to be done to establish definitive conclusions…

An analysis of 5 randomized controlled studies involving more than 250 people taking CoQ10 supplementation for symptoms of statin-induced myopathy concluded that most of the participants experienced some reduction in their myopathy symptoms; however, the findings were not statistically significant.
So obtaining a baseline bilrubin and CoQ10 level and following these could be particularly important—perhaps even if not experiencing myopathy and while taking CoQ10 supplements—since they may reflect changes in mitochondrial health among people with such variants who take statins.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

Post by NewRon »

Ok, thanks! More research needed, so.

Ws there something a while back about lipophilic or hydrophilic statins?
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

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circular wrote:Another important thing to mention is there are genetic variants that raise the risk of statin myopathy.
For once, I seem to have hit the genetic lottery, but getting a baseline bilirubin and CoQ10 would be smart no matter what.
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

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SusanJ wrote: For once, I seem to have hit the genetic lottery…
Yea!
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

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NewRon wrote:Ok, thanks! More research needed, so.

Ws there something a while back about lipophilic or hydrophilic statins?
As I understand it, it's been thought that if one decides to take a statin, it would be better to take a hydrophilic one. Cholesterol is so important in the brain that it makes its own. The lipophilic statins can cross the blood-brain barrier and then lower cholesterol levels in the brain. Interestingly, this paper suggests ways that either kind of statin may be beneficial, but I would think it's still important to consider the fact that while lipophilic statins may boost some beneficial pathways, they may also lower cholesterol in brain. And, at the same time, how do we know there aren't some individuals whose brain is making too much cholesterol? There's still a lot we don't know, but this paper brings a lot to the table for consideration [she says not having carefully read or understood it! :lol: ].
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: 2020 Deep Dive into Statins with Roberta Brinton et al

Post by NewRon »

Thanks so much.... I must research hydrophilic statins now!
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