#282

Niacin in large doses increases the risk of diabetes. Pantethine should work well, I’m currently testing it (With Ezetimibe + low dose Rosuvastatin EOD)

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#283

Good point. I’ve just looked at things which help this: sauna, zinc, magnesium, vit c &e. Is there anything else?

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#284

Vitamin E is not recommended as a supplement due to a link to cancer. The others should be fine or at least harmless.

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#285

It would be better with atorvastatin 10 mg, as compared to rosuvastatin 5 mg in RCT it has lower diabetes risk and cataract surgery:

The rosuvastatin group had a higher incidence of new onset diabetes mellitus requiring initiation of antidiabetics (7.2% v 5.3%; hazard ratio 1.39, 95% confidence interval 1.03 to 1.87; P=0.03) and cataract surgery (2.5% v 1.5%; 1.66, 1.07 to 2.58; P=0.02). Other safety endpoints did not differ between the two groups.

Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial 2023

Atorvastatin is also a very popular drug on google trends, and it increased in popularity at the same time it became generic:

BCP-85-1614-g001
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Statins popularity: A global picture 2019

I am quite certain there is no difference between statins based on lipophilic vs. hydrophilic status, they all cross the BBB according to Thomas Dayspring and it was really a marketing term and there is probably no clinically relevant difference in hepatoselectivity etc, with same side effects, only useful in as far different metabolism for drug-drug interactions maybe or RCT evidence. I did say earlier there was a difference, but it was regarding more vs. less hepatoselectivity. I have seen a recent study showing all statins cross the brain barrier confirming what he said, but I can’t find it. I think it was a review on statins and dementia or alzh.

Based on secondary outcomes in RCT’s, statins have either a neutral or positive effect on dementia including vascular dementia and no difference between hydrophilic/lipophilic statins according to Peter Attia based on clinical trials he reviewed in a recent premium article on statins I think.

There is speculation based on association studies long ago on serum desmosterol being associated with AD and mild cognitive impairment. Serum desmosterol is highly correlated with spinal fluid desmosterol. It is a marker of synthesis of cholesterol.

All statins cross the BBB and decrease synthesis of cholesterol. However, most cholesterol is already made in childhood and there is little synthesis in adulthood. Serum LDL etc does not enter the brain: https://twitter.com/Drlipid/status/1755985081900900367

So if anything if I can speculate since we are speculating based on association studies, those who genetically have a tendency to overproduce cholesterol (LDL, apoB?) might’ve already made a lot of brain cholesterol during the stages of life where a lot is produced, with the long half-life of 5 years. Suppressing synthesis a bit might have less of an effect if so.

I don’t either know how it affects all cause dementia in apoE4 carriers, and not many studies stratify on apoE4 status. Either way what we know with most likelihood is that statins have a neutral or positive effect on all dementia based on secondary outcomes. And then you can ride the speculation train either direction. One option is to not take statins and focus on drugs that do not apparently cross the BBB like PCSK9i, and those that don’t for sure like ezetimibe, bempedoic acid. PCSK9i, Bempedoic acid and Ezetimibe, would be most warranted if serum desmosterol decreases as it’s based on this hypothesis.

At the moment I would probably say that PCSK9 inhibitors, Bempedoic Acid and Ezetimibe is better. But that statins are pretty good as well. They all lower apoB which is most important. If money doesn’t make a difference, I don’t know if statins would be preferred to be used. It could be argued for, based on apoE4 status / family history of dementia, serum desmosterol levels, because of the amount of data that exists for them and maybe they make a different in the brain if someone is overproducing cholesterol there (vascular dementia?) (depression?) (inflammation?).

Edit: But it could be worthwhile anyway to use rosuvastatin… different metabolism allows for use with grapefruit juice, it is more potent, maybe the hydrophilic nature of it make some difference.

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#286

I believe you are overthinking the finer details.

#287

Of course, it’s optimizing on the margin, lowering apoB is the goal.

“Never forget apoB is the goal not sterol levels per se. …”
https://twitter.com/Drlipid/status/1524919043727163396

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#288

As I said before, these studies tend not to include the second most common and fastest-growing neurodegenerative disease: Parkinson’s disease (and related Parkinson’s dementia). I emailed Brad Stanfield about that, suggesting a video “Statins and PD” similar to his recent one about dementia, he quickly answered: “Thanks Antoine for the support and video suggestion” :man_shrugging: .

Also: how are these trials designed? Let’s look at this 2008 trial of rosuvastatin:

Exclusion criteria were […] or another medical condition that might compromise safety or the successful completion of the study.

Such an exclusion criterion is not surprising. But would MCI or PD be considered such a condition? A few months or years is rarely enough to see a negative cognitive impact of a drug, with the exception of populations at risk such as people with MCI. Then:

All potentially eligible subjects underwent a 4-week run-in phase during which they received placebo. The purpose of this phase was to identify a group of willing and eligible participants who demonstrated good compliance (defined as the taking of more than 80% of all study tablets) during that interval. Only subjects who successfully completed the run-in phase were enrolled.

So basically, the trial was run only among statin-tolerant people. Are all statin trials designed like this? Per this source, “50% of patients prescribed a statin will cease therapy within the next 18 months”. Do statin RCTs also show a high non-adherence rate at 18 months? If not, then the population of these trials might be different, or they might exclude non-tolerant people as above. Also: how do they account for non-adherence in these trials? Could it be that statins have a negative impact on cognition only on some statin-intolerant people and that these people are somehow excluded from these trials or that they tend to quickly abandon statins after starting them?

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#289

No, it was to select those who would be compliant, they only gave placebo.

I don’t think so. I think it’s a few percentage points difference.

Treatment compliance
Of the eight trials that reported treatment compliance there was no difference between the two groups (Analysis 4.1). In the statin group 77% participants and 70% in the placebo group complied with treatment; RR 1.08 (0.98 to 1.18).

I haven’t read this study but I think it’s likely to be true:

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#290

By the way, I like Dr. Lipid as well, last month he shared this recent paper: https://twitter.com/Drlipid/status/1745458968603037884

The paper, Alzheimer’s disease risk reduction in clinical practice: a priority in the emerging field of preventive neurology, is well worth a read. On statins, it concludes: “Although high LDL-C has been linked to increased AD risk and statin use has been linked to decreased AD risk, without large prospective studies, the target lipid level for optimal AD risk reduction remains unknown.”

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#291

Damned, I’m really tired this morning… Thanks for catching this, so my concerns are unfounded on statin tolerance and treatment adherence. The only potential issue is exclusion of those most at risk but it’s OK I think.

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#292

I wonder how compliant people are for drugs in general. I think I have heard something similar for drugs treating blood pressure. And why that is the case.

edit: It happens. It depends on your prior, I think the large studies are well run so I assume they are not extremely flawed. :wink: But JUPITER has some criticism I took up somewhere else…

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#293

I also think the studies are well RUN, but I know (from friends in pharma) that they are designed to show a positive effect and that exclusion criteria and the choice of recruitment centers are the best way to improve your odds of success.

(and on drug compliance: yes. we discovered that our grandma was prescribed antihypertensive drugs a few months ago but never took them because she didn’t want to bother…)

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#294

I don’t believe in any one study, but if all points in one direction along with MR evidence etc makes me believe stronger.

Yeah I have a family member that got a gazillion strokes and basically got resurrected multiple times in the hospitals and barely takes their medication.

I would guess people don’t really believe in them, they don’t know what evidence is behind the drugs, nor what expected benefit they will get.

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#295

“it is estimated that adherence to chronic medications is about 50%” (Medication Adherence: The Elephant in the Room 2018)

Even lower for cardiovascular drugs: Adherence to cardiovascular medication: a review of systematic reviews 2019

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#296

sun exposure / vitamin D ?

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#297

Thought might be of interest:
Might EXCESS suppression of brain cholesterol synthesis by statins affect cognition? This Mendelian Study in JACC sort of supports that. In at risk pts, ? monitor desmosterol (a synthesis biomarker that associates with MCI) See https://www.sciencedirect.com/science/article/pii/S0735109722053086?via%3Dihub
And
https://www.jlr.org/article/S0022-2275(20)41373-2/fulltext

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#298

It’s always good to hear new benefits things I’m doing already! Go vit D3

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#299

Certainly, the manner in which pharmaceutical-sponsored studies are conducted is likely the most crucial aspect to consider. Additionally, it’s worth noting that raw data from these studies is typically inaccessible and closely guarded. We often only have access to processed data, and independent researchers seldom have the opportunity to validate the raw data. This lack of transparency is deeply concerning. While I don’t subscribe to conspiracy theories and wouldn’t assert that all drugs are ineffective or harmful, there is ample evidence suggesting the need for scrutiny.

If I had a genetic predisposition to any form of dementia or diabetes, I would definitely explore options other than statins for lowering apoB.

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#300

Bempedoic acid is not widely available unless you want to travel for it.
PCSK9 inhibitors cost $200/month which if you take it for 10 years would expected to compound to over $100 k 30 years in an index fund, with that money you can probably prevent Alzheimer’s in 30 years. I don’t think the expected benefit is worth $100k. I have lots of things I can optimize, why would I spend $100k on this specifically? Statins efficacy on LDL is partly explained by reducing synthesis, it is mostly by upregulating LDL receptors…
Ezetimibe is weak unless you are a hyperabsorber iirc.
Supplements are weak and there is not safety or mechanistic data to even come close to answer whether they are better.

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#301

You’re right but this is true for all studies. Not only those about drugs. Drugs are actually subject to way more scrutiny than supplements and non pharmaceutical interventions like diet and exercise (toxicology, drug interactions, RCTs, pharmacovigilance, longitudinal studies, etc.) Good luck getting data from whatever Iranian trial n=40 showing that berberine helps for this or that.

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