Saúde Cardiovascular

[A_User]

@tananth

It is hard to see mortality benefits from cholesterol lowering over 4 years.

In general it would require a 25x larger study, practically impossible and a waste of money, and non-fatal outcomes like those from stroke and MI are important to most people.

[RapAdmin]

Death rates from cardiovascular disease have fallen dramatically — what...

Drugs to prevent and treat heart disease

One major area of progress has been the development of drugs that can help people manage risks and treat heart conditions when they appear. This includes:

• Statins , which were first used widely in the 1980s, help millions keep their arteries cleaner by lowering LDL (“bad”) cholesterol levels and stabilizing plaque that can clog blood vessels.4 Newer drugs, like PCSK9 inhibitors introduced in 2015, help people lower LDL cholesterol when statins aren’t enough.5
• Blood pressure medications , like beta blockers, ACE inhibitors, ARBs, and diuretics, help keep high blood pressure under control, reducing the risk of strokes, heart attacks, and heart failure.6
• Clot-busting medicines are used to break up blockages and quickly restore blood flow, and dramatically improve survival rates for heart attack and stroke patients.7

[A_User]

As I’ve posted about before, you can see the start of decline in CVD mortality after figuring out the risk factors in 1954 (Framingham Heart Study). Everything is a result of finding the causal factors for disease, at the time all they had was their cohort study, however, but which is relatively good at inferring causation as we can see in examples like this. That’s important to take note of for other areas of medicine.

[RapAdmin]

You have to wonder how long it will be before we see in the data an increase in cardiovascular death with all the influencers now promoting high fat diets / keto / carnivore diets for people.

[BeatTheOdds]

I was one of those people taken in by keto, although it was a scientist, Dom D’Agostino, who persuaded me to try it.

Then, a few years ago, my LDL-C came back at 5.5 mmol/L (213 mg/dL). My triglycerides were sky-high as well. At that time, I was deep into a strict ketogenic diet, getting about seventy percent of my calories from fat. I loved my food, felt great, and was working out six times a week, but I was completely ignorant of any health concerns.

Amazingly, my GP at the time was not too concerned either, so it didn’t ring any alarm bells until I did a genetic test and found out I was APOE 4/4. This caused me to start looking into things more closely, and I decided to stop keto and try to improve my lipids with diet.

By late 2023, my LDL-C had fallen to 4.1 mmol/L (159 mg/dL), and my triglycerides were right down, which I partially credit to three grams a day of EPA and DHA fish oil (I was trying to raise my Omega-3 index). This was still way too high for my comfort, and by this time I was starting to educate myself more and more and trust my GP less (unfortunately).

After I added Brillo EZ while keeping my low-saturated-fat and high-fibre diet in place, by mid 2024 my LDL-C had dropped further to 2.22 mmol/L (86 mg/dL). A huge drop but the science seems to say that as low as possible is probably optimal in my case as my dad had a bad heart attack in his 50s.

Rosuvastatin didn’t agree with me, but 20 mg of atorvastatin has no side effects, and soon after starting, my LDL-C had dropped further to 0.70 mmol/L (27 mg/dL - btw I made a conversion mistake in another thread, so gave a different reading). My triglycerides were elevated, though, which I put down to experimenting with rapamycin at 1 mg every day for a month. I’ll do another test soon to make sure there’s nothing strange going on.

Anyway, I feel a lot better at 27 mg/dL than at 86 mg/dL, despite concerns about the statin potentially affecting brain cholesterol, I take Citicoline to help with this - not positive if it’s working of course or if it’s even a problem. Happy to have found this forum and made those changes via self-medicating from Indian pharmacies! It could save my life.

[A_User]

Glad to hear!

FYI, LDL-C is inaccurate and artificially low with high triglycerides, better to measure apoB – and that might be insulin resistance (diabetes), or a genetic reason, worth investigating with a doctor as they’ll have more information and ways of treating it.

Plug your numbers into apob.app for some ideas.

[DeStrider]

A friend of mine from university died from a heart attack today. He was 51. It just stresses how important all of this is.

[Beth]

Scary times. I just found out a casual friend with whom I had dinner with last month died suddenly from a heart attack.

He went to the restroom at a restaurant and never came out. Early 60s.

[BarryAllen]

Not sure I understand why you use Rapamycin 1mg daily vs interval dosing such as 5 mg once per week ?
Rapamycin acts thru both mTORC1 and mTORC2 depending on dosage and interval.
My sense is that we are trying to down regulate mTORC1 at intervals to increase autophagy and thereby get rid of intracellular garbage etc, but that we don’t want to continuously down regulate mTORC1.
Daily dosage is also more likely to also affect mTORC2 and give immune suppression, which is why it was used daily to prevent organ transplant rejection.

[John_Hemming]

@sallyjane asked for this which is now O5

Here’s a cleaned-up version of the transcript, followed by a summary and a critique.

---

Tidy Transcript

Visceral and Abdominal Obesity
If you lack PCSK9, you are at higher risk of visceral obesity — meaning fat accumulation in your liver, pancreas, and abdomen, and even higher fat deposition in the heart.

Mechanism
PCSK9 removes LDL receptors from the liver and pancreas. These receptors clear lipoproteins from circulation — lipoproteins that carry not just cholesterol but also triglyceride-rich fat. Without PCSK9, these receptors are overexpressed, pulling more fat into the liver and pancreas, causing fatty liver and fatty pancreas.

Genetic Evidence
People born with PCSK9 deficiency — effectively living as though they are taking a PCSK9 inhibitor — have a higher risk of diabetes and visceral obesity compared to the general population.

Trial Data
In the FOURIER trial (~28,000 patients), the PCSK9 inhibitor evolocumab (Repatha) reduced LDL to ~30 mg/dL (very low), compared to ~90–100 mg/dL in controls. Each group had ~14,000 patients. There was no overall mortality reduction; in fact, mortality was slightly higher in the treatment group.

Conclusion
Animal studies show higher diabetes and visceral obesity risk with PCSK9 inhibition. Genetic studies show the same. Large randomized trials show no mortality benefit despite massive LDL lowering. Therefore, the speaker calls PCSK9 inhibition an “abject failure” and criticizes attempts to spin the data as beneficial.

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Summary

The speaker argues that:

1. Mechanistic risk: PCSK9 inhibition increases LDL receptor expression, leading to excess fat uptake by the liver and pancreas, promoting fatty organ development and visceral obesity.
2. Genetic parallels: People with congenital PCSK9 loss-of-function mutations have higher rates of diabetes and visceral obesity.
3. Trial evidence: The FOURIER trial of evolocumab, involving 28,000 patients, achieved extremely low LDL levels but showed no mortality benefit, with a slight increase in deaths in the treatment group.
4. Overall assessment: Across animal models, genetic epidemiology, and large human trials, PCSK9 inhibition does not improve survival and may have metabolic downsides. The drug’s promotion is therefore misleading.

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Critique

Strengths

• The argument is clearly structured: mechanism → genetic evidence → trial outcomes.
• The concern about off-target metabolic effects (fatty liver, diabetes) is biologically plausible.
• The reference to large-scale RCT data (FOURIER) addresses clinical relevance, not just surrogate markers.

Weaknesses / Potential Issues

1. Oversimplified mechanism – The claim that PCSK9 inhibition necessarily leads to fatty liver is controversial; some studies show mixed or neutral effects on hepatic steatosis. The liver’s lipid metabolism is more complex than “more receptors = more fat storage.”
2. Genetic evidence interpretation – Mendelian randomization studies on PCSK9 variants show only a modest increase in diabetes risk, similar to that seen with statins. The absolute effect size may be small.
3. Mortality endpoint context – FOURIER was not powered for all-cause mortality reduction over the trial’s short duration (~2.2 years median follow-up). The primary endpoint was cardiovascular events (MI, stroke), which did show a modest benefit. Calling it an “abject failure” ignores its success on prespecified endpoints.
4. Selective trial citation – The speaker ignores the ODYSSEY Outcomes trial (alirocumab), which did suggest a mortality benefit in post-ACS patients at higher baseline LDL.
5. No discussion of patient subgroups – The blanket dismissal overlooks that PCSK9 inhibitors may benefit certain high-risk populations (e.g., familial hypercholesterolemia) where statins alone are insufficient.

Bottom line:
The critique raises valid caution about overhyping PCSK9 inhibitors and the potential metabolic trade-offs. However, it overstates the negative case by downplaying positive cardiovascular outcomes, ignoring study design limitations, and treating associative genetic evidence as causal proof.

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If you want, I can prepare a claim-by-claim accuracy check with direct links to primary sources for each point in the transcript so we can see which are solid and which are shaky. That would turn this into a much stronger evidence-based review.

[Neo]

Thanks @John_Hemming , can you include the prompt used

[BeatTheOdds]

Hi Barry. I’ve used different dosing regimens so even though I’ve tried higher doses with and without GFJ every two weeks, my usual dose is 6-7mg once a week. I just finish trialling the 1mg once a day for 1 month due to recent small studies that seem to suggest some brain benefits in APOE4 people like myself. One study was posted on this site by I’m pressed for time and can’t seem to find it, but that is the reason why. Now I’m back to 6mg a week.

[John_Hemming]

do a tidy transcript, summary and critique of https://www.youtube.com/watch?v=BJPDPh65clM
Transcript {transcript from google YouTube goes here]

[relaxedmeatball]

@RapAdmin

You have to wonder how long it will be before we see in the data an increase in cardiovascular death with all the influencers now promoting high fat diets / keto / carnivore diets for people.

It’s already happened. Maybe 200 posts ago we talked about it. The new “thing” is heart failure with preserved ejection fraction (HFpEF), which isn’t a ASCVD → MI pathway, but rather heart failure due to metabolic (diabetes) and mechanical (hypertension). It’s already increasing massively.

@BeatTheOdds

despite concerns about the statin potentially affecting brain cholesterol

Personally I reckon this fear is unjustified, mostly pushed by the anti-statin people. Children (normal ones) have pretty low circulating cholesterol’s and their brain is growing at a rapid rate. I’m not aware that anybody has actually shown statins passing the BBB, entering the relevant cells, inhibiting HMGCoA reductase and starving them to death. And people who genetically have very low cholesterols seem to be cognitively normal.

[dicarlo2]

High serum LDL has been associated with lower risk of hemorrhagic stroke. It seems like a strange association though given that LDL doesn’t cross the BBB.

[tananth]

Blood vessels (even in the brain) are outside the BBB and the blood flowing in the brain has the same serum LDL as anywhere else in the body. Humans evolved rising serum LDL (with age) to improve rapid wound healing (which requires massive amounts of LDL), since our ancestors were more likely to die of wounds from hunting accidents than heart disease. Hemorrhagic stroke presumably involves an injury of the blood vessels in the brain, with high blood pressure as the primary cause, and high LDL might allow small injuries to heal fast enough that no major leakage occurs. However if you treat high blood pressure there should be little benefit from high serum LDL : there are still other sources of injury to blood vessels, eg high transient sodium or glucose levels after salty/sweat meals, but they should be minor compared to the risk from high blood pressure.

[A_User]

@tananth

Blood vessels (even in the brain) are outside the BBB and the blood flowing in the brain has the same serum LDL as anywhere else in the body

It is called the blood-brain barrier after all.

I forgot about this.

Basically, when you’re laying down plaque in arteries across the body it’s equally embedded in the brain. So when people want to “deliver LDL” that can’t even cross into the brain, all they’re doing is laying down plaque in the blood brain vessels for a delivery that never arrived.

[Beth]

HI Everyone!

I’d love it if we can make a quick list of all the things to do if one finds out through a CTA that they have a large soft plaque burden…

My good friend, who had a 0 CAC a few years ago, just received a disappointing CTA result. She eats a great diet and does a ton of cardio.

What do you recommend other than the medicines that I’m encouraging her to start (her doc is suggesting a statin but she would instead like to just clean up her diet even more. I’m telling her that she should start the stain and possibly add ezetimibe, too). If those don’t do enough, which I’m sure they will, I know to then consider bempodoic acid or repatha)

She is on hrt now, including low dose Testosterone
I’ve told her to have a decent amount of vit k with her calcium, but I’ll reinforce that.

Anything else?

It’s fuzzy to me, but do I remember reading that if you stop making new plaque by getting your apob low enough that, in aprox 5 years, it could mostly or all go away?

Any opinions are appreciated.

[Bicep]

I think the no brainer supps for soft plaque are Gotu Kola and French Maritime Bark Extract. There was something about 25mg Melatonin nightly. I now use Neprinol, which is a very strong Nattokinase, Serrapeptase blend with AMLA and other stuff. Alpha Cyclodextrin, beta if you can stand it.

Only have to live another few years and we’ll get the cyclarity:

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