What is the current state of understanding on high cholesterol as a leading or trailing indicator of poor health? I vaguely remember reading one theory that cholesterol was used by the body to mitigate arterial damage from other causes?
the literature is very clear about the relationship between high LDL and Atherosclerosis. Are you referring to poor health in general, separate from Cardiovascular Disease?
We've been testing for cholesterol for a long time now and have had other meds to lower it. It should be possible to see if lowering cholesterol via medication results in improved life expectancy or reducing cardiac events. I would think this study has been done a few times already. As someone who does not have much medical knowledge, I'm not even sure how to look this up or be able to assess what I see if I did.
It turns out LDL has different subfractions based on size. Normally, the liver produces large ones which shuttle fat around the bloodstream, lose their payload and shrink then the liver reabsorbs them and the cycle continues.
The problem appears to begin when these LDL molecules hang around for too long. They are damaged by external factors in the bloodstream (eg. glycation due to high blood glucose, oxidation due to fragile polyunsaturated fats) and not recognized anymore for recycling. That's when they can start forming macrophages.
tl;dr LDL by itself is an incorrect measure of cardiovascular risk. Big pharma still profits by selling everyone LDL reducing drugs.
I have heard this too, and that cholesterol measurements are flawed because they don't account for particle size. That you can actually have better 'numbers' but worse results, if you reduce particulate size but also overall volume. It's frustrating that the science behind cholesterol is constantly in wild flux, but at any discrete moment you're expected to accept whatever the momentary consensus is.
Interestingly, my dentist, who also has a bit of a fixation on cholesterol on a personal level and is educated on the matter, has said that a heart calcium scan is the best way to determine what someone's target cholesterol number should actually be, and that it should not be the same from person to person.
This was after I voiced my frustration to him at having made lifestyle changes to get my cholesterol down in order to avoid getting put on statins (not wanting yet another daily drug if I can avoid it), getting the my number below the target of 110, only to shortly after that find out that they'd lowered it to 70. I talked to my endocrinologist about it, and she basically said "yeah, those numbers are more-or-less unachievable. But we want to be extra careful for type 1 diabetics, so we hold them to a higher standard. Either way, everyone gets put on statins at some point anyway, so who cares?"
I'm absolutely allergic to "everyone goes on x medication, so stop whining and go on x medication" as a medical argument, and will probably just deal with being labelled non-compliant over this one unless my cholesterol reaches a level I actually personally find to be too high at this point. Which sucks to have to do, but hey, it's my body after all, and so far doctors have failed to make a convincing case for me personally here.
The brain is the most cholesterol-rich organ in the body. While accounting for only 2% of body weight, it contains roughly 20% of the body's cholesterol. It is essential for nerve cell communication, learning, and memory.
cholesterol is one of the most crucial molecules for survival. It's used to create and maintain cell membranes, and other critical functions. The vast majority is created by the liver, and there are a lot of regulating signals for how much, which is where usually things go off. Low cholesterol production is an extremely serious condition. The "only" problem with high cholesterol is that it builds up inside artery walls, which eventually may or may not dislodge and may or may not cause a heart attack or an embolic stroke. (I'm not a doctor. I just get medication for high cholesterol and have done some research)
> Low cholesterol production is an extremely serious condition.
This is correct, but not in the way you mean it. We know people can effectively produce no LDL cholesterol in their liver and have positive health impacts - these MR studies are a big part of what drove this entire class of cholesterol medications. And the monoclonal antibody versions of PCSK9 inhibitors have shown basically the same results.
Virtually all human cells can produce cholesterol locally de novo, including your brain.
“Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein” [1].
Not really a new kind of pharmaceutical, pcsk9 inhibitors have been on the market for a while now. What’s new is that it’s an oral medication rather than an injectable
Hmmm, maybe but I wouldn’t expect a sea change myself. The reason insurance is able to get away with not covering pcsk9 inhibitors is because statins in theory provide a similar benefit for a fraction of the price, and so they can gatekeep access by requiring patients to take statins first before providing prior authorization.
Now, structurally Repatha is straight up more expensive to manufacture and deliver to patients than a peptide like enlicitide, as the former is a biologic. And if a competitor decides to manufacture a biosimilar when Repatha comes off patent in 2030 that could also help cut the price of drugs in this category. But there’s really nothing cheaper than statins, so I would expect insurance agencies to continue to withhold prior authorization.
Not to mention the gene-therapy version of the same PCSK9 inhibition pathway called VERVE-102 which Eli Lilly is putting through human trials as we speak.
I imagine that stacking the LP(a) antisense therapy with a PCSK9 inhibitor, and/or a statin or Nexlizet would probably lower odds of heart disease death by two to three orders of magnitude. But I guess there isn't solid mortality data to say for sure.
It works via the same mechanism as an incredible drug called Repatha (generic name evolocumab), but Repatha is quite expensive, requires refrigeration, and must be injected subcutaneously every two weeks. The news here is that this is administered orally.
Many people have high cholesterol due to genetics. In these cases even if you ate a 100% perfect diet it would only impact 25% of your cholesterol levels - which any physician would not be satisfied with.
Eating healthy is a sub-optimal solution. Typically we see the most significant results with lifestyle changes + medical interventions and pharmaceuticals - more than either alone.
There's a strange belief, I believe most born out of morality, that medicine undermines discipline or healthy lifestyle. But it does not, they work in tandem, each making the other stronger.
It is true that taking medication is "easy" - not that easy, though. But easy != evil or immortal. If it's so easy, that's a good thing. It means we can stack it on top of lifestyle changes for very little marginal cost. If you're already working out and eating good, that's great. Go to your cardiologist and see if you're a candidate for statins or hypertension medication.
You wouldn't tell someone with diabetes or asthma to just live healthier and avoid their medication. There's nothing wrong with taking a pill, we're not cavemen living off the land.
Lose weight, yes.
Exercise, yes.
Accept a potentially fatal genetic defect when an option is available? No.
Advise not callously generalizing your opinion on things like this. It's clear that you either spoke without knowing more, which happens, or you really don't seem to care to know more. I hope you're not in the latter.
eat healthy as in: only once a day and only six days a week. only water for drinking and only fresh stuff to eat, no meat, no eggs, nothing cooked, nothing baked, nothing fried, nothing grilled, nothing processed, no sugar and no salt.
Being a major shift from the good life one should start it with a 7 day water fast. (do I have to say "ask your doctor before embarking"? done)
The dietary impact on cholesterol in the blood is surprisingly low. Looking it up, this source says diet can affect 20-30% of your blood levels [1]. I don’t have a great statistic about exercise, but I’d encourage you to question what you think you know — at the very least I’ll claim you’re mistaken about the importance of dietary impacts on cholesterol, which perhaps should give you pause about your other beliefs
Dietary cholesterol has little impact on blood cholesterol. However the post that started this debate mentioned mass loss. And that does have a decent correlation. Go from obese to not obese and the median person's cholesterol will drop quite a bit.
It’s possible the comments have changed, but I see nothing in the thread about mass loss. I do agree about weight though — losing weight is largely diet.
> Go from obese to not obese and the median person's cholesterol will drop quite a bit.
This is really interesting, I don’t think I’ve heard that before. Do you have a source you could share?
Edit: this doesn’t necessarily prove you wrong, but this paper argues there’s little correlation between bmi and cholesterol [1]
There isn't. I'm 15% body fat, eat healthy (avoid saturated fats, prioritize fiber), exercise 5-6 times per week, and have hypercholesterolemia. I, along with my parents, have very high LDL and ApoB and nothing I can do about it in terms of diet, exercise, or weight.
I'm also not uncommon. They suspect as much of 30% of the population could be like this. There's a lot of ignorance in this thread.
There's a difference between always being hypercholesterolemia as a fit person and being obese and losing a bunch of weight when it comes to these conversations.
It's one f those things where some people's "I can't help it!" claims are true, but many are not. That doesn't invalidate the first category even though most people in the category are in the latter.
The thread above us discusses neither mass nor weight. Here it is copied in full -- I encourage you to use ctrl-f
> mediumsmart 1 hour ago
> One could eat healthy instead of course but hey, the good life.
> shlant 1 hour ago
> you didn't read the article did you? Or are you actually here to claim that people with hypercholesterolemia just need to eat better?
> Do you have the same simplistic ideas about GLP-1's?
> moi2388 1 hour ago
> For all people? No. For the vast majority of people? Yes. Eat healthy and exercise more
I'm a bit upset that I put in effort to genuinely engage in your claims, and you're not willing to go back and read the thread to confirm claims that _you made_. In fact, you suckered me into re-reading the same thread _for the third time_ looking for some throwaway line I missed about mass or weight. I could just decide that internet discussion doesn't matter, and stop engaging on HN, but I'd rather not do that. Can you please try a bit more?
I'm not going to reply to the Triglycerides & HDL comment without a link. It was your claim initially, and I was nice enough to provide a link with evidence against it, so surely you can do the same in support.
Just do fasting and lose weight. Had high cholesterol and did that lost 20 pounds and my cholesterol went back to normal without any medical intervention
I’m glad that worked for you. That doesn’t work for everyone, and there’s plenty of people with completely healthy weights who eat healthy as well who just have outrageous cholesterol. Any medical interventions that fix genetic conditions seem like a win for me. Even fixing lifestyle issues medically (eg GLP-1s) seem like a win for me.
I have familial hypercholesterolemia and none of that makes any difference. In fact 2 of my siblings and both my daughters have it too. My youngest sister had a stroke at 24 because of it.
Diet, statins, etc can't get us in healthy ranges and PCKS9 inhibitors is literally the only thing that moves the needle. I'm on Repatha, one of the injectable inhibitors, statins and Ezetimibe to manage it.
Needless to say I am super happy about this news, especially if it is affordable.
Really hopeful that Verve 102 passes trials and becomes generally available.
8% body fat, and I can run more in a day than most people do in a week. I’m taking statins. It’s not always as simple as you seem to assume. As others have said, genetics play role, for one.
There's a nice writeup by Derek Lowe on the synthesis of this molecule: https://www.science.org/content/blog-post/futuristic-synthes...
It's quite a beast!
It's articles such as this that truly make me sit back and marvel at our species. What an incredible accomplishment.
What is the current state of understanding on high cholesterol as a leading or trailing indicator of poor health? I vaguely remember reading one theory that cholesterol was used by the body to mitigate arterial damage from other causes?
It (Particularly ApoB/Combining LDL-C and Lp(a) is one of the single largest leading indicators of health risk we have.
If anything, the data we have is suggesting we've gotten wrong what the upper limits should be for what is considered OK.
https://www.lipidjournal.com/article/S1933-2874(25)00317-4/f...
Isn't diabete and metabolic syndrome way more predictive than ldl or apob?
Do you have a reference comparing the various factors?
the literature is very clear about the relationship between high LDL and Atherosclerosis. Are you referring to poor health in general, separate from Cardiovascular Disease?
Peter Attia had a great series of blog posts on this before his fall from grace:
https://peterattiamd.com/the-straight-dope-on-cholesterol-pa...
He also had a series of podcast interviews about this with Tom Dayspring.
I believe his explanations are all mainstream, except he favors treating LDL and LP(a) more aggressively than normal doctors
Wow the guy did Mechanical Engineering and Applied Math before going into medicine and surgery.
Wait, why did he fall from grace?
I didn't know either, not sure of veracity but https://share.gemini.google/0YDt55yyfITs
Epstein files showed he neglected to visit his seriously sick son because he was hanging out with Epstein. He still knows his stuff, asshole or not.
1700 mentions of his name in the Epstein files that Trump released.
There isn't a conflict between cholesterol having a useful role in the body and too much being harmful.
There are mountains of evidence establishing a causal relationship between elevated cholesterol levels and heart disease.
We've been testing for cholesterol for a long time now and have had other meds to lower it. It should be possible to see if lowering cholesterol via medication results in improved life expectancy or reducing cardiac events. I would think this study has been done a few times already. As someone who does not have much medical knowledge, I'm not even sure how to look this up or be able to assess what I see if I did.
It turns out LDL has different subfractions based on size. Normally, the liver produces large ones which shuttle fat around the bloodstream, lose their payload and shrink then the liver reabsorbs them and the cycle continues.
The problem appears to begin when these LDL molecules hang around for too long. They are damaged by external factors in the bloodstream (eg. glycation due to high blood glucose, oxidation due to fragile polyunsaturated fats) and not recognized anymore for recycling. That's when they can start forming macrophages.
tl;dr LDL by itself is an incorrect measure of cardiovascular risk. Big pharma still profits by selling everyone LDL reducing drugs.
one authentic source: https://www.youtube.com/watch?v=fVLZA0qp-wc
I have heard this too, and that cholesterol measurements are flawed because they don't account for particle size. That you can actually have better 'numbers' but worse results, if you reduce particulate size but also overall volume. It's frustrating that the science behind cholesterol is constantly in wild flux, but at any discrete moment you're expected to accept whatever the momentary consensus is.
Interestingly, my dentist, who also has a bit of a fixation on cholesterol on a personal level and is educated on the matter, has said that a heart calcium scan is the best way to determine what someone's target cholesterol number should actually be, and that it should not be the same from person to person.
This was after I voiced my frustration to him at having made lifestyle changes to get my cholesterol down in order to avoid getting put on statins (not wanting yet another daily drug if I can avoid it), getting the my number below the target of 110, only to shortly after that find out that they'd lowered it to 70. I talked to my endocrinologist about it, and she basically said "yeah, those numbers are more-or-less unachievable. But we want to be extra careful for type 1 diabetics, so we hold them to a higher standard. Either way, everyone gets put on statins at some point anyway, so who cares?"
I'm absolutely allergic to "everyone goes on x medication, so stop whining and go on x medication" as a medical argument, and will probably just deal with being labelled non-compliant over this one unless my cholesterol reaches a level I actually personally find to be too high at this point. Which sucks to have to do, but hey, it's my body after all, and so far doctors have failed to make a convincing case for me personally here.
You might be missing out on any benefits from statins that are independent of the cholesterol reduction. It’s non-zero and debatably substantial.
What are the other benefits?
All the answers are smart sounding and completely avoid to address your main point. Same with most doctors I asked it to.
You should check which part of your body has the most cholesterol.
How would I check the parts of my body for that?
The brain is the most cholesterol-rich organ in the body. While accounting for only 2% of body weight, it contains roughly 20% of the body's cholesterol. It is essential for nerve cell communication, learning, and memory.
I think they meant ask Google. It's the brain.
cholesterol is one of the most crucial molecules for survival. It's used to create and maintain cell membranes, and other critical functions. The vast majority is created by the liver, and there are a lot of regulating signals for how much, which is where usually things go off. Low cholesterol production is an extremely serious condition. The "only" problem with high cholesterol is that it builds up inside artery walls, which eventually may or may not dislodge and may or may not cause a heart attack or an embolic stroke. (I'm not a doctor. I just get medication for high cholesterol and have done some research)
> Low cholesterol production is an extremely serious condition.
This is correct, but not in the way you mean it. We know people can effectively produce no LDL cholesterol in their liver and have positive health impacts - these MR studies are a big part of what drove this entire class of cholesterol medications. And the monoclonal antibody versions of PCSK9 inhibitors have shown basically the same results.
Virtually all human cells can produce cholesterol locally de novo, including your brain.
o_O
“Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein” [1].
[1] https://en.wikipedia.org/wiki/Proprotein_convertase
Documentary: The Cholesterol Code
https://m.youtube.com/watch?v=57Z8bUb1P94
Not really a new kind of pharmaceutical, pcsk9 inhibitors have been on the market for a while now. What’s new is that it’s an oral medication rather than an injectable
But I vaguely remember them being expensive due to not being covered by insurance. Maybe this will change that?
Hmmm, maybe but I wouldn’t expect a sea change myself. The reason insurance is able to get away with not covering pcsk9 inhibitors is because statins in theory provide a similar benefit for a fraction of the price, and so they can gatekeep access by requiring patients to take statins first before providing prior authorization.
Now, structurally Repatha is straight up more expensive to manufacture and deliver to patients than a peptide like enlicitide, as the former is a biologic. And if a competitor decides to manufacture a biosimilar when Repatha comes off patent in 2030 that could also help cut the price of drugs in this category. But there’s really nothing cheaper than statins, so I would expect insurance agencies to continue to withhold prior authorization.
Next up is the lp(a) lowering drugs still in trials.
Yes, exciting stuff.
Not to mention the gene-therapy version of the same PCSK9 inhibition pathway called VERVE-102 which Eli Lilly is putting through human trials as we speak.
I imagine that stacking the LP(a) antisense therapy with a PCSK9 inhibitor, and/or a statin or Nexlizet would probably lower odds of heart disease death by two to three orders of magnitude. But I guess there isn't solid mortality data to say for sure.
It works via the same mechanism as an incredible drug called Repatha (generic name evolocumab), but Repatha is quite expensive, requires refrigeration, and must be injected subcutaneously every two weeks. The news here is that this is administered orally.
Oat cookies. I get them imported from Europe. High calorie but works.
I just mix rolled oats into my yoghurt. Much cheaper.
What brand?
One could eat healthy instead of course but hey, the good life.
Many people have high cholesterol due to genetics. In these cases even if you ate a 100% perfect diet it would only impact 25% of your cholesterol levels - which any physician would not be satisfied with.
That's the good news! It fixes that genetic problem (PCSK9 Inhibitor)
Eating healthy is a sub-optimal solution. Typically we see the most significant results with lifestyle changes + medical interventions and pharmaceuticals - more than either alone.
There's a strange belief, I believe most born out of morality, that medicine undermines discipline or healthy lifestyle. But it does not, they work in tandem, each making the other stronger.
It is true that taking medication is "easy" - not that easy, though. But easy != evil or immortal. If it's so easy, that's a good thing. It means we can stack it on top of lifestyle changes for very little marginal cost. If you're already working out and eating good, that's great. Go to your cardiologist and see if you're a candidate for statins or hypertension medication.
You wouldn't tell someone with diabetes or asthma to just live healthier and avoid their medication. There's nothing wrong with taking a pill, we're not cavemen living off the land.
Lose weight, yes. Exercise, yes. Accept a potentially fatal genetic defect when an option is available? No.
Advise not callously generalizing your opinion on things like this. It's clear that you either spoke without knowing more, which happens, or you really don't seem to care to know more. I hope you're not in the latter.
eat healthy as in: only once a day and only six days a week. only water for drinking and only fresh stuff to eat, no meat, no eggs, nothing cooked, nothing baked, nothing fried, nothing grilled, nothing processed, no sugar and no salt.
Being a major shift from the good life one should start it with a 7 day water fast. (do I have to say "ask your doctor before embarking"? done)
Yeah, when you grow up, get back to this comment to look how childish it is.
https://www.youtube.com/watch?v=RuOvn4UqznU
you didn't read the article did you? Or are you actually here to claim that people with hypercholesterolemia just need to eat better?
Do you have the same simplistic ideas about GLP-1's?
For all people? No. For the vast majority of people? Yes. Eat healthy and exercise more.
The dietary impact on cholesterol in the blood is surprisingly low. Looking it up, this source says diet can affect 20-30% of your blood levels [1]. I don’t have a great statistic about exercise, but I’d encourage you to question what you think you know — at the very least I’ll claim you’re mistaken about the importance of dietary impacts on cholesterol, which perhaps should give you pause about your other beliefs
[1] https://my.clevelandclinic.org/health/articles/16867-cholest...
Dietary cholesterol has little impact on blood cholesterol. However the post that started this debate mentioned mass loss. And that does have a decent correlation. Go from obese to not obese and the median person's cholesterol will drop quite a bit.
It’s possible the comments have changed, but I see nothing in the thread about mass loss. I do agree about weight though — losing weight is largely diet.
> Go from obese to not obese and the median person's cholesterol will drop quite a bit.
This is really interesting, I don’t think I’ve heard that before. Do you have a source you could share?
Edit: this doesn’t necessarily prove you wrong, but this paper argues there’s little correlation between bmi and cholesterol [1]
[1] https://link.springer.com/article/10.1007/s11695-010-0170-7
There isn't. I'm 15% body fat, eat healthy (avoid saturated fats, prioritize fiber), exercise 5-6 times per week, and have hypercholesterolemia. I, along with my parents, have very high LDL and ApoB and nothing I can do about it in terms of diet, exercise, or weight.
I'm also not uncommon. They suspect as much of 30% of the population could be like this. There's a lot of ignorance in this thread.
There's a difference between always being hypercholesterolemia as a fit person and being obese and losing a bunch of weight when it comes to these conversations.
It's one f those things where some people's "I can't help it!" claims are true, but many are not. That doesn't invalidate the first category even though most people in the category are in the latter.
for the most part mass == weight on Earth.
Triglycerides & HDL are affected by weight (tho more triglycerides than anything else), e.g. Wing 2011.
> for the most part mass == weight on Earth.
The thread above us discusses neither mass nor weight. Here it is copied in full -- I encourage you to use ctrl-f
> mediumsmart 1 hour ago
> One could eat healthy instead of course but hey, the good life.
> shlant 1 hour ago
> you didn't read the article did you? Or are you actually here to claim that people with hypercholesterolemia just need to eat better?
> Do you have the same simplistic ideas about GLP-1's?
> moi2388 1 hour ago
> For all people? No. For the vast majority of people? Yes. Eat healthy and exercise more
I'm a bit upset that I put in effort to genuinely engage in your claims, and you're not willing to go back and read the thread to confirm claims that _you made_. In fact, you suckered me into re-reading the same thread _for the third time_ looking for some throwaway line I missed about mass or weight. I could just decide that internet discussion doesn't matter, and stop engaging on HN, but I'd rather not do that. Can you please try a bit more?
I'm not going to reply to the Triglycerides & HDL comment without a link. It was your claim initially, and I was nice enough to provide a link with evidence against it, so surely you can do the same in support.
Fiber intake has a dose-dependent effect on cholesterol levels.
Obviously some people still need medication if they have particularly unfortunate genetics.
I was responding to the glp-1 question.
And yes, exercising and dieting absolutely reduces the need for these medications.
It also reduces the amount of people who have high cholesterol, although again, in both cases not all
You will still die you know, no matter your diet. And no god will reward your righteous corpse for eating healthy.
Just do fasting and lose weight. Had high cholesterol and did that lost 20 pounds and my cholesterol went back to normal without any medical intervention
I’m glad that worked for you. That doesn’t work for everyone, and there’s plenty of people with completely healthy weights who eat healthy as well who just have outrageous cholesterol. Any medical interventions that fix genetic conditions seem like a win for me. Even fixing lifestyle issues medically (eg GLP-1s) seem like a win for me.
This is more about lp(a) type of cholesterol which is largely driven by genetics, and barely responds to lifestyle/diet.
lp(a) is not part of routine blood tests - you probably didn't measure it unless you specifically asked for it.
I have familial hypercholesterolemia and none of that makes any difference. In fact 2 of my siblings and both my daughters have it too. My youngest sister had a stroke at 24 because of it.
Diet, statins, etc can't get us in healthy ranges and PCKS9 inhibitors is literally the only thing that moves the needle. I'm on Repatha, one of the injectable inhibitors, statins and Ezetimibe to manage it.
Needless to say I am super happy about this news, especially if it is affordable.
Really hopeful that Verve 102 passes trials and becomes generally available.
8% body fat, and I can run more in a day than most people do in a week. I’m taking statins. It’s not always as simple as you seem to assume. As others have said, genetics play role, for one.
Are you seriously suggesting to cut into pharma profits?