Current recommended 'healthy' level is below 200, while it looks like the study found 200-240 is the best range. Is this accurate? Should people that have under 200 get it up to the 200-240 range? Or does it depend on family history of heart disease?
Animals need cholesterol for their cell membranes; particularly for neurons. It's a precursor for Vitamin D, testosterone, and estrogen and is needed in the blood to help transport fat-soluble vitamins (A, D, E, K).
It doesn't seem at all strange that there should be an optimum level that is non-zero.
Odd? Odd because we've been taught what are amounting to myths[1] about cholesterol. Afaik, humans - especially the human brain - need a healthy supply of cholesterol. You literally can't think straight without it. And how many people are being pumped with statins?
When you do your study without accounting for treatments that are given to people with high risk of disease and which reduce cholesterol, you will find that lower cholesterol corresponds with disease due to those treatments. In other words, they have performed a large study that is likely to be confounded by indication.
I remember back in the 1980s that the Japanese researchers, whose population has (had?) very low cholesterol, were arguing with the US researchers, saying that cholesterol too low was bad as it led to (perhaps allowed for) strokes- which was one of their young-people-killers.
I read it as: 200 is the lowest point of the U curve they found. Below 200 mortality decreases as TC increases, and above 200 mortality increases as TC increases, meaning anything close to TC seems to be the value with the lowest mortality rate.
> U-curve associations were found. In the TC ranges of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group).
This is certainly not correct. One does not need to eat organic foods to be healthy. I'll add that not everyone has in season fruits around. I live in Norway. Do you know what is in season during January in Norway?
Nothing. Absolutely nothing. Doubly so if you aren't eating animal products.
I'll add that avoiding all animal products has its own perils, namely the sort that results in vitamin deficiencies. And while a diet filled with whole grains and mostly plant-based foods is considered healthy, we simply don't know enough about nutrition to have one way or another. Or even to get vitamin doses right. I say all this while eating mostly vegetarian myself. I eat fish about once a week. I don't like it so much, but it is healthy.
Raw fruit is fine, veggies not really. Many contain substances that should deter animals from eating them. The digestibility of veggies usually increases when they are cooked.
The is good evidence to suggest that human ancestors started to use fire to cook meat and/or starchy vegetables more than million of years ago. It is enough for evolutionary adaptation.
There are even suggestions that it was cooking by opening untapped sources of calories that allowed for a bigger brain to evolve.
Check out the Daily Dozen. It does require a vitamin B12 supplement. If you take a B complex it will include niacin as well which will help with cholesterol.
Nice, that sounds amazing to take pills instead eat natural food. B12 synthetic, or Cyanocobalamin, is the most dangerous thing you can eat. You can become inmune to B12, and increase your deficiency and, die faster, basically. Check papers about this. The best higher quality methylcobalamin is only obtained from nature.
I think a practical guide might be to look at the groups of people who live longest, such as in Japan and Greece. Some factors off the top of my head include strong community, moderate exercise, a simple diet - mostly veg and some fish and low pollution.
Eat a varied diet, leaning towards plant-based foods. Whole grains if you can. Don't unreasonably cut out whole categories of food. Being vegan is HARD, vegetarian (or mostly so), not so much. Watch the sugar, including the fake type. Eat your calories instead of drink them.
Also, get some activity. Walking for 15 minutes daily is better than nothing, but try to get more than that most days. IF you can have fun doing it, great! If you lack motivation, do something on the easy side as it is easier to talk yourself into. It is better to this half-assed than not at all, after all, because it still counts.
Keep an eye on stress as much as possible. If you smoke, try quitting (I suggest a vape or e-cig). Drink in moderation, but do have some coffee.
Once you get these general things done, you are well on your way.
It's not, it's mildly tricky, and there's not much evidence that people following a vegan diet are nutritionally worse off than the people who don't think about their food at all, many of whom don't eat any fresh fruit or veg across a week.
It's much harder to eat out, apart from specialised places. And those are much more common in large cities than small towns. This makes social meetings harder as a result.
Compared with being vegetarian or mostly vegetarian, it is. One must pay much more attention to their diet and intake. In addition, most folks need to take supplements. As the other response said, it is also harder to eat out. Vegetarian is much easier - the addition of things like eggs and cheese helps out tremendously. I read ingredients, sure, but it isn't an issue most times. It would take more mental work to keep out all animal products.
I might be mostly vegetarian and eat eggs and cheese and fish once a week, but I usually tell folks to reduce their eat. Sometimes I say instead to make sure they eat enough fruit and veg and whole grain. I say this stuff because it is easier for most folks to concentrate on things like this to improve overall diet without feeling like they have to spend days figuring things out.
It's perfectly accurate to point out that sticking to a vegan diet is hard, never mind giving up leather and wool.
Also, it's worth noting that the difficulty of going vegan varies greatly with your location. For example, eating vegan in Japan is a legitimate pain in the ass.
I nearly posted this yesterday, and decided to today. Losing one's period doesn't mean the diet was unhealthy. Seriously.
There are lots of reasons a person can not have a period. Sure, you can be malnourished, but I'm guessing the more likely contributor was not having enough body fat. IF a woman's body fat is too low, she stops having periods. It happens in a broad cross section of people. A person with an eating disorder will do it as will a woman that works out a lot and eats healthily. Coincidentally, weighing too much can do it as well.
I'm guessing a nutrient deficiency can do it, but I'm unsure on that one. It can be a hormonal imbalance too!
And there are a bunch of other reasons as well. It isn't even necessarily harmful - after all, people quit having periods when they are on birth control with no ill effects.
But the above comment suggests a varied diet "leaning" towards plant-based foods, not a plant-based diet. That's the standard recommendation for a healthy diet from pretty much every public health body, currently.
I’m not sure I follow: I believe the person you are replying to is encouraging eating a diverse set of foods, including meat, per some health body guidelines.
You also seem to believe that eating meat, not only fruits/veggies/vegan, is good.
Wouldn’t that make you in agreement with the current system of balanced intake?
Leaning towards plant based is far too close to the “meat is bad, minimize it” camp for my taste. I think meat is not only good for humans, but strictly necessary for healthy development and functioning. In my assessment we aren’t eating enough high quality (important caveat) meat.
I dont' know what you mean about "the utter collapse of western health".
Public health organisations are staffed by experts who have spent most of their lives studying the relevant subjects. How likely is it that you, or anyone who hasn't dedicated that much time and effort in studying those subjects, will know better than those who have?
I'm not saying it's impossible, mind. But just what are the chances that your opinion is right and that of thousands of experts is wrong?
It’s easy; evaluate based on the results. Since the 1970s the US government and other public health organizations has attempted tell Americans what to eat more of, and what to eat less of. Nearly 50 years later we can take a step back and realize that Americans are fatter, sicker, and weaker than they were before then.
There have been some successes, we are now very good at catching CVD early, and should you have a heart attack you are now much more likely to survive than before. But on the food front, what we’re talking about here, it has been a complete and unmitigated disaster.
Because of that, I don’t trust public health officials one iota when it comes to food and diet. That doesn’t mean I’m right, but I know that they have a track record of failure and unintended consequences.
I don't know that you can attribute bad eating habits to the recommendations of public health organisations. Perhaps the public is just not following those recommendations? My understanding is that processed foods and sugary drinks are consumed in great numbers, but that is certainly not in accordance with the recommendation of any public health organisations that I know of.
Also, as far as I know, public vaccination programmes have greatly reduced, and almost eliminated many diseases like measles, tetanus and typhoid, not just in the US but the world over, although of course measles is making a comeback.
Are you perhaps drawing a conclusion about public health bodies in western countries in general, from an experience with health services in the US? The US seems to be very peculiar in how it treats public health. I live in the UK and I wouldn't say that the national health service (the NHS) has collapsed. It has its problems and it's being attacked constantly but for the time being, it's working fine. The same is true for most central European countries.
> I don't know that you can attribute bad eating habits to the recommendations of public health organisations.
Americans have actually followed the recommendations of the USDA for years. They replaced saturated fat with “heart healthy” seed oils, and they diligently consumed low fat diets.
Keep in mind that official recommendations will affect what foods are available for sale too.
> My understanding is that processed foods and sugary drinks are consumed in great numbers, but that is certainly not in accordance with the recommendation of any public health organisations that I know of.
In the United States nutrition labels have a maximum daily amount of most nutrients, except sugar. The official line has been that saturated fat causes heart disease, and that replacing fat in packaged goods with sugar was ok. This is why we have candy in the United States proudly labeling itself as a “fat free food”, and we used to have marketing campaigns touting the weight loss benefit of sugar.
This is finally starting to turn around, but the public health agencies have been laggards when it comes to the realization of how bad sugar is, not at the forefront.
And that’s not even getting into the whole bailiwick about how they process foods, which has changed in accordance with public health recommendations. They used to at least use natural fats in the few processed foods we used to eat, such as lard, but all of those were changed years ago to seed oils that were nominally less bad.
> Also, as far as I know, public vaccination programmes have greatly reduced, and almost eliminated many diseases like measles, tetanus and typhoid, not just in the US but the world over, although of course measles is making a comeback.
As I clearly stated, all public health programs should be judged by their outcomes, and the results of public vaccination have been an unqualified success.
But just because the official recommendations on vaccinations have worked, it doesn’t follow that the official recommendations on diet will too.
> Are you perhaps drawing a conclusion about public health bodies in western countries in general, from an experience with health services in the US?
Yes, that’s a fair criticism.
> I live in the UK and I wouldn't say that the national health service (the NHS) has collapsed.
That’s not what I said. I said that our health has collapsed, i.e. we’re fat and sick.
>> The official line has been that saturated fat causes heart disease, and that replacing fat in packaged goods with sugar was ok. This is why we have candy in the United States proudly labeling itself as a “fat free food”, and we used to have marketing campaigns touting the weight loss benefit of sugar.
Did US public health organisations actually recommend replacing fat with sugars? I find this very surprising, if it is the case. I wouldn't be surprised if that was instead a practice adopted by industry, despite and against official recommendations.
For example, Wikipedia tells me that diet Coke was first sold in 1982. That must mean that there was, already, a clear awareness of the detrimental effect of sugar, and sugary drinks in particular, on health. That awareness can't have come from the soft drinks industry itself so it must have come from public health officials.
USDA guides have historically referred to “sweets” as something to consume “sparingly” without any concrete recommendations around maximum grams per day. Up until 2015 they have provided no guidance around added sugars in other products, including in the 6-11 servings of bread (!!) recommended per day.
In 2015 they finally released a recommendation that sugar make up no more than 10% of an American’s daily calories, which is insane.
Also at a practical level, a recommendation to remove fat from diets is a recommendation to add sugar. A wide variety of foods are just absolutely disgusting if you have neither fat nor sugar, and if you declare that the reduction of dietary fat is the main goal for Americans, the result will necessarily be more added sugar. The dietary guidelines still recommend that Americans eat leaner cuts of meat and switch to 1% milk, as if they haven’t already done that.
No, not at all. Do not lean to plant based foods or grains. Grains and plants contains antinutrients. Plants don't want to be eaten, same grains. They've contain not only toxins but also many antinutrients.
If anyone wants to have a healthy life, I recommend you to read the book Nutrition and Physical Degeneration from Weston Price. Basically, eat animal products, the more local based, the best. Grass feed cattle will be the best food source for your body. Cut all carbs (sugar), fruits (man made).
There are 15 nutrients that you can only get from animal products. You can get all minerals and vitamins from animal products you don't need plants at all.
I suspect that both keto and vegan work as diets because they both cut out processed hyperpalatable foods from ones diet. We should look at the things neither vegans nor keto people are eating, and those are probably what’s bad for us.
The worst offenders for weight gain are foods that don’t trigger a satiation response, like chips and dip or French fries. Foods where the fat to carbohydrate ratio is nearing 1:1 will cause people to overeat. Processed foods tend to have these ratios.
You suspect wrong. Plants don't have 15 basic nutrients. Including Vitamin D, B, B12, A, K. All from animals. Carnosite, Carnitite, etc. If you eat grass feed animals, fish, local diary products, quit carbs, sugar and processed food you will be ok. I am ex vegan. And, yes, I know the answer already: "you did it wrong", but no, I didn't.
I find it strange that research of this scale is looking exclusively at a compound metric. TC is HDL (apo A-I), LDL, VLDL, IDL (apo B) and few more things. Its different proportions of these things that define how healthy your cardiovascular system is, not the total sum. To complicate even more - those things are usually measured as concentrations (mass/volume) while much more important metric is particle count, but that’s not easy/cheap to measure.
Considering how complex this system is, measuring TC is like measuring average body temperature in the hospital.
It’s cool that they found a U-shape but this approach just makes patients(and doctors) hack the TC number without understanding how that affects lipoprotein composition and, subsequently, patient’s health.
In the tweet that I linked to, we noted that failure to account for statin use can invert the causal relationship between cholesterol and mortality.
With regard to the point of the study, they start by saying, "It is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age."
So, interpreting their statement, I would say that their goal with this study was to investigate whether the relationship between total cholesterol and mortality was consistent across age and sex. That is a different point from assessing the strength of the relationship between cholesterol and mortality.
I do agree, however, that there is no single biomarker aside from age that is a particularly powerful predictor of mortality in the general population.
I don't understand why it matters for the conclusion whether lower cholesterol (or specifically LDL) is caused by diet or statins or something else altogether (if the assumption is that high LDL affects mortality).
I agree, it doesn’t fit the definition. I still call it that in casual conversation when getting the point across while being more precise would be more wordy.
It is fundamentally not the same though. You are saying that there isn’t any reliable bio marker other than “age,” but you can’t measure age. So what reliable bio marker are you talking about? What would be measured?
If you mean there are no reliable bio markers, period, it would be more clear to just say that.
We actually can measure the biological age. There are clinical biomarkers for that. It is not commonly done. The best one, epigenetic signature, is yet to be clinically approved or widely available.
Now, in that paper, they use broad range of age as a descriptor, confounding many age-associated phenotype and genotypes, which also translate into risk factors. You can definitely say that the 18-34 cohort is different 45-54, and that the later as more risk factors, the same a specific mutation might be associated with higher or even guaranteed chance of developing a disease, and hence will be use as a biomarker.
That being said, it is not typical to measure the biological age of healthy individuals. Actually, we don't know what an healthy individual is. We know a great deal more about diseased individuals. The current status seems to be that if you are not diseased you are healthy. I don't agree with that. That's how science is done. And that is how we end up with half-baked studies in one of the most impactful journal .
> We actually can measure the biological age. There are clinical biomarkers for that. It is not commonly done. The best one, epigenetic signature, is yet to be clinically approved or widely available.
What is the precision and accuracy of the best biomarker? ie. if I gave you the necessary sample, how close can you get to the correct age and what are the error bars?
That's not what I said, though. There are plenty of reliable biomarkers. They consistently relate with disease in an expected way across populations. They just aren't, individually, powerful. They don't do a great job discriminating who will get disease and who won't - but using them is still much better than not using them.
>> In the tweet that I linked to, we noted that failure to account for statin use can invert the causal relationship between cholesterol and mortality.
I didn't get enough from the tweets to understand how that was accounted for in the data. But I have questions.
By "inverts the causal relationship" I assume you threw "causal" in there by mistake. Nobody is going to think mortality causes high cholesterol. More importantly, if ignoring statin use reverses the slope to weaken the relationship "high cholesterol causes mortality" doesn't that suggest a lack of efficacy for statins? We know they lower cholesterol, but if that also reduces mortality the relationship (between cholesterol and mortality) should hold weather they are accounted for or not. Right?
> Nobody is going to think mortality causes high cholesterol.
Prevalent cardiovascular disease, or having a high risk for cardiovascular disease, causes low cholesterol. It does so by your doctor recognizing your elevated risk and putting you on statins.
Statins, like all drugs for prevention, do not prevent all subsequent disease. Perhaps most importantly, they only reduce cholesterol from the time you start taking them (as opposed to a genetically-driven low cholesterol throughout life). All of the drugs for chronic disease prevention tend to have a pretty small effect on the disease risk. Therefore, detecting that someone is taking a statin is a great signal that the person is at high risk for disease. They would be at an even higher risk if they weren't on a statin, but the statin does not erase all risk. That is why failing to account for statin use will lead to low cholesterol looking protective, if there are people in the population taking statins.
> First, the use of lipid-lowering medication was unaccounted for. The risk associated with high cholesterol might have been underestimated. However, in Korea, IHD mortality accounted for only approximately 5% of all-cause mortality, and only 10% of people with hypercholesterolemia received lipid-lowering therapy[39]. Therefore, the impact of not considering medication use is likely to be modest, and the TC levels in this study generally reflect levels without lipid-lowering medications
And yet, if you look a the twitter thread I pointed out, it turns out that in a large biobank of 500,000 people, their aspiration is refuted: if you fail to account for treatment effects, the association results will be inverted.
> only 10% of people with hypercholesterolemia received lipid-lowering therapy
Wouldn't this be much higher in the UK cohort? Also,
> The sex- and age- specific levels of TC in the current study of Koreans were lower than those reported in other high-income countries, including Japan, England, and the US
Which would reduce the effect (relative to what was found in the analysis of UK data) even further.
I don't think it adds a whole lot to talk about the confounding variables of this nature - it's an observational study, so of course it will have all sorts of confounding variables. If you are going to make a strong case that controlling for a specific confounding variable would reverse the relationship though, you should quantify the impact. It's unclear to me that statin usage would make a large difference, given that the study notes it wasn't a popular treatment.
My general feeling is that these types of studies tend to end up measuring overall health - given that most of the factors that lead to high cholesterol level were controlled for (BMI, physical activity, smoking status, drinking, etc) - and the average person in any population is relatively healthy and well-adjusted to the common diet, any large deviation from the norm in any direction statically makes it likely that the subject has some health issues.
What would be interesting to see in a meta-study is whether the optimal level of cholesterol either was consistent across populations that had very different averages or it tends to be near the median in each population. The former would be evidence that it's an independently meaningful biomarker; the latter would be evidence that it's just measuring how normal you are.
You don’t think that talking about confounding by indication is important? Confounding by indication inverts the entire discussion section of the article.
Again, observational studies are going to have all kinds of confounding variables - if you're going to make an argument that one of them is important enough to reverse the conclusion, you should have some evidence and certainly more than a just-so-story.
Please note that the author of that thread has strong financial interests which would be damaged by this result. (He is the CEO of a company that seeks to use CRISPR to alter genes which lead to cholesterol production.)
How is his potential conflict of interest, which you have stated accurately, relevant to the need to adjust for treatment effects?
Also, I created those graphs and sent them to him, so (1) he didn't create the graphs or influence how they were created, and (2) and I have no financial interests in that company. His company plans to produce a molecule that disrupts PCSK9 production, thereby reducing LDL-cholesterol.
If you think that the conflict of interest influenced the analysis in a way that you would have done differently, what is the alternative approach by which you suggest analyzing the data?
Originally found in Red Yeast and patented. Red Yeast Rice lowered my cholesterol and TG dramatically. Has the same side effects (muscle aches) as statins if you take too much.
My question is that whether the U-shaped curve found here is caused by similar phenomena as the J-shaped curve previously found for alcohol. That is, for alcohol, individuals who drank no alcohol tended to have disease or be recovering alcoholics, and so that association made it seem that drinking no alcohol was less healthy than drinking some alcohol. Here too, is it possible that having low cholesterol is associated with individuals with disease? We don't know what caused different individuals to have low TC here.
Absolutely. In fact, because statins have such a powerful effect on cholesterol, there is a good chance that a bunch of the people in the low cholesterol strata are taking statins. So, at the risk of being a broken record in this thread, these results are likely to be confounded by indication. That is, the low-cholesterol groups are enriched for people who have low cholesterol because they are taking statins. And they are taking statins because a physician has deemed them to be at elevated risk of disease (or already have disease), and are thus more likely to die.
because they had high cholesterol for decades and the damage is already done. Decreasing cholesterol helps them, but they are not as healthy as someone with naturally such low cholesterol.
This study doesn't tell us if these participants had naturally low cholesterol or artificially low cholesterol (i.e., from medications). So no such conclusion can be determined.
Agreed, yet that conclusion (that low cholesterol is somehow harmful) cannot be excluded either. I agree that it would be interesting to see how the results of the Korean study would change if statin-takers were excluded.
Not all mortality risk operates through cholesterol-dependent mechanisms. And even for those that do, decades of exposure to high cholesterol can’t be totally reversed by medications.
Ultimately you want a readout of CAD risk, and we know that only a portion of CAD risk is attributable to LDL. We're always on the lookout for better biomarkers, but right now there isn't a comprehensive CAD biomarker (aside, perhaps, from coronary calcium - but we can't go around exposing everyone to radiation every year just to observe disease progression).
Last time I’d read into it, statins didn’t move mortality numbers for most members of the population.
Edit: they do decrease your risk of a heart attack a bit, but the increased incidence of cancer and diabetes actually eliminates the benefit for most users. The only people who showed any measurable reduction in mortality were non-elderly patients with a history of cardiovascular disease.
Also interesting:
Current physician guidelines don't recommend treating to a specific number, like <200. When I trained (<5 years ago) we were taught to check cholesterol levels and if LDL > n then start a statin and increase the dose until LDL < n.
Hmm...but doesn't this suggest then that cholesterol levels are merely a biomarker of something else that causes the mortality, and not a direct cause of it?
That is a good question. These results tell you that statins don't take your risk to zero. If you were totally protected from CAD as soon as you took a statin, then I agree that confounding by indication would not be a thing.
But, across all fields of medicine, we know that confounding by indication is a problem. Preventive medicines, by and large, are not sufficiently powerful to reduce risk to zero.
Right, but I suppose the model for what's occurring then is: High cholesterol either is a marker of some otherwise unrelated health issue, or high cholesterol causes damage to accumulate over time. Beginning to take a statin would prevent the accumulation of further damage, but presumably not reverse that damage that has already occurred. Since I assume there is some benefit of statin intake in terms of actual outcomes, it would seem the latter model fits the data more closely. However, you could imagine a world where statin intake is actually just correlated with "being concerned enough about your health to visit a doctor and follow their instructions", which may be correlated with a turn towards a healthier lifestyle, etc.
It doesn't look like they directly test for this kind of thing, but they do address it:
Reverse causality has been suggested as an explanation of higher mortality associated with low cholesterol levels. However, a long term follow-up study in a Japanese-American population showed that individuals with low cholesterol levels maintained over a 20-year period had the worst all-cause mortality, and concluded that reverse causality was unlikely to account for the higher mortality associated with low cholesterol entirely14.
My reading of "reverse causality" here is that people with high TC have more cardiovascular disease and take more statins that lower their cholesterol. I haven't read the referenced study.
Cholesterol / lipid science is a mess. First it was LDL-C that was bad, then that doesn’t actually correlate, then it’s LDL-P, oh wait, then it’s LDL size, and then it’s ApoB that’s going to “clog your arteries”. Once you dive into the “hard” science like pathology of atherosclerosis, you’ll find that the lipid hypothesis makes no sense.
For the life of me I really don’t understand why the regulators haven’t clamped down on statins. Sure, it lowers your cholesterol, but unless if you’re in a very specific population it doesn’t move your all cause mortality risk one iota. All while costing the patient money and causing some pretty nasty side effects too.
Probably because most data disagree with this comment. There's a ~20% relative risk reduction in vascular events & mortality per ~40 mg/dL decrease in LDL.
> "~20% relative risk reduction in vascular events & mortality per ~40 mg/dL decrease in LDL."
Is that a composite endpoint of vascular events AND mortality?
From TheNNT:
"It takes 5 years of daily statin therapy to achieve a 1.6% chance of avoiding a heart attack, and a 0.37% chance of avoiding a stroke. Most disappointing, statins seem unable to prevent death in this group. And most concerning, the drugs may increase diabetes, a serious and life-altering disease." (Primary Prevention)
That would be the same CTT that makes money from the makers of Statins and has been accused of being insufficiently transparent around their studies[0].
Well, the study in the posted article examined Total Cholesterol (TC), not LDL, and the conflicting results you say were found in different studies were all about LDL, which suggests there really is some involvement of LDL in CVD. I wonder whether you might have misinterpreted these studies as conflicting when they are merely complementary in nature.
Additionally, I think you will not find many studies that claim that high HDL is bad for you, whereas you will find many that claim it's good (because it protects from CVD). I can't say I see much of "a mess" here- just ordinary, progressing scientific understanding of a complex system.
Are there really any studies that attribute atherosclerosis to bacteria, or some of the other conditions you describe? If so- are there many of those and are they good quality studies? I am very skeptical of your comment's suggestion that the immune system may be involved in atherosclerosis.
My comment is more general, not specifically in response to the specifics of the article on TC. FWIW, TC is probably not a great measure on an individual basis, but sort of interesting population-wide.
Yes, folks agree high HDL is good, high LDL is bad. However, drug trials to raise HDL didn't work so well.
> "Are there really any studies that attribute atherosclerosis to bacteria, or some of the other conditions you describe?"
Thank you for the links. My understanding is also that TC is not a very good predictor of cardiovascular health, but I'm not any kind of expert on the matter, or even close.
Just so other readers are aware, this view of cholesterol and lipidology is far outside the mainstream medical understanding of the topic.
LDL-c is bad. LDL-p (the particle number), LDL size, and ApoB (which is the protein part of LDL) are all very well correlated with LDL-c. So, while some people prefer one measurement or another, they're all proxies for one another.
We have lifelong exposure to our genetics-and-diet-induced cholesterol levels, whereas clinical trials run for a few years. The long-term follow up of the statin trials show mortality reduction. PCSK9 inhibitors reduce all-cause mortality, and the long-term follow-up of the PCSK9 trials may or may not show the same for cardiovascular specific mortality. However, everyone in the field thinks they will, because those with loss-of-function PCSK9 variants live longer with less cardiovascular disease. Also, adjudicating the cause of death is hard - autopsy, if done, overturns the diagnosis nearly 60% of the time[1].
Cholesterol isn't the only risk factor for cardiovascular disease, so other things (like autoimmune conditions) will contribute to risk as well, but this isn't an either/or phenomenon.
If LDL-c correlated with LDL-p, those two metrics would have been similarly good as CVD predictors, but they aren’t, LDL-c is basically useless. (Don’t have sources atm, can link later if you’re interested)
Do the statin follow-up studies correct for participants seeing a doctor more often? Even if the statins do nothing I would expect mortality to be lower among the group that takes them just by having more interactions with doctors.
> "PCSK9 inhibitors reduce all-cause mortality, and the long-term follow-up of the PCSK9 trials may or may not show the same for cardiovascular specific mortality."
Check the evalocumab trial I posted, ACM was actually slightly worse in the PCSK9 side of the trial.
> "LDL-c is bad. LDL-p (the particle number), LDL size, and ApoB (which is the protein part of LDL) are all very well correlated with LDL-c. So, while some people prefer one measurement or another, they're all proxies for one another."
Yes, this tends to be true, however discordance between them is possible - and generally not a good thing.
> "Cholesterol isn't the only risk factor for cardiovascular disease"
Sure, but I think the whole of the field has rabbit-holed on lipids for too long, ignoring actual causal factors.
> LDL cholesterol is by far the best established causal risk factor for coronary artery disease.
Is it causal, or is it a risk factor? I'd say at best it is "necessary but not sufficient". CVD risk calculators don't even take LDL-C into account, that's how good of a marker it is.
Mainstream medical understanding can move as we understand more about the nuances of the target populations. Here are some issues that I’m confused about:
- studies that incorporate statins don’t seem to segregate impact of anti-inflammatory effect of some statins vs cholesterol lowering.
- some docs are prescribing statins to healthy individuals based on only cholesterol scoring, also not taking into account more expensive but better imaging like coronary calcium scoring
- Are there studies that show proactive use of statins on otherwise healthy individuals lead to decreased overall mortality?
- there’s less question in my mind that a subpopulation with cardiovascular disease could benefit from statins but mainstream medical care seems far more aggressive that that, especially when dealing with asymptomatic elderly.
> "- studies that incorporate statins don’t seem to segregate impact of anti-inflammatory effect of some statins vs cholesterol lowering."
How would you tease that apart? CAD requires some amount of inflammation, since macrophages have to enter the blood vessel wall to become foam cells. So, it may be mechanistic that reducing LDL also reduces some markers of inflammation. If you have a method of testing statins' anti-inflammatory effects in some way that is independent of their LDL lowering effects, by all means someone would do that study.
> "- some docs are prescribing statins to healthy individuals based on only cholesterol scoring, also not taking into account more expensive but better imaging like coronary calcium scoring"
Coronary calcium scoring can be a good tiebreaker when someone's risk factors suggest that they should be on a statin, but they don't want to take a statin.
> "- Are there studies that show proactive use of statins on otherwise healthy individuals lead to decreased overall mortality?"
There are many primary prevention statin trials. They all involve people with at least one risk factor (high blood pressure, etc). I consider them trials in "healthy" people, since they don't yet have coronary artery disease, but if you meant people with zero risk factors, these wouldn't answer your question. Primary prevention trial examples: ASCOT https://www.ncbi.nlm.nih.gov/pubmed/14997313 and Jupiter https://www.ncbi.nlm.nih.gov/pubmed/18997196
> How would you tease that apart? CAD requires some amount of inflammation ...
This was my point. On one hand, statin supporters use these studies to say "cholesterol lowering" is warranted, but there's no quantification on how much protective effect is from its anti-inflammatory properties vs the cholesterol lowering aspects. The anti-inflammatory effect is also not tied to reducing LDL alone, but has separate mechanisms (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394171/). Rather than try to isolate the cholesterol lowering aspect, I'd be interested in studies that compared a range of anti-inflammatory drugs (other than just low-dose aspirin) to a variety of statins that also differ in the degree of their anti-inflammatory effects. But as far as I know (and I'm definitely no expert in this field), such studies have not been done.
> Coronary calcium scoring can be a good tiebreaker when someone's risk factors suggest that they should be on a statin, but they don't want to take a statin.
I know a healthy guy who has sky high LDL-P, didn't want to take a statin, and then got CAC imaging with a score of zero. If he hadn't talked his cardiologist into that scan, he'd be on a statin with all the side-effects it entails. That to me seems at odds with the "do no harm" mantra, especially when the CAC imaging seems more directly indicative of underlying CVD in asymptomatic individuals. There are many examples of people with low cholesterol (not on statins) who have underlying CVD as well as people with high cholesterol who have no CVD.
> There are many primary prevention statin trials. They all involve people with at least one risk factor (high blood pressure, etc). I consider them trials in "healthy" people, since they don't yet have coronary artery disease
Similar to your critique of the OP research paper, I am troubled with studies that treat all asymptomatic individuals the same and don't assess state of atherosclerosis (i.e., a CAC score) and differentiate types of risks (high blood pressure vs high cholesterol). The question is whether high cholesterol itself _in the absence of underlying pathology_ leads to worse outcome. If we have no idea whether the starting population has underlying pathology to begin with, IMHO there's a problem with extrapolating those results to asymptomatic people with those risk factors. Other risk factors like HBP may actually be causal.
What you're describing sounds like exactly what the CAC score is good for. Most people don't mind taking a statin if guidelines indicate that they should. But if they really want to avoid a statin, then a CAC of zero is reassuring.
I'm suggesting that the reliance on a very fallible test (LDL Cholesterol) for asymptomatic individuals is bad. People could be started on statin treatment and yet have no underlying pathology. I understand CAC imaging is expensive, but so is decades of statin treatments and potential side effect issues.
CAC imaging is expensive and exposes people to (a very small amount of) radiation. Statins are safe and well tolerated. Side effects are treated by temporarily stopping the medication. In people with an appropriately elevated risk, they are cost effective for risk reduction. I.e., they keep people alive longer. So, I don't agree that CAC screening is necessary or helpful prior to initiating therapy in most cases. CAC imaging is a good choice when there is equipoise or disagreement.
> In people with an appropriately elevated risk, they are cost effective for risk reduction.
And this is where this is disagreement. What is appropriately elevated risk? In the case of asymptomatic high cholesterol individuals, especially those without additional risk factors beyond cholesterol, (1) there are flawed studies that include people with underlying pathology together with people who have none to assess statin "benefit", and (2) there are flawed studies that show statins might actually be detrimental with regard to overall mortality. Mainstream medicine currently is fine with #1 (your "they keep people alive longer") and disregard #2 ("they are inversely associated with mortality").
I completely disagree with your dismissal of statin side effects and definite overplaying of the radiation dose of CAC scanning. Nobody has complete understanding of the full side-effect profile of long-term statin treatment let alone all the different types of statins. You have a point with expense, but lets not kid ourselves about the relative side effect profile of long-term statins vs a CAC scan. There's also the management advantages knowing CAC score vs just using LDL.
http://imaging.onlinejacc.org/content/10/3/304
"The presence of CAC is both a sensitive and specific indicator of atherosclerosis, while the total CAC score is a strong predictor of both short- and long-term clinical outcomes. A zero CAC score has become the most definitive predictor of low risk, mild CAC score elevations are indicators for initiating optimal prevention strategies, and high CAC scores may indicate the need for more aggressive management and follow-up. Furthermore, the test has become inexpensive and, with current imaging technologies, is associated with radiation exposure that has decreased to 1.0 to 1.5 mSv per study and to even lower radiation exposure with the newer low-dose imaging protocols (34)."
Average person receives about 3 mSv per year from natural sources. The annual dose for flight attendants is 1.5-1.7 mSv. Mammograms and CAC imaging is similar and less than what flight attendants get in a year.
As I have been doing throughout this thread, I'll continue to agree that a zero CAC score is a really valuable piece of prognostic data, and that the radiation dose is very small. But I'll continue to disagree that we need to scan every adult who qualifies for a statin. And I don't agree that the statin literature is a set of flawed studies. The statin literature is robust - this topic is one of the best-studied topics in medicine. Within medicine, this topic isn't controversial. Even the conservative USPSTF recommends statins for primary prevention above some cutoff: https://www.uspreventiveservicestaskforce.org/Page/Document/...
Re: there's robust literature on statins and it's settled. We're not talking about statin studies on CVD patients. We're talking about asymptomatic treatment. I'm not aware of any study that partitioned asymptomatic high-cholesterol individuals on underlying pathology, e.g., by CAC score, and then seeing if statins were of any benefit to the zero score group. That's because we wouldn't treat those individuals. Instead, all studies (used to argue for treatment of asymptomatic high-LDL) I'm aware of lump "high-risk" individuals together, give them all statins, and then say the outcome is improved for the whole group.
So on one hand, you argue the OP article is fatally flawed because the low-cholesterol group contains high-risk people given statins. On the other hand, you don't concede that the studies lumping all asymptomatic "high risk" individuals together suffer from the same issue. The EISNER study started with "an older population with baseline risk factors" and found 52% had CAC abnormality. I would be interested to see what percentage of asymptomatic high cholesterol people have CAC zero scores and would be treated with statins anyway under current guidelines.
There is a categorical difference between the OP, in which failure to account for statins creates the observation, and a clinical trial that successfully reduces mortality even though the event rate in the control arm wasn’t 100%. That difference is so great that there is almost no relationship between those scenarios.
You don’t know how many people in the low-cholesterol group were on statins in OP article, correct? And despite you completely downplaying it with “the event rate in the control arm wasn’t 100%”, you don’t know how many people in the high-cholesterol group in asymptomatic studies had zero CAC scores (e.g., 50% from EISNER). In both cases you are drawing a conclusion based on incomplete partitioning.
There’s also no consideration of non-CVD mortality and especially morbidity in most of these studies. Despite your unequivocal statement that (all) statins are safe, there’s still a lot we don’t know about long-term use including effects on cognition (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830056/).
My understanding of "the statin issue" is that in the 1970's drug companies found new chemicals to poison the liver's ability to manufacture cholesterol. They reasoned, "as cholseterol is a major part of the arteriosclerosis that hardens blood vessels, people whose bodies are depositing cholesterol where it shouldn't will benefit from poisoning their liver," and promoted the new patent medicines to medical professionals as anti-heart-disease medications.
The medical profession is rather vulnerable the promise of miracle cures to offer their patients, and prescribed the new anti-cholesterol drugs with gusto. Later studies have found the benefit of statin therapy to be minuscule: the "number needed to treat" to prevent one fatal cardiac event is rather high, on the order of 217 for low-risk patients [1]. That is, ~216 patients get to experience the side effects of artificially-reduced cholesterol levels while only 1 person avoids the problem the pill was prescribed to prevent.
In the holistic way of looking at the role of cholesterol, it is more important to think about why the body is manufacturing excess cholesterol and depositing it where it does. As you indicated above, inflammation is an important consideration. Another line of thinking is that there is a roadblock in the steroidogenesis pathway, and that supporting the body's effort to make steroids takes care of the elevated cholesterol levels too.
But our medical professionals tend to develop tunnel vision as they specialize, and assume their specialty's understandings of their domain is basically correct. The drug companies find it much more profitable to peddle anti-cholesterol drugs than to address patients' actual problems.
At least patients who are harmed by statins have the freedom to discontinue their anti-treatment.
Ravnskov, Uffe, Michel de Lorgeril, David M. Diamond, Rokuro Hama, Tomohito Hamazaki, Björn Hammarskjöld, Niamh Hynes, et al. 2018. “LDL-C Does Not Cause Cardiovascular Disease: A Comprehensive Review of the Current Literature.” Expert Review of Clinical Pharmacology 11 (10): 959–70. https://doi.org/10.1080/17512433.2018.1519391.
This review summarized the evidence in a way that most of the rest of the field would not. Fringe views are valuable, but unless they can actually refute the underlying hypothesis or provide a better model, the work is not very impactful. Particularly so with a review article.
As a somewhat overweight male approaching 60 with elevated cholesterol who has been on and off statins for years, the ridiculously inconclusive state of this research is very depressing.
I finally decided to stop taking them as they have annoying side effects and the cynic in me believes the science may have been pushed a bit off center by monetary incentives to the makers of these patented treatments.
I have absurdly high LDL levels, but can't tolerate them because they make all of my muscles stiff -- which consequently lead to a foot injury. My doctor considers me allergic to them, but I haven't been able to get my insurance to pay for another other treatments since they require that I also be on statins.
600K / 12M = 0.05 or 5% over 10 years. This means roughly 500 deaths / 100,000 annually. According to CDC (https://www.cdc.gov/nchs/fastats/deaths.htm) the death rate in the US is 850 deaths / 100,000. These aren't exactly apples to apples but that seems enough to say this doesn't look especially high-risk.
So if I am understanding the results correctly, lowering cholesterol beyond a certain limit can increase morbidity. The results are not at all surprising. The science behind cholesterol and statin drugs is not settled science. Drug companies are making 100s of billions of dollars selling statin drugs, and this money flows to researchers too, so the truth is very hard to know. “It’s almost impossible to find someone who believes strongly in statins who does not get a lot of money from industry,” says Dr. Rodney A. Hayward, professor of internal medicine at the University of Michigan Medical School. Read more here: https://medium.com/@petilon/cholesterol-and-statins-e7d9d8ee...
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[ 2.4 ms ] story [ 220 ms ] threadhttps://medlineplus.gov/cholesterollevelswhatyouneedtoknow.h...
It doesn't seem at all strange that there should be an optimum level that is non-zero.
[1] https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-in...
The body sythesizes sexual hormones from cholesterol.
> U-curve associations were found. In the TC ranges of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group).
Nothing. Absolutely nothing. Doubly so if you aren't eating animal products.
I'll add that avoiding all animal products has its own perils, namely the sort that results in vitamin deficiencies. And while a diet filled with whole grains and mostly plant-based foods is considered healthy, we simply don't know enough about nutrition to have one way or another. Or even to get vitamin doses right. I say all this while eating mostly vegetarian myself. I eat fish about once a week. I don't like it so much, but it is healthy.
wheat contains Phytic acid for example: https://en.wikipedia.org/wiki/Phytic_acid which can be reduced with the correct dough process.
The beta-carotene in carrots is fat soluble and the cells are pretty robust, so you get more out of them if you cook them in fat.
Champignons contain a mild poison, which is not deadly for humans but destroyed when heated, digestibility increases too.
There are even suggestions that it was cooking by opening untapped sources of calories that allowed for a bigger brain to evolve.
Are you part of a proper subculture that engages with this? If so, where do you all hang out, what do you read?
https://youtube.com/watch?v=MqmSMunAtss
Also, lose weight. The body induces some beneficial activity while fasting.
eg see https://www.aplaceformom.com/blog/2013-03-29-where-people-li...
Eat a varied diet, leaning towards plant-based foods. Whole grains if you can. Don't unreasonably cut out whole categories of food. Being vegan is HARD, vegetarian (or mostly so), not so much. Watch the sugar, including the fake type. Eat your calories instead of drink them.
Also, get some activity. Walking for 15 minutes daily is better than nothing, but try to get more than that most days. IF you can have fun doing it, great! If you lack motivation, do something on the easy side as it is easier to talk yourself into. It is better to this half-assed than not at all, after all, because it still counts.
Keep an eye on stress as much as possible. If you smoke, try quitting (I suggest a vape or e-cig). Drink in moderation, but do have some coffee.
Once you get these general things done, you are well on your way.
Perhaps the topic is complex and nuanced but the advise in the comment seems fairly good in the general healthy spectrum.
Besides some opinion being thrown in, what do you disagree with?
It's not, it's mildly tricky, and there's not much evidence that people following a vegan diet are nutritionally worse off than the people who don't think about their food at all, many of whom don't eat any fresh fruit or veg across a week.
I might be mostly vegetarian and eat eggs and cheese and fish once a week, but I usually tell folks to reduce their eat. Sometimes I say instead to make sure they eat enough fruit and veg and whole grain. I say this stuff because it is easier for most folks to concentrate on things like this to improve overall diet without feeling like they have to spend days figuring things out.
Also, it's worth noting that the difficulty of going vegan varies greatly with your location. For example, eating vegan in Japan is a legitimate pain in the ass.
There are lots of reasons a person can not have a period. Sure, you can be malnourished, but I'm guessing the more likely contributor was not having enough body fat. IF a woman's body fat is too low, she stops having periods. It happens in a broad cross section of people. A person with an eating disorder will do it as will a woman that works out a lot and eats healthily. Coincidentally, weighing too much can do it as well.
I'm guessing a nutrient deficiency can do it, but I'm unsure on that one. It can be a hormonal imbalance too!
And there are a bunch of other reasons as well. It isn't even necessarily harmful - after all, people quit having periods when they are on birth control with no ill effects.
You also seem to believe that eating meat, not only fruits/veggies/vegan, is good.
Wouldn’t that make you in agreement with the current system of balanced intake?
Public health organisations are staffed by experts who have spent most of their lives studying the relevant subjects. How likely is it that you, or anyone who hasn't dedicated that much time and effort in studying those subjects, will know better than those who have?
I'm not saying it's impossible, mind. But just what are the chances that your opinion is right and that of thousands of experts is wrong?
There have been some successes, we are now very good at catching CVD early, and should you have a heart attack you are now much more likely to survive than before. But on the food front, what we’re talking about here, it has been a complete and unmitigated disaster.
Because of that, I don’t trust public health officials one iota when it comes to food and diet. That doesn’t mean I’m right, but I know that they have a track record of failure and unintended consequences.
Also, as far as I know, public vaccination programmes have greatly reduced, and almost eliminated many diseases like measles, tetanus and typhoid, not just in the US but the world over, although of course measles is making a comeback.
Are you perhaps drawing a conclusion about public health bodies in western countries in general, from an experience with health services in the US? The US seems to be very peculiar in how it treats public health. I live in the UK and I wouldn't say that the national health service (the NHS) has collapsed. It has its problems and it's being attacked constantly but for the time being, it's working fine. The same is true for most central European countries.
Americans have actually followed the recommendations of the USDA for years. They replaced saturated fat with “heart healthy” seed oils, and they diligently consumed low fat diets.
Keep in mind that official recommendations will affect what foods are available for sale too.
> My understanding is that processed foods and sugary drinks are consumed in great numbers, but that is certainly not in accordance with the recommendation of any public health organisations that I know of.
In the United States nutrition labels have a maximum daily amount of most nutrients, except sugar. The official line has been that saturated fat causes heart disease, and that replacing fat in packaged goods with sugar was ok. This is why we have candy in the United States proudly labeling itself as a “fat free food”, and we used to have marketing campaigns touting the weight loss benefit of sugar.
This is finally starting to turn around, but the public health agencies have been laggards when it comes to the realization of how bad sugar is, not at the forefront.
And that’s not even getting into the whole bailiwick about how they process foods, which has changed in accordance with public health recommendations. They used to at least use natural fats in the few processed foods we used to eat, such as lard, but all of those were changed years ago to seed oils that were nominally less bad.
> Also, as far as I know, public vaccination programmes have greatly reduced, and almost eliminated many diseases like measles, tetanus and typhoid, not just in the US but the world over, although of course measles is making a comeback.
As I clearly stated, all public health programs should be judged by their outcomes, and the results of public vaccination have been an unqualified success.
But just because the official recommendations on vaccinations have worked, it doesn’t follow that the official recommendations on diet will too.
> Are you perhaps drawing a conclusion about public health bodies in western countries in general, from an experience with health services in the US?
Yes, that’s a fair criticism.
> I live in the UK and I wouldn't say that the national health service (the NHS) has collapsed.
That’s not what I said. I said that our health has collapsed, i.e. we’re fat and sick.
Did US public health organisations actually recommend replacing fat with sugars? I find this very surprising, if it is the case. I wouldn't be surprised if that was instead a practice adopted by industry, despite and against official recommendations.
For example, Wikipedia tells me that diet Coke was first sold in 1982. That must mean that there was, already, a clear awareness of the detrimental effect of sugar, and sugary drinks in particular, on health. That awareness can't have come from the soft drinks industry itself so it must have come from public health officials.
In 2015 they finally released a recommendation that sugar make up no more than 10% of an American’s daily calories, which is insane.
Also at a practical level, a recommendation to remove fat from diets is a recommendation to add sugar. A wide variety of foods are just absolutely disgusting if you have neither fat nor sugar, and if you declare that the reduction of dietary fat is the main goal for Americans, the result will necessarily be more added sugar. The dietary guidelines still recommend that Americans eat leaner cuts of meat and switch to 1% milk, as if they haven’t already done that.
Because HN is full of people who subscribe to fad diets like keto, carnivore, gluten-free, etc.
If anyone wants to have a healthy life, I recommend you to read the book Nutrition and Physical Degeneration from Weston Price. Basically, eat animal products, the more local based, the best. Grass feed cattle will be the best food source for your body. Cut all carbs (sugar), fruits (man made).
There are 15 nutrients that you can only get from animal products. You can get all minerals and vitamins from animal products you don't need plants at all.
The worst offenders for weight gain are foods that don’t trigger a satiation response, like chips and dip or French fries. Foods where the fat to carbohydrate ratio is nearing 1:1 will cause people to overeat. Processed foods tend to have these ratios.
https://www.nejm.org/doi/full/10.1056/NEJMoa1605086
Considering how complex this system is, measuring TC is like measuring average body temperature in the hospital.
It’s cool that they found a U-shape but this approach just makes patients(and doctors) hack the TC number without understanding how that affects lipoprotein composition and, subsequently, patient’s health.
That is really interesting, do you have a source you can recommend for reading further?
The whole series is a gold mine tbh
If they failed to account for statin use, then they will get the wrong answer due to confounding by indication.
https://twitter.com/skathire/status/1110909549811322880
Edit: Found it - they are not accounting for statin use! None of their conclusions seem warranted.
Why would you need to account for it? Trying to understand the logic here.
The study goes to showing the association between high cholesterol and all-cause mortality (which is what we really care about right?) is weak.
This would seem to diminish the benefits of statin use, all other things being equal.
With regard to the point of the study, they start by saying, "It is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age."
So, interpreting their statement, I would say that their goal with this study was to investigate whether the relationship between total cholesterol and mortality was consistent across age and sex. That is a different point from assessing the strength of the relationship between cholesterol and mortality.
I do agree, however, that there is no single biomarker aside from age that is a particularly powerful predictor of mortality in the general population.
[Edit] I just read another one of your comments that answers my question, and I think you're right: https://news.ycombinator.com/item?id=20138685
If you mean there are no reliable bio markers, period, it would be more clear to just say that.
We actually can measure the biological age. There are clinical biomarkers for that. It is not commonly done. The best one, epigenetic signature, is yet to be clinically approved or widely available.
Now, in that paper, they use broad range of age as a descriptor, confounding many age-associated phenotype and genotypes, which also translate into risk factors. You can definitely say that the 18-34 cohort is different 45-54, and that the later as more risk factors, the same a specific mutation might be associated with higher or even guaranteed chance of developing a disease, and hence will be use as a biomarker.
That being said, it is not typical to measure the biological age of healthy individuals. Actually, we don't know what an healthy individual is. We know a great deal more about diseased individuals. The current status seems to be that if you are not diseased you are healthy. I don't agree with that. That's how science is done. And that is how we end up with half-baked studies in one of the most impactful journal .
What is the precision and accuracy of the best biomarker? ie. if I gave you the necessary sample, how close can you get to the correct age and what are the error bars?
I didn't get enough from the tweets to understand how that was accounted for in the data. But I have questions.
By "inverts the causal relationship" I assume you threw "causal" in there by mistake. Nobody is going to think mortality causes high cholesterol. More importantly, if ignoring statin use reverses the slope to weaken the relationship "high cholesterol causes mortality" doesn't that suggest a lack of efficacy for statins? We know they lower cholesterol, but if that also reduces mortality the relationship (between cholesterol and mortality) should hold weather they are accounted for or not. Right?
Prevalent cardiovascular disease, or having a high risk for cardiovascular disease, causes low cholesterol. It does so by your doctor recognizing your elevated risk and putting you on statins.
Statins, like all drugs for prevention, do not prevent all subsequent disease. Perhaps most importantly, they only reduce cholesterol from the time you start taking them (as opposed to a genetically-driven low cholesterol throughout life). All of the drugs for chronic disease prevention tend to have a pretty small effect on the disease risk. Therefore, detecting that someone is taking a statin is a great signal that the person is at high risk for disease. They would be at an even higher risk if they weren't on a statin, but the statin does not erase all risk. That is why failing to account for statin use will lead to low cholesterol looking protective, if there are people in the population taking statins.
> First, the use of lipid-lowering medication was unaccounted for. The risk associated with high cholesterol might have been underestimated. However, in Korea, IHD mortality accounted for only approximately 5% of all-cause mortality, and only 10% of people with hypercholesterolemia received lipid-lowering therapy[39]. Therefore, the impact of not considering medication use is likely to be modest, and the TC levels in this study generally reflect levels without lipid-lowering medications
> only 10% of people with hypercholesterolemia received lipid-lowering therapy
Wouldn't this be much higher in the UK cohort? Also,
> The sex- and age- specific levels of TC in the current study of Koreans were lower than those reported in other high-income countries, including Japan, England, and the US
Which would reduce the effect (relative to what was found in the analysis of UK data) even further.
I don't think it adds a whole lot to talk about the confounding variables of this nature - it's an observational study, so of course it will have all sorts of confounding variables. If you are going to make a strong case that controlling for a specific confounding variable would reverse the relationship though, you should quantify the impact. It's unclear to me that statin usage would make a large difference, given that the study notes it wasn't a popular treatment.
My general feeling is that these types of studies tend to end up measuring overall health - given that most of the factors that lead to high cholesterol level were controlled for (BMI, physical activity, smoking status, drinking, etc) - and the average person in any population is relatively healthy and well-adjusted to the common diet, any large deviation from the norm in any direction statically makes it likely that the subject has some health issues.
What would be interesting to see in a meta-study is whether the optimal level of cholesterol either was consistent across populations that had very different averages or it tends to be near the median in each population. The former would be evidence that it's an independently meaningful biomarker; the latter would be evidence that it's just measuring how normal you are.
Also, I created those graphs and sent them to him, so (1) he didn't create the graphs or influence how they were created, and (2) and I have no financial interests in that company. His company plans to produce a molecule that disrupts PCSK9 production, thereby reducing LDL-cholesterol.
If you think that the conflict of interest influenced the analysis in a way that you would have done differently, what is the alternative approach by which you suggest analyzing the data?
Not all mortality risk operates through cholesterol-dependent mechanisms. And even for those that do, decades of exposure to high cholesterol can’t be totally reversed by medications.
Edit: they do decrease your risk of a heart attack a bit, but the increased incidence of cancer and diabetes actually eliminates the benefit for most users. The only people who showed any measurable reduction in mortality were non-elderly patients with a history of cardiovascular disease.
https://www.marksdailyapple.com/the-evidence-continues-to-mo...
Also interesting: Current physician guidelines don't recommend treating to a specific number, like <200. When I trained (<5 years ago) we were taught to check cholesterol levels and if LDL > n then start a statin and increase the dose until LDL < n.
Now, its (almost) entirely risk assessment based: https://www.acc.org/latest-in-cardiology/ten-points-to-remem...
They may lower cholesterol some amount, but in many populations this has almost 0 impact on morality. Watch out for those relative risk ratios.
But, across all fields of medicine, we know that confounding by indication is a problem. Preventive medicines, by and large, are not sufficiently powerful to reduce risk to zero.
Reverse causality has been suggested as an explanation of higher mortality associated with low cholesterol levels. However, a long term follow-up study in a Japanese-American population showed that individuals with low cholesterol levels maintained over a 20-year period had the worst all-cause mortality, and concluded that reverse causality was unlikely to account for the higher mortality associated with low cholesterol entirely14.
My reading of "reverse causality" here is that people with high TC have more cardiovascular disease and take more statins that lower their cholesterol. I haven't read the referenced study.
We have drugs (PKCS9 inhibitors: https://www.nejm.org/doi/full/10.1056/NEJMoa1615664, bile acid sequesterants, CETP Inhibitors: https://www.nejm.org/doi/full/10.1056/NEJMoa1609581) that can lower LDL to 10-20mg/dL — the later even increased HDL. No impact on cardiovascular mortality. The studies all use composite endpoints.
What might cause Atherosclerosis?
- Bacteria
- Bacterial lipid byproducts
- Endothelial damage from toxins (lead, mecury, etc)
- Endothelial glycation from high blood sugar (Diabetics have a lot of CVD)
- Bad genetics resulting in excess hemodynamic stress at coronary branch points (fun fact: CVD only develops in a few specific spots)
- Autoimmune conditions (higher rates of CVD in this population)
What most of these things have in common is they trigger the activation of the immune system.
Have you got a link to some relevant research?
https://www.marksdailyapple.com/the-evidence-continues-to-mo...
The CTT is probably the best summary of these data: https://www.cttcollaboration.org/
Is that a composite endpoint of vascular events AND mortality?
From TheNNT:
"It takes 5 years of daily statin therapy to achieve a 1.6% chance of avoiding a heart attack, and a 0.37% chance of avoiding a stroke. Most disappointing, statins seem unable to prevent death in this group. And most concerning, the drugs may increase diabetes, a serious and life-altering disease." (Primary Prevention)
http://www.thennt.com/nnt/statins-for-heart-disease-preventi...
0 http://www.drjohnm.org/2014/06/growing-doubt-on-statin-drugs...
Additionally, I think you will not find many studies that claim that high HDL is bad for you, whereas you will find many that claim it's good (because it protects from CVD). I can't say I see much of "a mess" here- just ordinary, progressing scientific understanding of a complex system.
Are there really any studies that attribute atherosclerosis to bacteria, or some of the other conditions you describe? If so- are there many of those and are they good quality studies? I am very skeptical of your comment's suggestion that the immune system may be involved in atherosclerosis.
Yes, folks agree high HDL is good, high LDL is bad. However, drug trials to raise HDL didn't work so well.
> "Are there really any studies that attribute atherosclerosis to bacteria, or some of the other conditions you describe?"
Yes! Many!
- "Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases" https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA....
- "Deposition and hydrolysis of serine dipeptide lipids of Bacteroidetes bacteria in human arteries: relationship to atherosclerosis"
- "The immune system in atherosclerosis" https://www.nature.com/articles/ni.2001
- "Is atherosclerosis an autoimmune disease?" https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-...
- "Atherosclerosis and the role of immune cells" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391004/
I keep getting the impression that using TC as a guide the ratio of number needed to treat vs morbidity reduced is kinda dismal.
https://www.youtube.com/watch?v=vBKa6d6j9_8
LDL-c is bad. LDL-p (the particle number), LDL size, and ApoB (which is the protein part of LDL) are all very well correlated with LDL-c. So, while some people prefer one measurement or another, they're all proxies for one another.
We have lifelong exposure to our genetics-and-diet-induced cholesterol levels, whereas clinical trials run for a few years. The long-term follow up of the statin trials show mortality reduction. PCSK9 inhibitors reduce all-cause mortality, and the long-term follow-up of the PCSK9 trials may or may not show the same for cardiovascular specific mortality. However, everyone in the field thinks they will, because those with loss-of-function PCSK9 variants live longer with less cardiovascular disease. Also, adjudicating the cause of death is hard - autopsy, if done, overturns the diagnosis nearly 60% of the time[1].
Cholesterol isn't the only risk factor for cardiovascular disease, so other things (like autoimmune conditions) will contribute to risk as well, but this isn't an either/or phenomenon.
1 = https://www.ncbi.nlm.nih.gov/pubmed/12913844
Check the evalocumab trial I posted, ACM was actually slightly worse in the PCSK9 side of the trial.
> "LDL-c is bad. LDL-p (the particle number), LDL size, and ApoB (which is the protein part of LDL) are all very well correlated with LDL-c. So, while some people prefer one measurement or another, they're all proxies for one another."
Yes, this tends to be true, however discordance between them is possible - and generally not a good thing.
> "Cholesterol isn't the only risk factor for cardiovascular disease"
Sure, but I think the whole of the field has rabbit-holed on lipids for too long, ignoring actual causal factors.
LDL cholesterol is by far the best established causal risk factor for coronary artery disease.
> "Check the evalocumab trial I posted, ACM was actually slightly worse in the PCSK9 side of the trial."
All cause mortality was significantly lower in Odyssey: https://www.nejm.org/doi/full/10.1056/NEJMoa1801174
Is it causal, or is it a risk factor? I'd say at best it is "necessary but not sufficient". CVD risk calculators don't even take LDL-C into account, that's how good of a marker it is.
- studies that incorporate statins don’t seem to segregate impact of anti-inflammatory effect of some statins vs cholesterol lowering.
- some docs are prescribing statins to healthy individuals based on only cholesterol scoring, also not taking into account more expensive but better imaging like coronary calcium scoring
- Are there studies that show proactive use of statins on otherwise healthy individuals lead to decreased overall mortality?
- there’s less question in my mind that a subpopulation with cardiovascular disease could benefit from statins but mainstream medical care seems far more aggressive that that, especially when dealing with asymptomatic elderly.
How would you tease that apart? CAD requires some amount of inflammation, since macrophages have to enter the blood vessel wall to become foam cells. So, it may be mechanistic that reducing LDL also reduces some markers of inflammation. If you have a method of testing statins' anti-inflammatory effects in some way that is independent of their LDL lowering effects, by all means someone would do that study.
> "- some docs are prescribing statins to healthy individuals based on only cholesterol scoring, also not taking into account more expensive but better imaging like coronary calcium scoring"
Coronary calcium scoring can be a good tiebreaker when someone's risk factors suggest that they should be on a statin, but they don't want to take a statin.
> "- Are there studies that show proactive use of statins on otherwise healthy individuals lead to decreased overall mortality?"
There are many primary prevention statin trials. They all involve people with at least one risk factor (high blood pressure, etc). I consider them trials in "healthy" people, since they don't yet have coronary artery disease, but if you meant people with zero risk factors, these wouldn't answer your question. Primary prevention trial examples: ASCOT https://www.ncbi.nlm.nih.gov/pubmed/14997313 and Jupiter https://www.ncbi.nlm.nih.gov/pubmed/18997196
This was my point. On one hand, statin supporters use these studies to say "cholesterol lowering" is warranted, but there's no quantification on how much protective effect is from its anti-inflammatory properties vs the cholesterol lowering aspects. The anti-inflammatory effect is also not tied to reducing LDL alone, but has separate mechanisms (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394171/). Rather than try to isolate the cholesterol lowering aspect, I'd be interested in studies that compared a range of anti-inflammatory drugs (other than just low-dose aspirin) to a variety of statins that also differ in the degree of their anti-inflammatory effects. But as far as I know (and I'm definitely no expert in this field), such studies have not been done.
> Coronary calcium scoring can be a good tiebreaker when someone's risk factors suggest that they should be on a statin, but they don't want to take a statin.
I know a healthy guy who has sky high LDL-P, didn't want to take a statin, and then got CAC imaging with a score of zero. If he hadn't talked his cardiologist into that scan, he'd be on a statin with all the side-effects it entails. That to me seems at odds with the "do no harm" mantra, especially when the CAC imaging seems more directly indicative of underlying CVD in asymptomatic individuals. There are many examples of people with low cholesterol (not on statins) who have underlying CVD as well as people with high cholesterol who have no CVD.
> There are many primary prevention statin trials. They all involve people with at least one risk factor (high blood pressure, etc). I consider them trials in "healthy" people, since they don't yet have coronary artery disease
Similar to your critique of the OP research paper, I am troubled with studies that treat all asymptomatic individuals the same and don't assess state of atherosclerosis (i.e., a CAC score) and differentiate types of risks (high blood pressure vs high cholesterol). The question is whether high cholesterol itself _in the absence of underlying pathology_ leads to worse outcome. If we have no idea whether the starting population has underlying pathology to begin with, IMHO there's a problem with extrapolating those results to asymptomatic people with those risk factors. Other risk factors like HBP may actually be causal.
And this is where this is disagreement. What is appropriately elevated risk? In the case of asymptomatic high cholesterol individuals, especially those without additional risk factors beyond cholesterol, (1) there are flawed studies that include people with underlying pathology together with people who have none to assess statin "benefit", and (2) there are flawed studies that show statins might actually be detrimental with regard to overall mortality. Mainstream medicine currently is fine with #1 (your "they keep people alive longer") and disregard #2 ("they are inversely associated with mortality").
I completely disagree with your dismissal of statin side effects and definite overplaying of the radiation dose of CAC scanning. Nobody has complete understanding of the full side-effect profile of long-term statin treatment let alone all the different types of statins. You have a point with expense, but lets not kid ourselves about the relative side effect profile of long-term statins vs a CAC scan. There's also the management advantages knowing CAC score vs just using LDL.
http://imaging.onlinejacc.org/content/10/3/304 "The presence of CAC is both a sensitive and specific indicator of atherosclerosis, while the total CAC score is a strong predictor of both short- and long-term clinical outcomes. A zero CAC score has become the most definitive predictor of low risk, mild CAC score elevations are indicators for initiating optimal prevention strategies, and high CAC scores may indicate the need for more aggressive management and follow-up. Furthermore, the test has become inexpensive and, with current imaging technologies, is associated with radiation exposure that has decreased to 1.0 to 1.5 mSv per study and to even lower radiation exposure with the newer low-dose imaging protocols (34)."
Average person receives about 3 mSv per year from natural sources. The annual dose for flight attendants is 1.5-1.7 mSv. Mammograms and CAC imaging is similar and less than what flight attendants get in a year.
So on one hand, you argue the OP article is fatally flawed because the low-cholesterol group contains high-risk people given statins. On the other hand, you don't concede that the studies lumping all asymptomatic "high risk" individuals together suffer from the same issue. The EISNER study started with "an older population with baseline risk factors" and found 52% had CAC abnormality. I would be interested to see what percentage of asymptomatic high cholesterol people have CAC zero scores and would be treated with statins anyway under current guidelines.
There’s also no consideration of non-CVD mortality and especially morbidity in most of these studies. Despite your unequivocal statement that (all) statins are safe, there’s still a lot we don’t know about long-term use including effects on cognition (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830056/).
The medical profession is rather vulnerable the promise of miracle cures to offer their patients, and prescribed the new anti-cholesterol drugs with gusto. Later studies have found the benefit of statin therapy to be minuscule: the "number needed to treat" to prevent one fatal cardiac event is rather high, on the order of 217 for low-risk patients [1]. That is, ~216 patients get to experience the side effects of artificially-reduced cholesterol levels while only 1 person avoids the problem the pill was prescribed to prevent.
In the holistic way of looking at the role of cholesterol, it is more important to think about why the body is manufacturing excess cholesterol and depositing it where it does. As you indicated above, inflammation is an important consideration. Another line of thinking is that there is a roadblock in the steroidogenesis pathway, and that supporting the body's effort to make steroids takes care of the elevated cholesterol levels too.
But our medical professionals tend to develop tunnel vision as they specialize, and assume their specialty's understandings of their domain is basically correct. The drug companies find it much more profitable to peddle anti-cholesterol drugs than to address patients' actual problems.
At least patients who are harmed by statins have the freedom to discontinue their anti-treatment.
[1] http://www.thennt.com/nnt/statins-persons-low-risk-cardiovas...
Is it really? For example:
Ravnskov, Uffe, Michel de Lorgeril, David M. Diamond, Rokuro Hama, Tomohito Hamazaki, Björn Hammarskjöld, Niamh Hynes, et al. 2018. “LDL-C Does Not Cause Cardiovascular Disease: A Comprehensive Review of the Current Literature.” Expert Review of Clinical Pharmacology 11 (10): 959–70. https://doi.org/10.1080/17512433.2018.1519391.
This review summarized the evidence in a way that most of the rest of the field would not. Fringe views are valuable, but unless they can actually refute the underlying hypothesis or provide a better model, the work is not very impactful. Particularly so with a review article.
I finally decided to stop taking them as they have annoying side effects and the cynic in me believes the science may have been pushed a bit off center by monetary incentives to the makers of these patented treatments.