6 ms·

No, everything you mentioned says that LDL-C levels correlates with cardiovascular disease rather than causes. Mutation in LDLR gene is a cause. LDL-C level is

No, everything you mentioned says that LDL-C levels correlates with cardiovascular disease rather than causes. Mutation in LDLR gene is a cause. LDL-C level is a correlate. The mutation may or may not have additional repercussions other than just higher level of LDL-C. Like with many metabolic issues - the problem sometimes truly is the high level of (toxic) product, sometimes overload of the compensatory mechanism (competitive inhibition etc.), sometimes the product is innocent but the mutation has other effects. PCSK9 inhibitors... I would be very careful. These might be just as inconsistent as statins with equivocal evidence. For now, Cochrane agrees. (Cochrane cancelled 2018 rereview of statins due to methodology update, the 2013 one is somewhat suspect. Later fluvastatin review shows it's not potent enough etc. But this is all tangential.) At least they will shine more light on the LDL-C hypothesis than statins which have more complex effects. They are still not sensitive enough to rule out other mechanisms. The drugs only recently exited phase III trials. To accurately conclude LDL-C causes cardiovascular disease you will have to figure out a way to increase LDL-C in absence of other relevant factors. Or perhaps strongly control for those factors. This is actually hard. (among them: obesity, smoking, diet and excercise, gene variants) This should be quite possible to verify in animal model by pumping them with relevant lipids regularly. Not entirely sure how to extend this to human trials, but a way can be found. If you have such results, I'd like to read them.

resters 8y ago
I hope et2o replies. This is an interesting back and forth already.
- et2o 8y ago
  See above :-) I hope he/she replies to me!
et2o 8y ago
There are literally hundreds to thousands of papers where they have done exactly this: Feed animals a high-cholesterol diet and compare the results to control animals fed a normal diet. Usually they will also compare different drugs in separate experimental arms. The LDL diet is a positive control, the normal diet is a negative control, and the drug arms are usually the intervention being tested. How much evidence do you want? This (molecular imaging of atherosclerosis) is an entire subfield of medicine with tons of work. I myself have done this in rabbits, followed by by molecular imaging (Tc-99m bound to various ligands) which directly image atherosclerosis in the animal. We use single photon emission computed tomography (SPECT) as well as position emission tomography (PET) to quantitatively measure atherosclerotic burden. We also sacrifice the animals and remove their arteries–upon unmagnified visual inspection of the plaques in the arteries, I can tell you which animals get which diet. I'm not going to debate all of your points. Sure, it's possible there are other potential explanations for FH or PCSK9. However, they are not likely. Also, mendelian randomization studies are use a causal inference strategy via instrumental variable analysis, getting around the idea that we are measuring only correlations. It's a very nice technique which mimics a randomized controlled trial via the random assignment of genetic material during gametogenesis. So I don't agree with you. Last thing: The equivocal evidence of statin therapy is only in primary prevention, not in secondary prevention. No one is really challenging that statins work, the question is what population is of high enough risk that they should get statins. This is widely misreported in the popular media and pretty harmful to patients who see a headline and stop taking their drugs.
- AstralStorm 8y ago
  High cholesterol diet is not the same as high blood level of lipids. There are many steps inbetween. It is additionally not the same as the high occurence of atheroma. Even more steps. You've introduced an additional super complex variable (diet) where there should be none (blood level of LDL-C). I do not dispute accuracy of atheroma measurements at all. This is easy enough technicality. What is this "LDL diet" anyway? Do you feed animals with lipids? If you mean high saturated fat diet, then that's a different beast. It does many more things than just increase LDL-C levels - it also increases TG levels, LDL levels in total, places metabolic burden on liver and more interesting things. Even there, the trials are rightly calling these levels correlates. Not causes. And it is not a pedantic point, it is critical and informs the way we should be dealing with related CVD. Secondary prevention wrt statins, hmm, I see one good USPTF study. It includes primary prevention too and has well defined results which are mildly positive. It actually says you're not allowed to attribute statin results to LDL-C levels as LDL-C dose/response strategies were not superior to plain fixed dose. More importantly, this area has not been evaluated with enough power. https://jamanetwork.com/journals/jama/fullarticle/2584057 https://jamanetwork.com/journals/jama/fullarticle/2584057 Key point 1b. No dose response, likely no direct causation. Suspected mechanism is thus different from direct LDL-C levels. Most importantly: "Benefits of statins did not appear to be restricted to patients with severely elevated lipid levels, because similar effects were observed in subgroups stratified according to baseline levels." We have barely enough statistical power to say they're superior, not even figure out the dosage in 3 levels. Interesting fact there being that biggest trials reported smallest relative risk reduction. (~15% with pretty big error bars on this.) Absolute risk values are even more funny, like ~0.5% reduction... in high risk groups.
  - et2o 8y ago
    We feed the animals regular chow mixed with a percentage of pure cholesterol (0.5% by mass, if I recall, but I might be wrong). I do not mean a high saturated fat diet. This is not the introduction of complex "diet" variables as in humans whatsoever. I am quite aware of the differences in various lipids. Feeding animals pure cholesterol is about as close as we can get. There might be studies that have literally infused LDL in animals, I am not exactly sure. It sounds like a huge pain to do experimentally since we would need to obtain vascular access at least each day and risk infection, stress and pain in the animals, etc. We measure animal blood using the same machines used on humans and see primarily increases in total cholesterol and LDL cholesterol following the diet. There is not "one good" study for secondary prevention of statins, there are dozens. There is very good evidence for the effectiveness of dose-response in statins. Again, I don't even know where exactly to start with this body of literature. Look up "high intensity statin therapy." This review for primary prevention, which is probably why it was underpowered in this meta-analysis of 19 trials in primary prevention (where I said the evidence was more equivocal; this study actually shows pretty good evidence for the effectiveness of statins. in 1° prevention). A RR of 0.86 in only 1-6 years is pretty damn good for a chronic disease. Finally, I think you misunderstand statistics when you say that this review (in which there were only three studies which could be used to analyze dose-response) implies there is no dose response. When they analyze dose-response (which is done through increasing statin dosage until the LDL-C levels are low enough), I quote: "RR for cardiovascular mortality, 0.61 [95% CI, 0.37 to 1.02]" Yes, this is underpowered because the CI includes 1 but the point estimate of 0.6 is pretty impressive. This is a poor conclusion by the authors via incorrect application of the NHST framework, and not evidence that there is no dose-response effect. The best evidence is actually pretty strong (RR of 0.6 is big!). I personally doubt it's even that big. Furthermore, RR for composite cardiovascular outcomes, 0.63 [95% CI, 0.53 to 0.76] was very statistically significant and again with a pretty strong signal. So I don't think this paper says what you say it does. You didn't feel the need to address mendelian randomization studies in 500,000 plus people?

resters 8y ago

I hope et2o replies. This is an interesting back and forth already.

et2o 8y ago
See above :-) I hope he/she replies to me!

et2o 8y ago

There are literally hundreds to thousands of papers where they have done exactly this: Feed animals a high-cholesterol diet and compare the results to control animals fed a normal diet. Usually they will also compare different drugs in separate experimental arms. The LDL diet is a positive control, the normal diet is a negative control, and the drug arms are usually the intervention being tested. How much evidence do you want? This (molecular imaging of atherosclerosis) is an entire subfield of medicine with tons of work. I myself have done this in rabbits, followed by by molecular imaging (Tc-99m bound to various ligands) which directly image atherosclerosis in the animal. We use single photon emission computed tomography (SPECT) as well as position emission tomography (PET) to quantitatively measure atherosclerotic burden. We also sacrifice the animals and remove their arteries–upon unmagnified visual inspection of the plaques in the arteries, I can tell you which animals get which diet. I'm not going to debate all of your points. Sure, it's possible there are other potential explanations for FH or PCSK9. However, they are not likely. Also, mendelian randomization studies are use a causal inference strategy via instrumental variable analysis, getting around the idea that we are measuring only correlations. It's a very nice technique which mimics a randomized controlled trial via the random assignment of genetic material during gametogenesis. So I don't agree with you. Last thing: The equivocal evidence of statin therapy is only in primary prevention, not in secondary prevention. No one is really challenging that statins work, the question is what population is of high enough risk that they should get statins. This is widely misreported in the popular media and pretty harmful to patients who see a headline and stop taking their drugs.

AstralStorm 8y ago
High cholesterol diet is not the same as high blood level of lipids. There are many steps inbetween. It is additionally not the same as the high occurence of atheroma. Even more steps. You've introduced an additional super complex variable (diet) where there should be none (blood level of LDL-C). I do not dispute accuracy of atheroma measurements at all. This is easy enough technicality. What is this "LDL diet" anyway? Do you feed animals with lipids? If you mean high saturated fat diet, then that's a different beast. It does many more things than just increase LDL-C levels - it also increases TG levels, LDL levels in total, places metabolic burden on liver and more interesting things. Even there, the trials are rightly calling these levels correlates. Not causes. And it is not a pedantic point, it is critical and informs the way we should be dealing with related CVD. Secondary prevention wrt statins, hmm, I see one good USPTF study. It includes primary prevention too and has well defined results which are mildly positive. It actually says you're not allowed to attribute statin results to LDL-C levels as LDL-C dose/response strategies were not superior to plain fixed dose. More importantly, this area has not been evaluated with enough power. https://jamanetwork.com/journals/jama/fullarticle/2584057 https://jamanetwork.com/journals/jama/fullarticle/2584057 Key point 1b. No dose response, likely no direct causation. Suspected mechanism is thus different from direct LDL-C levels. Most importantly: "Benefits of statins did not appear to be restricted to patients with severely elevated lipid levels, because similar effects were observed in subgroups stratified according to baseline levels." We have barely enough statistical power to say they're superior, not even figure out the dosage in 3 levels. Interesting fact there being that biggest trials reported smallest relative risk reduction. (~15% with pretty big error bars on this.) Absolute risk values are even more funny, like ~0.5% reduction... in high risk groups.
- et2o 8y ago
  We feed the animals regular chow mixed with a percentage of pure cholesterol (0.5% by mass, if I recall, but I might be wrong). I do not mean a high saturated fat diet. This is not the introduction of complex "diet" variables as in humans whatsoever. I am quite aware of the differences in various lipids. Feeding animals pure cholesterol is about as close as we can get. There might be studies that have literally infused LDL in animals, I am not exactly sure. It sounds like a huge pain to do experimentally since we would need to obtain vascular access at least each day and risk infection, stress and pain in the animals, etc. We measure animal blood using the same machines used on humans and see primarily increases in total cholesterol and LDL cholesterol following the diet. There is not "one good" study for secondary prevention of statins, there are dozens. There is very good evidence for the effectiveness of dose-response in statins. Again, I don't even know where exactly to start with this body of literature. Look up "high intensity statin therapy." This review for primary prevention, which is probably why it was underpowered in this meta-analysis of 19 trials in primary prevention (where I said the evidence was more equivocal; this study actually shows pretty good evidence for the effectiveness of statins. in 1° prevention). A RR of 0.86 in only 1-6 years is pretty damn good for a chronic disease. Finally, I think you misunderstand statistics when you say that this review (in which there were only three studies which could be used to analyze dose-response) implies there is no dose response. When they analyze dose-response (which is done through increasing statin dosage until the LDL-C levels are low enough), I quote: "RR for cardiovascular mortality, 0.61 [95% CI, 0.37 to 1.02]" Yes, this is underpowered because the CI includes 1 but the point estimate of 0.6 is pretty impressive. This is a poor conclusion by the authors via incorrect application of the NHST framework, and not evidence that there is no dose-response effect. The best evidence is actually pretty strong (RR of 0.6 is big!). I personally doubt it's even that big. Furthermore, RR for composite cardiovascular outcomes, 0.63 [95% CI, 0.53 to 0.76] was very statistically significant and again with a pretty strong signal. So I don't think this paper says what you say it does. You didn't feel the need to address mendelian randomization studies in 500,000 plus people?