4 ms·

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 a

by 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?
  - AstralStorm 8y ago
    I'm not disputing effectiveness of statins one bit. They're effective, though not as hugely effective as we're led to believe by marketing. (15% RRR is probably worthwhile even if we don't know how these work.) I'm disputing that the effect is related to LDL-C. There were no important differences in trials that titrated based on LDL-C or used fixed dose. Compare RR 0.63 vs 0.71 and full error bar overlap. There were also no relevant differences of outcome based on stratification by LDL-C levels. I did not feel the need to address "genetic"/"metabolomic" studies. (Also known as data sifting.) Standard MR is essentially n-D crosscorrelation of LDL-C levels with LDLR genetic variant and CHD occurences. We know that beforehand. It doesn't tell us anything of causation nor anything we don't know. The authors like to misuse R as "explains". The stronger MR variant results suggest adiposity causes LDL-C levels. Which we already know, again, does not give us a clear treatment target. The other advanced studies pinpoint specific lipids as the cause of CHD, but cannot say where they are from. And no, they're not quite LDL-C. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816855/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816855/ I'm not entirely sure how the authors got the rationale from what they're writing about. The better MR-like methods as mentioned are like stepwise crosscorrelation and median clustering. Not entirely sure how they can actually show causality. When the statistical guesswork method (MR is one kind of) does not match the observations... it is likely that either the method is incorrect or that our treatment is misapplied and reality does not match it. MR suggests RRR 3.5 for all LDL-C lowering drugs. We see 1.15 on statins and none on PCSK9 inhibitors vs CVD mortality. I'd bet on MR being invalid/confused.

by et2o 8y ago

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?
- AstralStorm 8y ago
  I'm not disputing effectiveness of statins one bit. They're effective, though not as hugely effective as we're led to believe by marketing. (15% RRR is probably worthwhile even if we don't know how these work.) I'm disputing that the effect is related to LDL-C. There were no important differences in trials that titrated based on LDL-C or used fixed dose. Compare RR 0.63 vs 0.71 and full error bar overlap. There were also no relevant differences of outcome based on stratification by LDL-C levels. I did not feel the need to address "genetic"/"metabolomic" studies. (Also known as data sifting.) Standard MR is essentially n-D crosscorrelation of LDL-C levels with LDLR genetic variant and CHD occurences. We know that beforehand. It doesn't tell us anything of causation nor anything we don't know. The authors like to misuse R as "explains". The stronger MR variant results suggest adiposity causes LDL-C levels. Which we already know, again, does not give us a clear treatment target. The other advanced studies pinpoint specific lipids as the cause of CHD, but cannot say where they are from. And no, they're not quite LDL-C. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816855/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816855/ I'm not entirely sure how the authors got the rationale from what they're writing about. The better MR-like methods as mentioned are like stepwise crosscorrelation and median clustering. Not entirely sure how they can actually show causality. When the statistical guesswork method (MR is one kind of) does not match the observations... it is likely that either the method is incorrect or that our treatment is misapplied and reality does not match it. MR suggests RRR 3.5 for all LDL-C lowering drugs. We see 1.15 on statins and none on PCSK9 inhibitors vs CVD mortality. I'd bet on MR being invalid/confused.