6 ms·

Cardiovascular geneticist/statistician and physician-in-training here: This is a completely bogus and scientifically illiterate review. This small group of peop

by et2o 8y ago

Cardiovascular geneticist/statistician and physician-in-training here: This is a completely bogus and scientifically illiterate review. This small group of people in Sweden keep publishing crap like this and it's frankly kind of annoying. It's hard to even know where to start with the overwhelming amount of evidence that elevated levels of LDL cholesterol causes cardiovascular disease. Since I'm a geneticist, I'll point out just a handful of strong genetics-guided experiments: 1) Familial hypercholesterolemia - Mutations in the LDLR Gene causing basically only elevated LDL lead to 10x increased odds for coronary artery disease 2) PCSK9 inhibitors - essentially only reduce LDL concentration, dramatically reduce risk 3) Mendelian randomization techniques - statistical causal inference in massive datasets shows pretty conclusively LDL increases CVD Yes, LDL cholesterol causes CVD. Yes, there are other factors as well (especially hemodynamics and chronic inflammation).

avip 8y ago
Without any prior opinion or familiarity, the fact the paper opened with Karl Popper was enough to make me very skeptic about the content.
- resters 8y ago
  It simply locates the article as being anchored in the philosophy of science championed by Popper. I should hope any meta-critique would be similarly rooted.
alexandercrohde 8y ago
Why do you think the journal accepted it for publication?
- et2o 8y ago
  Could be a number of reasons: 1) Bad stuff sneaks in everywhere if you get lucky with two reviewers and an editor asleep at the wheel. Even good journals. Not usually this bad, though. 2) This isn't a particularly good journal and isn't a cardiovascular journal, so they probably got two reviewers who are not knowledgeable about the field. 3) It might also have been an invited paper. These medoum-low journals often solicit reviews, and it's pretty rare to reject a paper that you've solicited.
AstralStorm 8y ago
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.
resters 8y ago
What would you say are the weakest aspects of the scientific consensus on LDL-C? Not doubting your 3 main points, just curious what you would identify as the weakest links in the reasoning as someone within the profession.
- et2o 8y ago
  This is a really good question. I'll list a few in no particular order: From my perspective, cardiology for a while was misunderstanding the contribution made to CVD from exogenous cholesterol (what you eat) vs. endogenous cholesterol (what your body makes/transports around). Initially there was a lot of focus on reducing dietary cholesterol. This isn't "Wrong" with a capital "W", but emerging evidence seems to indicate that dietary cholesterol doesn't play as big of a result as a person's endogenous cholesterol processes. However, it's still good to eat a lower cholesterol diet. A lot of the resistance to LDL-C evidence comes from people who want patients to eat less refined sugar. This is 100% a great idea; refined sugar is bad for you metabolically for a number of reasons. However, it's not an either-or proposition and I can't understand why people keep making this case. Finally, I think we are still working out the role chronic inflammatory processes play in cardiovascular disease. They are an important component of the atherosclerotic process and one of the three main "knobs" we have available to twist with medication (the major other ones being blood pressure via antihypertensives and LDL via statins/PCSK9is). However, our typical anti-inflammatory drugs don't really work for cardiovascular disease yet the most common ones work on the COX pathway, which (I don't want to get into it, but it's pretty well studied) in chronic use actually causes increased risk for things like heart attack via upregulation of various prostaglandins that you don't want upregulated. There's some really interesting work on monoclonal antibodies targeting different inflammatory pathways that seems promising, but it's (1) still a ways in the future and (2) seems to be less powerful (so far) than is managing BP and LDL. Edit: Also, if you had asked me five years ago, I'd say that the evidence for the pleiotropic effects of statins (e.g., effects of statins on things other than LDL cholesterol) were pretty interesting. And they were, 5 years ago! However, a lot of good evidence has come out since then showing that most of the effects of statins can be attributed by their action on LDL. It seems like the pleiotropic effects of statin therapy are getting less and less significant as we study them more. For me, this emerging evidence was actually kind of disappointing as I had been planning a few studies to look at statin pleiotropy.
BeetleB 8y ago
As someone who is not expert, what's annoying is having to play the game of "Who do I believe?" You have your points, and they have their meta-study. I don't want to dismiss their study just because you don't like their journal, which is a bit of an ad hominem. And the problem is you are making your case, but not actually addressing their study. So my request to you: If you were a journal referee and this paper landed on your desk for review, what would your response to the editor be? I think many here would like to hear your criticism of the actual study. Thanks.
- et2o 8y ago
  To give an analogy, I feel a bit like a global warming scientist (I don't actually know anything about global warming-I just understand it's a scientific consensus with a really vocal but marginal minority). It's not just me, it's me and 99% of cardiovascular scientists vs. a few people scattered around the world. Extraordinary claims require extraordinary evidence, and this paper glosses over literally hundreds of contradictory studies, cherry picks a few that sort of support it, and wraps it all with some rhetorical flourishes. It's not science. I usually take at least two Or three hours to review a paper. I'm not sure if I want to waste my time writing out line by line all of the mistakes. something like this will require even more time since I would feel the duty to to dig up dozens and dozens and dozens of papers which would contradict them. If that would change your mind, I'll think about doing it. Finally, I said it's "annoying" because I work really hard on all my reviews and papers to make sure what I am publishing is right. The goofballs slap some crap together with only a passing understanding of the evidence and get another line on their CV. Feel free to ignore this ad hominem but hopefully it helps to understand my perspective.

by et2o 8y ago

avip 8y ago

Without any prior opinion or familiarity, the fact the paper opened with Karl Popper was enough to make me very skeptic about the content.

resters 8y ago
It simply locates the article as being anchored in the philosophy of science championed by Popper. I should hope any meta-critique would be similarly rooted.

alexandercrohde 8y ago

Why do you think the journal accepted it for publication?

et2o 8y ago
Could be a number of reasons: 1) Bad stuff sneaks in everywhere if you get lucky with two reviewers and an editor asleep at the wheel. Even good journals. Not usually this bad, though. 2) This isn't a particularly good journal and isn't a cardiovascular journal, so they probably got two reviewers who are not knowledgeable about the field. 3) It might also have been an invited paper. These medoum-low journals often solicit reviews, and it's pretty rare to reject a paper that you've solicited.

AstralStorm 8y ago

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.

resters 8y ago

What would you say are the weakest aspects of the scientific consensus on LDL-C? Not doubting your 3 main points, just curious what you would identify as the weakest links in the reasoning as someone within the profession.

et2o 8y ago
This is a really good question. I'll list a few in no particular order: From my perspective, cardiology for a while was misunderstanding the contribution made to CVD from exogenous cholesterol (what you eat) vs. endogenous cholesterol (what your body makes/transports around). Initially there was a lot of focus on reducing dietary cholesterol. This isn't "Wrong" with a capital "W", but emerging evidence seems to indicate that dietary cholesterol doesn't play as big of a result as a person's endogenous cholesterol processes. However, it's still good to eat a lower cholesterol diet. A lot of the resistance to LDL-C evidence comes from people who want patients to eat less refined sugar. This is 100% a great idea; refined sugar is bad for you metabolically for a number of reasons. However, it's not an either-or proposition and I can't understand why people keep making this case. Finally, I think we are still working out the role chronic inflammatory processes play in cardiovascular disease. They are an important component of the atherosclerotic process and one of the three main "knobs" we have available to twist with medication (the major other ones being blood pressure via antihypertensives and LDL via statins/PCSK9is). However, our typical anti-inflammatory drugs don't really work for cardiovascular disease yet the most common ones work on the COX pathway, which (I don't want to get into it, but it's pretty well studied) in chronic use actually causes increased risk for things like heart attack via upregulation of various prostaglandins that you don't want upregulated. There's some really interesting work on monoclonal antibodies targeting different inflammatory pathways that seems promising, but it's (1) still a ways in the future and (2) seems to be less powerful (so far) than is managing BP and LDL. Edit: Also, if you had asked me five years ago, I'd say that the evidence for the pleiotropic effects of statins (e.g., effects of statins on things other than LDL cholesterol) were pretty interesting. And they were, 5 years ago! However, a lot of good evidence has come out since then showing that most of the effects of statins can be attributed by their action on LDL. It seems like the pleiotropic effects of statin therapy are getting less and less significant as we study them more. For me, this emerging evidence was actually kind of disappointing as I had been planning a few studies to look at statin pleiotropy.

BeetleB 8y ago

As someone who is not expert, what's annoying is having to play the game of "Who do I believe?" You have your points, and they have their meta-study. I don't want to dismiss their study just because you don't like their journal, which is a bit of an ad hominem. And the problem is you are making your case, but not actually addressing their study. So my request to you: If you were a journal referee and this paper landed on your desk for review, what would your response to the editor be? I think many here would like to hear your criticism of the actual study. Thanks.

et2o 8y ago
To give an analogy, I feel a bit like a global warming scientist (I don't actually know anything about global warming-I just understand it's a scientific consensus with a really vocal but marginal minority). It's not just me, it's me and 99% of cardiovascular scientists vs. a few people scattered around the world. Extraordinary claims require extraordinary evidence, and this paper glosses over literally hundreds of contradictory studies, cherry picks a few that sort of support it, and wraps it all with some rhetorical flourishes. It's not science. I usually take at least two Or three hours to review a paper. I'm not sure if I want to waste my time writing out line by line all of the mistakes. something like this will require even more time since I would feel the duty to to dig up dozens and dozens and dozens of papers which would contradict them. If that would change your mind, I'll think about doing it. Finally, I said it's "annoying" because I work really hard on all my reviews and papers to make sure what I am publishing is right. The goofballs slap some crap together with only a passing understanding of the evidence and get another line on their CV. Feel free to ignore this ad hominem but hopefully it helps to understand my perspective.