8 ms·

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

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. 1 = https://www.ncbi.nlm.nih.gov/pubmed/12913844 https://www.ncbi.nlm.nih.gov/pubmed/12913844

keymone 7y ago
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)
- carbocation 7y ago
  This is simply incorrect.
  - keymone 7y ago
    https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1519391 https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1...
Joeri 7y ago
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.
- carbocation 7y ago
  You're correct, which is why these trials are placebo controlled and double blinded.
virtuallynathan 7y ago
> "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.
- carbocation 7y ago
  > "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 https://www.nejm.org/doi/full/10.1056/NEJMoa1801174
  - virtuallynathan 7y ago
    > 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.
DocSavage 7y ago
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.
- carbocation 7y ago
  > "- 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 https://www.ncbi.nlm.nih.gov/pubmed/14997313 and Jupiter https://www.ncbi.nlm.nih.gov/pubmed/18997196 https://www.ncbi.nlm.nih.gov/pubmed/18997196
  - 7y ago
insulanus 7y ago
Hi there, by "this view", I take it you mean the article, not what virtuallynathan was saying. Is that correct?
- carbocation 7y ago
  No, what virtuallynathan said is not mainstream.
ar-jan 7y ago
> LDL-c is bad. 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 https://doi.org/10.1080/17512433.2018.1519391.
- carbocation 7y ago
  You can find fringe material in any topic. 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.

keymone 7y ago

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)

carbocation 7y ago
This is simply incorrect.
- keymone 7y ago
  https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1519391 https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1...

Joeri 7y ago

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.

carbocation 7y ago
You're correct, which is why these trials are placebo controlled and double blinded.

virtuallynathan 7y ago

> "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.

carbocation 7y ago
> "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 https://www.nejm.org/doi/full/10.1056/NEJMoa1801174
- virtuallynathan 7y ago
  > 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.

DocSavage 7y ago

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.

carbocation 7y ago
> "- 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 https://www.ncbi.nlm.nih.gov/pubmed/14997313 and Jupiter https://www.ncbi.nlm.nih.gov/pubmed/18997196 https://www.ncbi.nlm.nih.gov/pubmed/18997196
- 7y ago

insulanus 7y ago

Hi there, by "this view", I take it you mean the article, not what virtuallynathan was saying. Is that correct?

carbocation 7y ago
No, what virtuallynathan said is not mainstream.

ar-jan 7y ago

> LDL-c is bad. 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 https://doi.org/10.1080/17512433.2018.1519391.

carbocation 7y ago
You can find fringe material in any topic. 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.