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>You will do well to note that I said statins I did note that, and in my reply said that they (statins) don't treat the root cause. However, I used the exampl

• carbocation 16y ago
  Hmm, the point of torcetrapib was to increase HDL cholesterol, not reduce cholesterol. Most likely, it increased mortality via totally off target effects (see Rader's 2008 NEJM review on the topic). Looking at coronary calcification is no better than looking at lipoprotein fractions; both are intermediate endpoints. I see no reason to trust calcification if you don't trust LDL. Reduction in LDL correlates so well with reduction in mortality (statin trials) that fibrates got licensed on those grounds without showing reduced mortality. That is a problem, but not the fault of statins. It's an FDA-got-bought-out-by-pharma sort of problem. To reject the overwhelmingly data-backed LDL hypothesis, I'd need to see something much more compelling, I must say. Edit: your pubmed article addresses insulin resistance. Hypercholesterolemia is usually independent of that. In fact, high LDL is not even part of the metabolic syndrome... It seems as though you and I are not so much in disagreement as we are talking about different things entirely. I've been focusing on high cholesterol.
  • nunb 16y ago
    > both are intermediate endpoints. I see no reason to trust calcification if you don't trust LDL. I respectfully disagree. Cardiac deaths, including strokes, heart attacks etc., have many causes. One of the leading proximate causes is stenosis due to coronary atherosclerosis (which causes infarcts in heart muscle over time), and the mechanism involved there is the development of plaque in the intima of the coronary arteries: this plaque consists of [1] calcium deposits, fibrinogen and lipoprotein. It seems high CRP, fibrinogen and possibly homocysteine trigger calcium deposition and lipoprotein/platelet aggregation, thereby leading to plaque formation. Does insulin predispose cells to secrete calcium [2] (this would exacerbate the problem of inadequate vasodilation) ? [1] http://www.ncbi.nlm.nih.gov/pubmed/20551578 http://www.ncbi.nlm.nih.gov/pubmed/20551578 (yes, I am aware they found a low correlate with CRP and others, but that they're investigating indicates that the hypothesis exists) [2] http://www.ncbi.nlm.nih.gov/pubmed/17606264?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum http://www.ncbi.nlm.nih.gov/pubmed/17606264?ordinalpos=1&#38... In other words, I see CAC scores (Agatston scores) as far better markers of cardiac events. > Reduction in LDL correlates so well with reduction in mortality (statin trials) that fibrates got licensed on those grounds without showing reduced mortality. That is a problem, but not the fault of statins. It's an FDA-got-bought-out-by-pharma sort of problem. To reject the overwhelmingly data-backed LDL hypothesis, I'd need to see something much more compelling, I must say. As for "reduction in mortality", what about this study.. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12499611&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=S... In fact, if you would be so kind as to refer to some studies where, as you say "Reduction in LDL correlates so well with reduction in mortality (statin trials)", I would be very grateful, because, afaik usually those studies found "reduction in cardiac mortality", but all-cause mortality figures are more important (IOW, what if there are off-target effects with statins too, just not at the levels of clofibrate/torcetrapib?). From the abstract: > The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin. Since they found a J-curve, IOW, reduction in LDL does not correlate well with reduction in mortality. If LDL caused heart disease one would expect a dose-dependent relationship. Also would you agree that if there is, for example a U-shaped curve, average reductions in mortality, P-values etc. mean nothing and are misleading? IOW, it's a case of the aggregation hiding a vast disparity in outcome? It's a very interesting paper, and the full paper is available, which increases its value substantially. > your pubmed article addresses insulin resistance. Hypercholesterolemia is usually independent of that. Exactly. Hypercholesterolemia is independent of insulin resistance (IR), but IR (aka metabolic syndrome) is highly associated with cardiac mortality. IMHO this supports my point that in most cases, actual cholesterol numbers have very little to do with cardiac mortality (except for a few pathological cases of hypercholesterolemia as defined above some 500mg/dl etc). > In fact, high LDL is not even part of the metabolic syndrome. Again, that's exactly where I'm coming from. Metabolic syndrome (easiest identified by high triglycerides, low HDL, IR, intra-abdominal obesity [3]) is the "best" precursor/predictor for cardiac mortality. [3] http://www.ncbi.nlm.nih.gov/pubmed/19839225 http://www.ncbi.nlm.nih.gov/pubmed/19839225 > not so much in disagreement as we are talking about different things entirely. To loosely paraphrase Feynman, where there is unexplained data is where science has the potential to advance most. I think (and so do others, I'm not a lone loony) that IR, metabolic syndrome, diabetes, etc. have basically a common trigger, which is carbohydrate/omega-6 induced metabolic dysfunction (systemic dysfunction, I should add) -- this is basically a summary of the second part of Taubes' book. > I've been focusing on high cholesterol. What do you mean by cholesterol exactly? What method of assay do you refer to, and what do you consider as the significant numeric values? We have so many better markers now, ApoA/B ratios, HDL/Triglyceride ratios, homocysteine, inflammation factors and fibrinogen. Cholesterol by itself has been recognized as a completely inadequate explanatory factor, heck, everyone now knows that eating eggs and their cholesterol has no effect (other than a small beneficial one) on cardiac events. Tangential at this point: > Reduction in LDL correlates so well with reduction in mortality (statin trials) that fibrates got licensed on those grounds without showing reduced mortality. That is a problem, but not the fault of statins. It's an FDA-got-bought-out-by-pharma sort of problem. I agree with you overall, that it seems fibrates sneaked in under the wire, but (conspiracy hat on) if the pharmas are devious enough for that, are they not devious enough to also massage data and corrupt researchers? :-) One hopes not, but I am trying to point out that the fibrates fiasco (again, other fibrates are still, afaik, under consideration, though it's probably harder now that they have the clofibrate rap to contend with) is a symptom of the pervasive "treat the numbers" mentality. I wish they would adopt a "find the mechanism" attitude instead.