Monday, March 31, 2008
Cholesterol; statins kill?
Just a quickie.
Go read Dr Eades' blog here. For anyone who has read the J-litt study, or more especially line one of table 6 on page 1092, none of this will come as a surprise. There is a level of LDL below which repair cells just won't get enough cholesterol and lipid to patch the hole in the intima left by the apoptosis of an endothelial cell. The repair will then be botched with a next best like Lp(a).
Interesting development.
Peter
Go read Dr Eades' blog here. For anyone who has read the J-litt study, or more especially line one of table 6 on page 1092, none of this will come as a surprise. There is a level of LDL below which repair cells just won't get enough cholesterol and lipid to patch the hole in the intima left by the apoptosis of an endothelial cell. The repair will then be botched with a next best like Lp(a).
Interesting development.
Peter
Monday, March 10, 2008
Brain on a statin
Apoptosis is an essential component of the maintenance process of our bodies. It is a highly controlled and organised technique for removing unwanted cells from any organ by the process of induced metabolic suicide.
Tinkering with this process is a potentially catastrophic game, that good old law of unintended consequences could have a field day here.
Statins promote apoptosis. They do it in diseased tissues, including cancer cells; hooray for Lipitor. Unfortunately they also do it in normal tissues too; boo for Lipitor.
Statins promote apoptosis in heart muscle. You just have to imagine what having heart muscle cells commit suicide does for your pumping ability. Most of the work on statins and myopathy focuses on coenzyme Q10 depletion. This looks to be an additional problem.
Statins promote apoptosis in the vascular epithelium. Again you just have to wonder what the death of vascular lining cells does for your circulation. Brings to mind those folks in Japan who were highly susceptible to simvastatin. This is the effect on mortality from cardiac causes when you really respond to a statin.
Statins also promote apoptosis in brain cells, or at least do so in a lab prep designed to mimic brain cells. This is your brain on a statin. Last sentence of the paper:
"These findings could contribute to elucidate the molecular mechanisms by which statins induce growth suppression and/or apoptosis in neuronal cells, and may also help to explain the CNS side effects associated with statin therapy."
Just going back to that J-Litt paper, the death rate from accidents/suicides were increased just under three fold in the TC <160mg/dl group. Seems like low cholesterol causes you to throw punches at a well armed wide boy in a down town bar.
However all is not doom and gloom. Here is your brain on chocolate!
OK, that's a complete cheat. I've absolutely no idea how much of the stearic acid in the topping of a dessert cheesecake ever gets remotely near a human brain neurone in real life. Much less activate PPAR gamma there. But I'd prefer (real) chocolate to a statin any day if I was looking to avoid Alzheimer's (or anything else for that matter).
Peter
Tinkering with this process is a potentially catastrophic game, that good old law of unintended consequences could have a field day here.
Statins promote apoptosis. They do it in diseased tissues, including cancer cells; hooray for Lipitor. Unfortunately they also do it in normal tissues too; boo for Lipitor.
Statins promote apoptosis in heart muscle. You just have to imagine what having heart muscle cells commit suicide does for your pumping ability. Most of the work on statins and myopathy focuses on coenzyme Q10 depletion. This looks to be an additional problem.
Statins promote apoptosis in the vascular epithelium. Again you just have to wonder what the death of vascular lining cells does for your circulation. Brings to mind those folks in Japan who were highly susceptible to simvastatin. This is the effect on mortality from cardiac causes when you really respond to a statin.
Statins also promote apoptosis in brain cells, or at least do so in a lab prep designed to mimic brain cells. This is your brain on a statin. Last sentence of the paper:
"These findings could contribute to elucidate the molecular mechanisms by which statins induce growth suppression and/or apoptosis in neuronal cells, and may also help to explain the CNS side effects associated with statin therapy."
Just going back to that J-Litt paper, the death rate from accidents/suicides were increased just under three fold in the TC <160mg/dl group. Seems like low cholesterol causes you to throw punches at a well armed wide boy in a down town bar.
However all is not doom and gloom. Here is your brain on chocolate!
OK, that's a complete cheat. I've absolutely no idea how much of the stearic acid in the topping of a dessert cheesecake ever gets remotely near a human brain neurone in real life. Much less activate PPAR gamma there. But I'd prefer (real) chocolate to a statin any day if I was looking to avoid Alzheimer's (or anything else for that matter).
Peter
Sunday, November 18, 2007
Best ever statin study?
I missed this landmark paper last year, full text here. Possibly because, as it continues the demolition of the cholesterol hypothesis, it received absolutely zero publicity. I posted about the J-Litt study here, but this one is even better.
The paper is from the Essen group (in Germany) and describes their study comparing normal dose atrovastatin (10mg/d) with high dose atrovastatin (80mg/d).
Same drug, different dose rates, different cholesterol levels. Follow your patients for a year and have the coronary artery calcification progress tracked by electron-beam computed tomography. This is a reasonably well designed study, except see the "phew" comment below.
How much difference does it make if you drop your LDL-cholesterol to 87mg/dl as compared to 109mg/dl?
I think the answer is technically known as "diddly squat". Or zero, zilch, nuthin, nowt.
The answer as to why is pretty clear from table 3 shown here.
Look at the falls in hsCRP and fibrinogen on low vs high dose atrovastatin. They're the same between groups. Ie the anti inflammatory effect and anti thrombotic effects are maxed out at 10mg, so no further benefit is seen at 80mg. From my point of view this is fortunate. Had these pleiotropic effects not maxed out the study might have suggested lowering cholesterol was beneficial. But 80mg of atrovastatin is no better an anti inflammatory agent than 10mg is. Phew.
The paper discussion is an amusing catalogue of excuses and references to studies "better" designed to show the benefits of aggressive statin use. The trick is to use different drugs and give the best anti inflammatory statin at the highest dose rate. Then the lowest cholesterol correlates with, but is not responsible for, the least CV problems. It is also sensible NOT to measure CRP or fibrinogen, otherwise you end up with a study like this one, where people can see what's going on.
This group strike me as genuine medics who believe in the lipid hypothesis and are genuinely surprised that they have trashed the cholesterol hypothesis by accident. Still, I'll leave them with the best line from their conclusions, ignoring the squirming in the discussion and the plea for more time to get an effect. Here it is:
"we did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis"
Peter
Thank you to Dr Davis of Track Your Plaque for citing this unheard of paper
and to
Drs Axel Schmermund, MD; Stephan Achenbach, MD; Thomas Budde, MD; Yuri Buziashvili, MD; Andreas Förster, MD; Guy Friedrich, MD; Michael Henein, MD; Gert Kerkhoff, MD; Friedrich Knollmann, MD; Valery Kukharchuk, MD; Avijit Lahiri, MD; Roman Leischik, MD; Werner Moshage, MD; Michael Schartl, MD; Winfried Siffert, MD; Elisabeth Steinhagen-Thiessen, MD; Valentin Sinitsyn, MD; Anja Vogt, MD; Burkhard Wiedeking, MD; Raimund Erbel, MD
for this excellent study, published in a full-text-for-free journal.
The paper is from the Essen group (in Germany) and describes their study comparing normal dose atrovastatin (10mg/d) with high dose atrovastatin (80mg/d).
Same drug, different dose rates, different cholesterol levels. Follow your patients for a year and have the coronary artery calcification progress tracked by electron-beam computed tomography. This is a reasonably well designed study, except see the "phew" comment below.
How much difference does it make if you drop your LDL-cholesterol to 87mg/dl as compared to 109mg/dl?
I think the answer is technically known as "diddly squat". Or zero, zilch, nuthin, nowt.
The answer as to why is pretty clear from table 3 shown here.
Look at the falls in hsCRP and fibrinogen on low vs high dose atrovastatin. They're the same between groups. Ie the anti inflammatory effect and anti thrombotic effects are maxed out at 10mg, so no further benefit is seen at 80mg. From my point of view this is fortunate. Had these pleiotropic effects not maxed out the study might have suggested lowering cholesterol was beneficial. But 80mg of atrovastatin is no better an anti inflammatory agent than 10mg is. Phew.
The paper discussion is an amusing catalogue of excuses and references to studies "better" designed to show the benefits of aggressive statin use. The trick is to use different drugs and give the best anti inflammatory statin at the highest dose rate. Then the lowest cholesterol correlates with, but is not responsible for, the least CV problems. It is also sensible NOT to measure CRP or fibrinogen, otherwise you end up with a study like this one, where people can see what's going on.
This group strike me as genuine medics who believe in the lipid hypothesis and are genuinely surprised that they have trashed the cholesterol hypothesis by accident. Still, I'll leave them with the best line from their conclusions, ignoring the squirming in the discussion and the plea for more time to get an effect. Here it is:
"we did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis"
Peter
Thank you to Dr Davis of Track Your Plaque for citing this unheard of paper
and to
Drs Axel Schmermund, MD; Stephan Achenbach, MD; Thomas Budde, MD; Yuri Buziashvili, MD; Andreas Förster, MD; Guy Friedrich, MD; Michael Henein, MD; Gert Kerkhoff, MD; Friedrich Knollmann, MD; Valery Kukharchuk, MD; Avijit Lahiri, MD; Roman Leischik, MD; Werner Moshage, MD; Michael Schartl, MD; Winfried Siffert, MD; Elisabeth Steinhagen-Thiessen, MD; Valentin Sinitsyn, MD; Anja Vogt, MD; Burkhard Wiedeking, MD; Raimund Erbel, MD
for this excellent study, published in a full-text-for-free journal.
