Comments on: The torcetrapib disaster: Blogosphere response http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html medical blog Sun, 22 Nov 2009 07:50:13 -0500 http://wordpress.org/?v=2.8.4 hourly 1 By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69777 Anonymous Thu, 21 Dec 2006 15:50:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69777 Epidemiological studies have already shown that people with CETP deficiency have increased incidence of coronary heart disease. See Zhong et al. (1996) J. Clin. Invest. 97:2917-2923, "Increased Coronary Heart Disease in Japanese-American Men with Mutation in the Cholesteryl Ester Transfer Protein Gene Despite Increased HDL Levels" (<a HREF="http://www.jci.org/cgi/content/full/97/12/2917" REL="nofollow">full text</a> available). In that study the people with CETP deficiecy had 35% less CETP activity, 10% elevated HDL, and 1.4-fold greater risk for coronary heart disease. Given that CETP enables the flow of cholesterol from the peripheral tissues (including cholesterol deposits in arteries) to the liver, it makes sense that inhibiting this process should be deleterious. It is not the amount of HDL that is relevant but the flow of cholesterol from the periphery to the liver, that is normally mediated by HDL. Evidently, the HDL particles whose concentration rises when CETP is inhibited or deficient are different from the normal mix of HDL particles that exist in normal physiology. I am surprized that Pfizer decision makers subscribed to the simple view that high HDL is good, no matter what type of HDL and at what physiological cost. Epidemiological studies have already shown that people with CETP deficiency have increased incidence of coronary heart disease. See Zhong et al. (1996) J. Clin. Invest. 97:2917-2923, “Increased Coronary Heart Disease in Japanese-American Men with Mutation in the Cholesteryl Ester Transfer Protein Gene Despite Increased HDL Levels” (full text available). In that study the people with CETP deficiecy had 35% less CETP activity, 10% elevated HDL, and 1.4-fold greater risk for coronary heart disease. Given that CETP enables the flow of cholesterol from the peripheral tissues (including cholesterol deposits in arteries) to the liver, it makes sense that inhibiting this process should be deleterious. It is not the amount of HDL that is relevant but the flow of cholesterol from the periphery to the liver, that is normally mediated by HDL. Evidently, the HDL particles whose concentration rises when CETP is inhibited or deficient are different from the normal mix of HDL particles that exist in normal physiology. I am surprized that Pfizer decision makers subscribed to the simple view that high HDL is good, no matter what type of HDL and at what physiological cost.

]]> By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69703 Anonymous Tue, 19 Dec 2006 02:03:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69703 Finding patients with low HDL, <60 mg/dl, would be relatively easy.<br/>RE: 40 year old data, Framingham Study, the most common lipid [cholesterol] defect is NOT elevted LDL. It is low HDL. If you use a directly measured lipid panel with ALL the lipid fractions [as they did in the Framingham, ultracentrifuge / Beta-quantification ] vs. a Friedewald calculation / “Guesstimate” based lipid panel,.. as was known then [~40 years ago] is well known now. The Vertical Auto Profile, the VAP test, is a modern, high-volume commercial version of Beta-Quant.The MOST frequently observed lipid defect in ALL of the tested population for the year 2002, was LOW HDL2. The prevalence was ~74%. Far exceeding LDL > 130 mg/dL or even 100. ISOLTED Low HDL2, the ONLY lipid defect on the panel, was found in 30% of those tested. Nearly 1/3rdof the tested population. In the Framingham Study, traditional lipid factors [A Friedewald calculated LDL, total cholesterol/TC, triglycerides/TGs and HDL] accounted for only 40% of premature CAD. 75% of patients with an MI, Myocardial Infarction / heart attack, have “normal” levels of LDL and HDL. 80% of patients in the Framingham who experienced an MI or a stroke had ‘traditional’ lipid levels IDENTICAL to those patients who were event-free.<br/><br/>The fractions & ratios of the totals RE: TC/HDL being the most accurate, are far more specific at identifying risk of CAD, as well as predicting events. The single most powerful predictor of risk for CAD & vascualr events is NOT LDL, but using Beta-Quant [or the inexpensive commercial version, the VAP] it has been found to be the large buoyant fraction of HDL,.. HDL2 or HDL2b. Food for thought. Niacin @ 1 gm/day increases HDL2 / HDL2b by 113% at the 1st year,.. and continues its increase for up to 3 years. 2 gms/day increases HDL2 or HDL2b by 189% at the 1st year. The flush is transient, and when put in the hands of an EXPERIENCED clinician [>30% of his/her dyslipidemic patients on at last 1 gm/day of niacin] it is not that difficult. The lost art form is key: Patient education. 5 minutes at the initiation of therapy. 3 TBS applesauce,.. followed by washing the niacin down with 3-4 z water containing one dissolved Alka-Seltzer tablet [325 mg ASA aqueous]. Worked for Dr Wm Castelli of the landmark Framingham study 40 years ago & still works today. 50 years of safety, efficacy, regression of CAD, reduction of mortality & outcomes data [MI & stroke]. The short memory , or selective memory currently witnessed in medicine re: niacin is rather frightening. See Dr Bradley Bale`s video on Google. 3800 patients at risk followed for 10 years. 25% had already been cath`ed / PTCA or had a CABG, open heart sx. Only one MI & no deaths. TEN YEARS. <br/>89% on statins and 66% on niacin. The future is already here,.. and has been for 40 years. Isn`t it time we mandated training for the SUCCESSFUL administration of prescription niacin ?? Not enough Big-Pharma $$$ to fund this ??<br/>Ad infinitum, ad nauseum.<br/>SDMc Finding patients with low HDL, <60 mg/dl, would be relatively easy.
RE: 40 year old data, Framingham Study, the most common lipid [cholesterol] defect is NOT elevted LDL. It is low HDL. If you use a directly measured lipid panel with ALL the lipid fractions [as they did in the Framingham, ultracentrifuge / Beta-quantification ] vs. a Friedewald calculation / “Guesstimate” based lipid panel,.. as was known then [~40 years ago] is well known now. The Vertical Auto Profile, the VAP test, is a modern, high-volume commercial version of Beta-Quant.The MOST frequently observed lipid defect in ALL of the tested population for the year 2002, was LOW HDL2. The prevalence was ~74%. Far exceeding LDL > 130 mg/dL or even 100. ISOLTED Low HDL2, the ONLY lipid defect on the panel, was found in 30% of those tested. Nearly 1/3rdof the tested population. In the Framingham Study, traditional lipid factors [A Friedewald calculated LDL, total cholesterol/TC, triglycerides/TGs and HDL] accounted for only 40% of premature CAD. 75% of patients with an MI, Myocardial Infarction / heart attack, have “normal” levels of LDL and HDL. 80% of patients in the Framingham who experienced an MI or a stroke had ‘traditional’ lipid levels IDENTICAL to those patients who were event-free.

The fractions & ratios of the totals RE: TC/HDL being the most accurate, are far more specific at identifying risk of CAD, as well as predicting events. The single most powerful predictor of risk for CAD & vascualr events is NOT LDL, but using Beta-Quant [or the inexpensive commercial version, the VAP] it has been found to be the large buoyant fraction of HDL,.. HDL2 or HDL2b. Food for thought. Niacin @ 1 gm/day increases HDL2 / HDL2b by 113% at the 1st year,.. and continues its increase for up to 3 years. 2 gms/day increases HDL2 or HDL2b by 189% at the 1st year. The flush is transient, and when put in the hands of an EXPERIENCED clinician [>30% of his/her dyslipidemic patients on at last 1 gm/day of niacin] it is not that difficult. The lost art form is key: Patient education. 5 minutes at the initiation of therapy. 3 TBS applesauce,.. followed by washing the niacin down with 3-4 z water containing one dissolved Alka-Seltzer tablet [325 mg ASA aqueous]. Worked for Dr Wm Castelli of the landmark Framingham study 40 years ago & still works today. 50 years of safety, efficacy, regression of CAD, reduction of mortality & outcomes data [MI & stroke]. The short memory , or selective memory currently witnessed in medicine re: niacin is rather frightening. See Dr Bradley Bale`s video on Google. 3800 patients at risk followed for 10 years. 25% had already been cath`ed / PTCA or had a CABG, open heart sx. Only one MI & no deaths. TEN YEARS.
89% on statins and 66% on niacin. The future is already here,.. and has been for 40 years. Isn`t it time we mandated training for the SUCCESSFUL administration of prescription niacin ?? Not enough Big-Pharma $$$ to fund this ??
Ad infinitum, ad nauseum.
SDMc

]]> By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69473 Anonymous Sat, 09 Dec 2006 20:45:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69473 Kevin-<br/><br/>You said (I think it was you, might have been a quote ...) that you thought Pfizer was stupid to test combination therapy vs lipitor instead of mono tx vs placebo. <br/><br/>I suspect that they couldn't find an IRB that would approve that design. I don't know off hand, but how big a market is there for people needing only to raise their HDL without lowering LDL? Presumably in order to recruit enough subjects they would have needed people with elevated LDL and the ethics panel would never have approved a protocol that had a placebo control arm when those people definitely needed a statin. Kevin-

You said (I think it was you, might have been a quote …) that you thought Pfizer was stupid to test combination therapy vs lipitor instead of mono tx vs placebo.

I suspect that they couldn’t find an IRB that would approve that design. I don’t know off hand, but how big a market is there for people needing only to raise their HDL without lowering LDL? Presumably in order to recruit enough subjects they would have needed people with elevated LDL and the ethics panel would never have approved a protocol that had a placebo control arm when those people definitely needed a statin.

]]> By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69472 Anonymous Sat, 09 Dec 2006 20:41:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69472 Two points:<br/><br/>Anon 0158-Most clinical trial protocols have very specific guidelines on if/when data can be examined for a trial in progress. Imagine for a moment that instead at the end of each day they ran the stats to see if they had reached their adverse events threshold. It isn't so inconceivable that in the first month or two, by pure chance, there are excess deaths in the medicated group. In the extreme case, if you checked every day and by chance 1 person in the medicated group died before anyone in the control did, then would you stop the trial because there were infinity % excess deaths in the experimental arm?<br/><br/>Given that they only exceeded death threshold by 2 deaths, they were probably just under threshold at the last in-trial data analysis point. Two points:

Anon 0158-Most clinical trial protocols have very specific guidelines on if/when data can be examined for a trial in progress. Imagine for a moment that instead at the end of each day they ran the stats to see if they had reached their adverse events threshold. It isn’t so inconceivable that in the first month or two, by pure chance, there are excess deaths in the medicated group. In the extreme case, if you checked every day and by chance 1 person in the medicated group died before anyone in the control did, then would you stop the trial because there were infinity % excess deaths in the experimental arm?

Given that they only exceeded death threshold by 2 deaths, they were probably just under threshold at the last in-trial data analysis point.

]]> By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69467 Anonymous Sat, 09 Dec 2006 18:58:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69467 I also was a participant in the study and feel like I've been given a time-bomb.(I just had a blood test and my HDL is 89, so my guess is that I was taking the drug) Three questions: (1) How could Pfizer (or those running the study) not have known one, three or even six months before December 2 of the incresed mortality rate? Thirty people could n0t have died in November. (2) Will Pfizer (or someone) keep following those in the study to see what happens to the mortality rate after December 2(failure to do so seems highly irresponsible)? and (3) Who (aside from prisoners) would agree to paticipate in another clinical study of this kind of drug? I also was a participant in the study and feel like I’ve been given a time-bomb.(I just had a blood test and my HDL is 89, so my guess is that I was taking the drug) Three questions: (1) How could Pfizer (or those running the study) not have known one, three or even six months before December 2 of the incresed mortality rate? Thirty people could n0t have died in November. (2) Will Pfizer (or someone) keep following those in the study to see what happens to the mortality rate after December 2(failure to do so seems highly irresponsible)? and (3) Who (aside from prisoners) would agree to paticipate in another clinical study of this kind of drug?

]]> By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69455 Anonymous Sat, 09 Dec 2006 01:42:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69455 I also was participant in the study. It helped raise my HDL significantly. Wht concerns me about Pfizer is that it was at the vey least over a month after they knew of the dangers before they pulled the drug. To me that implies that they did not care about their volunteers. I also was participant in the study. It helped raise my HDL significantly. Wht concerns me about Pfizer is that it was at the vey least over a month after they knew of the dangers before they pulled the drug. To me that implies that they did not care about their volunteers.

]]> By: Chuck http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69428 Chuck Fri, 08 Dec 2006 01:49:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69428 As a participant in the Torcetrapib study and a user of the actual drug I am deeply saddened by the outcome of the study. What also appals me are the comments concerning putting Pfizer in its place due to its greed etc. As a victom of a heart attack, high blood pressure, and a 5 way bypass I felt that this drug would help me to continue my life by helping raise my HDL. Through diet and lifestyle changes I have managed to lower my cholesterol level, lower my triglycerides, lower my LDL and everyother item that I have been told to do. The only thing that I had no effect was a HDL level of 28. I want to thank P As a participant in the Torcetrapib study and a user of the actual drug I am deeply saddened by the outcome of the study. What also appals me are the comments concerning putting Pfizer in its place due to its greed etc. As a victom of a heart attack, high blood pressure, and a 5 way bypass I felt that this drug would help me to continue my life by helping raise my HDL. Through diet and lifestyle changes I have managed to lower my cholesterol level, lower my triglycerides, lower my LDL and everyother item that I have been told to do. The only thing that I had no effect was a HDL level of 28. I want to thank P

]]> By: Anonymous http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69357 Anonymous Wed, 06 Dec 2006 05:51:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69357 Let's just review some basic biochemical facts.Cholesterol has a hydrophobic end as well as a hydrophilic end. It is an essential component of cell membranes as it is "the bridge" between aqueous molecules and lipid molecules for holding them together. Cholesterol is insoluble in water and therefore also in blood. Cholesterol gets converted to cholesteryl ester and carried inside a surrounding covering of water (blood) soluble lipoprotein. CETP releases cholesteryl ester from LDL and HDL so that it can be used in cell membranes. Inhibiting CETP does two things...it stops cells from getting necessary cholesterol and you also now have a synthetic torcetrapib molecule (or any other toxic drug molecule) stuck to the non-functional CETP. The immune system now recognizes this complex as an antigen. Blocking this important transfer protein is the biochemical equivalent of cutting your telephone line or drilling holes in your boat. The immune system attacks the foreign synthetic drug molecule stuck to the CETP by oxidizing it which is the first stage of the immune response...the LDL particle is then immobilized on the vessel wall..it is attacked by monocytes which gobble it up. The monocytes pull the offending toxic LDL particle through the vascular endothelium and continue to attack it.If there is excess toxic material the monocytes burst releasing toxic material which is attacked again by other monocytes eventually leaving lots of dead cell debris in a pool of toxic chemical thus forming the plaque. You all know the rest of the story. The body can eventually repair this mess given the chance. The same applies to any medication. ..it has to be disposed of. If there is too much...the body can't cope in trying to contain the toxic material which leads to plaque formation. It simply does not make sense to block CETP. This pharmaceutical arrogance misleads everybody. There is no such thing as "good" or "bad" cholesterol. Cholesterol does not cause heart disease. (See www.thincs.org and www.statinalert.org) Diet has absolutely nothing to do with causing heart disease and saturated fat is better for you than poly-unsaturated fat. Statins can cause cardiomyopathy among many other side effects by blocking Co Enzyme Q10. Eggs are very healthy and contain the most cholesterol of any food known. The world has been conned by corporate fascism and political lobbying because they have manipulated science for their own financial gain instead of sticking to scientific fact for the good of humanity. Millions of people have been killed by well intentioned doctors prescribing toxic medication. The "guidelines" are written by pharmaceutical "whores" and do not reflect the truth. Your cholesterol level has a genetic set point and whatever your level is is right for you. See Wikipedia and enter SREBP (Sterol Regulatory Element Binding Protein). Eat good food,exercise,stop smoking and avoid drugs for optimal heart health.Ignore DTCA ads. on the media. Avoid trans-fats fats which also can make your cell walls leaky and cause Type 2 Diabetes according to some. Suggest also that you sell all your pharmaceutical shares immediately so that we don't have to listen to their lies anymore and start living healthier lives as is our God given right! Stuff the share-holders! Let’s just review some basic biochemical facts.Cholesterol has a hydrophobic end as well as a hydrophilic end. It is an essential component of cell membranes as it is “the bridge” between aqueous molecules and lipid molecules for holding them together. Cholesterol is insoluble in water and therefore also in blood. Cholesterol gets converted to cholesteryl ester and carried inside a surrounding covering of water (blood) soluble lipoprotein. CETP releases cholesteryl ester from LDL and HDL so that it can be used in cell membranes. Inhibiting CETP does two things…it stops cells from getting necessary cholesterol and you also now have a synthetic torcetrapib molecule (or any other toxic drug molecule) stuck to the non-functional CETP. The immune system now recognizes this complex as an antigen. Blocking this important transfer protein is the biochemical equivalent of cutting your telephone line or drilling holes in your boat. The immune system attacks the foreign synthetic drug molecule stuck to the CETP by oxidizing it which is the first stage of the immune response…the LDL particle is then immobilized on the vessel wall..it is attacked by monocytes which gobble it up. The monocytes pull the offending toxic LDL particle through the vascular endothelium and continue to attack it.If there is excess toxic material the monocytes burst releasing toxic material which is attacked again by other monocytes eventually leaving lots of dead cell debris in a pool of toxic chemical thus forming the plaque. You all know the rest of the story. The body can eventually repair this mess given the chance. The same applies to any medication. ..it has to be disposed of. If there is too much…the body can’t cope in trying to contain the toxic material which leads to plaque formation. It simply does not make sense to block CETP. This pharmaceutical arrogance misleads everybody. There is no such thing as “good” or “bad” cholesterol. Cholesterol does not cause heart disease. (See http://www.thincs.org and http://www.statinalert.org) Diet has absolutely nothing to do with causing heart disease and saturated fat is better for you than poly-unsaturated fat. Statins can cause cardiomyopathy among many other side effects by blocking Co Enzyme Q10. Eggs are very healthy and contain the most cholesterol of any food known. The world has been conned by corporate fascism and political lobbying because they have manipulated science for their own financial gain instead of sticking to scientific fact for the good of humanity. Millions of people have been killed by well intentioned doctors prescribing toxic medication. The “guidelines” are written by pharmaceutical “whores” and do not reflect the truth. Your cholesterol level has a genetic set point and whatever your level is is right for you. See Wikipedia and enter SREBP (Sterol Regulatory Element Binding Protein). Eat good food,exercise,stop smoking and avoid drugs for optimal heart health.Ignore DTCA ads. on the media. Avoid trans-fats fats which also can make your cell walls leaky and cause Type 2 Diabetes according to some. Suggest also that you sell all your pharmaceutical shares immediately so that we don’t have to listen to their lies anymore and start living healthier lives as is our God given right! Stuff the share-holders!

]]> By: Cary http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69320 Cary Mon, 04 Dec 2006 19:12:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69320 I to think that "easy “targets” such as heart disease and diabetes may be nearing their natural limits for medication therapy". Many of the health problems today are over-medicated, and the positive results from things such as a healthy diet and daily exercise are overlooked and under-utilized. I to think that “easy “targets” such as heart disease and diabetes may be nearing their natural limits for medication therapy”. Many of the health problems today are over-medicated, and the positive results from things such as a healthy diet and daily exercise are overlooked and under-utilized.

]]> By: Dr. A http://www.kevinmd.com/blog/2006/12/torcetrapib-disaster-blogosphere.html/comment-page-1#comment-69311 Dr. A Mon, 04 Dec 2006 15:33:00 +0000 http://clients.emmense.com/kevinmd/2006/12/the-torcetrapib-disaster-blogosphere-response.html#comment-69311 Ah, I was wondering why Pfizer just announced that it was cutting 20% of its sales force. That news coupled with the torcetrapib announcement now makes sense. Ah, I was wondering why Pfizer just announced that it was cutting 20% of its sales force. That news coupled with the torcetrapib announcement now makes sense.

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