Today’s Flawed and Fake Medical Trials

 

Recently I was presented with unsolicited lab data ( above) on a patient whom I am not charged to divulge, who is the typical patient I have cared for in the last 18 years and unwittingly poorly throughout my earlier career. This case has what appears to be an unbelievable astounding but in reality not infrequent response, to a single anti-cholesterol medication & vitamins; despite lacking my usual work up which includes inflammatory, absorption and production markers as well as insulin resistance parameters. 

I was struck by the upstream effort against the tide of this individual to spread affordable and effective knowledge and experience what I and hopefully many others have been applying for years .

Recently because of the accelerated pricing of Niaspan consistent with gouging, similar to the recent EpiPen scandal, I was at a Walmart pharmacy inquiring about the immediate release form of crystalline niacin which was the vitamin involved in the above patient’s treatment . Thereupon, the pharmacist proceeded to denigrate niacin insinuating that I did not know the literature. Now I did not quite agree with this gentleman and walked out to another Walmart. However, this incident is not stand alone event. I have had many other providers and would be providers even ivory tower institutions disparage niacin, in fact attempting to interrupt successful treatment of the dyslipidemia of some of my patients and I am quite sure others.

In college I started of in the premed program but switched to Physics because I leaned more to analytical thinking. Premed and medical school was mostly about regurgitation of vast amounts of facts with little time devoted to analysis which does require some experience. Unfortunately the medical literature dictum of publish or perish leaves little time for peer-review with correlation & application to the real world. 

It is one thing to know what the literature states and another to be able to critically evaluate, usually referred to as peer review. Now peer-reviewers to me are the readers of the articles. Others think that the peer review involves the editors and those who chose the articles for publication. As a Board-Certified Cardiologist since 1973 along with 2005 inaugural year certification in Clinical Lipidology and my recently successful completion of Clinical Lipidology recertification exam in which I am now grandfathered and exempt from any future examination, I believe I have a bit more critical and analytical perspective than the lay public, the vast majority of physicians and pharmacists who lack peer review capability as well as proponents of big Pharma. 

The above pharmacist’s impression emanates from two flawed trials, which in my opinion much like our news media which in last 50 years has generated fake news, has generated data inconsistent , inconsequential or mal-applied in the real world and therefore have drawn false conclusions. Whenever I see data inconsistent with my near 45 year experience I always think of a phrase I learned in medical school about Willie Sutton’s robbing banks i.e. “ Sutton’s law”, ascertain or observe where the money is involved then evaluate who benefits.

Recently upon viewing the Agenda at a National Seminar Symposium, I noticed an interesting discussion about the Niaspan topic; unfortunately not well emphasized because it was on the last day near adjournment. I was unable to attend this session but I decided before the lecture to compose and send to the presenter my peer-reviewed assessment about the status of niacin including Niaspan, in addition to still contemplating about placing this discussion on social media. I never received a response because it may not have been successfully sent. I felt that the data from the relatively recent Mega trials would be emphasized and the older trials would be ignored. Later upon viewing the presenter’s synopsis from another source, my belief was buttressed.

There have been other flawed trials. An example is the Seven Countries Trial( which in my opinion started the obesity epidemic) which is still revered when the history of trials are reviewed at symposiums.

The recent PCSK9i inhibitor trials Odyssey and Fourier are examples of over exaggerated ballyhoo which in short is for a medication that in the future will be vastly underutilized because of its lack of affordability, much less than the statins when they were initially introduced. PCSK9i are set up to be an add-on and not a competitor of the statins. Its powerful LDL-C lowering into the teens results in outrageous cost inefficacy. We should not be concentrating on a transient sojourn of LDL-C into the teens but on the product of ApoB particles over years. Some of PCSK9i other beneficial effects are being glossed over, ignored or relegated to non-significant status. Further discussion an exploration of this topic will be better served in the future

The Complete Cardiologist and Why He or She is so Rare

 

What is the difference between most cardiologists and a complete cardiologist? Most Cardiology training programs involve extensive time within the coronary care and ICU units addressing cardiovascular symptoms and problems once they have surfaced. Usually symptoms of Cardiovascular Disease are manifested when 80% or greater of the body vasculature is already compromised. Eighteen years ago I wondered where I stood on this spectrum and turned myself to advanced lipid testing, which I was already utilizing with my patients. Lo and behold I discovered I was similar to them. I then wondered if my recently discovered secondary prevention concepts would work for me as primary prevention and applied them. I did not want for myself any part of what I was seeing with my patients. It was at that time that I became a complete cardiologist and I then proceeded to try to identify others at risk years before may would become symptomatic. 

Being a complete cardiologist means preventing arresting or stabilizing cardiovascular disease progression years before it is allowed to take a stronghold and manifest symptoms. Unfortunately despite statements to the contrary our statistics really expose the truth about our failure which in my opinion is secondary to the failure of our physician’s training institutions especially cardiologists. 

Equally obstructive are the variety of guidelines of great disparity, published by various National and International associations. which are at odds with the real world of medicine and only serve the financial needs of corporations involved in medicine. A complete cardiologist circumvents all these obstacles and prescribes an effective affordable plan for cardiovascular disease prevention in keeping with the whole families financial needs rather than allowing one compromised family member to siphon resources from other family members.

Unfortunately with the medical insurance industry, it is much more profitable to withhold any treatment before symptoms appear (i.e. how the greatest profit from the premiums is realized) The Insurance companies are well aware that many clients over the years will change to different competing medical insurance programs based upon the availability and rising costs and it is not profit-effective to prevent CVD disease in individuals, most of whom will end up leaving them. 

Once symptoms appear, the medical vendors have a picnic followed by a picnic for the pharmaceuticals companies with their multiple medications, a fraction of which should have been used to prevent cardiovascular disease prevention. It is simply not profitable for the Insurance companies to do primary prevention years before although it appears they espouse this concept, but in reality are only paying lip service. 

If a patient is to become involved in primary prevention of cardiovascular disease they must bear the costs, not the insurance company, and reap the benefits although they may have difficulty in determining to take the plunge or if they will or will not benefit. Either way even if no event is experienced, one’s longevity and quality of life will be extended as atherosclerosis is impeded.

Other factors that are limiting effective primary cardiovascular disease prevention is the disparity in training of physicians. Most physicians sell to their patients what they know or what the pharmaceutical companies medical vendors hospitals, Insurance companies  drug plans, all of whom have control of the medical literature. 

Today the overwhelming new therapeutic options i.e. vast number of new outrageously expensive medications with supposedly statistically significant beneficial effect and most only with a minimal 1-2% absolute risk reduction benefit in which 100% of patients are recommended for the treatment is being huckstered at an outrageous cost which gouges into each family’s budget leaving little available for future education etc.. All this is is a long way from the Capitalism of reasonable profit upon which I was raised.

My Peer-Review of AIM-HIGH & HPS-THRIVE II

 

 

 

 

Fake Medical trials: Do they exist?

Today we are reputed to have fake news. What is fake news? My understanding is that it is the substitution, distortion or withholding of true facts (reality) and the substitution of partial (semi-true) or completely untrue altered facts or opinions, or just flat out unwittingly or wittingly incorrectly or inaccurately drawing conclusions from facts to justify an ulterior objective. A medical trial that ignores, neglects or mistakes the effective mechanism of action of a tested drug could lead to a fake trial. Even Harold Bays recognizes that fact in his Annual Summary presentation delivered at the National Lipid Association meeting in New Orleans in 2016

Most providers know that penicillin or antibiotics are ineffective with viral infections. Most URIs are viral infections. If we were unaware or ignored this fact and conducted a trial in which penicillin was employed in URIs against a control (no antibiotics for a URI. it would be a negative trial. Subsequently, if some trial participants developed anaphylactic shock or other penicillin associated side effects, penicillin would have been deemed harmful and without benefit. Now we all know with regard to penicillin that is not true.

From my observations AIM-HIGH and HPS THRIVE-2 are such examples of fake trials in the sense that they tested HDL hypothesis (a red Herring) which from the AFCAPS-TEXCAPS should have been suspected as flawed and were an injudicious waste of money. Administration of any medication involves a risk/ benefit ratio and if one tests or utilizes medications inappropriately, one will have risk with little or no benefit.

In the case of AIM-HIGH and HPS II Thrive II, an already questionable or non beneficial mechanism of action was invoked as the hypothesis i.e. elevating HDL-C to decrease cardiovascular risk which in my opinion should have been suspect with the U-shaped HDL mortality curve of AFCAPS-TEXCAPS and since has been disproved by Mendelian Randomization Studies. Niaspan was unfortunately selected as the agent because of the large increase in HDL-C mostly contributed by the hepatic holo-particle receptor mechanism inhibition. Subsequently there have been major failures of the HDL hypothesis with the CETP trials and subsequent Mendelian randomization studies having all but put the HDL raising hypothesis to rest. Unfortunately Niaspan became the punching bag for a flawed hypothesis trial.

Laropiprant an unknown new medication not previously studied was added to Niaspan. What was the effect of this brand-new medication on Niaspan’s effectiveness? Niaspan’s true effective mechanism of action (DGAT2 & HSL hormone sensitive lipase inhibition did not appear to be a considered. Under present development is a DGAT inhibitor Pradigastat which when and if it gets to market will most probably be unaffordable as are many of today’s new medications. But Pradigastat lacks adipose tissue hormone sensitive lipase inhibition which is responsible for 60 to 70% contribution to VLDL and triglycerides produced in the bloodstream .

For the most part low HDL is product of latent or overt insulin resistance with or without obvious unfavorable triglyceride values. High HDL is a product of hyper-absorption of cholesterol or dysfunctional HDL both of which are atherogenic.The HDL hypothesis may have been put to rest but with its multiple putative beneficial actions one or more of which may resurface with more knowledge. However, it will not be the HDL level but rather it’s biochemistry.

I often refer to a Data Graph of the Framingham heart Study (FHS) study conducted over a 25 year time period, not 3-5. In analyzing this graph I observed that cardiovascular events below a total cholesterol of 150 is not discernible, at least statistically. Assuming a normal HDL of 45, normal triglycerides of 100-150, the average LDL calculation for this event free group is around 75 -80 mg/dL which is near the 5th percentile. The vast majority of those in AIM-HIGH and HPS II Thrive II were already at this LDL level and would had have little statistical discernible separation. Also from the Framingham Heart Study FHS for those individuals below a total cholesterol of 150 mg/dL, I would certainly have difficulty discerning a statistical mortality separation from those who had elevated LPa > 50 mg/dL or not.

Over the last nearly 20 years I was not in the habit of prescribing Niaspan to somebody with an LDL-C around 70 mg/dL unless they had substantial LDL-P, LDL-C discordance. In the past when I ran across undesirable medications and rapidly discovered their deficiencies, I removed them from my prescription list. That never happened with Niaspan. Niaspan’s benefit in appropriately indicated patients greatly and markedly outweighs the risk.

Although I achieved board certification in Clinical Lipidology in the inaugural class of 2005, I do not consider myself a Clinical Liidologist, rather with my board certification in Cardiology I consider myself a Preventive Cardiologist. Recently I have earned the title of Grandfathered Diplomate of the American Board of lipidology. Approaching 20 years now, I had used Niaspan on an estimated to 750 to 1000 patients, and possibly more, secondary prevention cardiovascular disease patients, but disappointedly much less with primary prevention. The vast majority had FCH or Familiar Combined Hyperlipidemia or by my recognition I prefer “the metabolic syndrome”. Niaspan with its mechanism of action as an inhibitor of DGAT2 & Hormone Sensitive Lipase HSL was easily the best medication for treating ApoB, LDL particle number, LDL-P, VLDL-C, VLDL-P & which today has a newly coined name, “Remnant Cholesterol”. Surprisingly except for Zetia, in my hands Niaspan had the best tolerability even with its flushing symptoms. Niaspan’s occasionally increased insulin resistance was manageable. I found the Fibrates and Bile Acid Sequestrates to be more problematic By far the worst side effect profile were and still are the statins and that was before we learned about the association with diabetes. Prior to this recognition, I many times could have mistakenly completely and inappropriately attributed a decrease in insulin sensitivity to Niaspan as statins means were for the most part on board.

From my experience Niaspan was not in general a potent total cholesterol and LDL-C lowering drug but it was and is a potent LDL particle number, non-HDL ApoB and if you prefer remnant cholesterol lowering drug, something the AIM-HIGH & Thrive HPS II investigators appeared to have ignored or overlooked. The statins have limited effectiveness for remnant cholesterol and herein lies the residual risk so commonly seen in FCH patients on only statins e.g. Tim Russert. Tim Russert’s LDL on a Statln was 63 mg/dL but his low HDL-C of 32 and high triglycerides 300mg/dl belied his substantial residual risk, i. e. an elevated remnant cholesterol, non-HDL with an extrapolated astronomical LDL-P estimated to be 2000 nm/L, which was never addressed and today is still not addressed by the vast majority the practitioners.

What I am most disappointed is that since, AIM-HIGH and HPS THRIVE II, there has been and is an ongoing denial to the vast number of non-atherosclerotic and atherosclerotic disease patients with FCH, the one medication that most effectively addresses their biochemical abnormality through an attempt to remove what I consider the most effective medication for FCH Niacin without a better contemporary or adequate replacement, which I consider reprehensible.

On the horizon I see unaffordable medications touted to treat the triglyceride disorder associated with FCH as a probable hollow promise for the future. Pradistat will probably be insufficient compared to Niaspan & the ASO ApoCIII when it arrives will probably be unaffordable for the vast majority as well as the recalcitrant insurance companies.

Thus in my opinion AIM-HIGH & Thrive HPS II were fake trials and I have my opinions as to the reasons. Since AIM-HIGH and HPS THRIVE II, I have become more critical and circumspect of the conclusions of a plethora of medical trials, even outside of Clinical Lipidology; always raising the suspicion or possibility that ulterior motives are involved, specifically money. Today I often wonder if our fake news concepts have seeped into our medical trials and indeed, to some extent I even have lost some confidence in so called “evidence based medicine”.

Today’s Flawed and Fake Medical Trials

Recently I was presented with unsolicited lab data ( above) on a patient whom I am not charged to divulge, who is the typical patient I have cared for in the last 18 years and unwittingly poorly throughout my earlier career. This case has what appears to be an unbelievable astounding but in reality not infrequent response, to a single anti-cholesterol medication & vitamins; despite lacking my usual work up which includes inflammatory, absorption and production markers as well as insulin resistance parameters.

I was struck by the upstream effort against the tide of this individual to spread affordable and effective knowledge and experience what I and hopefully many others have been applying for years .
Recently because of the accelerated pricing of Niaspan consistent with gouging, similar to the recent EpiPen scandal, I was at a Walmart pharmacy inquiring about the immediate release form of crystalline niacin which was the vitamin involved in the above patient’s treatment . Thereupon, the pharmacist proceeded to denigrate niacin insinuating that I did not know the literature. Now I did not quite agree with this gentleman and walked out to another Walmart. However, this incident is not stand alone event. I have had many other providers and would be providers even ivory tower institutions disparage niacin, in fact attempting to interrupt successful treatment of the dyslipidemia of some of my patients and I am quite sure others.

In college I started of in the premed program but switched to Physics because I leaned more to analytical thinking. Premed and medical school was mostly about regurgitation of vast amounts of facts with little time devoted to analysis which does require some experience. Unfortunately the medical literature dictum of publish or perish leaves little time for peer- review with correlation & application to the real world.

It is one thing to know what the literature states and another to be able to critically evaluate, usually referred to as peer review. Now peer-reviewers to me are the readers of the articles. Others think that the peer review involves the editors and those who chose the articles for publication. As a Board-Certified Cardiologist since 1973 along with 2005 inaugural year certification in Clinical Lipidology and my recently successful completion of Clinical Lipidology recertification exam in which I am now grandfathered and exempt from any future examination, I believe I have a bit more critical and analytical perspective than the lay public, the vast majority of

physicians and pharmacists who lack peer review capability as well as proponents of big Pharma.

The above pharmacist’s impression emanates from two flawed trials, which in my opinion much like our news media which in last 50 years has generated fake news, has generated data inconsistent , inconsequential or mal-applied in the real world and therefore have drawn false conclusions. Whenever I see data inconsistent with my near 45 year experience I always think of a phrase I learned in medical school about Willie Sutton’s robbing banks i.e. “ Sutton’s law”, ascertain or observe where the money is involved then evaluate who benefits.

Recently upon viewing the Agenda at a National Seminar Symposium, I noticed an interesting discussion about the Niaspan topic; unfortunately not well emphasized because it was on the last day near adjournment. I was unable to attend this session but I decided before the lecture to compose and send to the presenter my peer-reviewed assessment about the status of niacin including Niaspan, in addition to still contemplating about placing this discussion on social media. I never received a response because it may not have been successfully sent. I felt that the data from the relatively recent Mega trials would be emphasized and the older trials would be ignored. Later upon viewing the presenter’s synopsis from another source, my belief was buttressed.

There have been other flawed trials. An example is the Seven Countries Trial( which in my opinion started the obesity epidemic) which is still revered when the history of trials are reviewed at symposiums.

The recent PCSK9i inhibitor trials Odyssey and Fourier are examples of over exaggerated ballyhoo which in short is for a medication that in the future will be vastly underutilized because of its lack of affordability, much less than the statins when they were initially introduced. PCSK9i are set up to be an add-on and not a competitor of the statins. Its powerful LDL-C lowering into the teens results in outrageous cost inefficacy. We should not be concentrating on a transient sojourn of LDL-C into the teens but on the product of ApoB particles over years. Some of PCSK9i other beneficial effects are being glossed over, ignored or relegated to non-significant status. Further discussion an exploration of this topic will be better served in the future

page3image5790256