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”.

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