Will PCSK9 Inhibitors Be the Next Blockbusters in Cardiovascular Disease?

DOC GUMSHOE EXAMINES A NEW CLASS OF NON-STATIN DRUGS

By Michael Jorrin, "Doc Gumshoe", April 24, 2014

[Ed note: Here is our latest piece from “Doc Gumshoe”, who is a medical writer (not a doctor) who shares his wisdom with us at Stock Gumshoe a couple times a month. As always, Michael’s words and opinions are his own.]

Lots of analysts and prognosticators give these cholesterol-lowering agents a big thumbs up. The dollar figures they throw around are in the $10 billion per year range in the aggregate, or upwards of $3 billion for any one of these drugs, which are:

• From Amgen (AMGN), evolocumab …
• From Pfizer (PFE), bococizumab …
• And from Regeneron (REGN) (with Sanofi [SNY]), alirocumab.

Before I go much farther with this, I need to reveal an underlying uneasiness whenever the term “blockbuster” turns up in connection with the prospects for a new drug, or, indeed, a new anything else. My initial association with that all-too-trendy word is that it might just as easily refer to a really big bomb – big enough to reduce to rubble an entire city block.

Eyes wide open, I do not think that potential potholes in the development path of any of these are deep enough to cause significant damage to any of those pharmas, nor do I think that their potential is large enough to be genuinely transformative to the developers, except Regeneron; another $3 billion or so would be nice for Amgen and Pfizer, but it wouldn’t rocket them to the moon.

But I do think that the path to becoming blockbusters, in that pleasing figurative sense, is complicated by more than the usual number of factors – which I will try to look at with a critical and skeptical eye and lay before you.

So, what are PCSK9 inhibitors & how do they work?

The full name of PCSK9 is proprotein convertase subtilisin/kexin type 9 (we won’t say that again). It plays a role in regulating cholesterol levels in the blood by affecting the number of receptors for low-density-lipoprotein cholesterol (LDL-C) receptors on cell surfaces. When this protein is overactive, it breaks down LDL-C receptors. These LDL-C receptors in the liver absorb LDL-C particles from the bloodstream for eventual excretion. As a result, overactive PCSK9 blocks one of the pathways through which our bodies get rid of excess cholesterol.

The discovery of PCSK9 came about accidentally, as do many discoveries in science. It started with the finding that some individuals have what might be considered freakishly low levels of LDL-cholesterol – somewhere in the range of a quarter or a fifth of the LDL-C levels in healthy individuals in the general population. In other words, if a normal healthy person has an LDL-C level around 100 milligrams per deciliter, there are a few – very, very few – persons whose LDL-C levels are down around 25 or 20 mg/dL.

After testing and analyzing every conceivable factor in these individuals, it was found that some had inherited genetic mutations in the production of PCSK9 from both parents, so that the protein that diminished the activity of the LDL-C receptors that took that form of cholesterol out of the circulation was not present in those persons. In short, no PCSK9 → undiminished LDL-C receptor activity → highly effective clearing of LDL-C from the circulation → extremely low LDL-C levels.

The number of people with inherited genetic mutations from both parents must be miniscule. However, there is a small but significant percentage – 2% to 3% – of persons with a single genetic mutation affecting the expression of PCSK9, and these persons also have quite low levels of LDL-C, although not as low as the “double-knock-out” individuals.

These findings were catnip to some pharma companies, which immediately launched programs to find drugs that would affect the cholesterol-raising activity of PCSK9. Initial findings from several drug companies were highly encouraging, and at least those three outfits mentioned above – Amgen, Regeneron/Sanofi, and Pfizer – have put the pedal to the metal with good results.

  • Amgen’s evolocumab is, at the moment, in the lead. Amgen has completed six Phase 3 clinical trials with that agent, which lowered LDL-C by 53% to 75% compared with placebo (the 75% decrease was seen in combination with atorvastatin). As many as 8 more Phase 3 trials are recruiting or in progress. Amgen plans to file for FDA approval for evolocumab late this year.
  • Regeneron/Sanofi’s alirocumab has completed one Phase 3 clinical trial, in which LDL-C levels were lowered by 48% compared with placebo. They expect to file for FDA approval for alirocumab early in 2015, as more trial results become known. Regeneron/Sanofi has 14 more clinical trials under way.
  • Pfizer’s bococizumab, in contrast, has completed one Phase 2b trial, in which their drug lowered LDL-C by 52% in patients taking statins. Six more trials are recruiting or in progress. The plans for filing for FDA approval are at this time uncertain.

All three of these agents are injectable rather than oral, and it’s expected that they will be quite expensive, in the range of a thousand dollars a month or more. Both of these features are likely to be obstacles to the kind of widespread adoption that would lead to blockbuster status.

What kinds of patients would likely benefit from these drugs?

The obvious patients for PCSK9s are those who are at very high risk for cardiovascular events who have not been able to lower their LDL-C levels to the 70 mg/dL target using conventional drugs – i.e., statins – or who are intolerant to statins. Another group would be individuals with very high cholesterol levels related to genetic anomalies – a disorder called heterozygous familial hypercholesterolemia, which manifests in high levels of LDL-C unrelated to lifestyle.

Persons with this genetic disorder are prone to develop heart disease at an earlier age than the general population, i.e., in their 40s or even in their 30s. This defect is relatively uncommon, occurring in about 1 in 500 persons. Most people with this form of elevated LDL-C respond well to treatment with statins, so it’s by no means obvious that the entire global population of people with abnormally high LDL-C levels due to familial hypercholesterolemia would need treatment with PCSK9s.

(Note: the heterozygous familial hypercholesterolemia population inherited the culprit gene from one parent only. Unfortunate individuals who got the bad gene – i.e., homozygous – from both parents are at even higher risk for cardiovascular disease (CVD), and may have serious CV events much earlier in life, even in childhood. I hesitate to use the word “fortunately,” but it is a fortunate fact that homozygous familial hypercholesterolemia is extremely rare, affecting a tiny fraction of the total population, perhaps 1 in 25,000. It is doubtful whether clinical trials will be mounted in these patients, although they would surely be eligible for treatment with PCSK9 agents in an effort to do whatever possible to lower their LDL-cholesterol.)

What will it take to demonstrate efficacy?

Most efficacy trials to date have focused entirely on bringing down LDL-C levels, working on the premise that doing so will lessen CV risk and reduce the number of acute CV events such as heart attacks, strokes, and episodes of severe heart pain (angina) at rest. In fact, there is plenty of evidence that lowering LDL-C results in very clear benefits for patients with established heart disease or at high risk for heart disease. For example, the famous 4S trial (Scandinavian Simvastatin Survival Study, which enrolled patients with existing coronary heart disease and baseline mean total cholesterol of 261 mg/dL, reduced coronary death by 55% at 5.4 years.

Subsequent studies, in patients who were at somewhat lower risk reported somewhat less dramatic results. An example was the Heart Protection Study Collaborative Group trial in the UK, which enrolled patients with lower baseline lipid levels. In this case, mean LDL-C levels were 131 mg/dL, which, at the time of the trial, was below the recommended cut point for initiating drug treatment except in patients at very high risk. Treatment with simvastatin lowered all-cause mortality in these patients by 13%, and lowered the risk for any major coronary event by 27%.

So, those studies would certainly seem to support the use of statins in patients at significant risk for cardiovascular events.

The question remains, do PCSK9s need to do more than demonstrate that they can lower LDL-C by margins equal to or greater than what the statins can achieve? And do they need to demonstrate that lowering LDL-C in patients at low risk for cardiovascular events results in significant clinical benefit? In other words, in order to achieve blockbuster status and justify their high price, do PCSK9s need to demonstrate a benefit in primary (as distinct from secondary) prevention.

The distinction between primary and secondary prevention is more pragmatic than absolute. Primary prevention mostly means taking fairly routine precautions against medical threats that might affect anybody; e.g., we should all get our flu shots, because the flu is out there, and, believe me, you don’t want to catch it. Secondary prevention means addressing specific factors that put an individual at elevated risk for some bad medical outcome. The evidence supporting the benefits of cholesterol-lowering treatment in persons with acute coronary syndromes such as history of stroke or heart attack or unstable angina is extremely strong. But in the larger population, with less severe risk factors, the evidence is less robust.

Some of the evidence for cholesterol-lowering as primary prevention might be called circumstantial. It is a fact that heart disease rates in the U. S. have declined quite substantially in the past 50 years. For example, the American Heart Association calculates that if the CVD mortality rate had remained at its 1963 peak, 621,000 additional CVD deaths would have taken place annually just from about 1996 onward – that’s almost 10 million people.

What could account for that huge decrease? In part, it might be because lots of people quit smoking. And many more people were controlling their blood pressure. But it’s also a fact that it was in the mid-1990s that lots of Americans began to take statins. So, based on that association, an argument can be made that cholesterol-lowering treatment constitutes a form of primary prevention for cardiovascular disease. And the new statin guidelines, promulgated in November 2013, are clearly an effort to increase primary prevention of heart disease.

But how will the PCSK9 agents fit in with the new statin guidelines?

When these guidelines were handed down from on high (i.e., the American College of Cardiology and the American Heart Association – ACC/AHA), the controversy erupted immediately. Doc Gumshoe had his say about them in a piece in December, and at the risk of repeating myself, here are the essentials of what these guidelines state:

  • They attempt to quantify total cardiovascular risk by arriving at a percentage figure for a ten-year risk of cardiovascular events (heart attack or stroke), based on an algorithm. Individuals aged 40 – 75 whose ten-year risk is 7.5% or higher are recommended to take statins.
  • They recommend that persons whose LDL-cholesterol levels are 190 mg/dL or higher should take statins.
  • They also recommend that all persons with existing heart disease or Type 2 diabetes should take statins.
  • However, specific LDL-cholesterol goals are not part of the new guidelines.
  • And regular monitoring of blood cholesterol levels is not necessary. The effects of treatment should not be based on how much cholesterol-lowering takes place.

It has been estimated that implementing these guidelines would result in 70 million people in the US being on statins.

It was pointed out immediately by some of the top cardiologists in the land that the guidelines overestimated risk by a significant percentage, so that a great many people who did not need statins would be taking them. In particular, the algorithm overweighted age, so that many older persons with no risk factors at all would be prescribed statins.

And, because LDL-C goals were not part of the guidelines and regular cholesterol monitoring is not part of the drill, there’s no way for doctors or patients to have any idea of whether the statin treatment is actually doing them any good. Patients would have to take it on faith, and this would likely lead to poor patient adherence to treatment.

A nod to the cholesterol skeptics …

There are among us those who are doubtful whether cholesterol is really the source of the cardiac problems. Instead, they point to a number of other related factors: inflammation, endothelial dysfunction, oxidative stress.

These are indeed real. But cholesterol is involved with all of them.
If you already know all about cholesterol, you can skip this – and I’ll try to keep it short. But here are some basics that a lot of people don’t know about.

Cholesterol is a simple molecule, solid at body temperature, and not soluble in water. In itself, cholesterol is neither “good” nor “bad”– the distinction is between the little bundles of lipids and proteins that carry cholesterol in our circulatory system. The larger, looser ones – low-density lipoproteins – are the ones called “bad” cholesterol (i.e., LDL-cholesterol), because they are more apt to shed cholesterol molecules, which can be deposited in the walls of our arteries. The smaller, denser ones – high-density lipoproteins (i.e., HDL-cholesterol) – convey the cholesterol molecules back to the liver, where they are taken up by the bile and carried in the bile duct to the colon, where they are eliminated in feces. Therefore, HDL-C is “good” cholesterol.

But remember that cholesterol is absolutely essential to life. It is present in all our tissues, providing structural integrity. And cholesterol is essential to the synthesis of every hormone in our bodies. We synthesize about 80% to 90% of our cholesterol; only a small fraction enters our bodies as cholesterol. You may read somewhere that cholesterol is only synthesized from animal sources. This is entirely untrue. Vegans make cholesterol just fine; if they didn’t, they would be dead.

LDL-C particles are not all the same size. It now appears that the smaller LDL-C particles are more susceptible to oxidative damage, and may also inhibit the synthesis of nitric oxide, which is thought to be one of the body’s natural mechanisms to combat atherosclerosis. The larger LDL-C particles are comparatively benign. And HDL-C has another decidedly beneficial effect. Its principal lipoprotein, apo A-1, plays a part in preventing particles involved in atherosclerosis from adhering to arterial walls.

So, indeed, those other factors play an important part in coronary artery disease and heart disease in general. But it’s hard to get away from the basic fact that what gets deposited in the arterial walls is cholesterol. That has been known for over a hundred years. What we’re beginning to understand better is how it gets there and how it causes damage.

What’s this about the “innocence” of saturated fats?

Recent evidence points to further complications in the cholesterol story. The accepted wisdom, up until recently, has been that the arch-villain in our diets is saturated fat. Now, at least some data seems to exonerate saturated fat as a principal cause in heart disease.

In a December piece (“Tidings: Mostly Glad”), Doc Gumshoe referred to a 2009 analysis of 21 studies in almost 350,000 subjects, observed for up to 21 years, which found that the persons who consumed the highest amounts of saturated fats did not have any increased risk of cardiovascular disease, compared with the persons who consumed the smallest amounts of saturated fats. (Siri-Taurino PW, Am J Clin Nutr 2009)

And in March of this year, another analysis was published, this one looking at 72 studies in more than 600,000 subjects. Again, these the results were that people who consumed the most saturated fats did not have more heart disease than people who consumed less saturated fats. And people who consumed more mono- or polyunsaturated fats, (e.g., olive oil or corn oil) did not have less heart disease. (Chowdhury R, Ann Int Med 2014)

Different types of fat were associated with varying levels of cardiovascular risk. Omega-3 fats, mostly found in fish, appeared to be protective, as did some fats found in dairy products. (Note: this doesn’t apply to omega-3 supplements, which have not been found to deliver cardiac benefit.) On the other hand, omega-6 fats, found in some vegetable oils and processed foods, were related to elevated risks.

Saturated fats do increase the levels of some LDL-cholesterol, but not of the smaller, denser LDL-C particles that deposit plaque in the arteries. These more dangerous LDL-C particles are linked to high carbohydrate diets and foods with a high glycemic index – i.e., “sugary” or high-fructose . This finding reinforced the conclusions of a Danish study that found that persons who substituted low-fat, sweet foods for higher fat foods experienced more cardiovascular events. (Astrup A, Am J Clin Nutr 2011)

So, what does all this have to do with PCSK9 agents?

As of now, Doc Gumshoe’s prognostication is that at least Amgen’s and Regeneron’s drugs will get fairly prompt FDA approval. What happens after that remains to be seen. There was a flurry of worry about possible cognitive side effects in connection with evolocumab, but careful analysis of the data did not reveal any increased risk. They do lower LDL-C by big margins, and, at least in the short term, the side effects profiles seem to be benign.

To get comparable LDL-C reductions with statins, high doses have to be employed, with an elevated risk of side effects. Statin side effects, particularly the muscle aches – and in the most severe cases, destruction of muscle tissue – are by now very well known, statins having been on the market for more than 20 years. There certainly may be side effects with the PCSK9 agents. It may just be too early for them to emerge.

There is likely to be considerable resistance from the payers. Statins now are inexpensive, and in most cases it would be difficult to justify substituting an expensive drug, given by injection, for a cheap oral drug. The response from the insurance companies will be, “You need to justify to us, on a case-by-case basis, why you need this expensive new drug.”

Compliance may also be a big deal. For the PCSK9 inhibitors to attain blockbuster status, it’s going to be necessary to get a lot of new patients on those drugs – not just the ones who aren’t getting satisfactory results on statins. Many of those new patients will have to be people who don’t currently know they’re supposed to be on cholesterol-lowering medications – the ones who get swept in under the new ACC/AHA guidelines. Most of those patients have no current symptoms – they’re merely “at risk” based on the numbers in the new algorithm. How many physicians are going to prescribe an expensive new drug to those patients? And how many patients, with no symptoms to remind them that they have a condition that needs treatment, are going to stick with the treatment plan?

And there’s yet another body of inconvenient data that does not bode well for the PCSK9s. The studies showing that the evils of saturated fats are greatly overestimated are only part of a trend that goes back to the Exoneration of the Egg. (Remember when the Evil Egg was the embodiment of what we had to avoid in order to keep out cholesterol?) Saturated fats were to be avoided not only because they cause us to gain weight, and there’s no doubt that obesity contributes to ill health in lots of ways. But when we’re considering heart health, the link was always between saturated fats and elevated levels of LDL-cholesterol.

Now, there’s evidence that what saturated fats do is increase the levels of the larger LDL-C particles, which don’t appear to be particularly harmful. It’s the smaller, denser LDL-C that most contributes to atherosclerosis, and those are more related to sugars and carbohydrates – not to saturated fats.

But cholesterol-lowering drugs, whether statins or PCSK9s, don’t discriminate between the “innocent” LDL-C and the “guilty” LDL-C. It seems possible, and even likely, that people who are not specifically at high risk for heart disease can manage their risk quite adequately by following a diet, and a not-particularly-stringent diet at that.

The benefits of cholesterol-lowering drugs for the high-risk population are very well established, and Doc Gumshoe doesn’t anticipate any change in that perception.

But for the rest of the population, not at high risk based on clinical evidence, but only on statistical modeling, this new class of drugs, the PCSK9 inhibitors, may be swimming against the tide.

* * * * * * *

Please keep the comments coming! Doc Gumshoe got a couple of demerits for the HRT blog, including one for just referring to hormone replacement therapy in the title as HRT, which looked like a stock symbol to some folks. But I want to know what people are interested/curious about, as well as when I hit or miss the mark with these pieces. Miss Truesdell didn’t shrink from telling me, “Michael, you made a mistake on line 3 of that proof – fix it!” I (eventually!) was grateful to her, and I’ll be grateful to you for correcting any goofs. Thanks again, Michael Jorrin (aka Doc Gumshoe)

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103 Comments on " Will PCSK9 Inhibitors Be the Next Blockbusters in Cardiovascular Disease?"

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Joseph E Fasciani
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0

There’s a simple solution to all this medical folderol over cholesterol.
You see, it is easily dissolved by a common organic solvent, so much so that people who consume this solv ent on a regular and generous basis have sq

JoelJ. Carlson
Guest
0

So, what is it????????????

archives2001
Irregular
66

Organic solvent?? Doesn’t make any sense. Where’s the rest…???

bncn
Guest
0

Alcohol I presume???

DrKSSMDPhD
Member
47644

Nice commentary Michael.

Alnylam is merely waiting to see if, in an evidence-based-medicine way, the PCSK9 inhibitors change outcomes. if they do, they will deploy RNAi to silence PCSK9.

And if Alnylam does so, Benitec will then follow with liver-directed AAV8 loaded with shRNA to shut down PCSK9 expression.

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)

I’ve been watching Alnylam for quite a while, with increasing dissapointment, As for Benitec, will they have the resources to get this to market, or will they get scooped up?

DrKSSMDPhD
Guest
0
Michael…oh, I am not suggesting taking a position in Alnylam. It has been heinously overvalued. Its anti-TTR siRNA for amyloidosis will never earn back what it has cost to develop it, and in fact the company is concealing that stem cell transplantation works for the condition. But they are clever….they will sit back and let the EBM’ers have at the PCSK9 mAb’s: these antibodies do cause LDL to fall by 75 per cent but that they improve outcomes isn’t yet proven. If it is proven, then they will move ahead with their PCSK9 siRNA (which they have patented). Whether Benitec… Read more »
analog68
Irregular
373

They need to induce labor or change the protocol for cohort 1…..No?

DrKSSMDPhD
Guest
0
Michael: Oh, don;t get me wrong. I am not espousing Alnylam as in investment thesis. Its anti-TTR si RNA will get to market for amyloidosis though no one mentions that stem cell transplantation works for this and no one mentions the disease is rare enough that the company is not likely to recoup development costs. Also, no one is factoring in the issue that long term exogenous RNA has not been proven safe (may agonize TLRs). Alnylam is watching this, Sun Tzu-like, to see if there is EBM-worthy data that PCSK9 mAB’s alter outcomes. If they do, it will then… Read more »
DrKSSMDPhD
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0

Two replies because the first seemed to disappear into an interweb void and I then tried to replicate it. The void regurgitated it.

George
Guest
0
NIce, quick overview. As someone who has work in this field for a while: 1. I wouldnt worry too much about the new guidelines. Part of the reason they are what they are is the lack of morbidity and mortality (M&M) data: only statins have that and if the only drugs recommended were ones with M&M data, well.. there was nothing but statins to consider. 2. Statins have a lot of unpleasant side effect and people stop taking them. The fact that it is a silent disease also depressed compliance. 3. Dosing will be important for acceptance: these will be… Read more »
rubber
Irregular
46

For 40 years when first checked my cholesterol has remained above 270. Had I been on statins this long, might not have been living due to other statin related complications. I am 72 now.

astrid
Irregular
3

Mine has never got down to 270, i also passed on statins, and i am fine at 78

Ira H Monosson
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0

As a physician who specializes in internal medicine and a cardiology fellowship in my resume’, I wish to compliment the author for the accuracy and clarity of this first class article. Well done! As for the new LDL-C guidelines, there are leading cardiologists who disagree. I side with them, but that is a discussion for another time and place.

Leo
Irregular
152

Thanks Travis for a great article.

nortie
Member
0
“Now, there’s evidence that what saturated fats do is increase the levels of the larger LDL-C particles, which don’t appear to be particularly harmful. It’s the smaller, denser LDL-C that most contributes to atherosclerosis, and those are more related to sugars and carbohydrates – not to saturated fats.” I have been following an Italian doctor who proposes the theory that blood type determines compatibility with food types. He has also been saying for years that it is carbohydrates (as in cereals) and refined sugars are the cause of elevated cholesterol, not fats which upon ingestion are broken down anyway. I… Read more »
megfk
Member
11
This subject intrigues me. And I really enjoyed your approach to it, as well as your lively writing style. I became interested in cholesterol in 1954, when my father (a PhD research chemist who specialized in fatty acids and oils) joined a group of chemists to give a presentation at the AMA. Their message was similar to yours regarding the crucial role of cholesterol in the body. They also presented findings from numerous studies about health problems that are associated with cooking with vegetable oils. For several years, the recommendation had been for people to get rid of lard, bacon… Read more »
Joel J. Carlson
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0

K3 and K7. What are these?

megfk
Member
11
Joel – I neglected to add VITAMIN K. We are familiar with the variety we get in leafy vegetables…that promote blood clotting. We get a different variety of Vitamin K in meat. This variety assists in the utilization of calcium, and prevents calcium from being deposited into organs or being laid down in arteries as plaque. Vitamin K3 and Vitamin K7 are particularly high in a food eaten in Japan, called Natto or Nattokinese (a fermented soybean dish that I’m told smells awful). The Vitamin K that I take is derived from Natto. A study was done at Bethesda Hospital… Read more »
Kris Prasad
Guest
0

Margaret, Did you mean Vit K2, which is in fermented foods like Natto, which chaperones Calcium to bone rather than to heart? I take that along with Vit D3 and they are the only Vitamins I take. As for K3 (menadione), it is not a naturally occurring vitamin and is a synthetic. One company selling menadione (Sciencelab.com /see its MSDS section) warns that menadione is “toxic to kidneys, lungs, liver, mucous membranes. Repeated or prolonged exposure to the substance can produce target organ damage.”

megfk
Member
11

Kris, I’m glad that you caught my mistake. I checked my bottle – – and you are correct. It is Vitamin K2 that I take. And now I know that K3 is one to avoid.

Michael Jorrin,
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0
Michael Jorrin (aka Doc Gumshoe)

Thanks, Margaret. I would love to see the study that you mention – if you can provide the citation I will get it. There’s be more on cardiac-related developments as things come up.,

megfk
Member
11
Doc GumShoe – I did not keep my copy of the study on Vitamin K. And I do not know whether it was published. In 1999, my doctor (who held to the party-line of anti-supplements) went with other doctors from his clinic to a presentation at Bethesda Hospital, and was stunned by the results of their Vitamin K study. My uncle (the cardiologist) was instrumental in starting the study. His own health history drove a lot of his work. He was one of seven boys. Their father died at age 41 from a heart attack. And my uncle’s 6 brothers… Read more »
Rusty Brown in Canada
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0
Rusty Brown in Canada

According to my research, K3 and K7 are either:
models of Kia automobiles;
a type of motorcycle;
alternate forms of vitamin K.
Take your pick.

tanglewood
Irregular
312

Hi Margaret, I use a coffee grinder to grind up about 25 grams (not ounces) of Flaxseed and add it to my cereal every day. Do you know if that is an adequate replacement for Flaxseed oil?

megfk
Member
11
tanglewood – Dr. Johanna Budwig (in Germany) treated cancer patients with Flaxseed oil, based on the work of oil chemists that revealed deficiencies of linoleic acid in people with cancer). Even though all the patients were viewed as beyond help, the Flaxseed-oil cure rate was impressive. Maybe you saw things about her work, that sparked a bit of a craze about 12 years ago. The Flaxseed oil was mixed in a sulfur-producing protein (milk or cottage cheese) and aerated by mixing vigorously. The patients also added Flaxseeds to food. My guess is that it takes a LOT of Flaxseeds to… Read more »
Solyom
Guest
0

Are the individuals with this type of PCSK9 genetics located in a particular locale in Italy? If so ischemic Cerebral-vascular Disease and Cardio-vascular Disease are not found in that population no matter the age.

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)

There are probaably people everywhere who have the gene from one parent & thus less CVD; those who have it from both sides are much rarer. I think the case that piqued the curiosity of reseaarchers was a young woman in Texas, if I remember correctly.

Joseph E Fasciani
Guest
0

OK, Something Happened and there isn’t an Edit feature, so here we go again.
MDs have long known that heavy drinkers of any form of alcoholic beverages have little cholesterol to clog their arteries, etc., so it’s clean tubes vs liver damage & brain cell death! Ya picks yer poison and takes yer choice: that’s what makes fer freedom in North America!

Rusty Brown in Canada
Guest
0
Rusty Brown in Canada

Can you substantiate that claim re alcohol consumption?
I wish it were true, but my cholesterol is “too high” according to my G.P. and the local cardiologist told me years ago that he was surprised that a guy with arteries as badly clogged as mine would still be alive at this point. All this despite years of enthusiastic application of the panacea you seem to prescribe.
Conversely, on the other hand, there are lots of credible articles on the net about “Alcoholic Cardiomyopathy”.

DrKSSMDPhD
Member
47644
I don’t regard it as accurate or evidence based to assert that alcohol consumption is associated with blanket protection from vascular disease. it isn’t. Moderate consumption may be associated with diminutions in all-cause mortality, but absolutely no cause-effect relationships have ever been demonstrated. Meanwhile, any cardiologist or intensivist will tell you that among the most notorious patients in hospitals are the men who have MI’s and conceal their drinking history and go into withdrawal while recovering. Drinkers have strokes and MI’s all the time. It is my job to deal with alcoholics, and to assert that they are less likely… Read more »
Joseph E Fasciani
Guest
0

Sorry, but I was combining humour w/some factual stuff.
Alcohol is an organic solvent, but I wasn’t advocating drinking vats of it as a cure-all.
By the bye, what is an MI? I’ve never had withdrawals of any kind.

arch1
Irregular
7744

Joseph; I think MI is myocardial infarction,,,heart attack. If you like humor don’t try this at
home, for professionals only!! Theorem of brain cleaning: as it is well known that predators lead to the overall fitness of the herd by eating the ill & the weak,The very old & young….
Since ethanol is said to kill brain cells perhaps the same sort of thing goes on with daily use. You wind up with fewer brain cells but faster??? Think I can sell that? fa

Ira H Monosson
Guest
0

Yes, MI is myocardial infarction (heart attack). Heavy drinkers who develop liver disease do have low cholesterol because the liver can’t synthesize it anymore. However, heavy drinkers usually develop hypertension, and that causes arteriosclerosis that leads to heart attacks and strokes. That’s if they don’t die from cirrhosis first.

Rusty Brown in Canada
Guest
0
Rusty Brown in Canada

No argument there, but, by the bye, the silly notion that alcohol “destroys brain cells” was discredited years ago. Simply not true, as far as my experience is concerned.

archives2001
Irregular
66

Rusty, Here’s an opposing presentation from an MD:
http://www.wctu.org/alcohol_and_the_body.html

megfk
Member
11
Rusty – A liver increasingly damaged by alcohol cannot function effectively…resulting in a build-up of ammonia. Ammonia then mixes with blood and does a number on the brain. Ammonia is one of few substances that readily passes the brain/blood barrier. The high ammonia levels are evidenced in an uneven gait when walking and difficulty writing. A further increase of ammonia is evidenced in slow, slushy speech, and inability to communicate intelligibly. When the ammonia level gets higher, the person becomes more and more groggy. Then the ammonia snuffs consciousness. In all stages of hepatic encephalopathy, brain cells are harmed by… Read more »
Rusty Brown in Canada
Guest
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Rusty Brown in Canada

Thank you both for your concern. In reply, I would mention Winston Churchill as an example of someone who consumed alcohol regularly, lived a very long life, was knighted and won the Nobel Prize for literature (1953). There are other examples, such as
“…that oldest woman in France, who was supposed to have said in her last
interview, at age 112, that she owed her long life to a certain local wine…”
The evidence just doesn’t seem to support the idea that intemperate (but not extreme) drinking causes brain deterioration.

Joseph E Fasciani
Guest
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Thank you both for these illuminations. At 71, w/a pretty vigorous life [so far!] behind me, I’m always amazed by what the human body can do when it REALLY has to perform or lose its owner’s life! I should have died several times over, but like that damned rabbit, I take a licking and keep on ticking! I’m familiar w/genetics from my career in horticulture, and developing new cultivars of improved species. There are plenty of other factors that enter into one’s life that are far from free choices, and we must accept & live w/them. I recall reading about… Read more »
DrKSSMDPhD
Member
47644

Ammonia has absolutely nothing to do with altered mental status owing to liver disease. Not sure why or how that notion persists.

Alcohol does not so much directly harm the brain as it does lead to long-term excitotoxicity from chronically augmented brain glutamate synthesis and release.

Diminished synthesis is not necessarily the basis for cirrhotic hypocholesterolemia.

jonken
Member
57

Doctor KSS. Now that this subject of alcohol has arisen I have the temerity to ask a question on a subject on which I really would like YOUR opinion. My oncologist (remission of NHL) says that alcohol kills WBCs – a poison for me). My primary care MD says a glass won’t hurt me. I love big Zins and Syrahs and used to drink about 12 ounces 4-5 days/week.
Many many thanks for YOUR take on this.
Ken M.

megfk
Member
11
Dr. KSS – Nonetheless, ammonia levels are measured when a patient is in liver failure (decompensation). And patients are given a product such as Lactulose to help expel ammonia and bring down the levels. As ammonia levels rise, speech and movements of the patient do become become uncertain. And after ammonia levels pass a “tipping point,” the patient lapses into a coma (a state of non-responsiveness). In a situation of a patient with liver disease, who has not consumed alcohol for years, to what do you attribute the altered mental state during decompensation, if not to elevated ammonia levels?
Rusty Brown in Canada
Guest
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Rusty Brown in Canada

NHL = non-Hodgkins lymphoma
WBC = white blood cells
apparently, if my Googling is accurate.
Maybe save a few readers from having to look this up.

Al
Guest
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Speaking of cholesterol: A year ago last February my doctor said I had high cholesterol and if I didn’t do something about it, I would have to start taking medication. The doctor also said I had some indication of gout. So I gave up red meat and ate mainly chicken and in general tried to eat more vegetables and fruit. At my appointment last February, the doctor said my cholesterol was way down!

Bud Wood
Guest
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Many years ago. a physician told me that I had better take his suggested statins to lower my cholesterol. I said “no statins”. He responded saying that I knew a little, but what I didn’t know would kill me.
Well, here I am at 87 and I suspect that he was done-in by ingesting statins to lower his cholesterol.

Judy
Guest
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Ii has been discovered that high LDL cholesterol level is a symptom and not a cause of a heart disease. The inflammation is the cause of heart disease, hence statins will supress the symptoms and hurt your liver. A typical side-effect of being on statins is muscle weakness; isn’t a heart a muscle?

DrKSSMDPhD
Member
47644

Statins affect skeletal muscle. Which the heart isn’t.