Will PCSK9 Inhibitors Be the Next Blockbusters in Cardiovascular Disease?[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)
From my experience unless there is a life or death situtation people do not like injectable drugs. Many patients have problems adjusting to injectable insulins, which explains the research into inhalable insulin. As i read the article, i can see a place for these drugs but not as first line agents.
In the subject of arterial plaque, I have seen no posts regarding University of Israel 3 year research that had 35% plaque reduction in a group of people with significant carotid artery blockage. They used a standardized extract from pomegranate. I had very high levels also, one being over 95% plugged and surgery clean-out and have been on the extract for five years, experiencing big time, significant drops in blood pressure and reduction of plaque; additional subsequent memory recovery and several other health related wonderful improvements. To see results, google University of Haifa pomegranate plaque research. My sister died of very high plaque levels at age 67, and I am now 72 with good health!
Amen, and thnx frm me too!
Gonna begin drinking lots of it!
The original Haifa research used the juice extract standardized to 30% punicalagins, and an article I read at the time suggested 8 oz per day juice off the shelf, but because I had cancer at the same time, I was avoiding most sugar/glucose sources; as a result, I searched for the capsule extract and found both 400 and 800 mg standardized 30%, so it is best to go for the capsules. I purchased a year supply of the 800mg for under 200$ (5 bottles of 60). I still use some of the juice but mix 6 oz juice to 4 oz water a couple of times per week. I like the fruit, but the extract concentrate costs much less and has more punicalagins that efficiently work on the plaque – a molecule at a time. The side effects for me have been a blessing: Besides the B.P. and plaque level dropping, within six months my lost memories began to return (As previous stroke symptoms diminished): L. T. memories of Vietnam and of childhood cleared up in living color, some good, some not so good, but they have all let me return to realities that I can now live with! I added about six other supplements that also support arterial health and kill cancer cells.it’s amazing what the right substances can do, without the drug wipe-out. This is a natural product that is not a thinner and best used for several years, but still best to run it by your NMD. Be well and healthy!
Ray
Hi Ray, How do you take your pomegranate? Juice, extract or the actual fruit? How much?
I’ll bet the ‘real fresh stuff’ wud be best if u can afford a crate of ’em!
Don’t be too sure about that. My understanding is that pomegranate juice is extracted from the entire fruit, peel and all, and that the peel – which is inedible – contains much higher concentrations of the “good stuff” which then ends up in the juice instead of being discarded. A damn sight more convenient, too.
Rusty,
When I eat a pomegranate, I EAT a pomegranate, skin and all.
I simply use a wire brush scrapping just a little off the skin to make
certain I don’t ingest any wax or pesticides. I then place the rest
in a blender with some other juice and herbs and guzzle it down.
Thank-you, Ray, for telling about this study.
Margaret: I am a hepatologist. If you are not going to listen to my explanations about portosystemic encephalopathy, advanced in many of the threads, I am genuinely not sure who you will listen to. This is my field, my specialty, what I have published and spoken on nationally.
No one measures ammonia levels. In fact, I do not even know of hospitals that will run them. They have no validity, no utility. A clinician who would actually order an ammonia level is so out of touch with clinical medicine and so lacking in clinical acumen as to need retraining. Even if they DID indicate something, encephalopathy is so clearly and definitively diagnosed by bedside maneuvers requiring mere seconds that no lab testing would ever be warranted.
If you honestly want a detailed discussion about portosystemic encephalopathy’s causes and management, I can amply and ably provide it, but since you are disputing everything I say about the topic, a subject that again I have researched, written on, trained other physicians to manage, spoken about and above all else treated for decades, I am not sure there is much point in me spending time laying out explanations. It’s NOT ammonia.
Dr. KSS — Please know that it was not my intention to “dispute” everything you say about a topic. I simply asked you a question.
I will ask it again, providing more detail about the patient’s situation. I posed a situation in which the patient has liver disease, and has not consumed any alcohol for 10 years. This patient is hospitalized due to symptoms of liver decompensation (raised liver enzymes, low blood platelets, raised bilirubin, loss of physical co-ordination, and slurred speech). In this hospital (year 2013), ammonia levels WERE examined, and WERE found to be high.
In this hospital, the patient’s altered mental state was attributed to increased ammonia. The doctor prescribed Lactulose for the express purpose of lowering the ammonia levels. But the patient’s ammonia levels continued to rise. The patient lapsed into a state of being non-responsive. In this specific case, the hospital was St. Mary’s at Mayo Clinic.
I posed the question: To what would you attribute the altered mental state during liver decompensation, if not to increased ammonia levels?
On this subject, I am inclined to agree with Margaret. My Textbook of Medical Physiology (Guyton & Hall) notes that ammonia is released during the process of protein metabolism. In a healthy liver, this ammonia is converted to urea and excreted in the urine. To quote Guyton & Hall, “In the absence of the liver or in serious liver disease, ammonia accumulates in the blood, often leading to a state called hepatic coma.”
Uh, OK. A textbook that got the relationship between clothing and evaporative heat loss in humid hot climates wrong. And that has said that stress causes gastric ulcers. By a man whose polio was treated by the rigid splinting technique subsequently shown to be the worst possible way to manage the disease.
Miasma and phlogiston were once surefire absolute certainties too.
And if the tidy little model propounded by the urea hypothesis is correct, then why do encephalopathic patients whose kidneys work not merely urinate away their toxin so readily and rapidly incorporated into urea??? And why does urea never rise even one percentage point during encephalopathy?
Neither Guyton nor Hall were hepatologists, Michael, and for them to be pontificating on what I do for a living and have done for decades is to me kinda like a eunuch in a seraglio discussing the erotic proclivities of the ladies therein. Car, car-penter. Do you call a carpenter when your car breaks?
So a gas that is nearly insoluble in water at core body temperature and that can be at most evanescent at physiologic redox potential is to blame. If you believe that then you also believe that quenching fever hastens recovery from a viral illness, that killing pain in an injured joint makes the joint better, and that steroids make infectious disease better. Backpacking in Indonesia, I once saved the life of someone from a “local doctor.” This person was sick and febrile, and the doctor told him the problem was “too many white blood cells” and gave him chloroambucil, a chemotherapy pill to “lower” the white blood cell count. He had “too many white blood cells” because he had pneumonia and needed antibiotics!
Thanks dr good one
Following…thank you!
Dr KSS
Any reason for delay in first patient dosing by Benitec? Can you please find out from your company contacts? Thanks a lot for your insightful and knowledge enhancing articles and comments.
Thanks Rex. I’ll be happy to discuss it. Not sure if you are an irregular or not, but the bulk of the Beni investors are over on those threads and it might be easiest to put it there in one place so all can have at it. Yes, I do know what’s going on.
Gadzooks, but we have a solemn bunch of folks here!
Yo, Rusty Brown, many thanks for your typically Canuckian sage observations re life, liquor, and livers, such as they are. It looks as if our lives up here are moderated by our climate, so that we have different outcomes from the similar inputs in those South of the border.
At any rate , I note this is going to be one of the blog’s longest-ever running commentaries, so apparently alcohol brings out the spiritual juice in most readers. And boy! Are we ever SOLEMN instead of serious on this!
Look: no one gets out alive, and from all that I know, read, and have experimented w/in a lab, it looks to me that genetics is 95% and life-style or choices is the remaining 5% in re of our life’s span and quality. Fear has killed far more people than food has.
Let me conclude w/a classic anecdote about Churchill. At the end of a dinner he had given, a woman sitting across from him said to him, “Lord Churchill, don’t you think you’ve had enough to drink?”
To which Winnie replied: “Madame, I have taken far more out of alcohol than alcohol has taken out of me.”
End of story, and good night all! 3:01 PST, Victoria, BC
You’re only an alcoholic if you drink more than a hepatologist Joseph.
Very good, and glad to see you do have a sense of humour, as well as a deep knowledge of your healing arts!
I had an inguinal hernia repair Wednesday night, and while I arrived at 9:00 a.m., I wasn’t in the Operatory until 3:10. I elected for my first lumbar spinal block, so I could remain conscious throughout the procedure, as I did w/my cardiac catherisation @ age 36. Both experiences were very instructive on multiple levels.
While I’ve always been a fast-healing sort, since I started taking laminine regularly on August 03, 2012, the amount of recovery and the wide spectrum of relief has been truly phenomenal, a word I use once every ten years. You may wish to look into laminine’s manifold curative properties and actions: http://eggoflife.com/josephbc/.
It has been clinically tested, peer-reviewed, and rigorously evaluated for twenty years in Europe, but only recently in North America.
All best, Joseph
Thanks Joseph. I hope you are recovering well from what can be a quite painful procedure.
I know that you mean it well and are well-intended, but I would be quite cautious as regards laminine. I have known about it for a while, and I have to be honest: it has all the makings of a scam. A person cannot do a randomized controlled trial on self, and so while it seems to have helped you in some way, in fact there is no data that your experience is generalizable. Companies marketing this are being sued for scamming, the putative mechanisms by which it works make no scientific sense at all, and what I am guessing is that you got better because of the charming organismal vitality you seem to show and that the laminine had nothing to do with it. There are no Holy Grails, panaceas, elixirs of life, and things with manifold curative properties are invariably things that are dispatched by matchstick men to have manifold ways of curATing money, of separating your from yours.
That 95%-5% theory is what I’ve believed for decades!
Margaret: Go to Outback, or go to a Ruth’s Chris, and eat a huge piece of whatever cut of red meat strikes your fancy. Lap it up. Enjoy it. Revel in it. Then draw your blood. I will wager my entire position in Benitec, which is quite large that, mirabile dictu, your blood ammonia level will be sky-high! And yet, I will also raise you another 10,000 shares that you will not be confused, dysarthric, stumbling or unable to add 2 and 2.
You said almost nothing about what the friend has, about what the liver tests are, about what is felt to be the cause of the ostensibly decompensated cirrhosis. I am deeply disappointed that a Mayo-affiliated hospital would be wasting money on an ammonia level, but can also say I am not surprised. Mayo floats a lot on..uh, image, perception….one that I cannot honestly say is justified.
Physicians who do actually order ammonia levels are doing so for two reasons…..lack of ability to make a bedside diagnosis and, two, to create and perpetuate an utterly bogus paradigm to give patients and interested people a false thing to seize upon and follow. Basically, it is an affront to intelligence. Meanwhile, decades of careful study have shown that ammonia testing is absolutely nothing more than a random diagnosis generator, that it is so often spuriously and misleadingly elevated as to be of no value at all. It is assumed, wrongly, that because a patient is confused and ammonia level is high, that one is caused by the other and this is the antithesis of scientific thinking. Patients with cirrhosis often become deeply portosystemically encephalopathic with stone-cold normal ammonias, and meanwhile often walk around and mentate with perfect lucidity when ammonias are high. They are of no value. You never ever order a test in medicine unless it will change the management. Here it did not change management. It was the soup’s stone.
The ammonia notion is one of those dumb old ideas that became dogma from half-cocked thinking and is now “received wisdom” that does not withstand merest scrutiny. Like the nutty idea that vitamin C helps fight colds (disproven hundreds of times), that fiber prevents colon cancer (disproven), that lots of water is good for everybody (disproven), or that cracking your knuckles causes arthritis it’s one of those things everybody knows to be true that isn’t true at all.
In portosystemic encephalopathy, comprehensive laboratory testing in search of one definitive parameter that is compromised has disclosed one, and only one, item: that glutamine levels in cerebrospinal fluid are high during encephalopathic episodes. Doing spinal taps on such patients as a diagnostic test, however, is hardly practical. I have gone into lengthy disquisitions in these threads before about the role of glutamate in the central nervous system: glutamate is the principal regulator of alertness, the neurotransmitter that activates. (Alcohol does not directly damage the brain, but in fact leads, because of its inhibitory effects on brain, to counterregulation in the form of higher glutamate production. High glutamate is “excitotoxic”….enough of it can bind to nerves and kill them.) Glutamate is not glutamine. Their three-dimensional structures are quite different, and when glutamate is converted into glutamine (by reductive amination but NOT by ammonia), there is no glutamate to stimulate the brain to work.
Think of nerves like transmission lines or wires. The brain is a bunch of nerves, a bunch of wires. What is “noise”? Well, to me noise would be when there is no intended signal on the line, and then there are adventitious, spurious, not-intended bits of signal. Noise on a nerve line would be when your arm or face is relaxed and a muscle starts twitching.
I regard portosystemic encephalopathy as what I would call inverse noise. What do I mean by that? To me inverse noise would be when there IS an intended signal on a line, and it gets falsely wrongly interrupted. And this is what the encephalopathy of liver disease is. Glutamine accumulates and the glutamine pool represents a sumping or sequestering away of glutamate. For signals to be steady and maintained from the brain, there MUST be glutamate. As a result, encephalopathy is when there are continuous transmissions (motor signals or thoughts) that get dampened, interrupted, made unsteady and impure….not by noise on the line, but by inverse noise, but spurious, sporadic, unwanted momentary lapses in signal.
When I have a patient with suspected portosystemic encephalopathy I do one thing: I hold out my arms in front of me and raise my palms as if I am stopping traffic. I ask patients to stop traffic with me, and sometimes I raise my arms over my head and say “raise the roof with me”. Keeping one’s palms in that position requires continuous motor tone. An encephalopathic patient cannot maintain that, and so will have sporadic momentary lapses in or wavings of the palms. I then also place a finger in from of them and move it in an arc that I ask them to follow with their eyes. If they cannot do this is a smooth arc, if there is a saccade, this patient has ipso factor portosystemic encephalopathy. So why would ANY blood test be needed? These two bedside diagnostic maneuvers cost nothing and are thousands of times more reliable than lab testing. And if a clinician does not know how to do them or does not trust his clinical acumen, then another clinician is needed. I don’t know a kinder gentler way to put it. If a clinician enters a patient’s room, smells melena, and sees a trail of vomited blood from bathroom to bed, does that clinician REALLY NEED to do a blood count to confirm that the patient has lost blood? NO. Same with encephalopathy. It is a bedside diagnosis that takes a second or two. Why ignore and mistrust the evidence of your eyes (“you know why the good lord made your eyes so don’t shade your eyes” sang Tom Lehrer)??? But instead, certain doctors engage in mumpsimus thinking….and order a test that—-guess what?—is going to be positive! Why? I do not know. Maybe to look smart.
When a patient with established cirrhosis becomes encephalopathic, one of the following things is ALWAYS, ONE HUNDRED PER CENT of the time going on:
(1) the patient is hypokalemic (low serum potassium), which activates a renal vein glutaminase…patient needs potassium!
(2) the patient is dehydrated from overzealous use of diuretics for ascites and needs iv albumin
(3) the patient has blood in the GI tract being absorbed (evinced by melena, hematochezia, or hematemesis)
(4) the patient is in starvation biochemical kinetics, has not eaten for some reason, and is catabolizing muscle, which releases nitrogenous products
(5) the patient is septic
I GUARANTEE you that one or more of these things triggered this in your friend. And the remedy for the presentation is to treat the cause. When I have a patient like this, I lab the patient up….I culture urine and blood, I check the serum for cryptococcal antigen, I get very picky weight data because they are often dry. I check K and Mg. If they are quite ill, i begin vanc and meropenem til cultures are negative. If they have ascites that gets tapped to exclude spontaneous bacterial peritonitis. I generally also give a slug of iv albumin to reconstitute central volume as these patients are ALWAYS central volume contracted. And I insist that they eat and eat a lot. Another of the great big asinine dumb ideas out there is that you should starve cirrhotic patients of dietary protein. How stupid. A thousand studies have disproven this. Cirrhotic patients ARE starved becasue they do not absorb nutrients as a result of portal hypertension. So, some idiot doctors take these patients who are in DEEP, profound protein-calorie malnutrition and tell them to avoid protein. Yeah…SMART! This GUARANTEES encephalopathy because the body DEMANDS protein and will find it….it will begin eating up its own muscle and bone to meet its needs and when it does so nitrogenous adventitious flotsam gets released. Nothing provokes encephalopathy like starving a starved patient of the thing the patient is most starved for!
Why is lactulose used? It is lysed by gut bacteria to acidic components. It promptly lowers stool pH to about 5, and doing this protonates some or another nitrogen-containing evil humor that is not ammonia. No one knows what it is. Whatever it is, it gets into brain and reductive transamination happens to convert glutamate to glutamine. Laxatives do not achieve what lactulose does…..lactulose works by stool acidification. Encephalopathy that is truly refractory to lactulose does not exist. If your friend has worsened or has not improved, see my checklist above. Again, I will bet ALL my lovely precious Benitec shares that one or more (probably more than one) of those things is the cause. And until that cause is fixed, she will keep lapsing into encephalopathy.
Ammonia is a gas with negligible solubility at body temperatures (gasses prefer cold to remain dissolved in liquids). Anyway, please file ammonia in the same place where one files data about Loch Ness monsters, BigFoot, anal probing by aliens, Area 51, morgellonosis, chronic Lyme disease, mermaids, and the ideas that NVLX, PVCT, and CVM are good investments.
Thanks Doc. I learned a very useful new word today:
mump·si·mus
noun
1. a traditional custom or notion adhered to although shown to be unreasonable.
Dear Mr Jorrin
I recently attended the annual ACC meeting in DC (american college of cardiology). The excitement over these new agents was very evident and the word “blockbuster” was frequently heard. As an advanced practice nurse who has been treating cardiac patients with hyperlipidemia since the mid 1980s (PRE-statin era!), I want to compliment you on your excellent and coherent explanations of lipid metabolism and pathways. And your ability to explain the drug mechanisms and interpret research data is beautifully done.
Mary Ann White, NP
Kaiser Permanente CO, dept of cardiology
Dr. KSS you are our true medical Gumshoe as you help all of us cut through the hype and crud to get at the truth. You do so in a way that is understandable as well. It is a pleasure being able to dialogue with you and to learn from you.
Dr. KSS — Thank-you for conveying so thoroughly your approach to treating hepatic encephalopathy. But I do still expect to see a mermaid, and the Loch Ness monster, too.
As I understand your view of ammonia in regard to mental confusion…although protein-metabolism’s bi-product of ammonia much increases when the liver is not functioning properly, your position is that the elevated ammonia is inconsequential – and that Lactulose is administered to lower pH, not ammonia. Many liver specialists continue to view the ammonia itself as relevant to the mental confusion exhibited during liver decompensation. So clearly, understandings of those specializing in liver disease are not uniform (as is the case, I’d guess, in all matters).
I was particularly interested in things you said about protein. In so far as I am capable of understanding, I think you indicated that mental confusion is also an aspect of protein deprivation with consequential “nitrogenous adventitious flotsam being released.” Your position regarding protein, and the need to avoid cannibalization of muscle and bone, is also a significant change from positions of the past.
I’m wondering whether changes in the treatment of “liver failure” …such as administering IV albumin, encouraging consumption of lots of food, and providing a high protein diet… have improved the survival rate (that had been 20%).
Margaret: to borrow from a president, “there you go again.”
I know what confusion is. But “mental confusion”? What is that? I do not understand. If by mental confusion you mean confusion then, hey, why not let’s call it confusion? It confuses me, mentally you know, to call it mental confusion.
I think you need to re-read what I wrote, perhaps a few times. Your fixation on old hypotheses is framing the way you approach this. As I said, lactulose, in acidifying stool, protonates certain nitrogen-containing moieties. The goal is therapeutic acidification to achieve defecation of those protonated moieties. Lower pH, more free protons, greater ability for nitrogenous products to act as weak bases. But ammonia is NOT the moiety in question. If you think it is, then inhale deeply your friend’s defecated stool and notice that it does not smell like Ajax.
You say my protein hypothesis is a departure from the past….whatever do you mean by that? If by past you mean 1970’s and 1980s, which was certainly dim and distant past in medicine, yes, but no person of my generation would ever dream of withholding protein from a protein-starved patient as all patient with cirrhosis are. And I am trying to be gentle here but I cannot help but note that you are going on about this in the context of having also recently made claims in posts about acetaminophen causing cirrhosis (which it never does) and statins causing cirrhosis (which they never do). I sincerely think you need to take all your preconceptions about liver disease and toss them, shake the mental Etch-a-Sketch free here of all its old lines and drawings. I am happy to teach but first you must vacate the strictures and assumptions that ensnare you.
My colleagues in hepatology and me do not
(1)check ammonia levels
(2) withhold protein from people with cirrhosis
We joke and snicker about people who do just as we giggle when we get referrals from doctors sending us patients with abnormal liver tests that they fear are from statins. You assert that “many liver specialists continue to…” REALLY? Name one. And while you are at it, tell me what is actually wrong with the patient in question. I am a liver specialist. You aren’t. There are very possibly things of indispensable importance you are leaving out because you lack the context and experience to really have at this.
Survival rate 20 per cent? To what are you referring? What disease? 20 per cent of what? If you are asking about quality of life and keeping people with cirrhosis out of hospitals, albumin and nutrition make colossal differences and this is widely vaunted and practiced.
I think a big part of the lesion here is that you think if someone at Lettuce and Mayo does it, it is state of the art. It is not. I could write a 5000 word essay here on cases mismanaged there I have cleaned up after. It is my personal perspective that Mayo practices medicine in what I would call an unctuous and ingratiating style in which things are massively oversimplified for patient and family consumption whilst literally millions of dollars are frolicked away on pointlessness….like ammonia testing! Don’t you see??? Patient is confused. Patient has cirrhosis. The ammonia level’s gonna be, 90 per cent pre-test probability, high….let’s send it, make some bucks, and tell the patient and visitors with all due gravity that hmmmm, we think the ammonia level is high so when it IS, which we know it will be, we can look SMART and so we can tell them It’s a good thing you had us here to diagnose that high ammonia! Margaret, you are being suckered in by it!! Be better than this! Meanwhile, I sincerely do not think you have grasped what I have said about glutamine. Ammonia-centrism in liver disease is like geocentrism in cosmology. Scary to think there are people that still believe in either, and yet America actually has religious people who believe in geocentrism and that God made the earth 6000 years ago.
I honestly think that one of the real problems here is that you are assuming that what others achieve by spending 4 years in medical school, 4 years doing a PhD in liver biochemistry, 3 years doing a residency in medicine, 3 years doing a fellowship in GI, a year doing a fellowship in liver, and years doing post-docs and being faculty in those things AND HITTING THE BOOKS AND THE JOURNALS EVERY DAY DURING THOSE PROCESSES, that you can casually achieve the same thing in your spare time….what I am hearing is that you think that that counts for naught and that the principles, concepts, and truth that are apparent only after such years of hard work should be immediately accessible to you in a facile way. They aren’t Margaret. I think you need to respect process here and recognize there is reason people spend all those years. They don’t do it as rite of passage, they do it because that is how long mastering this material takes! Liver doctors bust their arses to master this material and it is elliptical, slippery, enormously complex material that you are trying to reduce to a few highly digestible trivialities. This is difficult material. If a creature exists in and is constrained by 2 dimensions, it is cognitively and rationally impossible to address that person from 3 dimensional space and explain what the third dimension is all about.
I am sorry your friend is ill, really I am. What I am hearing is that you think the way she is being managed, which landed her in the hospital, is state of the art! Instead, I think she should be managed my way and we’ll just see who gets her feeling better and living more.
Her only dietary constraint should be limitation of sodium intake to 2 gms per day. No other rules! No fluid restrictions and definitely no dietary proscriptions at all except sodium, She needs to weigh herself at precisely the same time every day in kg and record the weight, and take action as regards volume status and diuretics when that weight fluctuates by more than 1 kg. She needs enough lactulose daily to cause her to stool two or three times (no more, no less). And since she likely has ascites, she needs to be on ciprofloxacin 750 mg once weekly. If she is on spironolactone and Lasix, she needs to be empowered to adjust those doses as her weight fluctuates. And we’ll just see whether the KSS way or the Great Big Almighty Mayo way keeps her out of the hospital longer. But I already know who will win! This is why Margaret an entire middle Eastern nation cancelled its ties years ago with the system you like to come to the system I was in. Their way was about keeping patients in hospital and keeping them in the dark about how to manage themselves. My way was about teaching them to manage themselves (mass, mental status, diet, sodium intake, defecation, fluid status) to STAY OUT of hospitals. All depends on what your aim is: making money for a system, or making people well. I like you and am not trying to assail you, but I know for sure I would never ever argue with Alan Harris about plumbing because there is this serious issue of knowledge and experience, and in fact plumbing is not a trivial calling. Likewise, do not trivialize my calling and my expertise. Your hang-up about ammonia ammonia ammonia is like the story of the great naturalist who, upon, arriving in Australia, saw a kangaroo bounding and bounding and bounding off into the horizon. “Your grasshoppers are QUITE different to ours in England,” he said, sniffing. You are enchaining yourself, keeping yourself intellectually earthbound with what you are dead certain you know and I am trying to open your mind and make you see it is WAY more beautiful and less simple than you think. Meanwhile I do not know whether to be sad or angry to hear that there is a hospital anywhere that still performs ammonia assays. Shock me with insulin, frontal lobotomize me and give me some leeches. There were doctors that long ago encouraged patients to smoke too Margaret.
Checking further, Sherlock and Dooley (Diseases of the Liver and Biliary System) cite an association between ammonia and hepatic coma, but do not assert a clear causal link. Goetz and Pappert (Textbook of Clinical Neurology) mention azotemia, among others, as a likely cause. Despite Dr KSS’s assertions, I think the case is not proven either way. And what does it have to do with anything that Guyton was put in splints when he had polio?
By this analogy, one should be able to spend an hour at a library and completely get, from flipping through a physics book, everything there is to know about the Higgs boson and totally grasp what supercolliders do. When people are not part of a profession and have no formal training in it but then try to harangue those that are on the basis of flipping through a textbook (totally out of date by the time they are published and not something anyone in medicine actually reads), it conveys something quite discomfiting to me about the state of intellection that there is out there. Because of the internet, people now confuse virtual with real. People cannot understand bricklaying without laying bricks. Through glass darkly, Doc Gumshoe. It’s a clinical diagnosis managed clinically that needs NO lab testing at all, but clinicians can’t grasp that because they aren’t clinicians and have never made clinical decisions. It is just so funny to me that a non-physician non-clinician thinks he can read some golden prose in a textbook and then really be knowledgeable about something. Obviously and unfortunately, you are not interested in actually coming away knowing more. I’m a bird and you are holding forth on what I am and am not, what I do, and how I fly, on the basis of an ornithology book you just borrowed and read the table of contents for.
And what, by the way, does hepatic coma have to do with this discussion of portosystemic encephalopathy? Hepatic coma is a completely and utterly different issue. But, never having treated a liver patient, you might not know that, and might conflate these two different entities. Which is my point. Caddies may know an awful lot about golf, but in all other pursuits, it is safe to bet that spectators will never have the ability, facility, and utility of doers.
Dr. KSS… If I failed to appropriately respond to things you said to me, you maybe can chalk that up to my lack of comprehension, and certainly to my perspective regarding “truth.” I do not think that anyone has fully grasped “truth” about anything. Understandings in both medicine and science significantly changed during my lifetime and will, I hope, continue to change.
Given my perspective about “truth,” I recoiled from what you said about me “enchaining” myself, keeping myself “intellectually earthbound with what [I] am dead certain [I] know.”
I certainly have no basis for being “dead certain” that I know the role of ammonia during liver decompensation, and surely have no motivation to have a “hang-up about ammonia.” Instead, I was intrigued by changes in the treatment of liver failure since 1993 (when I was told that there was a 20% survival rate at The Ohio State University Hospital), and by current differences in understanding and in treatment from place to place.
You concluded that I “trivialize” your calling and your expertise. I apologize for anything I said that conveyed disrespect. I am aware, though, that my life experiences disincline me from being in awe of expertise and of educational degrees. My Father had a PhD, and 2 Uncles had PhD’s…all three encouraging conversation about their fields, as did my Uncle the cardiologist. My Husband had a PhD, also inviting conversation about his field. People with a PhD in my field (remedial education) are low down on the educational totem pole and would not likely claim expertise. Friends, almost all professors, also initiate discussions related to their fields.
Keep in mind, you CHOSE to be in dialogue with people such as I am. We are not in dialogue as liver specialist to liver specialist, but as someone with specialized education and experience in dialogue with someone who subscribed to Stock GumShoe.
I “chose” to be in dialogue because you asked Margaret. I am a bona fide expert on this subject and have spoken on it all over the country in academic medical centers, Because I am a nice guy, I took time out a Saturday afternoon to explain it to you, only to get what seems to be your replies that you don’t buy it and that you know better. Very very odd, I think. Most people would be merely grateful that someone took aside the time to explain it. Instead, you are citing data from 1993.
!993! Medical knowledge, the sum total of it, double every 5 years. Which means that in 1993, when I was still in medicine residency, we knew 6.25 per cent of what we know now. But somehow you think nothing has changed.
Every person is born with 3 metaphorical beakers, Margaret, on their bedside table. On the left is the beaker “Things I Know.” It can be enlarged, telescoped, so that it holds quite a lot more than its size at your birth would allow.
Next to it, on the right is a second beaker, “Things I Know I Do Not Know.” It also can be enlarged and made to hold as much as you want to put in it.
On the far right is the beaker of “Things I Do Not Know that I Do Not Know.” There is a problem here. It is big but cannot be enlarged, and has the faucet of growing human understanding dripping into it all the time, every day and night. Although few of us realize it, our teachers are there to teach us because if the third beaker fills to overflowing and begins to spill out, bad things befall us because life wants you to keep all knowledge in one of those three beakers. Therefore, in a life well lived, one is always using spoons, droppers and syringes to draw up liquid from the third beaker and move it to one of the first two.
There is a mirage fourth beaker, with a sign above it: Things I Think I Know. But in fact this beaker holds nothing. But because the mirage is closer to the third beaker than either of the first two are, many people pick up a book, Google something, spend 20 minutes reading a Wikipedia entry, and spoon material from the beaker called “Things I Do Not Know I Do Not Know” into “Things I Think I Know.” When they do this it makes a mess that has to be mopped up…always.
Where this subject is concerned, I feel your third beaker is overflowing and so I tried to help. I did not mention the octopamine hypothesis, the mercaptan hypothesis, the role of astrocytes, the deployment of antibiotics and why they may work and which ones seem to help, data from studies of portosystemic encephalopathy in transjugular intrahepatic portosystemic shunting, the ornithine cycle, the citrulline cycle, ornithine phenylacetate, ornithine transcarbamylase, flicker testing, Reitan trailmaking, and glycerol phenylbutyrate. I cannot move into these because first you must move beyond ammonia and lactulose and protein restriction and 20 per cent survival and missing out on the 93.75 per cent uptick in knowledge since 1993.
“The distinction between primary and secondary prevention is more pragmatic than absolute.”
Uh, no. Primary prevention is preventing the first vascular event. Secondary is preventing an event after a patient has had a first one. This is absolute. And right now, no one is considering deploying PCSK9 inhibitors for primary prevention except possibly in the familially dyslipidemic.
As I have discussed before in my threads, primary prevention is always a matter of negotiation and wiggle-room where the role of cholesterol modulation is incompletely understood. Quite different from secondary prevention, where statins or what may follow them are ignored at one’s peril.
Alnylam Pharmaceuticals, Inc. ALNY +8.08% announced today the presentation of new pre-clinical data from ALN-PCSsc, targeting PCSK9 for the treatment of hypercholesterolemia.
Here is more detail –
http://seekingalpha.com/pr/9767223-alnylam-presents-new-pre-clinical-data-on-subcutaneously-delivered-rnai-therapeutics-for-cardiovascular-metabolic-disease-at-arteriosclerosis-thrombosis-and-vascular-biology-2014-scientific-sessions
ALNY is working on Single dose of ALN-PCSsc for ALN-PCS program.
The most common types of cardiovascular disease include hypertension, ischemic heart disease, cerebrovascular disease (stroke), peripheral vascular disease, heart failure, rheumatic heart disease, valvular heart disease and congenital heart disease.
Besides PCSK9 inhibitors, there are many other inhibitors that functions the same in curbing cardiovascular disease. More can be reached at http://www.bocsci.com/tag/cardiovascular-and-blood-system-382.html