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[ed note: Michael Jorrin is longtime medical writer who has been sharing his thoughts with our readers as “Doc Gumshoe” for several years (he’s not a doctor, I gave him the name). He generally covers medical and health news and sometimes health promotions and hype, but he rarely opines about investments or specific stocks. All of his past commentaries can be seen here]
The key word there is “responses” – not answers, but responses. Many of the comments from the Gumshoe Literati are in the form of specific questions – what’s the correct dose of a specific supplement to achieve a particular result? The answer to such a question – coming from Yr Obt Svt at any rate – would be “I haven’t the foggiest.” But I can and will respond. Your questions and comments set my mind to wondering and pondering and exploring, and I’m happy to expose the inner workings of my little grey cells to you all. And, needless to say, to expose my conclusions, tentative as they may be, to your shrewd appraisal.
Niacin as a treatment for elevated cholesterol?
One such comment, which I replied to briefly in the comments thread, was this:
“What did you think about the quote in the N Y Times (about a decade ago?), where the President of the college of cardiology states that the absolutely best drug for cardiovascular disease is Niacin (aka: Nicotinic acid), because it raises “good” HDL, lowers “bad” LDL, & lowers Triglycerides, as no statin can do?”
My reply did not satisfy the reader, particularly my noting that niacin had fallen out of favor as a treatment option for elevated cholesterol. He commented that “fallen out of favor” is not science, and mentioned other potentially beneficial effects of niacin/nicotinic acid which, to be frank, I had never heard of. This prompted some sleuthing.
In previous pieces, I have tried to present a kind of summary of the history of the management of heart disease related to arterial obstruction.
Hardening of the arteries, or arteriosclerosis, had been observed for a really long time – many centuries – but it was only in the early 20th century that it became associated with cardiovascular disease. In the first decade of the 20th century, the stuff that was deposited in the artery walls, and in some cases also clogged the lumen of the arteries, was identified as cholesterol, although some calcium was also deposited in artery walls. The term “arteriosclerosis” was gradually replaced by “atherosclerosis,” which pinned the blame on fat. The emphasis on cholesterol as the culprit is about a century old, but for most of that time, clinicians didn’t have any effective means of dealing with cholesterol or atherosclerosis.
The initial focus, quite reasonably, was to try to manage cholesterol by dietary means – that is, by restricting foods that were highest in cholesterol. Unfortunately, with regard to the population in general, this approach does not work. The principal reason for the failure of this approach is that we, along with most animals, have an excellent capacity for synthesizing cholesterol (cows make it out of grass). That capacity, after all, is necessary for our survival, since cholesterol is an essential component of most body tissues (bones excepted) and is also essential to the synthesis of the hormones on which we depend for body functions. So we make at least 80% of the cholesterol in our systems, and take in perhaps 20% as cholesterol in our food; therefore, lowering dietary cholesterol just doesn’t do the job.
Therefore, the medical community looked around for drugs that might have the effect of lowering cholesterol, and in the mid-1950s niacin was the first one found to have that property. Up to then, niacin, also termed Vitamin B3, had been known as an essential factor in preventing pellagra, a disease caused by deficiency of niacin/ B3 in some people’s diet.
Niacin lowers levels of LDL-cholesterol and VLDL-cholesterol, as well as lowering triglycerides and increasing HDL-cholesterol levels. The principal drawback of niacin as treatment for elevated blood lipids is that many patients find it quite difficult to tolerate niacin at the dosing levels necessary to effect the desirable changes. Many or most patients experience severe flushing, which can be accompanied by severe and persistent itching anywhere in the body. This has greatly affected adherence to treatment with niacin – that’s to say, patients try it, but find that they can’t stick to it.
There are other cholesterol-lowering options other than statins. Fibrates tend to have a beneficial effect on VLDL, and in particular, on triglycerides. Their effects on LDL and HDL are variable. Bile acid sequestrants tend to lower total cholesterol and LDL and produce small increases in HDL. Omega-3 fatty acids may be useful in persons whose lipid imbalance is primarily a matter of elevated triglycerides; these need to be taken in very large doses.
Unfortunately, neither niacin nor these alternatives lower C-reactive protein, which is a marker for systemic inflammation. Inflammation is thought by many to be the key factor in arterial disease, resulting in what’s called vulnerable plaque. It’s this plaque that breaks apart, dispatching the little blood clots that can cause deadly damage to lungs, brain, or heart. But statins do lower the specific type of C-reactive protein associated with vulnerable plaque.
And statins produce significantly larger reductions in both total cholesterol and LDL than those other agents; at high doses, statins can lower LDL levels by as much as 60%. Their effect on HDL levels is much smaller. The effectiveness of statins (HMG-CoA reductase inhibitors) in inhibiting cholesterol synthesis in the liver began to be understood in the 1970s, but it was not until the mid-1990s that it was clearly demonstrated in a large, well-controlled clinical trial, that statin treatment had a direct effect in reducing the mortality of persons with elevated cholesterol who had established heart disease. The trial in question, published in 1994, was 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, and reduced coronary death by 55% at 5.4 years.
That was when treating elevated cholesterol with niacin “fell out of favor.”
It’s certainly the case that many people have problems with statins, specifically, muscle aches, or in the most severe cases, actual destruction of muscle tissue, called rhabdomyolysis. This last condition is exceedingly rare; in the neighborhood of ten cases per million statin prescriptions.
A recent review in Lancet weighing the efficacy of statins against the risk of side effects concluded that the harms of statin treatment have been greatly overestimated. For example, a reduction in LDL-cholesterol of 77 mg/dL, such as might be achieved with a 40 mg dose of a statin such as atorvastatin (Lipitor) would prevent major vascular events in about one out of ten patients, while it might result in fewer than one in a hundred new cases of diabetes, and fewer than one in a thousand hemorrhagic strokes. The authors pointed out, however, that those adverse events are not necessarily caused by statin therapy, noting, for example, that persons with elevated cholesterol are more apt to develop diabetes whether or not they are treated with statins. To sum up, the benefits hugely outweigh the harms.
This is not to say that recent algorithm-based guidelines that result in prescribing statins to another billion people or so, primarily based on their age, would not also result in unnecessary treatment for lots of those people, some of whom would likely experience adverse effects. The recommendations for such broad treatment remind me of a proposal in the UK, some years back, to put everybody over the age of 40 or so on a daily pill that combined a couple of different antihypertensives, aspirin, a statin, and I forget what else. That’s EVERYBODY – no questions, no medical examination, no tests. The idea was it wouldn’t hurt most people, and it would prevent some heart disease and strokes, and it would save a lot of money. Fortunately, the proposal didn’t take wing.
To go back to niacin for just another moment, this chemical has other presumed benefits, including, perhaps, that schizophrenia is due to a niacin deficiency, much as pellagra is due to a niacin deficiency, and might be corrected with niacin supplementation. Whether this theory is borne out in practice or not has little to do with niacin being preferable to statins for management of elevated cholesterol. The crux of the matter is the dose. To have any effect on cholesterol, the necessary niacin dose is far larger than the amount needed to correct a deficiency.
Niacin has been classified as a vitamin precisely because it is present in the normal diet and is essential for life. Vitamins as a group have little in common except for that simple characteristic. Most people get enough of the vitamins they need in the food they eat, but the difference between vitamins and other supplements is that a number of serious health conditions have been strongly linked to vitamin deficiencies, and giving vitamins to people with those health conditions addresses the problem efficiently. The origin of the word “vitamin,” by the way, is “vita” (Latin, “life”) plus “amines”; it was originally spelled “vitamine” due to the mistaken belief that niacin was an amine. In 1920 the error was pointed out, and the spelling was changed to the present form, without the final “e.”
What about co-enzyme Q10?
Co-Q10, as it is called, comes in for a great deal of speculative discussion. There are a lot of boosters, some detractors, and, certainly, quite a few skeptics, among whom I count myself. It’s an antioxidant, and as such is among the favorite supplements of the contingent that believes that oxidative stress is one of the health arch-villains. It is a factor in the conversion of food into energy, and it also has some anti-clotting capacity.
The comment in the Doc Gumshoe piece that I entitled “Thanksgiving Leftovers” came from a reader who reported hearing the head of cardiology at the Mayo Clinic say that he would take Co-Q10 in preference to a statin. I wonder about when exactly that happened, and also about the context. But it is true that Co-Q10 is promoted – or should I say “presented?” – by many as being a useful supplement in many cardiovascular conditions, including elevated cholesterol and high blood pressure. It may also help control diabetes and prevent migraines, and because it’s active in metabolism, it may boost energy and help deal with fatigue.
Unfortunately, the evidence for these beneficial effects is thin, and in some cases, contradictory. The absence of solid evidence should not necessarily be taken as evidence of absence of benefit, however. The question is open, subject to confirmation – or rejection – by well-conducted clinical trials.
I recognize that the phrase “well-conducted clinical trials” is certain to raise hackles in the Gumshoe contingent that is solidly in the supplements camp. Their argument, which has merit, is that clinical trials with enough statistical weight to convince the likes of the medical establishment, the FDA, and Yours Truly, are exceedingly expensive, and that pharmaceutical outfits with the necessary capital are simply not going to pour a billion and a half bucks into demonstrating the benefits of a supplement that they cannot possibly patent and make any money from. This is true in a general sense, but that doesn’t mean that Co-Q10 hasn’t been the subject of considerable clinical scrutiny. A quick PubMed search turns up 630 published papers about Co-Q10, and from what I could see, none of them confirm its efficacy with any confidence. By no means did I examine all of these papers, but I looked at titles and read many abstracts. It was clear that the effects of this agent were being discussed in a speculative manner, and caveats were the rule.
The chief argument against Co-Q10 as a statin replacement is the possibility of a number of drug interactions, including with other cholesterol-lowering drugs (statins, fibrates), antihypertensives (beta-blockers), and antidepressants. What Co-Q10 appears to do is accelerate the elimination of those drugs, reducing their concentration and effectiveness.
My guess is that interest in Co-Q10 will remain high and that scientists will continue to try to figure out whether, and exactly how, it might convey substantial benefit in clinical use. When that happens, you can bet that a pharmaceutical company will tinker with the molecule or the formulation, patent it, and go ahead with whatever they need to do to turn it into a profitable product.
Carnosine to prevent cataracts?
Another reader asked whether I could report on the amount of carnosine needed to prevent cataracts. I had no idea even whether carnosine would prevent cataracts, let alone how much was necessary, but I decided to take a peek. By the way, this reader strongly suggested that my sources were, um, too narrow. Here’s what he said:
“I agree Michael Jorrin writes and derives conclusions from a very selective and limited perspective of available research.
For example, would you like longer or shorter telomeres? I want longer telomeres. Tell me Mr. Jorrin, which foods and food supplements will lengthen them and the correct dosage.
Or, how much Carnosine would it take to reduce formation of cataracts? Research suggests 1,000 mg per day. How much of what foods would that be, and wouldn’t it be easier and cheaper to supplement?”
When sleuthing about the anti-cataract potential of carnosine, it doesn’t take more than a few minutes before the name of M. A. Babizhayev comes into prominence. He is a Russian scientist who holds the patent on eye drops containing one form of carnosine, N-acetylcarnosine (NAC). The eye drops are sold as Can-C, and they are the most prominently-promoted of the several eye drops sold to prevent cataracts.
There appears to be at least some substance behind the claim that carnosine can prevent or at least delay cataracts. One of the factors that contributes to the formation of cataracts is the oxidation of lipids in the lens, and carnosine is active as an antioxidant. Another of the carnosine forms, L-carnosine, may inhibit glycation, in which glucose binds with lipids. The antioxidant properties of the L-carnosine form are minor, but inhibiting glycation in the eye may have some effect in delaying the formation of cataracts, especially in persons with poorly controlled diabetes. Thus, some eye specialists recommend L-carnosine for diabetic patients.
Dr Babishayev holds L-carnosine in low regard, instead emphasizing the potential of his own patented carnosine compound, NAC. Even so, his most recent paper (BBA Clin. 2016 Apr 19;6:49-68) is far from a confident assertion of the efficacy of NAC in preventing cataracts. It’s more of an exploration of the mechanisms through which NAC might prevent or delay cataracts, specifically the effects of reactive oxygen species on mitochondrial activity.
The Royal College of Ophthalmologists in the UK has taken a look at carnosine for cataract prevention and turned thumbs down – the evidence so far does not support the claims for efficacy or safety. More research is needed, especially by workers who do not hold patents on carnosine supplements.
The general view among the community of eye doctors is that the best way to prevent cataracts is to wear sunglasses, not smoke, and eat a normal diet including fruits and vegetables containing natural antioxidants. When people develop cataracts, which many people inevitably will, surgical treatment is straightforward and has a very high success rate.
Some readers will say that OF COURSE the Royal College of Ophthalmology is not going to go along with an inexpensive supplement that will prevent cataracts, because they want their patients to develop cataracts so that they can perform the surgeries that they depend on to maintain their luxurious town houses on Belgrave Square and their fox-hunting properties in Sussex. For my part, I wonder what Dr Babishayev’s country estate looks like?
… and what about telomeres?
In case you forgot, telomeres are short repetitive DNA sequences at the ends of chromosomes whose function seems to be to protect the chromosomes as cells divide; in themselves they don’t code for anything, they’re just little protective bumpers. Telomeres naturally get shorter as people age, contributing to chromosome damage. So, protecting telomeres is thought to be an excellent means of slowing the aging process. An analysis based on the Nurses’ Health Study, carried out by Brigham and Women’s Hospital and the Harvard Medical School, reported that adherence to the Mediterranean diet (fruits, vegetables, nuts, legumes, unrefined grains, olive oil, fish, and, yes!, wine) helps preserve telomeres.
The study, very carefully carried out and published in the British Medical Journal in December 2015 followed 4,676 women in the Nurses’ Health Study and assessed their adherence to the Mediterranean diet on a 9 point scale. Each increase of 1 point on this scale corresponded to about 1.5 fewer years of telomere aging. A 3 point score on the Mediterranean diet adherence scale corresponded to about 4.5 fewer years of telomere aging, which is similar to the difference between smokers and non smokers, and between inactive and active women (that is, smokers and inactive women had about 4.5 years more telomere aging). The largest single cohort in the study, 1201 women, had a score of greater than 6, equivalent to about 9 fewer years of telomere aging.
Whether this works out to be 9 additional years of life has yet to be determined, but it’s clearly a good sign!
And, by the way, the only significant correlation was between the Mediterranean diet overall and telomere length. Individual components of the diet did not yield significant correlations.
So, to the reader quoted above, and to Gumshoe Nation at large, my best answer to the question is that I do indeed want to protect my telomeres, and the best way I can come up with to attain that goal is to (more or less!) follow the Mediterranean Diet. For dinner tonight I am having a fish stew consisting of haddock, shrimp, several vegetables sautéed in olive oil, a salad, whole grain bread, and a nice Pinot Grigio.
A tuberculosis vaccine as a cancer treatment
This was more a suggestion than a question. It came from an Irregular, many of whose comments have led me down interesting paths. This one in particular was a familiar path, for reasons that I will explain, but one which led to fascinating prospects.
The tuberculosis vaccine is the bacillus Calmette-Guérin (BCG) vaccine, certainly one of the most widely-used vaccines in the world. Two French scientists, Albert Calmette and Camille Guérin were tinkering with the tuberculosis bacillus and accidentally found a way to greatly dial down the severity of its infectiousness. It would elicit an immune response, but not result in the clinical disease, thus making it a potential vaccine. That, as you remember, is the modus operandi for creating any vaccine – an inactivated or attenuated pathogen that creates immunogenicity in the host.
Calmette and Guérin started working on the tuberculosis bacillus in the early years of the 20th century, and along about 1920 they started using it in humans with some success. The discovery that the BCG vaccine was effective in treating cancer took another 30 years or so. A seminal paper in 1963, “The Clinical Use of BCG Vaccine in Stimulating Host Resistance to Cancer,” (Phillip J, Cancer 1963;5:387-400) pointed to the essential mechanism of the BCG vaccine. The vaccine itself does not attack cancer cells; instead it somehow recruits the host’s immune system to attack the cancer cells.
The particular cancer for which BCG is most frequently used is bladder cancer. It happens that about 25 years ago, I worked on a continuing medical education program on this subject, so when I saw the comment pointing to recent developments on the BCG front I was ready to jump on it.
That comment led me to a paper, published just two weeks ago, which pointed to the mechanism whereby BCG stimulates trained immunity (Arts RJ, Cell Rep 2016;17:2562-2571). The process itself leads into the thickets of an area of research that it arousing a great deal of interest. This field is relatively new. It is called epigenetics.
The term “epigenetics” describes factors that are not part of the genetic material itself, but can exert changes in its activity. Recent research demonstrates that changes in the activity of genes can be triggered by agents external to the DNA strands themselves, but within the capsule containing the DNA strands, which are tightly wound around proteins called histones. In turn, the histones are organized into tight clusters called chromatins. The full DNA double-helix, consisting of 146 to 147 base pairs of DNA, would be over 2 meters long extended to its full length, but the diameter of the chromatin is about one 6-millionth of a meter.
In the case of the BCG vaccine, changes in histones have been identified that modify certain immune cells called monocytes. In turn, the monocytes induce changes in cell metabolism that support the immunogenic characteristics of the BCG vaccine.
Scientists have been working on ways of editing DNA with the idea, for example, of creating a strain of sterile mosquitoes that would essentially cause a whole mosquito population to become extinct, as a way of controlling the Zika outbreak. However, it has generally been thought impossible to change the genetic material in midstream so as to effect changes in the immune system during the course of an infection or after a disease has set in. Targeting histones and chromatins through external agents can affect the activity of the genetic material without changing the DNA itself, therefore epigenetic modifications could be useful midstream.
An anticancer agent that employs epigenetics is panobinostat (Farydak, from Novartis), which was approved by the FDA in early 2015 for the treatment of multiple myeloma patients who have received at least two prior treatments. Treatment with panobinostat increased progression-free survival in such multiple myeloma patients from about 6 months to about 11 months. The specific mechanism of panobinostat is that it reverses the inactivation of enzymes that would normally attack cancer cells, in effect restoring the innate cancer-killing capacity of healthy cells.
There are currently 137 clinical trials listed as recruiting, underway, or completed, that investigate epigenetic factors in a number of cancers. These include breast cancer, pancreatic cancer, non small cell lung cancer, ovarian cancer, a number of lymphomas, esophageal cancer, lung cancer, thyroid cancer, brain tumors, colorectal cancer, leukemia, and castration-resistant prostate cancer.
It appears that the changes that Calmette and Guérin effected on the tuberculosis bacillus were epigenetic changes – changes to the chromatin that did not affect the DNA of the bacillus, but did modify its capacity to transmit active tuberculosis. They had no idea of what they were doing, only that they were working with a highly infectious pathogen in the hopes of achieving a good result, a la Pasteur. They knew nothing about DNA or about histones and chromatin. But they experimented, kept an eye on the results, and moved forward when they saw something good was happening.
That is often the way forward in medical research, and it applies not only to the bacillus Calmette-Guérin, but perhaps to some of the other interventions we discussed in this Doc Gumshoe episode. Maybe tinkering with Co-enzyme Q10 or carnosine will effect epigenetic changes that transform these substances into miracle drugs. There are Calmettes and Guérins out there still, and the likelihood is that we have not seen the end of great and valuable discoveries.
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Well. I only got to about half of the interesting comments that you sent my way. I will resume sleuthing after the holidays – put my nose to the grindstone, or whatever they call it. Your comments are valuable, especially when they stir me to performing calisthenics with the contents of my noggin. Even the slings and arrows are welcome, such as when someone suggests that I must be in the pay of the Pharmaceutical Cabal. (My excellent wife, when I mentioned that particular comment, chortled and said, “Well, we could use the moolah!”)
I am greatly looking forward to the holidays & I wish you all the joys of this season of merriment and cheer! Best to all, Michael Jorrin (aka Doc Gumshoe)
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