End of Winter Miscellany

Doc Gumshoe checks in on Alzheimer's, Coffee, Gluten, Diabetes, C. Diff and Fish

By Michael Jorrin, "Doc Gumshoe", March 8, 2017

[ed. note: Michael Jorrin, who I like to call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes about non-financial health and medical issues for us a couple times a month (past submissions can be found on his author page here). Like all of our authors, he chooses his own topics and his words and opinions are his alone. Enjoy!]

When I first started doing this kind of thing – by which I mean writing about health and medical subjects – I used to have to make my way to the New York Academy of Medicine Library, at Fifth Avenue and 103rd Street, to do my research.   There I would consult Index Medicus, a huge, comprehensive, multivolume index of medical journals all over the world.   I would quickly find the journal papers my particular project required, request those volumes of the journals from the library circulation desk, read those papers, request photocopies of those papers that I felt I would need to refer to in my mission, pay the 10 cents per page fee, and depart, feeling that I had accomplished the crucial first step in my task.

No more.   Index Medicus ceased publication in 2004, because, apparently, nobody but nobody used it anymore.   All research was being done on line.   And, in the meantime, the internet has deduced that I am interested in matters medical, and swamps my inbox with emails alerting me to every sort of medical and health news.   I welcome this, up to a point.   But it requires me to weed my inbox assiduously.   If I don’t keep on top of it, it will become disastrously overgrown.   Sometimes I miss the old way – I could skim Index Medicus a whole lot faster than PubMed or Medline.   I could decide in an Augenblick if a paper might be worth reading.   “Yes” to papers in Lancet or the New England Journal, “no” to papers in the Pseudomedical Consortium of Lower Slobbovia.

But among the daily internet weeds there are flowers of interest, and some of these merit, I hope, inclusion in Doc Gumshoe dispatches.   Here are a few.

Is there a link between elevated cholesterol intake and dementia or Alzheimer’s?

Based on a study in Finland (Ylilauri MPT, Am J Clin Nutr 2017), the answer appears to be no.   Whether this is good news or not good news depends on your appetite for meat, eggs, butter and cheese.

In the past, an association has been noted between elevated cholesterol levels and dementia.   In particular, a focus of attention has been the APOE4 gene, which appears to increase the risk of late-onset Alzheimer’s disease (AD), and also plays a role in the processing and use of cholesterol and other lipids in the brain.   However, elevated cholesterol is frequently observed in persons with high blood pressure as well as diabetes, so it is difficult to pinpoint cholesterol as the factor that contributes to AD.   The data that tends to support the link between elevated cholesterol and dementia is that persons who take statins have a somewhat lower risk of developing dementia.   But, as Doc Gumshoe never tires of pointing out, that is an association and not a proof of causation.   It’s possible that the population that takes statins is different from the non-statin users in other respects than having a high cholesterol level.   And it’s also possible that statins reduce the deposition of whatever brain-crud results in dementia or AD in a way that’s independent of their effect on cholesterol synthesis.

The study in Finland, however, is nothing if not robust.   It followed 2,497 men, ages 42 – 60 years, who were free from dementia at baseline, for a total of 21.9 years, and found no association whatever between the intake of dietary cholesterol and the development of dementia or AD.   Both total diet and egg intake were measured, and increased egg intake was associated with better performance on neuropsychological tests and executive function.   Better, not worse!

What this seems to say is that we cannot reduce our risk of developing dementia or AD by cutting back on dietary cholesterol.   I would, however, introduce a small Note of Caution: dietary cholesterol as cholesterol is by no means the only culprit in elevated cholesterol levels in the bloodstream.   Remember, we ourselves make somewhere around 80% of the cholesterol in our systems, and we need to keep doing it, because cholesterol is a key component of many of our bodily tissues.   So questions about the link between cholesterol and dementia are definitely still open.

Coffee, tea, and cardiovascular events

This was a substantial study (Miller PE, Am J Med 2016) in 6,508 persons described as “multi-ethnic” who were classified according to coffee and/or tea consumption.   The background to this is that the health effects of coffee drinking in particular are somewhat controversial.   Caffeine is known to increase heart rate, peripheral vasoconstriction, and blood pressure.   At the same time, coffee consumption has definitely been linked with decreased risk of developing diabetes.   The studies that demonstrated that link showed that diabetes benefit occurred with bona fide caffeinated coffee, but not with decaf.    Doc Gumshoe, ever the skeptic, had wondered whether it was because at least some of the non-coffee drinkers might chug down more soda pop, but the difference between drinking caf and decaf put his doubts to rest.   A fairly recent meta-analysis has also found that coffee-drinking is associated with somewhat lower over-all cardiovascular risk.

Part of the focus of this study was the deposition of calcium in the coronary arteries, which is sometimes considered to be an early sign of arteriosclerosis.   The results were a bit contradictory.   The single largest effect was seen in persons who drank one or more cups of tea per day.   These persons had an odds ratio for developing coronary artery calcium of 0.64, which translates to a risk reduction of 36%, compared with the group that never drank tea.   Overall caffeine intake was linked with lower coronary artery calcium deposition, by about 19%.

The single largest difference regarding cardiovascular events was between regular tea drinkers – more than one cup per day – and non-tea drinkers.   The regular tea drinkers had a 29% lower risk of cardiovascular events than the tea teetotalers.

The authors tentatively suggest that the benefits of tea may be through polyphenols such as flavonoids, which have antioxidant properties that decrease the oxidation of LDL-cholesterol, improve endothelial function, and decrease the progression of atherosclerosis.   They point out that intervention studies, in which subjects have been given flavonoids in their diet, have yielded conflicting results, but they endorse the Mediterranean diet for secondary prevention of cardiovascular disease.

So, if you are persuaded by those two studies, might breakfast consist of tea and a boiled egg?   But seriously, those studies are careful attempts to shed light on common threats to our health and their relationship with our daily diet.   The conclusions aren’t sweeping or revolutionary, but they are reassuring, up to a point.   To wit, you don’t have to go on a no-meat-no-eggs diet to avoid dementia, and a couple of cups of tea per day might just lower your cardiovascular risk.

Comparing drugs for type 2 diabetes mellitus (T2DM) 

What about another disease that affects huge and growing numbers of our species –T2DM?   Are any of the current drugs head and shoulders above the rest?   Considering the large number of drugs used to treat T2DM, that’s a question worth investigating carefully, and that’s what a huge JAMA meta-analysis has recently done (Palmer SC, JAMA 2016).

First, a bit of background.   Diabetes, as most of us know, is a particularly sneaky disease, because at least in its early stages no obvious symptoms manifest, while at the same time irreversible damage is taking place, particularly in the circulatory system and in the eyes.   Many diabetics are not diagnosed until their disease has progressed considerably, and then only if they have a medical emergency which requires a blood test.   In the US alone, about 25 million people have T2DM.   That’s about 8% of the population.   In about 7 million of these, diabetes is undiagnosed.   If present trends continue, about a third of all American adults will have diabetes by the year 2050.

The drug which nearly every newly-diagnosed T2DM patient gets is metformin (Glucophage), which slows down the release of stored glucose from the liver and also increases the sensitivity of insulin receptors and the uptake of glucose throughout the body.   But for most persons with T2DM, metformin is not a permanent answer; they will require a second or even a third drug with a somewhat different mechanism of action.   Doc Gumshoe posted a fairly comprehensive survey of T2DM treatment a couple of years ago, “The Why and the What of Diabetes Management,” which you can find in the archive.   But here’s a quick summary of those agents:

  • Sulfonylureas  stimulate the beta cells to produce more insulin.   Amaryl (glimepride), Diabeta (micronase), and Glucotrol (glipizide) are common sulfonylureas.
  • Meglitinides and d-phenylalanine derivatives act to boost the first-phase insulin response.   Prandin (repaglinide) and Starlix (nateglinide) are members of this class.
  • Thiazolidinediones, also known as glitazones, act on muscle and adipose tissue to increase glucose utilization, and on the liver to decrease glucose release.   Avandia (rosiglitazone) and Actos (pioglitazone) are members of this class.
  • DPP-4 (dipeptyl peptidase 4) inhibitors, also known as gliptins.   These agents enable the action of incretin, a digestive peptide that boosts the first-phase insulin response.   Januvia (sitagliptin), Onglyza (saxagliptin), and Tradjenta (linagliptin) are DPP-4 inhibitors.
  • Incretin mimetics, as the name implies, mimic the activity of incretins.   Byetta (exenatide) and Victoza (liraglutide) are incretin mimetics.
  • Alpha-glucosidase inhibitors work by preventing the digestion of carbohydrates, which are normally converted into simple sugars.   Precose (acarbose) and Glyset (miglitol) are α-glucosidase inhibitors.
  • SGLT-2 (sodium glucose transporter 2) inhibitors, the most recent T2DM agents, have an entirely different mechanism of action.   SGLT-2 inhibitors block the return of glucose from the kidney to the bloodstream, thus lowering blood glucose levels.   Invokana (canagliflozin) and Farxiga (dapagliflozin) are recently approved SGLT-2 inhibitors; others are in the works.

The JAMA study evaluated 301 clinical trials, including 177 trials in 56,598 patients of drugs as monotherapy, 109 trials in 53,030 patients of drugs added to metformin, and 29 trials in 10,598 patients of drugs added to dual therapy with metformin and a sulfonylurea.    Compared with metformin, the other drugs, including sulfonylureas, thiazolidinediones, α-glucosidase inhibitors, and DPP-4 inhibitors, resulted in somewhat higher HbA1C levels.   (HbA1C, in case you don’t remember, measures blood cells that are bound with glucose.   They remain in the bound state for several weeks, so HbA1C levels provide a better picture of a person’s blood glucose levels over time than a direct blood glucose measurement.)

When drugs from one of the other classes were added to metformin or to a dual therapy regimen including metformin, no differences in HbA1C levels were observed with the different classes of drugs.    And there were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with regard to odds of cardiovascular or all-cause mortality.

Why is this study worth paying attention to?   First, I would say that a physician would have to have a pretty good reason to prescribe a drug other than metformin as a first line agent for T2DM.   The JAMA study strongly supports the recommendations of the American Diabetes Association that metformin is the drug to go with for a newly diagnosed person with diabetes.

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But if you so much as scanned the list of drugs above, you surely noticed several that have been receiving exceedingly heavy promotion.   And, since most diabetics will require a second or even third drug, the question is, which drug is good for which patient.   That will depend on the individual patient, of course.   But a responsible physician will pay close attention to the patient’s life style, particularly as reflected in the patient’s dietary and exercise habits, weight, and overall health.   Some patients may particularly benefit from the classes of drugs that specifically boost the first-phase insulin response, while others may do better with drugs that increase the insulin response after a full meal.   Overall, the good news is that there are many effective drugs out there, as well as treatment plans that maximize the patient’s total health.   It’s more than ever before possible for a person with diabetes to live a long and healthy life.

Good news about C. diff

Clostridium difficile is not the most lethal “superbug,” but there’s no doubt that it has been a growing and difficult problem.   The usual scenario is that a person has an infection and gets treated with a common antibiotic.   The infection goes away, so, okay so far.   But then the person falls ill again, this time with an infection that simply doesn’t respond to treatment with the usual antibiotics.   Time to call in the heavy hitters.   No help for it – the patient then receives a much more powerful antibiotic with nasty side effects.   Metronidazole (Flagyl) or vancomycin are the usual recourse.   If those don’t work – and sometimes they don’t – it may be time to try a procedure that has been receiving quite a bit of attention lately.   That’s fecal transplantation, specifically the introduction of donor feces into the digestive tract of the patient, thus restoring the normal healthy bacterial population that dwelt in the innards of the patient before the antibiotic treatment.

But now comes an observational study in Lancet Infectious Diseases (Dingle KE, Lancet Inf Dis 2017).   Without going into unnecessary detail, here’s what the study reported:

Between 1998 and 2006, the incidence of C. diff  in hospitals in Oxfordshire and Leeds (in the UK) increased markedly, despite intense deep cleaning and sanitizing efforts.   This coincided with an increase in antibiotic use, not only in hospitals, but in the community.   Then, beginning in 2006, hospitals reduced the use of some antibiotics, especially fluoroquinolones and cephalosporins, and the incidence of C. diff  began to decline.   The genomes of more than 4000 C. diff  isolates were analyzed.     The findings were, to say the least, eye-opening.

The incidence of fluoroquinolone-resistant C. diff  isolates declined from 67% in 2006 to less than 3% in 2013.   C. diff  appears to be innately resistant to cephalosporins, thus, the overall decline in C. diff  infections was due only to the reduction in fluoroquinolone use, especially ciprofloxacin.   Or, to put it another way, cutting back on cephalosporins did not increase the prevalence of resistant C. diff  isolates, since this particular bug is mostly resistant to cephalosporins to start with.

The conclusions drawn by the study authors were that the labor-intensive and expensive “deep cleaning” procedures that hospitals had adopted to reduce C. diff infections were ineffective and could be dispensed with, while a reduction in fluoroquinolones would be highly effective in controlling C. diff.   

Those findings certainly do not imply that hospitals should simply stop employing fluoroquinolones, which will continue to be valuable drugs in the control of several infections.   That’s in spite of the fact that some of the fluoroquinolones have been linked with troubling toxicities, and some of the more recently-introduced fluoroquinolones have been taken off the market for that reason.   However, carefully targeted use is likely to continue.

The fluoroquinolone/C. diff  link is just one specific instance of the global threat posed by increasing and indiscriminate antibiotic use.   Health authorities characterize this as an imminent catastrophe, as resistant strains of pathogens emerge that do not respond to any currently-available antibiotic – the so-called “superbugs.”   Pharmaceutical companies are loath to invest hugely in developing new antibiotics, because if they should happen to bring an antibiotic to market that is indeed effective against some of the more dangerous resistant microbes, the medical community will – wisely! – refrain from using that new miracle drug unless it’s absolutely essential to do so.   So the pharm outfit spends billions on the new drug and it sits on the shelf waiting for the call to arms.   This is a huge and highly important topic, and Doc Gumshoe will take a deeper look at it in an upcoming post.

A bit more evidence supporting fish in our diets

The dietary guidelines issued jointly every five years by the US Department of Health and Human Services and the Department of Agriculture resemble a big playground where some kids run around together happily and cooperatively, some assume a bossy and dictatorial tone, and yet some others reveal their inner bullies.   Some kids are clearly outcasts (carbs, added sugars), some feel themselves unfairly discriminated against (salt, fats), some preen themselves as being loved by all (green leafy vegetables), and some feel certain of their worth but not as popular as they deserve (fish).

As it happens, about half of us Americans almost never eat fish, or when they do, it’s apt to be a tuna sandwich or something of the sort.   That’s despite the rock-solid evidence in support of the Mediterranean diet, which tends to be a “customary” diet rather than a “prescribed” diet.   In other words, it’s just what folks in that part of the world happen to eat as a regular thing, and that happens to include a high proportion of fish.   A study in Spain confirmed that people who followed the Mediterranean diet as a usual daily practice had a lower incidence of cardiac events than people who were on a prescribed diet emphasizing fruits, vegetables, and minimizing fats of any kind – more like the “food pyramid” diets and diets put forward by the American Heart Association.   Also, a study conducted under the Nurses’ Study program found that the Mediterranean diet was associated with longer telomeres.   Telomeres protect our DNA, and longer telomeres should lead to increased longevity; therefore the Mediterranean diet might favor increased longevity.

But despite recommendations from Federal departments, Americans seem to be unable to be persuaded to eat fish as often as we should, at least according to those experts.   Maybe a lot of us don’t like fish, maybe it’s inconvenient to shop for fresh fish, maybe we’d just rather have the chicken-fried steak.

So, how do we deliver the benefits of the Mediterranean diet to people who just don’t eat fish?

A widely-held view is that the benefits of eating fish essentially come from fish oil –the omega-3 fatty acids in fish – docosahexaenoic acid (DHA) eicosapentanenoic acid (EPA).   A surprising study (Del Gobbo LC, JAMA Int Med 2016) supports the position that those two omega-3 fatty acids reduce the incidence of fatal heart attacks, although they have a much smaller effect on the total incidence of heart attacks.   If we believe that study, which is a review of fourteen different cohort studies – i.e., not prospective randomized studies  – DHA and EPA don’t have much effect with regard to preventing the heart attacks.   Instead, they reduce the severity of the heart attacks.

Now, along comes a study that supports the benefit of those omega-3’s even more robustly.   The study (Alexander DD, Mayo Clinic Proc 2017) is a meta-analysis which included large retrospective studies as well as prospective randomized studies.   The large population-based studies compared persons who either ate fish regularly or took omega-3 supplements with those who did neither, and found that the fish or omega-3 consumers had an 18% lower overall risk of developing heart disease than the persons who abstained.

The prospective randomized trials, in which people were assigned either to take the omega-3 supplements or placebo, the omega-3 supplements demonstrated the greatest benefit in the individuals at the highest cardiovascular risk.   Persons with elevated LDL-cholesterol taking the omega-3 supplements had a 14% lower incidence of coronary heart disease incidents than their counterparts who were not taking the supplements, and persons with elevated triglycerides had a 16% lower incidence.

I find the prospective randomized trials much more persuasive than the population studies.    It’s quite likely that there are big life-style differences between people who regularly take omega-3 supplements and those who don’t.   My guess is that the supplement cohort are also more likely not to smoke, to watch their weight, to eat a somewhat healthy diet, to exercise, and in general to behave like good little boys and girls, while the non-supplement cohort are perhaps a bit more likely to break the rules.

But it’s also possible that some people in the supplement cohort figure that since they’re taking their omega-3 pills, they don’t need to eat fish.   Taking those pills gives them permission to eat whatever the heck they want.   Probably chicken-fried steak and soda pop.

Red yeast rice: not so healthy as some people had assumed?

Taking a statin to control cholesterol has a bad rap among some people.   There’s no doubt at all that there are individuals who cannot tolerate statins and experience significant adverse events when taking statins.   Happily, for those persons there are now quite effective but also quite expensive alternatives, such as the PCSK9 inhibitors.    But there’s also the community of drug-shunners, people who want nothing to do with drugs developed by Big Pharma, prescribed by the medical establishment, and approved by the FDA.   For many of those, a recourse for addressing elevated cholesterol has been supplements made from red yeast rice.

Red yeast is the product of rice fermented with Monascus purpureus yeast.  It turns out that the active ingredient in red yeast rice extracts is lovastatin, or Mevacor.   There have been squabbles between Merck, the manufacturer of Mevacor, and the makers of the red yeast rice extracts.   Logically, the side effects that are seen with lovastatin would also be likely to be seen with red yeast rice extracts.   These would likely be liver damage and muscle aches and pains.

A study now confirms this (Mazzanti G, British J Clin Pharmacol 2017).   The study was conducted by the Italian Surveillance System of Natural Health Products, and was based on adverse events reports that were received from 2002 to 2015.   Of a total of 1,261 adverse events reports, 52 were related to red yeast rice extracts.   The most common events were myalgia (19 events), GI reactions (12 events), and   liver injury (10 events).   There were nine hospitalizations and one case of rhabdomyolysis, in which the muscle tissue is destroyed.

Stopping the red yeast rice extract resolved the adverse effect in 73% of the cases.   The study authors noted that the short interval from taking the drug to onset of the adverse events as well as the absence of concomitant drugs or predisposing conditions strongly suggest that it was the red yeast rice extract that caused the adverse events.

Another factor to weigh is that while the dosage of prescription drugs is always part of the prescription, similar precision is not usually part of taking supplements.   The precise amount of the active ingredient in the supplement is not known, and users are more apt to be free with the supplement in a way that they would not be apt to be with a prescription drug.   Therefore, the likelihood is that the users of red yeast rice extract might be overdosing.

All in all, red yeast rice extract seems to be a poor choice for persons wishing to avoid a statin.

Perils of the gluten-free diet

A gluten-free diet is essential for persons with celiac disease.    Doc Gumshoe did a piece, “Celiac Disease and the Ubiquitous Gluten-Free Diet” just about two years ago, and not a whole lot has changed since then.   The essentials were, and are still, that less than 1% of Americans have celiac disease, and nobody else really requires a gluten-free diet.  The best data available on the prevalence of celiac disease in the US comes from NHANES, the National Health and Nutrition Examination Survey, conducted by the CDC.   They examined nearly 8000 people and found a total of 35 with celiac disease.   Of those 35, only 6 had received a diagnosis.   That survey was back in 2011; in the meantime, awareness of celiac disease has no doubt soared.   That may account for the increase in the diagnosis of celiac disease, but the actual prevalence of the disease remains around 1%.

At the same time, many of our fellow Americans have adopted a gluten-free diet based on a general supposition that it is healthier.   This seems to be the case whet