The Resveratrol Bust

Disappointing, but unsurprising, I say. At this point I’m willing to stake my bet that the wonderful promise of resveratrol isn’t going to pan out. What’s resveratrol? Let’s take a little journey back in our time machine

About Resveratrol

It goes back at least 70 years, to the discovery by Japanese investigators of the active ingredient in a plant used in some traditional healing practices, the white hellebore. It was then learned that grape vines, when attacked by a particular fungus, also secreted this substance, which was named resveratrol. It was speculated that resveratrol might be a natural defense agent for the grape vines, and protect them from rot and blight. And, who knows, it might be good for humans as well.

The French Paradox

Now, also going back quite a few years, we Americans began to look enviously across the pond at the French and the Italians. We were worried about cholesterol, and the Word was that we needed to cut way back on butter and eggs and bacon and well-marbled steaks. But those lucky French didn’t seem to fret too much about all those cholesterol-laden foods, and it didn’t seem to hurt them a whole lot. You would have thought they would be turning up daisies, but no, they enjoyed their filet mignon with sauce Bearnaise (butter, egg yolks, a splash of tarragon vinegar). Might it be because they washed it down with copious goblets of Chateau Margaux? In any case, the French had much lower heart disease rates than we did, and there had to be some reason for it.

In fact, there were beginning to be pretty rigorous studies that seemed to point to a clear benefit from consuming alcoholic beverages, especially in terms of heart disease and cardiovascular mortality. Not that those studies should have been all that surprising either!

Let me digress for a moment. Lots and lots of doctors knew that moderate alcohol consumption was, on the whole, beneficial. (Note, whenever I mention alcohol consumption, in this blog or anywhere else, please assume that there’s an autocorrect feature that inserts the word “moderate” in front of that phrase.) There was an English physician in the 18^th century by the name of Anstey who observed that among his patients the drinkers outlived the teetotalers by a comfortable margin, and he proposed a rule – a drink before dinner and a couple of glasses of wine with dinner – as a formula for a long life.

The studies I’m talking about began hitting the peer-reviewed medical journals in the 1970s, and in 1996 there was a big review in the British Medical Journal that more or less clinched the case for moderate alcohol consumption. Overall, the studies this review cited concluded that drinking alcoholic beverages, mostly wine, lowered heart disease risk by about 30%.

However, the mainstream medical establishment was not about to recommend alcoholic beverages to ward off heart disease. Alcohol – excessive alcohol – was known to cause all manner of health problems, not even counting all the other problems associated with alcohol. So it had to be something else!

The Resveratrol Promise

Might it be resveratrol? If it protected grape vines from rot and blight, might it not have beneficial effects in humans? From my perspective, as an initial assumption, that was quite reasonable. After all, as I said in a previous offering, many, many natural substances are the source of our most valuable drugs – and by drugs, I mean substances that we take that have curative powers. Also, resveratrol is present in red wine, and red wine is what the French and Italians mostly drink.

So they did tests in laboratory animals, mostly mice. They gave mice the mouse equivalent of filet mignon with Sauce Bearnaise, and, predictably, the mice became obese. Then they gave the mice resveratrol, and the obese mice that got resveratrol survived longer than the ones that didn’t get resveratrol.

At this point the researchers began to get very, very cheerful. Down the road, perhaps, here was a drug that would not only counteract the adverse effects of the American cholesterol-laden diet, but also, possibly, increase longevity. If this drug got approved, not only would it be hugely beneficial for lots of people, but the developers would reap unimaginable gains.

A little problem with these tests in mice, however, was that the smallest amount of resveratrol that had any beneficial effect in mice was many, many times larger than the amount of resveratrol in the amount of wine that any human being could possibly drink in a day. To get the amount of resveratrol equivalent to the lowest effective daily dose of resveratrol in the mouse studies, a person would have to drink 60 liters of wine per day, and in some mouse studies, the daily resveratrol dose was equivalent to 900 liters of wine. Impractical, to say the least!

That should have made it pretty clear that it wasn’t the resveratrol in the wine that was counteracting the evil effects of the French diet. But that didn’t stop the research from continuing. The pot of gold at the end of the rainbow beckoned.

The Resveratrol Promise Fades

Unfortunately, when they got to studies of resveratrol in humans, the golden promise all but vanished. Here’s a really quick summary of three clinical trials:

• One – in non-obese, post-menopausal women, 75 mg of resveratrol per day delivered no metabolic benefits whatever: no increase in metabolic rate, no beneficial effects on cholesterol or triglycerides, no change in markers of inflammation.

• Two – in 24 obese men, resveratrol produced no beneficial effects on blood pressure, fat content, inflammatory or metabolic markers.

• Three – in 27 normal weight men over the age of 65 all of whom were enrolled in an exercise program, 250 mg of resveratrol blunted the beneficial effects of exercise. Exercise increased oxygen uptake by 45% in the men who were not taking resveratrol, but resveratrol erased that benefit. Exercise also lowered blood pressure and lowered cholesterol and triglycerides, but resveratrol erased that benefit as well.

That third study really put the kibosh on resveratrol. The studies that showed no benefit they could swallow, and keep looking, hoping that more studies would detect some benefit eventually. But a study in which resveratrol nullified the very real benefits of exercise is hard to get around.

So, if it’s not resveratrol, might it, after all, be the alcohol in the wine that’s producing those benefits?

The Bona Fide Benefits of Alcohol

Just you won’t think that I’m pushing my own agenda, here are some excerpts from a publication of the Harvard School of Public Health:

Possible Health Benefits of Alcohol<

What are some of the possible health benefits associated with moderate alcohol consumption?

Cardiovascular Disease

More than 100 prospective studies show an inverse association between moderate drinking and risk of heart attack, ischemic (clot-caused) stroke, peripheral vascular disease, sudden cardiac death, and death from all cardiovascular causes. The effect is fairly consistent, corresponding to a 25 percent to 40 percent reduction in risk.

Beyond the Heart…

The idea that moderate drinking protects against cardiovascular disease makes sense biologically and scientifically. Moderate amounts of alcohol raise levels of high-density lipoprotein (HDL, or “good” cholesterol), and higher HDL levels are associated with greater protection against heart disease. Moderate alcohol consumption has also been linked with beneficial changes ranging from better sensitivity to insulin to improvements in factors that influence blood clotting, such as tissue type plasminogen activator, fibrinogen, clotting factor VII, and von Willebrand factor. Such changes would tend to prevent the formation of small blood clots that can block arteries in the heart, neck, and brain, the ultimate cause of many heart attacks and the most common kind of stroke.

So it’s not the red stuff in the wine, it’s the ethanol that confers those benefits. I need to add here, so that I don’t induce a dash to your local Rosie O’Grady’s, that “moderate alcohol consumption” is defined as two drinks per day for men and one drink per day for women; unfair some of you will say, but it’s based mostly on body weight, men being bigger and bulkier than women and thus have more body fluids for the alcohol to be distributed through. One drink is calculated as five ounces of wine or 12 ounces of beer or a jigger (an ounce and a half) of distilled spirits.

The J-Curve

That two drinks per day is actually the bottom of a J-curve. If we plot cardiovascular events (heart attacks, strokes, other serious cardiac events needing hospitalization) starting at its incidence in teetotalers, and then go on to measure its incidence in moderate drinkers, we find that this incidence is quite a bit lower in those moderate drinkers. But as consumption rises beyond the optimal two drinks per day point, the curve starts going up again, and by the time we get to about four drinks per day, it’s right back up to the rate for teetotalers, and it goes up from there. So the people who warn about the dangers of excessive alcohol consumption are right, of course, but it doesn’t become really excessive – i.e., more dangerous than being a teetotaler – until we get past that four drinks a day mark.

All that being said, we shouldn’t totally write off resveratrol. There’s at least a possibility that it may confer some benefit in other health-related areas, such as preventing osteoporosis and mimicking some of the benefits of a really strict diet. So far, not proven, but we’ll see.

And now, about something completely different …

The ARB Scare

This surfaced about two months ago, and the reverberations have been bouncing around in the medical community as well as among concerned patients. The scary possibility is that angiotensin receptor blockers, known as ARBs, might possibly “cause” an increase in cancers.

ARBs are antihypertensive, or blood-pressure lowering drugs. The appeared on the market about 15 years ago, and they have become a very widely-used and successful drug class. Drugs in this category are:

Atacand (candesartan), from AstraZeneca (AZN)

Avapro (irbesartan), from Sanofi (SNY)

Benicar (olmesartan), from Daiichi Sankyo (4568 Tokyo)

Cozaar (losartan), from Merck (MRK)

Diovan (valsartan), from Novartis (NVS)

Micardis (telmisartan), from Boehringer Ingelheim (BING.GR)

ARBs lower blood pressure by inhibiting the renin-angiotensin system (RAS), which affects both heart rate and peripheral arterial resistance – the squeezing pressure of arteries on the blood. The specific messenger that triggers this blood pressure increase is angiotensin 2, and ARBs block the receptors for this messenger by occupying the receptor sites so that the angiotensin 2 can’t link up with the receptor.

A previous category of drugs that did more or less the same thing were the ACE (angiotensin-converting enzyme) inhibitors, which interfered with the action of the enzyme that converted the inactive form of angiotensin into the active angiotensin 2. ACE inhibitors work quite well, but they shouldn’t be used in people with any kind of respiratory problems such as asthma, while ARBs do not have that issue. Most high blood pressure drugs have issues of one kind or another, and ARBs seem, so far, to have fewer. That explains why, at a recent meeting of the American College of Cardiology, when members were asked what antihypertensive drugs they would prescribe for themselves or a family member, the winning category was ARBs.

The possibility that ARBs might be associated with increases in cancer risk was raised by a study published in Lancet Oncology back in 2010. This was a meta-analysis by Dr Ilke Sipahi of clinical trials with ARBs. The conclusions of this meta-analysis were that the risk of new cancers in the 61,590 patients in the five trials they analyzed increased from 6.0% in patients who did not take ARBs to 7.2% in patients who did take ARBs. The only specific cancer that was significantly higher in patients taking ARBs was lung cancer, with an incidence of 0.9% compared to 0.7% in patients not taking ARBs. No significant differences in cancer deaths were found in this study.

The brouhaha got started when a regulator at the FDA, Dr Thomas A. Marciniak, went against the directions of his bosses, arguing that warnings about the safety of ARBs should be make known to the public. Marciniak, on his own initiative, combed through the immense amount of data submitted to the FDA by the pharmaceutical companies, and concluded that ARBs increased lung cancer risks by about 24%. Officially, the FDA doesn’t agree, and neither do European regulatory agencies.

What could account for these huge differences?

At this time, nobody knows how Marciniak did his analysis. Dr Ellis Unger, the FDA chief of the drug evaluation division, suggests that the data used by Marciniak includes a large number of patient-reported events, collected as part of post-marketing data, many of which could be interpreted as new cancers, but which have not been independently investigated. ARBs have been in wide use for 15 years, have been studied in at least 25 clinical trials, and only in this instance is there a suggestion of cancer risk.

An interesting comment on this issue comes from Dr Henry Black, past President of the American Society of Hypertension. He notes, first, that there’s no mechanism of action whereby blocking the angiotensin 2 receptor could stimulate cancer cell growth. He points out that in the immense quantity of pre-clinical studies in animals, no increase in tumor growth was detected – otherwise, drug development would have stopped cold.

But more to the point, he questions the validity of the Sipahi meta-analysis. None of the studies in the meta-analysis by themselves attained statistical significance for the increase in cancers, and almost all of the increase came from two of the studies, both of which used telmisartan (Micardis). Overall, 85.7% of the patients in the meta-analysis were on telmisartan, raising serious questions about the legitimacy of generalizing the conclusions of this meta-analysis to the entire class of drugs.

Dr Black also raises a serious point about the potential for harm. Patients pick up these scary findings (as reported in the media, frequently with an alarmist slant), and decide to stop taking their medications, with possibly serious consequences. His conclusion was that the study was “very irresponsible and junk science.”

None of this decides the issue one way or another. The possibility cannot be ruled out that there is a cancer risk associated with ARBs, albeit a small one – the difference in incidence of new cancers reported in the Sipahi study was 1.2 percentage points, and of lung cancers, 0.2 percentage points. Not nothing, but not a whole lot. If I had hypertension, would I take an ARB? Probably yes, but I might pick one of the other ones rather than telmisartan.

This reminds me of the farrago in relation to the Women’s Health Initiative a few years ago, when a tiny – really tiny! – increase in the incidence of heart attacks occurring in women taking hormone replacement therapy (HRT) was trumpeted as a colossal increase in heart attack risk. The real difference was that in women on HRT, there were 37 heart attacks per 10,000 patient-years, while in women not on HRT, there were 30 heart attacks per 10,000 patient-years. The difference in absolute risk was less than 0.1%, but this was released to the press as a difference in relative risk of 23%.

A Bit More About Salt

Several readers have asked questions or commented about the issue of salt in our diets. One reader said, wasn’t it really the sodium that should be measured and monitored, and not the salt. Yes, sodium ions play a vital role in a great number of physiologic processes, including muscle contractions. However, sodium enters and exits our bodies in salt (sodium chloride) and that’s how we can keep track of it.

Someone else asked whether anti-caking agents in salt (many different ones are used) might not be responsible for its effects on blood pressure. The answer is, it’s the salt! We regulate the sodium concentration in our bloodstream with exquisite precision. When it’s too concentrated, we’re thirsty, we add fluids to dilute the concentration, the excess fluid raises our blood pressure temporarily, but we eliminate the excess fluid over time. After a day or so, we’ve made enough visits to the loo to get rid of the excess volume, and our BP returns to normal. But if we keep bingeing on salty snacks, some of us reset out internal blood pressure detectors to a “new normal,” and develop high blood pressure. There’s a lot of individual variation. Some people seem to be programmed to retain salt, and they are more susceptible to that variety of hypertension.

The Ministry of Truth Redefines Cancer!

A working group under the aegis of the National Cancer Institute (NCI) has issued recommendations that the words “cancer” and “carcinoma” be eliminated from some lesions that they consider unlikely to progress to cancer, and therefore probably do not require treatment. The motivation for making these changes is to reduce overdiagnosis and overtreatment, which they say is in many cases not only unnecessary, but harmful. These recommendations were published in the Journal of the American Medical Association (JAMA) on 29 July, and immediately widely reported.

An example of the lesions they are proposing to rename is ductal carcinoma in situ (DCIS). They propose to remove the scary word “carcinoma” from the name and relabel it as an “indolent lesion of epithelial origin,” using the accronym IDLE. Other conditions currently labelled as cancers that they are proposing to rename include prostate cancer and Barrett’s esophagus. They acknowledge that in some cases, these lesions will progress to cancers, but not necessarily so in every case, and in the meantime it’s best to avoid frightening patients into demanding treatment, which might be unnecessary.

However, a paper currently in press in Molecular Oncology by Catherine Cowell and seven other investigators at Memorial Sloan Kettering puts the risk that DCIS will become metastatic breast cancer at about 40% if left untreated. The authors acknowledge that there is no current way of assessing which DCIS lesions will progress to metastatic breast cancer. The same thing is true for a number of the other so-called “IDLE” lesions that these NCI folks don’t want to scare patients about. Clearly, research is needed to identify the markers that predict which cancers will progress and which will not. But lulling patients into complacency so that they will not seek treatment strikes me as irresponsible and demeaning to patients. To the NCI and the collaborators in this exercise in semantic management of disease, I cry “Shame!”

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Doc Gumshoe is having a good time writing these. He likes to exercise his little grey cells and he enjoys swimming against the tide, when the occasion seems to warrant it. He pays attention to readers’ questions and, when he doesn’t have an immediate response, he tries to heed the advice of Miss Truesdell, his 11^th grade math teacher, whose usual response to “I don’t get it” was “Apply yourself!” He’ll keep applying himself! Best to all, Michael Jorrin (aka Doc Gumshoe)