Monday, January 28, 2008

The French Paradox and Vytorin

(Submitted for publication in the Bulletin of the Utah Medical Association, where I am an Editorial Board member.)

I just got back from Montreal, Canada, the home of Sir William Osler, M. D., father of modern medicine, where I gave a health talk to my frog cousins, the French Canadians. About the same time, I was asked to be the official doc for the French Embassy in Utah, and the news on vytorin hit the fan, I mean, the news stands. The combination of these events reminded me of a couple of French paradoxes. The best known French paradox is the fact that the French eat a lot of high cholesterol foods, yet their rate of heart disease is lower than Americans.

The less known French paradox is the fact that Americans never even thought to apologize to the French about the war in Iraq (the war has a lot to do with our health.) France was the most vocal in opposing this failed war from the outset. Americans then embarked on a shameless vilification of the French, without any restraints on the prejudicial undercurrents underlying the endless jokes at the expense of the French. Now that the majority of Americans have also come to oppose the war, a simple “je regrette” would be the polite thing to do.

Another “je regrette” may be in order from pharmaceuticals that have heavily promoted their cholesterol-lowering agents so aggressively that doctors and patients seldom put any significant efforts into changing patients’ diets before prescribing these drugs. The story on vytorin has resurfaced the French paradox, at least among doctors like myself who feel that “food is the best medicine.”

By now we are all familiar with the small study that showed no significant improvement in endothelial thickness in the carotids after taking vytorin. The study concluded in 2006, but the drug companies would not released the results until now, despite pressure from the FDA to do so since the conclusion. The companies even tried to change the study’s end points after the results were available: at the outset, they checked three places in the carotid artery for endothelial thickness, but they proposed to report only one place after the results were in.

Granted, the study was rather small and it has not been published, yet. Also, the patients they enrolled had LDL cholesterol levels above 300, which are not seen in our clinics on a regular basis. In all fairness, it is premature to abandon the use of these drugs on the strength of this study. But, the controversy on the cholesterol “theory” has gained new life. Many doctors are beginning to question the cholesterol theory, joining many other doctors who never quite bought into it from the beginning, as reported in the New York Times, January 17th and 27th, 2008. The letters to the editor in response to these articles reflected a wide gamut of opinions (NYT February 3rd. 2008,) despite the “evidence,” which tends to be interpreted with a subjectiveness that belies our medical commitment to objectivity.

An article in the J. Business Week reviewed what we have seen in our medical journals over the years, yet these kinds of articles, which are not financed by the pharmaceuticals, do not seem to be quoted too much at the dinners sponsored by them (“Do Cholesterol Drugs Do Any Good?” J. Business Week, Cover issue, January 28th, 2008, page 52.) Here are the main points:

  • Statins only help those who already have had a heart attack. No benefits for men over 65 and women of any age. A small benefit is seen for middle age men, but no reduction in total deaths, or hospitalizations.
  • If guidelines for cholesterol were followed, 40 million Americans would be taking these drugs. Who made the guidelines? A group of doctors whose majority was taking money from the companies that make these drugs.
  • The best Rx for cholesterol, the Mediterranean diet, is not emphasized enough.
  • Lipitor reduces the risk of heart attacks by 36%,” (*) says Dr. Jarvick, the team leader on the first artificial heart implantation in the early 80s. But, the asterisk on the package insert says that the 36% figure comes from the fact that 3% fewer patients taking a sugar pill had a heart attack, compared to 2% taking Lipitor: one fewer heart attack for 100 people taking the drug for five years, paying $1,000/year. When patients are made aware of these numbers, most opt out.
  • The only large study paid by the government showed no benefit from these drugs.
  • Avandia lowers sugar, but no benefits otherwise: “avandia is almost the poster child for everything that is wrong with our system,” Dr. Hoffman, NEJM article.
  • It is almost impossible to find someone who believes strongly in statins who does not get a lot of money from industry,” Dr. Hayward, U. Michigan Med School
  • I now see it as a myth that everyone should have their cholesterol checked,” Dr. Brody, U. of Texas.

Many doctors feel that the real problem is the oxidized-inflamed cholesterol that becomes sticky when the liver is not well nourished, and under the influence of too much insulin and glucose in the bloodstream. The same thing happens to the lining of our arteries, the endothelium, which becomes sticky from inflammation and oxidation, since they are also nutritionally compromised. This problem leads to “leaky arteries,” which the oxidized cholesterol tries to patch up. This healthy elevation of cholesterol is compromised by the stickiness of both the cholesterol and the lining of the arteries, resulting in a “Velcro-like” reaction that leads to plaque formation. Who said all this? Linus Pauling, whose emphasis on nutrition as an extremely important factor in health and disease has been vindicated by the explosion of solid research into the biochemistry of nutrition.

Why do the French have much lower incidence of heart disease, despite consuming more cholesterol than Americans? They eat the Mediterranean diet, which is higher in antioxidants.

Oxidized LDL in plasma is a prognostic marker of subclinical atherosclerosis development in clinically healthy men,” (J. Internal Medicine 2004;256:413) reviews this concept, and it even tells us that the oxidation of cholesterol can be used as a sign of future trouble in healthy men. The Mediterranean diet lowers oxidized LDL (J. Nutrition 2005;135:410,) and the CRP (J. Annals of Nutrition and Metabolism 2006;50:20, J. Ann Int Med 2006;145:1) Furthermore, insulin resistance contributes to LDL oxidation (J. Diabetologia 2005;48:741.)

One could argue that the Statin drugs are quite safe, so, we could use them liberally to lower cholesterol. This is probably correct, considering these drugs are derivatives of Fermented Red Rice, which has been use in China for Millennia to treat heart problems by lowering the oxidation of cholesterol. By extracting only the most powerful molecule from red rice, the one that acts on HMG Coenzyme reductase, the antioxidants from fermented red rice, which were contributing to the healing of “leaky arteries,” are not there to mitigate potential problems with the “stronger” statin drugs (European J. Cardiovascular Rehabilitation 2007;14:438.) However, muscle and liver inflammation have been reported with these drugs, even subclinically. Also, in November 2003, the HHS announced that babies whose pregnant mothers took these drugs have a higher rate of congenital defects.

The Lyon, France study of the Mediterranean diet (J. Circulation 1999;99:779) showed less heart attacks and angina in people eating this diet, compared to the Standard American Diet (SAD,) despite both groups having the same blood pressure, weight, and LDL cholesterol about 160. Consider this quote from the editorial on page 733:

“70% reduction in all-cause mortality and non-fatal sequelae... [with the Mediterranean diet.] At a time when health professionals, the pharmaceutical industries and the research funding and regulatory agencies are almost totally focused on lowering plasma cholesterol levels with drugs, it is heartening to see a well conducted study finding that relatively simple dietary changes achieved greater reductions in risk of all-cause and coronary disease mortality than any of the cholesterol-lowering studies to date... [this] unprecedented reduction in risk for CHD was not associated with differences in total cholesterol levels between the control and experimental groups.”

That the problem in heart disease is not fats and cholesterol was reported in the 70's by 5 studies sponsored by the NIH. However, Mevacor produced a study about the same time showing that lowering cholesterol reduced the risk of heart attacks, Despite the earlier negative studies, and thanks to aggressive marketing from the pharmaceutical producing this drug, most doctors were convinced that cholesterol was the problem. The New York Times magazine, on July 7th, 2002 (“What if Fat Doesn’t make you Fat?”) reemphasized what the most prestigious scientific journal in the world revealed about this concept a few months before (“The Soft Science of Dietary Fat,” J. Science 2001;291:2536.) Yet, why did the Mevacor study show a reduction of heart disease? Statin drugs are anti-inflammatory/antioxidant agents. This concept was again revisited in the NEJM, January 6th, 2005;352:20: these drugs showed better clinical outcomes by lowering the CRP, a marker of inflammation, “regardless of the resultant level of LDL cholesterol.”

No doubt many doctors will disregard these issues, that is, the French paradox itself, and continue to ignore the mounting evidence that the cholesterol story needs to be edited a bit. For sure, patients who have overwhelming genetic problems with their cholesterol will need to stay on pharmaceutical products with the help of doctors like Paul Hopkins.

In my opinion, our beliefs will likely be influenced by who signs our checks, notwithstanding the research available to us. One thing is for sure: the FDA is unlikely to help solve this thorny issue, unless it undergoes radical changes, because it lacks the science and the staffing to look at the controversy effectively: “today, not only can the FDA not lead, it cannot keep up with the advances in science” (“FDA’s Science Infrastructure Failing,” JAMA 2008;299:157.)

In my opinion, this controversy becomes a mute point when we truly believe and convince our patients that “food is the best medicine” (Hippocrates; Sir William Osler,) and strictly follow the American Heart Association’s recommendation to always use TLC first: Therapeutic Lifestyle Changes for the first 6 months, before reaching for the prescription pad. I seldom see a need to use statins, since my patients are highly motivated to do just that. Besides, fiber (“Guar Gum: a miracle therapy for hypercholesterolemia, hyperglycemia, and obesity,” J. Clinical Reviews in Food Science and Nutrition 2007;47:389,) resveratrol (“Resveratrol Improves Mitochondrial Function and Protects Against Metabolic Disease by Activating SRT1 and PGC-1 alpha,” J. Cell 2006;127:1109,) omega oils (J. Lancet 2007;369:1090,) fermented red rice (J. Chinese Medicine 2007:1:4,) vitamin D3 (“Are statins analogues of vitamin D?” J. Lancet 2006;368:83) isoflavones (American J. Clinical Nutrition 2007;86:938) and antioxidants in general (J. Arteriosclerosis Thrombosis & Vascular ogy 2006;26:689) have shown to be helpful.

Perhaps most important in matters of the heart is how we love and respect each other and other cultures. Clogged up coronaries can be reversed with diet and good relationships (Dr. Dean Ornish’s books “Reversing Heart Disease,” 1990 and “Love and Survival,” 1998.)

Je ne regretted pas” stirring the pot a bit…


At September 28, 2009 at 4:34:00 PM PDT , Blogger karl said...

resveratrol and other antioxidants in the diet don't often effect serum levels - this is misleading information if not complete.

At September 30, 2009 at 1:18:00 PM PDT , Blogger Dr. Hugo Rodier said...


Thank you for writing, but I'm afraid I disagree with you and so does the last issue of the Medical Letter.

Besides, resveratrol will become a pharmaceutical product next year, hardly a development consistent with your biased view of antioxidants.

Just in case you may be interested in reading some of the evidence, take a look at the latest study on antioxidants:

J. Nutr. First published August 26, 2009; doi:10.3945/jn.109.107870
Journal of Nutrition, doi:10.3945/jn.109.107870
Vol. 139, No. 10, 1964-1971, October 2009

And another summary here:

Nutritional Epidemiology

Total Antioxidant Performance Is Associated with Diet and Serum Antioxidants in Participants of the Diet and Physical Activity

Substudy of the Jackson Heart Study1,2

Total antioxidant performance (TAP) measures antioxidant capacities in both hydrophilic and lipophilic compartments of serum and interactions known to exist between them. Our objective was to assess TAP levels in a subset of Jackson Heart Study (JHS) participants and to examine associations with dietary and total (diet + supplement) intakes of -tocopherol, -tocopherol (diet only), ⼯i>-carotene, vitamin C, fruit, vegetables, and nuts, and serum concentrations of -tocopherol, -tocopherol, and ⼯i>-carotene. We conducted a cross-sectional analysis of 420 (mean age 61 y; 254 women) African American men and women participating in the Diet and Physical Activity Sub-Study of the JHS in Jackson, Mississippi. In multivariate-adjusted models, we observed positive associations between total -tocopherol, total and dietary ⼯i>-carotene, and total vitamin C intakes and TAP levels (P-trend < 0.05). Positive associations were also observed for vegetable, fruit, and total fruit and vegetable intakes (P-trend < 0.05). For serum antioxidant nutrients, -tocopherol but not ⼯i>-carotene was associated with serum TAP levels. There were inverse associations for serum -tocopherol and TAP levels. Associations for -tocopherol were seen at intake levels much higher than the current Recommended Dietary Allowance. It may, therefore, be prudent to focus on increasing consumption of fruit, vegetables, nuts, and seeds to increase total antioxidant capacity.


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