Saturday, May 28, 2011

Cholesterol, HDL Cholesterol, and Heart Disease

     I am sure that many if not all of you read or heard about the front page story in today's (Friday, May 27) NY Times that using Niacin to raise the level of HDL (the "good") cholesterol did NOT lower the incidence of heart disease. The false expectation of a benefit from raising HDL came from the common confusion (and wishful thinking, because doctors are always looking for ways to help  their patients) between correlation and causation. Remember that just because taller people (on the average) weigh more than do short people, it does not therefore follow that the way to increase a person's weight is to increase his/her height.

     We doctors have many suggestions to make to our patients about primary prevention of heart attacks . By primary, I mean  prevention of the first heart attack. Since the biggest risk of having a heart attack resides in those who have already had one, we have been very aggressive and successful in finding ways to prevent a second heart attack (hence the phrase "secondary" prevention). This is why a patient who has been on no medicine at all and who enters the hospital with a heart attack usually goes home on five medicines, since each of them has been shown to greatly reduce the risk of having a second heart attack.

     However, despite all our theories, and all our observations about commonalities in patients who have a first heart attack versus those "similar" patients who have not, very few interventions have been shown to reduce the risk of a first heart attack, and of these, stopping smoking leads the list. We also have over 30 years of strong evidence (but only in comparative studies) that mild intake of alcohol of any origin (beer, red or white wine, scotch, slivovits, etc.) reduces the relative and absolute risk of a first heart attack. Unfortunately, we have absolutely no idea how the C2H5OH molecule does this, and it certainly has not been linked to a reduction in cholesterol, but at autopsy mild alcohol ingesters have larger lumens (= less blockage) in their coronary arteries than do tee-totalers.We also have  no strong evidence for the benefits of daily aspirin, and we certainly cannot explain the results of a 30 year epidemiological study published in Lancet as to why in the Far East patients with a higher BMI (i.e. heavier patients) had a reduced risk of heart attacks, nor can we explain the studies that demonstrate that patients who are somewhat overweight (BMI between 26 and 29) have the greatest survival rate if they have a heart attack. It is trivial to note that stopping smoking does not affect your total cholesterol, LDL cholesterol, or fasting glucose (except insofar as  most ex-smokers gain 10 to 15 pounds the first year).

     In approximate numbers, survivors of a first heart attack have at least a 10% chance of a repeat heart attack in the following two years, so the results of a pharmacological intervention are readily seen. But patients with a high cholesterol who have never had a heart attack have a comparative  increased risk of a  heart attack in the next TEN years of 10%, so the results of an intervention have to be stronger or longer to show a statistical benefit, which is why it is difficult to show the benefits of any primary prevention in any forward double-blind study. In fact, the first double blind study of cholesterol lowering, done on male smokers in Finland with gemfibrizol, showed no benefit of reducing heart attacks until the statistical method of analysis was altered. I do not have the space here that is necessary to demonstrate why it is statistically unsound to vary your method of statistical analysis if you don't like the result of the first analysis.

     We are left with the result that elevated cholesterol, elevated LDL cholesterol and lowered HDL cholesterol are all statistically associated with an increased risk of a heart attack,  but only lowering the LDL has been shown to lower the risk of heart attacks consistently. The Zetia study showed that Zetia lowered total cholesterol, but did not decrease the heart attack risk. (Which only means that this first Zetia study failed to show a benefit, and a second and possibly a third study would be needed to validate this result as a clinical conclusion.) It may well be that the real value in the use of statins to lower cholesterol lies in their anti-inflammatory properties. We now have a study that shows that raising HDL did not reduce the risk of heart attacks. We have also known for years that elevated triglycerides are a statistical risk factor for heart attacks, but no study as yet has shown that lowering the TGL level lowers the heart attack risk. (Some doctors empirically lower the TGL of all their diabetic patients because diabetics have an increased risk of heart attacks, and a relative insulin deficiency causes a rise in TGL, but there is no cause-and-effect proof yet.) We also definitely do not understand why many patients, especially females, can have total cholesterols of over 280 with no evidence of an increased heart attack risk in them or their  mothers, and have very patent coronary arteries at autopsy, if one is done. We also don't know why (but we think we do) females have a lower risk for heart disease than do men, any more than we understand why lupus and anorexia are more common among women than men.

     Again, we must be very careful of assuming that any and every  statistical relationship is cause-and-effect, and that if elevated "A" is associated with disease "B" then pharmacologically lowering the value of "A" will lessen the incidence of disease "B". In other words, altering a statistical risk factor is not guaranteed to affect the incidence of the disease.  Very few facts are "obvious" in medicine: just recall the universal advice to patients with calcium oxalate kidney stones to lower the amount of calcium in their diet to prevent a recurrence, until a physician at UTexas, Galveston showed conclusively that INcreasing the amount of calcium in the diet DEcreased the recurrence rate of calcium oxide kidney stones. It was also thought that anti-oxidants had a protective effect against cancer, but when  50% of a matched group of Finnish cigarette smokers were given daily doses of anti-oxidants, it was found that those who took daily anti-oxidants had an INcreased incidence of lung cancer, a result to which the American Cancer Society has not given proper importance.

     Finally, we also have the Law of Unintended Consequences: When mothers throughout America gave their children pure bottled water to drink, there was an increase in the incidence of dental caries in children, until it was realized that bottled water contained no fluoride, so now they have returned to giving their children fluoride as prescription Poly-Vi-Flor fluoridated vitamins (or their equivalent), just as I did. And since they have lost the business of children with cavities, dentists are now pushing orthodontia and night guards in Medicare patients(!). In most states, when the mandatory drivers' seatbelt law was passed, the death rate for pedestrians INcreased in the first few years, and we still don't know why. And many, many doctors were guilty of prescribing combination estrogen-progesterone tablets for their post-menopausal female patients in an attempt to reduce their risk of a heart attack until the increased incidence of cancer was noted. When we advised patients to take daily Vitamin E (400 Units) on theoretical grounds to lower their heart attack risk, the first decent statistical analysis showed that daily pharmacological doses of Vitamin E INcreased the risk of having a heart attack. Similarly, when men with prostate cancer were given estrogen to decrease the effect of any androgen on the prostate, an increase in cerebral strokes was soon noted. And at the present, only God knows the effect of daily doses of CoEnzyme-Q, or the proper dosage if there is a benefit, or how many times a day it should be taken, if at all, and if so on an empty or a full stomach.

     "Life is short, art long, opportunity fugitive, experimenting dangerous, reasoning difficult....."--- Hippocrates

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