The concept of high blood cholesterol as a major cause of atherosclerosis is based on observations of severe early atherosclerosis in patients with congenital absence of LDL receptors in the liver so that blood cholesterol levels are very elevated. Brown and Goldstein received the Nobel Prize in 1985 for the discovery of these receptors. Fortunately, 99.99% of atherosclerosis is not due to a deficiency of these receptors but due to lifestyle which can easily be changed.
But the very crude correlation between total blood cholesterol and death from heart attacks in large populations led to the myth that lowering blood cholesterol would prevent heart attacks. This is an example of a classic error in reasoning, assuming that correlation is causation.
In 1987 the first statin, Mevacor, was licensed in the USA. If statins were the cure for atherosclerosis, one would think that atherosclerosis would have disappeared shortly thereafter. On the contrary mortality from atherosclerosis had been decreasing slowly since the late 1960’s and showed no dramatic decrease with the introduction of statins. The only thing that changed was a marked increase in the incidence of obesity and diabetes caused by the moral hazard effect of statins, their most serious side effect.
When lookiing at blinded, controlled trials of statins a number of points have to be considered:
1. Are the subjects eating a non-atherogenic diet and do they have BMI’s under 25 and/or a waist circumference under half their heights? We now know that diet and visceral obesity have a huge effect on atherosclerosis. Unless we can be assured that all subjects in the trial are eating a non-atherogenic diet and are monitored continuously for adherence to it, the study has no relevance to clinical practice. Subjects in the WOSCOPS and ASCOT-LLA trials were mostly overweight or obese and were never were instructed on a true non-atherogenic diet and monitored for adherence to the diet. Studies that fail to do so are as unethical as doing a drug trial in cholera patients before eliminating the source of contaminated water.
2. Is the study in done for “primary” prevention or “secondary” prevention? The 4S study is often quoted as showing decreased morality with statins. There is often no mention that 4S was a secondary prevention trial. The subjects all had symptomatic atherosclerosis. This trial has no applcation to the vast majority of the population. Primary prevention trials like WOSCOPS or ASCOT-LLA trials show no mortality benefit. At least 90% of statin prescriptions are given for primary prevention. But in 2003 the Therapeutic Initiatives group at the University of British Columbia, which has no connection with the drug industry, has stated categorically that ” …statins have not been shown to provide an overall health benefit in primary prevention trials.” The TI group is no threatened with elimination based on a report of a committee of drug dealers. Their conclusion was recently given support by a trial of Lipitor, the most prescribed drug in the world, in primary prevention iin people with a high coronary artery calcium volume, a crude measure of plaque volume. Even high dose Lipitor had absolutely no effect in halting the progression of plaque. Patients who have had a heart attack may represent a special group which has declared itself by plaque rupture. Statins may have a small effect in this group which is independent of blood cholesterol.
3. Has the trial considered the differences between the sexes? A meta-analysis of many statin trials has concluded that “For women without cardiovascular disease, lipid lowering does not affect total or CHD mortality. Lipid lowering may reduce CHD events, but current evidence is insufficient to determine this conclusively”.
4. Statins, llike drugs for hypertension and Type 2 diabetes do not treat disease but generally serve only to “treat” the symptoms of an unhealthy lifestyle, the numbers (cholesterol, blood pressure, blood glucose). They are not analogous to antibiotics or hormone replacements. All statin trials have been blinded; subjects did not know if they were taking the drug or a placebo and therefore had no incentive to change lifestyle. When statins are available to the general population it is implied that they will prevent heart attacks and people have less incentive to change lifestyle or even adopt a more atherogenic, obesogenic lifestyle – the moral hazard side-effect of statins. Thus the pandemic if obesity and Type 2 diabetes.
5. Non-blinded statin trials like JUPITER, have the potential for bias in subjective outcomes like the decision to do an angioplasty or coronary bypass, outcomes that constitute the vast majority of the combined endpoint. Also, it is quite likely that when the JUPITER subjects knew that their blood LDL was low because they were taking Crestor they had less incentive to change self-destructive lifestyles. That is probably why the group treated with Crestor had significantly more diabetes. In spite of the JUPITER trial in 2010 the Therapeutics Initiatives group at the University of British Columbia saw no reason to change its recommendations and concluded as before that “statins do not have a proven net health benefit in primary prevention populations and thus when used in that setting do not represent good use of scarce health care resources.”If statins were a cure for atherosclerosis, one would have expected a dramatic change in mortality after the introduction of Mevacor in 1987. What happened? No change in the pattern of the slow decline that began in the late ’60’s.