LDL-C Does Not Cause Cardiovascular Disease: a comprehensive review of current literature

October 5, 2018  18:13

Does high TC cause atherosclerosis?

No association between TC and degree of atherosclerosis
If high TC causes atherosclerosis, people with high TC should have more atherosclerosis than people with low TC. In 1936 Landé and Sperry found that corrected for age, unselected people with low TC were just as atherosclerotic as people with high TC [4]. Since then their seminal observation has been confirmed in at least a dozen studies . A weak association between TC and degree of atherosclerosis has been found in some studies [5], but the authors only studied patients admitted to a hospital and may therefore have included patients with familial hypercholesterolemia (FH). As the percentage of such patients in a cardiology department is much higher than in the general population, a bias may have been introduced. In accordance, the positive association between TC and degree of atherosclerosis noted in the study by Solberg et al. disappeared when those with TC above 350 mg/l (9 mmol/l) were excluded .

No exposure-responseIf high TC were the major cause of atherosclerosis, there should be exposure-response in cholesterol-lowering drug trials; e.g. the arteries of those whose lipid values are lowered the most should benefit the most. However, in a review of sixteen angiographic cholesterol-lowering trials, where the authors had calculated exposure-response, this correlation was only present in one of them, and in that trial the only treatment was exercise.

Does high TC cause CVD?

An idea supported by fraudulent reviews of the literature
If high TC was the major cause of CVD, people with high TC should have a higher risk of dying from CVD. The hypothesis that high TC causes CVD was introduced in the 1960s by the authors of the Framingham Heart Study. However, in their 30-year follow-up study published in 1987, the authors reported that “For each 1 mg/dl drop in TC per year, there was an eleven percent increase in coronary and total mortality”. Three years later the American Heart Association and the US National Heart, Lung and Blood Institute published a joint summary concluding “a one percent reduction in an individual’s TC results in an approximate two percent reduction in CHD risk”. The authors fraudulently referred to the Framingham publication to support this widely quoted false conclusion.

In two additional reviews written by authoritative supporters of the cholesterol hypothesis [9,10], more misleading information was reported. To see how these proponents explained results discordant with the cholesterol hypothesis, quotations from twelve papers with such findings were searched for in the three reviews. Only two of the papers were quoted correctly, and only in one of the reviews. About half of the contradictory papers were ignored. In the rest, statistically non-significant findings in favor of the cholesterol hypothesis were inflated, and unsupportive results were quoted as if they were supportive. Only one of six randomized cholesterol-lowering trials with a negative outcome was cited and only in one of the reviews.

The association between TC and CVD is weak, absent or inverse in many studies

During the years following the report of the Framingham Heart Study, numerous studies revealed that high TC is not associated with future CVD. with the strongest evidence of a lack of relation between TC and CVD in elderly people. For instance, a review published in 2002 included references to twelve such studies. A 2004 Austrian study published 2004 including 67,413 men and 82,237 women who had been followed for many years found that TC was weakly associated with coronary heart disease (CHD) mortality for men, except for those between age 50-64. For women, it was weakly associated among those below the age of 50 and no association was present after that age. No association was found between TC and mortality caused by other CVDs, except that low TC was inversely associated with CVD mortality for women above the age of 60.

In 2007, the Prospective Studies Collaboration [14], the writing committee of which included the same authors as those for Collins et al., published a meta-analysis including 61 prospective observational studies consisting of almost 900 000 adults, which concluded that TC was associated with CHD mortality in all ages and both sexes. We have not been able to obtain the original data . However, the authors had ignored at least a dozen studies, including the Austrian one, where no association or an inverse association was noted, and in several studies, the number of participants deviated from the number reported by the Prospective Studies Collaboration.

Does high LDL-C cause atherosclerosis?

An idea based on selected patient groups
If LDL-C is atherogenic, people with high LDL-C should have more atherosclerosis than those with low LDL-C. At least four studies have shown a lack of an association between LDL-C and degree of atherosclerosis, and in a study of 304 women, no association was found between LDL-C and coronary calcification [16]. One exception is a study of 1779 healthy individuals without conventional risk factors for CVD . Here the authors found that LDL-C was significantly higher among those with subclinical atherosclerosis (125.7 vs.117.4 mg/dl). However, association does not prove causation. Mental stress for instance is able to raise cholesterol by 10-50% in the course of half an hour, and mental stress may cause atherosclerosis by mechanisms other than an increase in LDL-C; for instance, via hypertension and increased platelet aggregation.

The benefit from statin treatment has been questioned

For some years, many researchers have questioned the results from statin trials because they have been denied access to the primary data. In 2004-2005 health authorities in Europe and the US introduced New Clinical Trial Regulations, which specified that all trial data had to be made public. Since 2005, claims of benefit from statin trials have virtually disappeared.

Adverse effects from statin treatment

According to Collins et al. adverse effects from statin treatment are extremely rare and the incidence of statin adverse effects can only be obtained from randomized controlled trials. However, many drug-related adverse effects in other therapy areas have only emerged from observational studies and post-marketing surveillance. Furthermore, most statin trials have included a run-in period, where participants received the drug for a few weeks, after which those who suffered adverse effects or who were unwilling to continue were excluded. The results from two trials without a run-in period and where a high statin dose was compared with a low dose, demonstrated that this is an effective way to minimize the number of reported side effects; in SAGE serious side effects were recorded in more than 20% in both groups, and in IDEAL the number was almost 50%.

According to Collins et al. myopathy occurs in only 0.01% of treated individuals per year, but in most statin trials myopathy is only recorded if creatine kinase is more than ten times higher than normal. However, in a study by Phillips et al., microscopic examinations of muscle biopsies from statin-treated patients with muscular symptoms and normal creatine kinase levels showed signs of myopathy. When patients stopped treatment, their symptoms disappeared and repeated biopsies showed resolution of the pathological changes.

To reject the frequent occurrence of muscular problems with the argument that muscle symptoms are nocebo effects is also invalid. In a study of 22 statin-treated professional athletes , the authors reported that 17 (77%) of the athletes terminated treatment because of muscular symptoms, which disappeared a few days or weeks after drug withdrawal. The explanation for statin-induced adverse muscle effects is probably that statin treatment not only blocks the production of cholesterol, but also blocks the production of several other important molecules, for instance coenzyme Q10, which is indispensable for energy production. As most energy is produced in the muscle cells, including those of the heart, the extensive use of statin treatment may explain the epidemics of heart failure that have been observed in many countries

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