Uffe Ravnskov

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

Objective It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue. Setting, participants and outcome measures We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population. Results We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found. Conclusions High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

Should we lower cholesterol as much as possible

Statins are portrayed as harmless drugs that almost everyone would benefit from, but little is known about the side effects at the high doses now being suggested

The statin-low cholesterol-cancer conundrum

Hundreds of millions of people all over the globe are currently being administered statins because it is believed that their lipid lowering actions provide cardioprotective benefits. Adverse effects are considered uncommon and mild, and authors of numerous case–control studies of patients on statin treatment and matched, untreated individuals have even suggested a protective effect against numerous non-cardiovascular diseases, including cancer. In contrast, four controlled, randomized statin trials have resulted in a statistically significant increase of cancer in the treatment group; and several case–control and cohort studies have also shown a significant risk of cancer associated with statins. To add further confusion to this issue, meta-analyses of controlled, randomized statin trials have shown neither an increased nor a decreased risk of cancer.1 Some of these discrepancies may result from the failure to recognize that the recordings of cancer in statin trials are biased for several reasons. Several cohort studies of healthy people have shown that low cholesterol is a risk marker for future cancer. The usual interpretation has been that the association is secondary, because in most studies the association disappeared after having excluded early cancer cases. A common explanation has been that preclinical cancers might use cholesterol, which would lead to lower levels. However, when searching Pubmed with the words ‘cancer AND cholesterol’ we identified nine cohort studies including more than 140 000 individuals, where cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years (Table 1).2–10 It seems unlikely that the liver would be unable to produce the extra cholesterol necessary for early tumor growth, considering that much larger amounts are steadily made for the constant renewal of our cells. Moreover, none of these cohort studies has been corrected …

How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease

We have provided a critical assessment of research on the reduction of cholesterol levels by statin treatment to reduce cardiovascular disease. Our opinion is that although statins are effective at reducing cholesterol levels, they have failed to substantially improve cardiovascular outcomes. We have described the deceptive approach statin advocates have deployed to create the appearance that cholesterol reduction results in an impressive reduction in cardiovascular disease outcomes through their use of a statistical tool called relative risk reduction (RRR), a method which amplifies the trivial beneficial effects of statins. We have also described how the directors of the clinical trials have succeeded in minimizing the significance of the numerous adverse effects of statin treatment.

Infections May be Causal in the Pathogenesis of Atherosclerosis

Abstract:There is a universal lack of exposure response between degree of lipid lowering and the outcome in clinical and angiographic trials questioning the current view on atherogenesis. However, there are numerous observations and experiments suggesting that microorganisms may play a causal role. A clue is the fact that the lipoproteins constitute an innate immune system by binding and inactivating microorganisms and their toxic products through formation of circulating complexes. Their size may increase in the presence of hyperhomocysteinemia because homocysteine reacts with low-density lipoprotein (LDL) to form homocysteinylated LDL aggregates. Autoantibodies against homocysteinylated or oxidized LDL may also enhance the aggregation. Because of the high extracapillary pressure, such aggregates may obstruct arterial vasa vasorum producing ischemia and cell death within the arterial wall leading to the creation of a vulnerable plaque. The many epidemiological observations, clinical findings and laboratory experiments that conflict with the cholesterol hypothesis are in good accordance with ours.

The Questionable Benefits of Exchanging Saturated Fat With Polyunsaturated Fat

ormanyyearswehavebeentoldthattoprevent cardiovascular disease (CVD), wemust lower our intake of saturated fattyacids (SFAs) and instead eat more carbohydratesand polyunsaturated fatty acids(PUFAs).Backedup by the National Cholesterol Education Pro-gram, the National Institutes of Health, and theAmerican Heart Association, the medical profes-sionhaspromotedthisideaeagerly,althoughthenumber of contradictory scientificreportsisalmost endless. There is in fact much evidencethat doing the opposite is more relevant.The ContradictionsThe main argumentforusingthis diethasbeenthatitlowerstheconcentrationofcholesterolinthe blood and thus prevents CVD. This ideawas proposed for the first time by Keys,

Statins Do Not Protect Against Cancer: Quite the Opposite

TO THE EDITOR: In their cohort study of statin-treated patients and nontreated controls, Cardwell et al concluded that statin treatment may prevent colorectal cancer. However, there are significant flaws in their study. At least nine studies have shown that cancer is associated with low cholesterol, measured 10 to 30 years before diagnosis. Because most patients receiving statin treatment have lived most of their lives with high cholesterol, risk for cancer mortality might have been lower even without statin treatment compared with the untreated cohort with normal or low cholesterol. A similar study by Nielsen et al supports this interpretation, because mortality was lowest among those who were treated with the lowest statin dose. Furthermore, adherence to statins is low, particularly when prescribed for primary prevention. In a Canadian study including 85,000 patients, 75% had stopped the treatment at 2-year follow-up. To claim that statin treatment protects against cancer is therefore impossible with the method used by Caldwell et al. Instead, cancer mortality should be related to the achieved lipid values, as reported by Matsuzaki et al, who administered simvastatin 5 to 10 mg per day to 47,000 patients. After 6 years, cancer mortality was 3 higher in patients whose total cholesterol was 160 mg/dL compared with those whose cholesterol was normal or high (P .001). In fact, evidence that statin treatment may cause cancer is much stronger. Several cholesterol-lowering drugs, including statins, have been found to be carcinogenic in rodents in doses that produce blood concentrations of the drugs similar to those attained in treating patients. In accordance, breast cancer occurred in 12 of 286 women in the treatment group of the CARE (Cholesterol and Recurrent Events) trial, but only in one of 290 in the placebo group (P .002). In the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial, cancer occurred in 245 of 2,891 patients in the treatment group, but only in 199 of 2,913 in the placebo group (P .02). In the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial, cancer occurred in 39 of 944 patients in the treatment group, but only in 23 of 929 in the placebo group (P .05). In the two first simvastatin trials, nonmelanoma skin cancer was seen more often as well, and with statistical significance if the results are calculated together (256 of 12,454 v 208 of 12,459; P .028). The latter finding may explain the current so-called epidemic of nonmelanoma skin cancer. Several case-control studies have also shown that patients with cancer have been treated with statins significantly more frequently than controls without cancer matched for age and sex. Furthermore, a recent study showed that 10 years of statin therapy increased women’s risk of invasive ductal carcinoma by 83% and their risk of invasive lobular carcinoma of the breast by 97%. An apparent contradiction is that meta-analyses of the statin trials have found no increase of cancer. However, since the publication of the HPS (Heart Protection Study) trial, the number of nonmelanoma skin cancers—the easiest malignancies to detect early—has not been reported in any trial. Furthermore, it may take 10 to 20 years before exposure to carcinogenic chemicals results in cancer. Bronchial cancer, for instance, does not appear until after 10 years of smoking, and the length of almost all the statin trials has only been 5 years at most. As noted, it may be that statins per se are not carcinogenic but rather that this adverse effect results from their ability to lower blood lipids. More than a dozen research groups have documented that lipoproteins, particularly LDL, partake in the immune system by binding and inactivating all kinds of microorganisms and their toxic products. Because certain microorganisms have been incriminated as a possible cause of different malignancies, including colorectal cancer, it is difficult to understand how lowering LDL cholesterol could prevent cancer. Association never proves causation. Although it may be difficult to prove that statins can cause or prevent cancer, the preponderance of evidence favors the former.

After the Failure of ENHANCEd Cholesterol Lowering in Familial Hypercholesterolemia, SEAS of Problems with Ezetimibe

In a recent issue of the Journal, Whayne analyzed the results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, and proposed several explanations to the lack of effect of a more intensive low-density lipoprotein (LDL) cholesterol lowering with ezetimibe (beyond the level achieved with simvastatin) in patients with familial hypercholesterolemia. Furthermore, he pointed out that the ENHANCE trial lasted only 24 months, and a longer period could be required to see benefit from cholesterol lowering by ezetimibe. However, he did not consider that the concentration of cholesterol by itself seems to be unimportant in familial hypercholesterolemia, and that a long-lasting therapy with ezetimibe and statin may raise some safety concerns. Mounting evidence suggests that in familial hypercholesterolemia neither the incidence nor the prevalence of cardiovascular disease is associated with the lipid levels. This striking observation has been explained by the narrow range of LDL concentrations. The argument is untenable, however, because total and LDL cholesterol in some individuals with familial hypercholesterolemia may be more than twice as high as in others. A possible cause of cardiovascular disease in familial hypercholesterolemia may be inborn errors of the coagulation system. Indeed, in cohorts of people with familial hypercholesterolemia, it has been found that plasma fibrinogen and factor VIII were significantly higher in those with coronary heart disease than in those without, whereas total and LDL cholesterol did not differ significantly. It has also been documented that polymorphism in the prothrombin gene is strongly associated with cardiovascular risk in people with this disorder. The reason why statin treatment is of benefit in familial hypercholesterolemia may therefore be mediated by their well-known antithrombotic effects, not their effect on cholesterol. However, the results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial have been recently published. During a follow-up of 52.2 months, simvastatin and ezetimibe, as compared with placebo, did not reduce the composite outcome of combined aortic valve events and ischemic events in patients with aortic stenosis. But, of more concern, an excess of incident cancers was observed in the simvastatin–ezetimibe group, with 105 in that group as compared with 70 in the placebo group (P 1⁄4 .01). In addition, deaths from cancer were more frequent in the active treatment group (39 deaths vs. 23 in the placebo group), achieving a borderline statistical significance (P1⁄4 .05). Of note, the average age in the ENHANCE trail was 46 years, and in the SEAS trial 68 years. It is well known that statins are immunomodulatory drugs, which might promote growth increase of occult cancers, especially in the elderly individuals who already harbor cancers. Furthermore, ezetimibe inhibits the absorption of phytosterols and other phytonutrients that are linked to protection against cancer. Therefore, the increased cancer incidence associated with cholesterol-lowering treatment cannot be dismissed as being coincidental, also because many observations from the statin trials are in accord. Although the ENHANCE trial was a treatment failure, it has contributed valuable knowledge about the pathogenesis of premature coronary disease in familial hypercholesterolemia. A relevant question to answer in future research is whether attempts to normalize the coagulation system may be more

Should medical science ignore the past

For their article on hypercholesterolaemia and its management Bhatnagar et al selected reviews only if they included “extensive recent references,”1 thereby missing important knowledge from the past [full list of references in rapid response].2 Let me elaborate:

Biofilms, Lipoprotein Aggregates, Homocysteine, and Arterial Plaque Rupture

The finding that bacteria form biofilms within the majority of carotid arterial plaques is a further demonstration of the important role played by microorganisms in the etiology of atherosclerotic vascular disease (1). Many investigators believe that the first step in atherogenesis is the creation of atherosclerotic plaques and that infection by microorganisms is a secondary phenomenon. In contrast, we believe that microbial infection is an essential component of the atherogenic …