Re: Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials
Statins, Cholesterol Levels, and the Risk of Infections
Neither van den Hoek et al.'s conclusion1 that statins do not reduce the risk of infections nor Golomb's accompanying editorial2 refer to the possibility that the cholesterol lowering effect of statins could actually have the reverse effect and increase the risk of infections. Golomb offered several possible explanations of the lower rate of infections in the statin arms of some trials, such as indication bias, fewer ill and elderly people, various healthy user effects, and bias from drug company sponsors. Another proxy for high cholesterol levels is lack of adherence to taking statins; in one study that included 85,020 patients without heart disease, 75% were no longer taking statins at the 2-year follow-up.3
Golomb´s most important argument is that the main indication for statins is an elevated cholesterol level, which is associated with resistance to infections and decreased hospital admissions for influenza and pneumonia.4 Additional support comes from the observation that prior to 1900, when infectious diseases were the leading cause of death, people with familial hypercholesterolemia lived longer than the average population of their country.5
An important function of lipoproteins explains why high cholesterol provides protection from infections. It is not generally appreciated that lipoproteins bind and inactivate numerous bacteria and viruses as well as their toxic products. This important function of lipoproteins in innate immunity was demonstrated over 60 years ago by Humphrey and has since been confirmed by more than a dozen research groups.6,7 For instance, lipoproteins inhibit replication and toxin formation by various microorganisms in vitro.6 Aggregates formed between human low-density lipoprotein (LDL) and various microbes and toxins have been visualized by electron microscopy, and these aggregates are suggested to obstruct vasa vasorum during formation of vulnerable plaques.6 Hypocholesterolaemic rats injected with lipopolysaccharide (LPS) endotoxin have a markedly increased mortality compared with normal rats, which is ameliorated if they are pre-treated with an injection of purified human LDL. Similarly, mice with genetic hypercholesterolaemia challenged with LPS or live bacteria have an eightfold increase of LD50 compared to normal controls.6
Thus, epidemiological, observational and laboratory studies all support the conclusion that elevated cholesterol levels reduce the risk of infections. Moreover, the study of 100,000 healthy individuals showed that those with low cholesterol levels at the start were admitted more often to hospital because of an infectious disease during a 15 year follow up.4 As 15-20% of human cancers are estimated to have a viral or bacterial aetiology,8 the anti-infectious properties of the lipoproteins may explain the many associations between low cholesterol levels and cancer.9
Uffe Ravnskov, MD, PhD; independent investigator
Magle Stora Kyrkogata 9, 22350 Lund Sweden
Paul J. Rosch, MD, FACP, Clinical Professor of Medicine and Psychiatry, New York Medical College: President, The American Institute of Stress 124 Park Ave.Yonkers, New York, USA.
Kilmer S. McCully, MD, Pathology and Laboratory Medicine Service VA Boston Healthcare System, West Roxbury MA, USA, Department of Pathology, Harvard Medical School, Boston MA, USA.
1. Van den Hoek HL, Bos WJW, De Boer A, van de Garde EMW. Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 2011; 343:d7281.
2. Golomb BA. Do statins reduce the risk of infection? BMJ 2011;343:d7134.
3. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288:462-7.
4. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Gross MD, Sadler M, Blackburn H. Serum total cholesterol and risk of hospitalization, and death from respiratory disease. Int J Epidemiol 1997;26:1191-202.
5. Sijbrands EJG, Westendorp RGJ, Defesche JC, de Meier PHE, et al. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study. BMJ 2001; 322:1019-1023.
6. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009;39:3-16.
7. Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol 2010;54:246–53.
8. Burnett-Hartman AN, Newcomb PA, Potter JD. Infectious agents and colorectal cancer: a review of Helicobacter pylori, Streptococcus bovis, JC virus, and human papillomavirus. Cancer Epidemiol Biomarkers Prev 2008;17:2970-2979.
9. Ravnskov U, McCully KS, Rosch PJ. The statin-low cholesterol-cancer conundrum. Q J Med, 2011, In Press.
Competing interests: No competing interests