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Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study

BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4266 (Published 08 December 2020) Cite this as: BMJ 2020;371:m4266

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Re: Association between low density lipoprotein and all cause and cause specific mortality. Still the lower the better?

Dear Editor,

It’s well established that treatment of low-density lipoprotein (LDL) cholesterol reduces the risk for cardiovascular disease in patients at high or very high risk of cardiovascular disease.1 However the optimal LDL-cholesterol level in the general population is not yet established.

It’s therefore with great interest that we read the paper of Johannesen et al. about LDL cholesterol levels and risk for all-cause mortality in a large general population cohort.2 In this paper the authors investigated which LDL cholesterol is optimal regarding mortality, cancer and myocardial infarction risk. In line with previous studies, patients treated with cholesterol lowering drugs, mortality is positively correlated with LDL cholesterol levels. However in patients without lipid-lowering therapy the optimal LDL cholesterol is higher than expected with even an increase in mortality in the lowest range of LDL-cholesterol.

To assess if reversed causality causes this unexpected results, patients with a follow up time less than five years and with specific chronic diseases (atherosclerotic cardiovascular disease, cancer, and chronic obstructive pulmonary diseases) were excluded. However patients with chronic auto-inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease who have an established increased risk of cardiovascular disease, cancer and subsequent mortality were not excluded.3 Interestingly a higher inflammatory burden reflecting an active disease is associated with lower lipid levels.4 Indeed the prevalence of these diseases is low in the general population, estimated as 1-2% for RA5 and IBD 0.5% for IBD6, however it would be interesting to assess if these patient might be overrepresented in the individuals with very low LDL-cholesterol. Moreover, in the list of confounders we missed body mass index (BMI). Previously in the same cohort an optimal BMI was also higher than expected and a low BMI was like a low LDL-cholesterol levels associated with increased mortality.7 In successive studies inverse causality was pointed out to be the most likely explanation for these unexpected findings.8 Therefore we are interested if the association between LDL cholesterol levels still remains significant after correction for BMI.

Besides we remain puzzled by the striking difference between the strong inverse relation of LDL cholesterol levels and all-cause mortality in individuals with genetic causes for low LDL cholesterol and the findings in this Danish-cohort.9 Therefore we cannot refrain from strongly suspecting that reverse causality remains the main driver from this finding.
While this study sheds new and interesting light on the discussion with regard to an optimal LDL-cholesterol level in a healthy population, we experienced already the mischievous miss use of this study by those who mistrust the association between LDLC-cholesterol in general and the favourable effects of lipid lowering therapy in particular. Therefore, addressing the issue of reverse causality remains crucial to preventing pseudoscientists from cherry picking parts of this study for false claims concerning cholesterol reduction and possibly harming general health.

1. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). European Heart Journal 2019;41(1):111-88.
2. Johannesen CDL, Langsted A, Mortensen MB, et al. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. Bmj 2020;371:m4266.
3. Symmons DP, Jones MA, Scott DL, et al. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998;25(6):1072-7.
4. Schulte DM, Paulsen K, Türk K, et al. Small dense LDL cholesterol in human subjects with different chronic inflammatory diseases. Nutr Metab Cardiovasc Dis 2018;28(11):1100-05.
5. Neovius M, Simard JF, Askling J, et al. Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden. Ann Rheum Dis 2011;70(4):624-9.
6. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142(1):46-54 e42; quiz e30.
7. Afzal S, Tybjærg-Hansen A, Jensen GB, et al. Change in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013. Jama 2016;315(18):1989-96.
8. Greenberg JA. Correcting biases in estimates of mortality attributable to obesity. Obesity (Silver Spring) 2006;14(11):2071-9.
9. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med 2016;375(22):2144-53.

Competing interests: No competing interests

22 December 2020
Koen Verdonk
Fellow vascular medicine
J. E. Roeters van Lennep
Erasmus MC, Rotterdam, Netherlands
Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands