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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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High low-density-lipoprotein is beneficial

Dear Editor

In their study of the general population in Copenhagen, Johannesen et al. concluded that high levels of LDL-C were associated with an increased risk of all-cause mortality. They claim that “no previous study has examined the concentration of LDL-C associated with the lowest risk of all-cause mortality in a general population cohort.” [1] The fact is that the association between LDL-C and longevity in community-dwelling people has been examined in Spain, [2] Italy, [3,4] the USA, [5] Finland, [6] Korea [7] and China. [8] In two of these studies, the association between LDL-C and mortality was inverse; [2,3] in four of the others [4-7] it was nonsignificant. In an Iranian study, only CVD mortality was reported, and it was inversely associated with LDL-C. [9]

In the Chinese study, [8] which included more than five million statin-naïve young people, high LDL-C was associated with mortality, but those with the highest LDL-C who died, included only 0.076 percent of the population. Most likely they may have had familial hypercholesterolemia (FH), but that does not mean that the cause of death was high LDL-C. There is much evidence that premature mortality among subjects with FH is increased coagulation factors which a few of them have inherited as well. [10]

As the authors mention, several studies of elderly people with high cholesterol have shown that after the age of retirement, they live just as long or longer than elderly people with normal or low cholesterol. These studies are rejected by Johannesen et al. because they consider them conflicting and historical. However, they are in accord with the result of a review of 19 follow-up studies of elderly people, [11] and at least seven other studies from all over the world published during the last four years. [3-6,12-14] In the review, [11] CVD mortality was reported as well in seven of the 19 studies, and it was unassociated with LDL-C in six of them. Furthermore, eight more follow-up studies including young and middle-aged people or patients have found that high LDL-C is unassociated or inversely associate with mortality. [15-22]

In their review, Johannesen et al. claim that a recent study of young Korean people without statin-treatment has shown a U-shaped association between LDL-C and mortality. [25] This study of two cohorts included 347,971 and 182,943 individuals, respectively. In the first cohort, the association was U-shaped, but it was only statistically significant for the association between low LDL-C and mortality. In the other cohort, the association was also U-shaped, but not with statistical significance.

Johannesen et al. suggest that the association between low levels of LDL-C and an increased risk of all-cause mortality is explained by reverse causation. However, there is much evidence that low cholesterol predisposes both to infectious diseases [23] and to cancer. [24]

As CVD is the most common cause of death in most countries, these follow-up studies contradict the idea that high LDL-C causes CVD; an idea which is contradicted by many other types of studies as well. [25]

References

1. Johannesen CDL, Langsted A, Mortensen MB, Nordestgaard BG. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. BMJ 2020;371:m4266 doi:10.1136/bmj.m4266
2. Orozco-Beltran D, Gil-Guillen VF, Redon J, et al. Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study. PLoS ONE 2017;12: e0186196.
3. Zuliani G, Volpato S, Dugo M, et al. Combining LDL-C and HDL-C to predict survival in late life: The InChianti study. PLoS One 2017 doi: 10.1371/journal.pone.0185307.
4. Montesanto A, Pellegrino D, Geracitano S, et al. Cardiovascular risk profiling of long-lived people shows peculiar associations with mortality compared with younger individuals. Geriatr Gerontol Int 2019;19;165-70. doi: 10.1111/ggi.13578
5. Maihofer AX, Shadyab AH, Wild RA, LaCroix AZ. Associations between serum levels of cholesterol and survival to age 90 in postmenopausal women. J Am Geriatr Soc 2020;68:288-96. doi: 10.1111/jgs.16306.
6. Sittiwet C, Simonen P, Gylling H, Strandberg E. Mortality and cholesterol metabolism in subjects aged 75 years and older: The Helsinki Businessmen Study. J Am Geriatr Soc 2020;68:281-7. doi: 10.1111/jgs.16305.
7. Lee H, Park JB, Hwang IC, et al. Association of four lipid components with mortality, myocardial infarction, and stroke in statin-naive young adults: A nationwide cohort study. Eur J Prev Cardiol 2020 doi: 10.1177/2047487319898571
8. Zhou L, Wu Y, Yu S, Shen Y, Ke C. Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study. BMJ Open 2020;10. doi: 10.1136/bmjopen-2020-036976.
9. Ghasemzadeh Z, Abdi H, Asgari S, TohidiM, Khalili D et al. Divergent pathway of lipid profile components for cardiovascular disease and mortality events: Results of over a decade follow-up among Iranian population. Nutr Metabol 2016;13:43-55. doi: 10.1186/s12986-016-0102-1
10. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60–3. doi: 10.1016/j.mehy.2018.09.019.
11. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016; 6: e010401. doi: 10.1136/bmjopen-2015-010401.
12. Bendzala M, Sabaka P, Caprnda M, et al. Atherogenic index of plasma is positively associated with the risk of all-cause death in elderly women. A 10-year follow-up. Wien Klin Wochenschr 2017;129:793–8. doi: 10.1007/s00508-017-1264-1.
13. Charach G, Argov O, Nochomovitz H, et al. A longitudinal 20 years of follow up showed a decrease in the survival of heart failure patients who maintained low LDL cholesterol levels. QJM 2018;111:319-25. doi: 10.1093/qjmed/hcy043
14. Dégano IR, Ramos R, Garcia-Gil M, et al. Three-year events and mortality in cardiovascular disease patients without lipid-lowering treatment. Eur J Prev Cardiol 2019 doi: 10.1177/2047487319862103
15. Park C H, Kang EW, Park JT, Han SH, Yoo TH et al. Association of serum lipid levels over time with survival in incident peritoneal dialysis patients. J Clin Lipidol 2017;11:945-54.
16. Tanamas SK, Saulnier PJ, Hanson RL, Nelson RG, Hsueh WC et al. Serum lipids and mortality in an American Indian population: A longitudinal study. J Diabetes Complications. 2018;32:18-26.
17. Penson PE, Long DL, Howard G, et al. Associations between cardiovascular disease, cancer, and very low high-density lipoprotein cholesterol in the reasons for geographical and racial differences in stroke (REGARDS) study. Cardiovasc Res 2019;115:204-12.
18. Berton G, Cordiano K, Mahmoud HT, Bagato F, Cavuto F, Pasquinucci M. Plasma lipid levels during ASC: Association with 20 year mortality: The ABC-5 study on heart disease. Eur J Prev Cardiol 2020;27:2176-9. doi.org/10.1177/2047487319873061
19. Yousufuddin M, Takahashi PY, Major B, et al. Association between hyperlipidemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis. BMJ Open 2019; 9: e028638.
20. Lee H, Park JB, Hwang IC, al. Association of four lipid components with mortality, myocardial infarction, and stroke in statin-naïve young adults: A nationwide cohort study. Eur J Prev Cardiol 2020;27:870-81. doi: 10.1177/2047487319898571.
21. Kobayashi D, Mizuno A, Shimbo T, Aida A, Noto H. The association of repeatedly measured low-density lipoprotein cholesterol and all-cause mortality: a longitudinal study. Internat J Cardiol 2020;311:97-103. doi: 10.1016/j.ijcard.2020.03.011
22. Zhou L, Wu Y, Yu S, Shen Y, Ke C. Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study. BMJ Open 2020;10:e036976. doi: 10.1136/bmjopen-2020-036976.
23. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM. 2003;96:927–34. doi: 10.1093/qjmed/hcg150.
24. Ravnskov U, Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM 2012;105:383–8. doi: 10.1093/qjmed/hcr243.
25. Ravnskov U, de Lorgeril M, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Exp Rev Clin Pharm 2018;11:959-70. doi: 10.1080/17512433.2018.1519391.

Competing interests: No competing interests

17 December 2020
Uffe Ravnskov
Independent researcher
de Lorgeril M, Laboratoire Coeur et Nutrition, TIMC-CNRS, Université Grenoble-Alpes. Faculté de Médecine, 38056 La Tronche, France. Diamond D, Professor, Departments of Psychology, Molecular Pharmacology & Physiology, University of South Florida, Tampa, FL, 33620 US. Hama R, Director, Japan Institute of Pharmacovigilance, Osaka, Japan. ORCID ID 0000-0002-3802-6754 Hammarskjöld B, Assistant professor, Strömstads Academy, Östervåla, Sweden. Harcombe Z, Independent researcher, Cardiff, UK. Kendrick M, East Cheshire Trust, Macclesfield District General Hospital, Macclesfield, Cheshire, UK. McCully KS, Pathology and Laboratory Medicine Service, Veterans Affairs Boston Healthcare System. Associate Professor, Harvard Medical School, Boston, MA, Sultan S, Professor, Department of Vascular & Endovascular Surgery, National University of Ireland, Galway, Ireland. Sundberg R. Independent researcher, Stockholm, Sweden
no affiliation
22350 Lund, Sweden