Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort studyBMJ 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 in Denmark: prospective cohort study
We thank Drs. Verdonk, van Lennep, and Henderson for their constructive interest in our work (1). They raise important points regarding other lipid measurements than low-density lipoprotein (LDL) cholesterol related to mortality, and the issue of reverse causation as explanation for some of our findings.
In our publication we studied LDL cholesterol as this is the focus of cardiovascular disease prevention guidelines in the UK, Europe, US, and Canada (2-5). However, we agree with Dr. Henderson that elevated triglyceride-rich lipoproteins or elevated remnant cholesterol (indicated by a high triglycerides/high-density lipoprotein (HDL) cholesterol ratio) likely will explain some additional risk for all-cause mortality and cardiovascular disease, and also high lipoprotein(a) will explain additional risk. Thus, elevated non-HDL cholesterol or apolipoprotein B that includes all three lipoproteins (LDL, remnants, and lipoprotein(a)) also explain more of the risk than LDL cholesterol alone. In accordance, we recently demonstrated in statin-treated patients that elevated apolipoprotein B and non-HDL cholesterol, but not elevated LDL cholesterol, were associated with residual risk of all-cause mortality and myocardial infarction (6).
We ourselves were puzzled by the association between low LDL cholesterol and increased all-cause mortality, and we believe that this phenomenon possibly could be explained by reverse causation, even though we tried to account for reverse causation in numerous analyses (1). Therefore, as suggested by Drs. Verdonk and van Lennep it would be interesting for future studies to elaborate on the possible reverse causation related to chronic autoinflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease.
We agree that LDL cholesterol is a potential mediator from diabetes and obesity to risk of cardiovascular disease and mortality; however, we recently observed that very low-density lipoprotein cholesterol, and not LDL cholesterol, explains a large fraction of the excess risk of myocardial infarction found in individuals with obesity (7). That said, we repeated the analyses reported in Figure 2 of our paper (1) without adjustment for diabetes, and found similar results: multivariable adjusted hazard ratios of all-cause mortality versus individuals in the 61st-80th centile were 1.34(95%CI:1.24-1.45) for 1st- 5th centile, 1.20(1.12-1.28) for 6th-20th, 1.09(1.02-1.16) for 21st-40th, 1.07(1.01-1.14) for 41st-60th, 1.03(0.97-1.11) for 81st-95th, and 1.16(1.05-1.28) for individuals in the 96th-100th centile. Furthermore, when additionally adjusting for body mass index, results were again similar with corresponding hazard ratios of 1.26(1.16-1.37), 1.19(1.11-1.27), 1.08(1.02-1.15), 1.07(1.01-1.14), 1.03(0.97-1.10), and 1.15(1.04-1.27), respectively.
We are saddened to learn that Drs. Verdonk and van Lennep already experienced mischievous misuse of our observational study by those who mistrust the causal association between LDL cholesterol and risk for cardiovascular disease in general and the favorable effects of cholesterol-lowering therapy in particular. Indeed, one of the rapid responses to our paper by Ravnskov and co-authors follow exactly this type of misuse, a potential misuse we discussed thoroughly before publication, and even considered whether we should publish this data or not. We were firmly convinced that the data should be published, as we believe in the truth and in evidence-based medicine. As stated in our paper, it is important to understand that our results are based on observational analyses. Thus, they say nothing about the causal role of LDL cholesterol in the development of cardiovascular diseases or mortality, and our results cannot be used to assess the potential effect of LDL cholesterol lowering therapies. For that we have abundance of strong experimental, genetic, and clinical trial evidence (2-5). We trust that the BMJ and readers of this excellent and evidence-based scientific journal will reject misuse of our results that harms public health.
We were surprised to read that Ravnskov and co-workers claim “No competing interest”. Through a simple Goggle search we found more than 20 books authored by Ravnskov in English, Danish, Italian, Turkish, German, Estonian, Dutch, Finnish, Polish, Swedish, Japanese, and Korean, from all of which he makes profits via selling through Amazon and elsewhere. These books contain information that in my opinion is questionable and that I worry could encourage patients not to follow evidence-based medicine and guidelines for preventing myocardial infarction and strokes by lowering cholesterol levels.
Importantly, the various comments discussed above do not change the conclusion of our paper (1): in individuals in the general population, low and high levels of LDL cholesterol were associated with an increased risk of all-cause mortality, and the lowest risk of all-cause mortality was found at an LDL cholesterol concentration of 3.6 mmol/L (140 mg/dL).
1. 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.
2. National Institute for Health and Care Excellence (NICE) Clinical Guideline CG181: Lipid modification - Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. National Clinical Guideline Centre, July 2014.
3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-88.
4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350.
5. Anderson TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016;32(11):1263-82
6. Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and non-HDL-Cholesterol better Reflect Residual Risk than LDL-Cholesterol in Statin-treated Patients with Atherosclerosis. J Am Coll Cardiol 2021; in press.
7. Johansen MØ, Nielsen SF, Afzal S, Vedel-Krogh S, Davey Smith G, Nordestgaard BG. Very low-density lipoprotein cholesterol may mediate a substantial component of the effect of obesity on myocardial infarction risk: the Copenhagen General Population Study. Clin Chem 2021; 67: 276-285.
Competing interests: 1) The Danish taxpayers, as they paid the vast majority of our personal educations through medical school, personal wages, and expenses for scientific research. 2) We believe in evidence-based medicine and the truth.
Re: Association between low density lipoprotein and all cause and cause specific mortality. Still the lower the better?
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
Re: Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study
I am puzzled that no conflicts of interest have been declared in this paper, when one author, Børge G. Nordestgaard, has declared several relevant conflicts of interest in another paper published this year (1). These are shown as "B.G.N. reports consultancies and honoraria for lectures from AstraZeneca, Sanofi, Regeneron, Amgen, Akcea, Kowa, Novartis, Novo Nordisk”.
(1) Boren J et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal (2020) 41, 2313–2330
Competing interests: Members of the international Network of Cholesterol Skeptics
Competing interests? Re: Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study
A relevant question is, why the authors have not considered more than 25 studies with the opposite result. According to their paper they have ”no financial relationships with any organisations that might have an interest in the submitted work in the previous three years.° Also, in the section Conflicts of interest in a paper published this year in European Heart Journal, you can read the following about Professor Børge G. Nordestgaard, the corresponding author of the Danish paper: “B.G.N. reports consultancies and honoraria for lectures from AstraZeneca, Sanofi, Regeneron, Amgen, Akcea, Kowa, Novartis, Novo Nordisk”.
1. Boren J, Chapman MJ, Krauss RM et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020;41: 2313–30. doi:10.1093/eurheartj/ehz962
Competing interests: No competing interests
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.”  The fact is that the association between LDL-C and longevity in community-dwelling people has been examined in Spain,  Italy, [3,4] the USA,  Finland,  Korea  and China.  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. 
In the Chinese study,  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. 
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,  and at least seven other studies from all over the world published during the last four years. [3-6,12-14] In the review,  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.  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  and to cancer. 
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. 
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
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Competing interests: No competing interests
The association between low density lipoprotein and mortality in Denmark may be significantly modified by other easily available biomarkers
Johannesen et al, in their study of the association between low density lipoprotein and mortality in Denmark state that different measuring methods were used when triglyceride concentrations were less than 4 mmol/L (352 mg/dL), compared with TG levels of 4 mmol/L or more (≥352 mg/dL).
If some subjects had TGs of 4 mmol/L or more, or lower levels of elevated TGs accompanied by depressed HDL, then it is not surprising that they experienced greater mortality and CVD events at any LDL-C level, but how was the risk associated with LDL-C modified by measurements that are known to be better risk predictors?
If it resembles all the other populations for which the TG and HDL data is available and has been published, then the fasting ratio of TG/HDL may be a stronger determinant of risk than LDL cholesterol, and the LDL-C association with risk may be almost entirely dependent on a higher TG/HDL ratio.[2,3]
This is very important information because the fasting TG/HDL ratio is easily improved by lifestyle interventions, because using it narrows down the section of the population at risk, and because it makes sense mechanistically given that TG/HDL is a marker of both insulin sensitivity and reverse cholesterol transport capacity.[4,5] It is also information that would lower the NNT for cholesterol-lowering drugs.
It is also the case that the results may be skewed by the adjustment for diabetes. LDL cholesterol is inversely associated with the risk of diabetes, e.g. in UK Biobank levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), a correlation causally supported by genomic analysis. Diabetes is a major cause of cardiovascular disease and mortality. Thus some morbidity and mortality through metabolic pathways associated with lower LDL may have been missed by this adjustment.
 Johannesen Camilla Ditlev Lindhardt, Langsted Anne, Mortensen Martin Bødtker, Nordestgaard Børge Grønne. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study BMJ 2020; 371 :m4266
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 Soška V, Jarkovský J, Ravčuková B, Tichý L, Fajkusová L, Freiberger T. The logarithm of the triglyceride/HDL-cholesterol ratio is related to the history of cardiovascular disease in patients with familial hypercholesterolemia. Clin Biochem. 2012 Jan;45(1-2):96-100. doi: 10.1016/j.clinbiochem.2011.11.001. Epub 2011 Nov 18. PMID: 22119890.
 Dobiášová M. Atherogenic impact of lecithin-cholesterol acyltransferase and its relation to cholesterol esterification rate in HDL (FER(HDL)) and AIP [log(TG/HDL-C)] biomarkers: the butterfly effect? Physiol Res. 2017 May 4;66(2):193-203. doi: 10.33549/physiolres.933621. PMID: 28471688.
 Bertsch RA, Merchant MA. Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk. Perm J. 2015;19(4):4-10. doi:10.7812/TPP/14-237
 Klimentidis YC, Arora A, Newell M, et al. Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank. Diabetes. 2020;69(10):2194-2205. doi:10.2337/db19-1134
Competing interests: No competing interests