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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: (Published 08 December 2020) Cite this as: BMJ 2020;371:m4266

Rapid Response:

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

Dear Editor,

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.

29 January 2021
Børge G. Nordestgaard
Consultant clinical professor
Camilla Ditlev Lindhardt Johannesen, registrar, Anne Langsted, senior registrar, Martin Bødtker Mortensen, senior registrar
Copenhagen University Hospital, University of Copenhagen, Denmark
Herlev and Gentofte Hospital, Herlev, Denmark