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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

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The association between low density lipoprotein and mortality in Denmark may be significantly modified by other easily available biomarkers

Dear Editor,

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).[1]

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.[5] 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.

[1] 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

[2] Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Intern Med. 2001 Feb 12;161(3):361-6. doi: 10.1001/archinte.161.3.361. PMID: 11176761.

[3] 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.

[4] 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.

[5] 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

[6] 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

09 December 2020
George D Henderson
Auckland New Zealand