Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Jul;59(7):1266-1275.
doi: 10.1194/jlr.R082271. Epub 2018 May 16.

Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding

Allan D Sniderman  1 , Patrick Couture  2 , Seth S Martin  3 , Jacqueline DeGraaf  4 , Patrick R Lawler  5 , William C Cromwell  6 , John T Wilkins  7 , George Thanassoulis  8
Affiliations
Review

Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding

Allan D Sniderman et al. J Lipid Res. 2018 Jul.

Abstract

Triglycerides are the conventional tool to measure VLDLs, whereas LDL cholesterol (LDL-C) is the conventional tool to measure LDLs. Multiple epidemiological studies, including a series of genetically based analyses, have demonstrated that cardiovascular risk is related to triglycerides independently of LDL-C, and this has led to a series of new therapeutic agents designed specifically to reduce plasma triglycerides. The triglyceride hypothesis posits that increased levels of triglycerides increase cardiovascular risk and decreasing plasma triglycerides decreases cardiovascular risk. In this work, we will examine the validity of the triglyceride hypothesis by detailing the biological complexities associated with hypertriglyceridemia, the genetic epidemiological evidence in favor of hypertriglyceridemia, the evidence from the fibrate randomized clinical trials relating triglycerides and clinical outcomes, and the completeness of the evidence from the initial studies of novel mutations and the therapeutic agents based on these mutations that lower triglycerides. Because of the multiple metabolic links between VLDL and LDL, we will try to demonstrate that measuring triglycerides and LDL-C alone are inadequate to document the lipoprotein profile. We will try to demonstrate that apoB must be measured, as well as triglycerides and cholesterol, to have an accurate estimate of lipoprotein status.

Keywords: angiopoietin-like 3 protein; apolipoprotein B; apolipoprotein CIII; apolipoprotein CIII inhibitor; low density lipoprotein; triglycerides; very low density lipoprotein.

PubMed Disclaimer

Conflict of interest statement

A.D.S., J.D., J.T.W, and P.R.L. report that they have no conflicts of interest. P.C. has received funding in the last 5 years from the Canadian Institutes for Health Research, Agriculture and Agri-Food Canada (Growing Forward program supported by the Dairy Farmers of Canada, Canola Council of Canada, Flax Council of Canada, Dow Agrosciences, Dairy Research Institute, Dairy Australia, Danone Institute, Merck, Pfizer, Atrium Innovations, and Kaneka Corporation. S.S.M. is listed as a co-inventor on a pending patent filed by Johns Hopkins University for an algorithm to estimate LDL cholesterol; has served on scientific advisory boards for Quest Diagnostics, Sanofi/Regeneron, Amgen, and Akcea Therapeutics; and has received research support from the PJ Schafer Cardiovascular Research Fund, the David and June Trone Family Foundation, the American Heart Association, the Aetna Foundation, CASCADE FH, the Maryland Innovation Initiative, Google, and Apple. W.C.C. is self-employed and is in private practice at the Lipoprotein and Metabolic Disorders Institute, PLLC, and is also an employee of LabCorp and is a consultant and lecturer for Amarin, Amgen, and Kiowa. G.T. is a consultant for Ionis Pharma; on the Advisory boards of Ionis Pharma, Amgen, and Servier Canada; a member of the Speaker’s Bureau of Amgen, Sanofi, Servier Canada, and Boerhinger Ingelheim; and has received a research grant from Ionis Pharma.

Figures

Fig. 1.
Fig. 1.
apoB lipoprotein particles.
Fig. 2.
Fig. 2.
Correlations between total apoB levels (A), VLDL apoB levels (B), VLDL-C levels (C), and plasma triglyceride levels in 2,023 patients (736 with IIa phenotype, 371 with IIb phenotype, 509 with IV phenotype, and 407 with normal lipid profile). The dashed lines indicate the 90% confidence intervals for the regression lines.
Fig. 3.
Fig. 3.
Decreases in total apoB are illustrated from statin and fibrate arms of Study 1 (14), Study 2 (15), and Study 3 (16), and the fibrate treatment arm of Study 4 (49). The proportion of the decrease in total apoB due to the decrease in VLDL apoB is indicated in black, whereas the decrease in total apoB due to the decrease in LDL apoB is indicated in white. S, statin; F, fibrate.
See this image and copyright information in PMC

References

    1. Jørgensen A. B., Frikke-Schmidt R., West A. S., Grande P., Nordestgaard B. G., and Tybjaerg-Hansen A.. 2013. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur. Heart J. 34: 1826–1833. - PubMed
    1. Varbo A., Benn M., Tybjaerg-Hansen A., Jørgensen A. B., Frikke-Schmidt R., and Nordestgaard B. G.. 2013. Remnant cholesterol as a causal risk factor for ischemic heart disease. J. Am. Coll. Cardiol. 61: 427–436. - PubMed
    1. Do R., Willer C. J., Schmidt E. M., Sengupta S., Gao C., Peloso G. M., Gustafsson S., Kanoni S., Ganna A., Chen J., et al. 2013. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45: 1345–1352. - PMC - PubMed
    1. De Graaf J., Couture P., and Sniderman A.. 2015. ApoB in Clinical Care. Springer, Houten, The Netherlands.
    1. Cantey E. P., and Wilkins J. T.. 2018. Discordance between lipoprotein particle number and cholesterol content: an update. Curr. Opin. Endocrinol. Diabetes Obes. 25: 130–136. - PubMed

Publication types

MeSH terms

Grants and funding