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Cited by 150Lipoproteins and Cardiovascular HealthLipid metabolism and disordersDiabetes, Cardiovascular Risks, and Lipoproteins

Addressing dyslipidemic risk beyond LDL-cholesterol

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Tall, Alan R., Thomas, David G., Gonzalez-Cabodevilla, Ainara G., Goldberg, Ira J.·2022·Journal of Clinical Investigation
DOI 10.1172/jci148559PMC PMC8718149
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Abstract

Trends in residual riskCVD, including myocardial infarction and stroke, is the leading cause of death in the United States and accounts for 28% of overall mortality (11).CVD risk factors include age, sex, hypertension, diabetes, smoking, body mass index, and increased levels of LDL-C or TGs or reduced HDL-C levels (1, 12).Current therapies for prevention of ischemic events focus on controlling risk factors, as well as suppressing thrombosis in at-risk individuals, and this approach has contributed to decades of improvement in CVD mortality (13).This trend has stalled in recent years, in part because of the rise of obesity, diabetes, and their associated dyslipidemias.The metabolic syndrome has become more prevalent in all sociodemographic groups in the United States, and now occurs in more than one-third of adults ( 14).Both fasting and nonfasting TG levels associate with CVD risk.In a European population, 27% of adults had nonfasting TGs greater than 176 mg/dL, a level that was associated with an approximately 1.9-fold increase in risk of CVD (15).In individuals with TGs greater than 580 mg/dL, the risk was increased even further to 5.1-fold for myocardial infarction and 3.2-fold for Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL.This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome.Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation.Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis.While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD.Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia.Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches.Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels.Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.

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Authors
Tall, A. R., Thomas, D. G., Gonzalez-Cabodevilla, A. G., & Goldberg, I. J.
Affiliations
  • Columbia University (US)
  • New York University (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2022-01-04
Volume
132
Issue
1
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci148559
PMC
PMC8718149
OpenAlex
W4205596334
Cited by
150
References
161
Citations by year
2026: 22 · 2025: 44 · 2024: 36 · 2023: 27 · 2022: 21
FWCI
7.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ionis Pharmaceuticals
  • Arrowhead Pharmaceuticals
  • National Institutes of Health (HL107653, HL-45095, HL151328)
  • National Heart, Lung, and Blood Institute (R01HL045095, R37HL045095, P01HL151328, R01HL107653)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
dyslipidemia, residual cardiovascular risk, triglyceride-rich lipoproteins, HDL cholesterol, metabolic syndrome, obesity, atherosclerosis, foam cells, fibrates, fish oil, apolipoprotein C-III, ANGPTL3, RNAi therapeutics, antisense oligonucleotides, monoclonal antibodies
MeSH terms
Angiopoietin-Like Protein 3, Animals, Foam Cells, Humans, Lipoproteins, HDL, Cholesterol, LDL, Obesity, Genetic Variation, Metabolic Syndrome, Dyslipidemias, Atherosclerosis, Apolipoprotein C-III

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