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Cited by 54Lipid metabolism and disordersLipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and Lipoproteins

Target Populations for Novel Triglyceride-Lowering Therapies

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Nordestgaard, Ask T., Tybjærg-Hansen, Anne, Mansbach, Hank, Kersten, Sander, Nordestgaard, Børge G., Rosenson, Robert S.·2025·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2025.02.035
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Abstract

Lipoprotein lipase regulates triglyceride hydrolysis and contributes to cellular uptake of triglyceride-rich lipoprotein remnants. Multiple pathways modulate lipoprotein lipase activity, which has prompted interest in the development of drugs that increase lipoprotein lipase activity as means to reduce risk for acute pancreatitis, atherosclerotic cardiovascular disease, and metabolic dysfunction-associated steatohepatitis through reduction of circulating triglycerides and remnant cholesterol. The authors provide an overview of the target populations for agents that lower triglycerides and remnant cholesterol through increased lipoprotein lipase activity, the drugs being developed for these indications, including apolipoprotein C-III and angiopoietin-like protein 3, 3/8, and 4 inhibitors, and the epidemiologic and genetic evidence supporting the use of these drugs for the prevention of atherosclerotic cardiovascular disease and acute pancreatitis. In addition, the authors provide a corresponding overview of fibroblast growth factor-21 analogues that share many characteristics with these novel triglyceride-lowering drugs. Apolipoprotein C-III inhibitors, angiopoietin-like protein 3, 3/8, and 4 inhibitors, and fibroblast growth factor-21 analogues have pronounced triglyceride-lowering and remnant cholesterol-lowering effects. In clinical trials, apolipoprotein C-III inhibitors have been shown to lower risk for acute pancreatitis in patients with severe hypertriglyceridemia and a…

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Crossref · 10.1016/j.jacc.2025.02.035

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  • Mild elevations in aminotransferase levels as well as small increases in glycated hemoglobin levels have also been seen with plozasiran and are similar to the now well-established safety profile of statins.

    “Mild elevations in aminotransferase levels as well as small increases in glycated hemoglobin levels have also been seen with plozasiran 18,23,29 and are similar to the now well-established safety profile of statins. 30,31”

    From Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia (2025) · cites this paper as [18]

  • Nordestgaard and colleagues demonstrated a graded association between triglyceride levels across a broad biological range (0.3-11.2 mmol/L) and cardiovascular risk.

    “More recently, Nordestgaard and colleagues expanded the evaluation of triglyceride levels across a broad biological range (0.3–11.2 mmol/L), demonstrating a graded association with cardiovascular risk and highlighting the need for clinical trials to include patients beyond the traditional 200–499 mg/dL range [22].”

    From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [22]

  • Lomitapide and pegozafermin may further expand therapeutic options for complex hypertriglyceridemia.

    “other emerging approaches, including lomitapide, a microsomal triglyceride transfer protein inhibitor, and pegozafermin, an FGF21 analog with combined triglyceride and hepatic fat–lowering properties, may further expand therapeutic options for complex hypertriglyceridemia [121]”

    From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [121]

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Authors
Nordestgaard, A. T., Tybjærg-Hansen, A., Mansbach, H., Kersten, S., Nordestgaard, B. G., & Rosenson, R. S.
Affiliations
  • Brigham and Women's Hospital (US)
  • 89bio (United States) (US)
  • Cornell University (US)
  • University of Copenhagen (DK)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Nordestgaard, Ask T.
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2025-05
Volume
85
Issue
19
Pages
1876-1897
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2025.02.035
OpenAlex
W4410303021
Cited by
54
References
49
Citations by year
2026: 35 · 2025: 19
FWCI
9.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
Independent Research Fund Denmark
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
triglyceride-lowering therapy, lipoprotein lipase, remnant cholesterol, acute pancreatitis, atherosclerotic cardiovascular disease, nonalcoholic steatohepatitis, hypertriglyceridemia, hepatic steatosis, liver fibrosis, target population
MeSH terms
Hypolipidemic Agents, Humans, Lipoprotein Lipase, Triglycerides, Hypertriglyceridemia

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