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The Angiopoietin-like Protein (ANGPTL) Axis in Dyslipidemia: Mechanisms, Cardiovascular Risk, and Emerging Therapies

Isabela C Bitencourt1, André Zimerman1,2, Nicholas A Marston3

  • 1MOVE Academic Research Organization, Hospital Moinhos de Vento, Moinhos de Vento Medical School, Porto Alegre, Brazil.

Current Atherosclerosis Reports
|July 11, 2026
PubMed
Abstract

Insights

Targeting the angiopoietin-like protein (ANGPTL) 3-4-8 axis offers a novel approach to lipid metabolism and cardiovascular risk reduction. ANGPTL3 inhibition shows significant promise for managing dyslipidemia, particularly in familial hypercholesterolemia.

Area of Science:

  • Cardiovascular Medicine
  • Metabolic Disorders
  • Pharmacology

Background:

  • The angiopoietin-like protein (ANGPTL) 3-4-8 axis is a key regulator of lipoprotein lipase and lipid metabolism.
  • Dyslipidemia contributes significantly to cardiovascular disease risk.

Purpose of the Study:

  • To review the mechanistic basis of ANGPTL pathway modulation.
  • To explore therapeutic implications for cardiovascular risk reduction in dyslipidemia.

Main Methods:

  • Review of genetic studies and clinical trials involving ANGPTL pathway modulation.
  • Examination of pharmacologic inhibition strategies (monoclonal antibodies, RNA-based therapies).

Main Results:

  • Loss-of-function variants in ANGPTL3/4 correlate with lower triglycerides and reduced coronary artery disease risk.
  • ANGPTL3 inhibition effectively reduces triglycerides, remnant cholesterol, LDL-C, and apoB, largely independent of the LDL receptor.
  • ANGPTL3 inhibitors have shown significant LDL-C reductions in homozygous familial hypercholesterolemia and mixed dyslipidemia.

Conclusions:

  • Modulating the ANGPTL-lipoprotein lipase axis is a novel strategy for addressing residual atherosclerotic risk.
  • ANGPTL-directed therapies offer promising cardiovascular risk mitigation for patients with dyslipidemia, including those with HoFH.
Keywords:
RNA InterferenceAngiopoietin-like proteinsAntibodies, monoclonalHypercholesterolemia, familialHypertriglyceridemiaLipoprotein lipase

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