ANGPTL3 Inhibition, Dyslipidemia, and Cardiovascular Diseases

Authors, Journal, Affiliations, Type, DOI

• Fei Luo, Avash Das, Sumeet A. Khetarpal, Zhenfei Fang, Thomas A. Zelniker, Robert S. Rosenson, Arman Qamar
• Trends in Cardiovascular Medicine 34 (2024) 215–222
• Second Xiangya Hospital (CSU); Harvard Medical School (BIDMC, MGH); Vienna General Hospital; Mount Sinai Icahn School of Medicine; NorthShore/University of Chicago
• Review article
• DOI: https://doi.org/10.1016/j.tcm.2023.01.008

Overview

ANGPTL3 is a liver-exclusive protein that inhibits lipoprotein lipase (raising TG) and endothelial lipase (raising HDL-C); loss-of-function variants cause familial combined hypolipidemia with pan-lipid lowering and robust protection against coronary artery disease. Genetic epidemiology studies including the DiscovEHR cohort (n=58,335) and MI Genetics Consortium (n=21,980 CAD cases) confirm ANGPTL3 LOF carriers have OR 0.59–0.66 for CAD. Pharmacological inhibition via evinacumab (anti-ANGPTL3 mAb) is FDA/EMA-approved for HoFH and achieves ~47–49% LDL-C and ~55% TG reduction through a mechanism independent of the LDL receptor. Antisense oligonucleotide therapy (vupanorsen) was discontinued due to dose-dependent hepatotoxicity; siRNA (ARO-ANG3) and CRISPR gene editing remain in active development, though no cardiovascular outcomes trial data yet exist.

Keywords

Genetics, Cholesterol, Triglycerides, Coronary artery disease, Monoclonal antibody, Antisense oligonucleotides, Vaccines

Key Takeaways

ANGPTL3 Biology and Function

• ANGPTL3 is a 460 amino acid hepatokine encoded on chromosome 1p31.1–p22.3; exclusively synthesised in the liver with expression regulated by LXR (oxysterol-responsive)
• Secreted protein undergoes O-glycosylation and furin-mediated cleavage in the linker region releasing an N-terminal coiled-coil domain and C-terminal fibrinogen-like domain; glycosylation adjacent to linker region inhibits cleavage
• The mature N-terminal fragment inhibits: (1) lipoprotein lipase (LPL) → elevated plasma TG; (2) endothelial lipase (EL) → reduced HDL phospholipid catabolism → elevated HDL-C
• ANGPTL8 forms a complex with ANGPTL3 that potentiates LPL inhibition; ANGPTL4 and ANGPTL8 regulate LPL only (not EL)
• ANGPTL3 promotes preferential TG uptake in white adipose tissue while suppressing TRL clearance in oxidative tissues (heart, skeletal muscle, brown adipose tissue)

Genetic Evidence of ANGPTL3 and Lipoprotein Metabolism

• Romeo et al. (Dallas Heart Study + ARIC replication; n=3,551): multiple nonsynonymous coding LOF variants in ANGPTL3 associated with low plasma TG independent of other metabolic phenotypes
• GWAS identified multiple polymorphisms near ANGPTL3 (rs1748195, rs12130333, rs2131925) associated with plasma TG
• Musunuru et al. 2010 (NEJM; landmark WES): family with two nonsense ANGPTL3 variants (E129X and S17X); heterozygotes — LDL-C 72 vs 109 mg/dL; TG 64 vs 130 mg/dL; compound heterozygotes — LDL-C 33 mg/dL, TG 21 mg/dL; confirmed autosomal dominant inheritance and gene dosage effect → named familial combined hypolipidemia
• Multiple subsequent studies confirmed ANGPTL3 LOF → pan-lipid lowering (LDL-C, TG, HDL-C all reduced)

ANGPTL3 and ASCVD Risk

• Minicocci et al.: homozygous ANGPTL3 LOF carriers — no history of cardiovascular disease (small cohort)
• DiscovEHR (n=58,335): 246 heterozygous ANGPTL3 LOF individuals (frequency 0.42%); LOF variants at lower frequency in CAD vs controls across 4 cohorts (n=23,317 CAD + 107,166 controls); OR 0.59 (P=0.004)
• Stitziel et al. / MI Genetics Consortium (n=21,980 CAD + 158,200 controls): ANGPTL3 LOF heterozygotes — lower TC, HDL-C, LDL-C, TG; decreased incident CAD OR 0.66 (P=0.04); 3 compound heterozygote family members had no coronary atherosclerosis on CT angiography
• Pakistan Risk of MI Study: lowest vs highest ANGPTL3 protein tertile → reduced incident MI; OR 0.65 (P<0.001)
• Cardioprotective mechanism independent of LDLR, as supported by evinacumab efficacy in null-null HoFH patients

Other Mechanisms

• ANGPTL3 LOF variants associated with increased insulin sensitivity and lower HOMA-IR (homozygous S17X carriers)
• However, vupanorsen (ASO) treatment for 6 months did NOT improve glycemic parameters or hepatic steatosis in patients with T2DM + hepatic steatosis + elevated TG — pharmacological inhibition ≠ genetic LOF in glycemia
• ANGPTL8 complex with ANGPTL3 increases potency of LPL inhibition; dual anti-ANGPTL3/8 antibody reduces TG in hypertriglyceridemic mice (early development)

Therapeutic Targeting — Monoclonal Antibodies

• Evinacumab (REGN1500): fully human anti-ANGPTL3 mAb from VelocImmune system (6 Mb murine immunoglobulin humanisation)
• Phase 1 single-dose (n=83; mild-moderate dyslipidemia): 20 mg/kg IV → 76% TG, 23% LDL-C, 18% HDL-C reduction; safe and well tolerated
• Phase 1 multiple ascending dose (n=56): 20 mg/kg IV → 88% TG, 25% LDL-C reduction; no dose-limiting toxicity
• Open-label proof-of-concept (n=9; HoFH; mean LDL-C 376±241 mg/dL): 4 weeks evinacumab → 49% LDL-C reduction; confirmed LDLR-independent mechanism
• Phase 2 refractory hypercholesterolemia (n=272; Rosenson): evinacumab 450 mg SC weekly → 56% LDL-C; 62% TG; 15 mg/kg IV → 50% LDL-C; no serious adverse events; LDLR-independent confirmed
• Phase 3 (Raal et al.; n=65; HoFH; 24 weeks; 15 mg/kg IV q4wk): LDL-C −47%, TG −55%; null-null LDLR −43.4% vs non-null −49.1% (placebo: +16.2% vs −3.8%); confirmed robust LDLR-independent effect
• FDA approved 2021 as adjunct therapy in HoFH (adults and children ≥12 years) on maximum tolerated LLT; IV 15 mg/kg q4wk
• EMA approved for identical indications in Europe

Therapeutic Targeting — ASO and siRNA

• IONIS ANGPTL3-LRx (Graham et al. Phase 1; n=44): GalNAc-ASO; single/multiple SC doses; multiple-dose achieved: LDL-C −33%, non-HDL-C −37%, VLDL-C −60%, TG −63%, ApoB −26%; no serious adverse events
• Vupanorsen (GalNAc-conjugated ASO; Pfizer/Ionis; Phase 2; n=105; T2DM + hepatic steatosis + TG ≥150): modest LDL-C reduction (7–12%); TG dose-dependent reduction; no improvement in glycemia or hepatic steatosis
• TRANSLATE-TIMI 70 (vupanorsen; n=286; 24 weeks): modest non-HDL-C and TG reduction BUT dose-dependent increases in liver fat and ALT/AST elevations → trial discontinued; raised concerns about upstream ANGPTL3 knockdown in liver vs downstream protein inhibition
• ARO-ANG3 (siRNA; Arrowhead Pharmaceuticals; Phase 1; n=30): −45% to −78% ANGPTL3 at 12 weeks; well tolerated; no adverse liver fat changes in steatotic subjects
• ARO-ANG3 ARCHES-2 (Phase 2; NCT05217667; n=180; HoFH; 16 weeks interim): dose-dependent ANGPTL3 reduction (50 mg: −15%, 100 mg: −71%, 200 mg: −67%); TG reduction (50 mg: −53%, 100 mg: −56%, 200 mg: −59%)

Therapeutic Targeting — Gene Editing

• BE3-Angptl3 (Chadwick et al.; pre-clinical mice): third-generation base editor + gRNA targeting murine Angptl3 Gln135; median editing rate 35%; no detectable off-target mutagenesis at 10 top predicted sites; −49% ANGPTL3, −31% TG, −19% LDL-C vs control
• Proof-of-concept for sustained ANGPTL3 reduction through base editing; preceded clinical-stage CTX310 and VERVE-201

Therapeutic Targeting — Vaccines

• VLP-based vaccine targeting ANGPTL3 aa32-47 (LPL-binding domain) in mice: robust TG clearance post-prandially; enhanced lipoprotein lipase activity
• 3 ANGPTL3 epitopes evaluated in ob/ob mice: significant TG, LDL-C, sd-LDL-C reduction; no major cytotoxic autoimmune responses; antibody production sustained 30 weeks; attenuated atherosclerosis in severe FH mouse model
• Human translation not yet established; vaccine approach theoretically advantageous (no repeated injections once immunized)

Limitations of the Document

• Review article — no original trial data; primarily synthesises existing published work
• Clinical trial data limited to short-term efficacy endpoints; no cardiovascular outcomes data for any ANGPTL3 inhibitor except HoFH (evinacumab approved on surrogate endpoint)
• Vupanorsen hepatotoxicity finding (TRANSLATE-TIMI 70) was cited as an emerging concern but causality assessment is incomplete
• Vaccine and gene-editing sections are early-stage animal/proof-of-concept data; not yet in human trials
• Small sample sizes in most HoFH trials (n=9–65)
• Cardioprotective mechanism (TG-lowering vs LDL-C-lowering vs LDLR-independent) remains incompletely characterised

Key Concepts Mentioned

• concepts/ANGPTL3-Inhibition — central subject of this review
• concepts/Familial-Hypercholesterolemia — HoFH as primary approved indication for evinacumab
• concepts/Dyslipidemia-Management — ANGPTL3 inhibition as emerging strategy for residual ASCVD risk
• concepts/Lipid-Gene-Therapy — BE3-Angptl3 base editing proof-of-concept predating CTX310
• concepts/Hypertriglyceridemia-Management — ANGPTL3 as pan-lipid target including TG

Key Entities Mentioned

• entities/Evinacumab — anti-ANGPTL3 mAb; FDA/EMA approved HoFH
• entities/Vupanorsen — GalNAc-ASO ANGPTL3 inhibitor; discontinued TRANSLATE-TIMI 70

Wiki Pages Updated

• Created wiki/sources/angptl3-inhibition-tcm-2024.md
• Created wiki/concepts/ANGPTL3-Inhibition.md
• Created wiki/entities/Evinacumab.md
• Updated wiki/concepts/Familial-Hypercholesterolemia.md
• Updated wiki/concepts/Lipid-Gene-Therapy.md
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md