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Inhibition of Angiopoietin-Like Protein 3 or 3/8 Complex and ApoC-III in Severe Hypertriglyceridemia

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Abstract

Purpose of Review

The role of the inhibition of ANGPTL3 in severe or refractory hypercholesterolemia is well documented, less in severe hyperTG. This review focuses on the preclinical and clinical development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory forms of hypertriglyceridemia to prevent cardiovascular disease or other morbidities.

Recent Findings

APOC3 and ANGPTL3 became targets for drug development following the identification of naturally occurring loss of function variants in families with a favorable lipid profile and low cardiovascular risk. The inhibition of ANGPTL3 covers a broad spectrum of lipid disorders from severe hypercholesterolemia to severe hypertriglyceridemia, while the inhibition of ApoC-III can treat hypertriglyceridemia regardless of the severity.

Summary

Preclinical and clinical data suggest that ApoC-III inhibitors, ANGPTL3 inhibitors, and inhibitors of the ANGPTL3/8 complex that is formed postprandially are highly effective for the treatment of severe or refractory hypertriglyceridemia. Inhibition of ANGPTL3 or the ANGPTL3/8 complex upregulates LPL and facilitates the hydrolysis and clearance of triglyceride-rich lipoproteins (TRL) (LPL-dependent mechanisms), whereas ApoC-III inhibitors contribute to the management and clearance of TRL through both LPL-dependent and LPL-independent mechanisms making it possible to successfully lower TG in subjects completely lacking LPL (familial chylomicronemia syndrome). Most of these agents are biologicals including monoclonal antibodies (mAb), antisense nucleotides (ASO), small interfering RNA (siRNA), or CRISPR-cas gene editing strategies.

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Abbreviations

ANGPTL:

Angiopoietin-like protein

Apo:

Apolipoprotein

ASO:

Antisense oligonucleotide

CVD:

Cardiovascular disease

FCS:

Familial chylomicronemia syndrome

GalNAc:

N-acetylgalactosamine

GPIHBP1:

Glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1

HDL-C:

High-density lipoprotein-cholesterol

HoFH:

Homozygous familial hypercholesterolemia

HyperTG:

Hypertriglyceridemia

LDL-C:

Low-density lipoprotein-cholesterol

LDLR:

Low-density lipoprotein receptor

LMF1:

Lipase maturation factor 1

LoF:

Loss-of-function

LPL:

Lipoprotein lipase

mAb:

Monoclonal antibody

MCT:

Medium chain triglyceride

mRNA:

Messenger RNA

NAFLD:

Non-alcoholic fatty liver disease

PLC:

Platelet count

siRNA:

Small interfering RNA

SRB1:

Scavenger receptor class B member 1

TG:

Triglyceride

TRL:

Triglyceride-rich lipoprotein

VLDL:

Very low-density lipoprotein

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ginsberg HN, Packard CJ, Chapman MJ, Boren J, Aguilar-Salinas CA, Averna M, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J. 2021;42(47):4791–806. This expert consensus paper highlights the importance of TRL in cardiovascular risk management and facilitates the classification of hyperTG.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brunzell JD, Deeb SS. Familial lipoprotein lipase deficiency, Apo C-II deficiency, and hepatic lipase deficiency. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill Education; 2019.

  3. Olivecrona G. Role of lipoprotein lipase in lipid metabolism. Curr Opin Lipidol. 2016;27(3):233–41.

    Article  CAS  PubMed  Google Scholar 

  4. Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64(23):2525–40.

    Article  CAS  PubMed  Google Scholar 

  5. Gaudet D. 35 - Special Patient Populations: Treatment of Familial Chylomicronemia Syndrome and Sustained Chylomicronemia. In: Ballantyne CM, editor. Clinical Lipidology (Third Edition). New Delhi: Elsevier; 2024. p. 336–44.e2. In this textbook in clinical lipidology, recent data on hyperTG vs cardiovascular risk and emerging therapies are presented (chap 4, 27, 28, and 35 specifically.

  6. Brisson D, Larouche M, Chebli J, Khoury E, Gaudet D. Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity. Clin Biochem. 2023;114:67–72.

    Article  CAS  PubMed  Google Scholar 

  7. Moulin P, Dufour R, Averna M, Arca M, Cefalu AB, Noto D, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an “FCS score.” Atherosclerosis. 2018;275:265–72. This is the first clinical diagnosis scoring system presented to distinguish between FCS and multifactorial chylomicronemia.

    Article  CAS  PubMed  Google Scholar 

  8. Berberich AJ, Hegele RA. A modern approach to dyslipidemia. Endocr Rev. 2022;43(4):611–53.

    Article  PubMed  Google Scholar 

  9. De Villers-Lacasse A, PaqueAe M, Baass A, Bernard S. Non-alcoholic faAy liver disease in patients with chylomicronemia syndromes. J Clin Lipidol. 2023;17(4):475–82.

    Article  PubMed  Google Scholar 

  10. Paquette M, Bernard S. The evolving story of multifactorial chylomicronemia syndrome. Front Cardiovasc Med. 2022;9:886266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brahm AJ, Hegele RA. Chylomicronaemia—current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352–62.

    Article  CAS  PubMed  Google Scholar 

  12. Williams L, Rhodes KS, Karmally W, Welstead LA, Alexander L, Sutton L, et al. Familial chylomicronemia syndrome: bringing to life dietary recommendations throughout the life span. J Clin Lipidol. 2018;12(4):908–19.

    Article  PubMed  Google Scholar 

  13. Wu SA, Kersten S, Qi L. Lipoprotein lipase and its regulators: an unfolding story. Trends Endocrinol Metab. 2021;32(1):48–61.

    Article  CAS  PubMed  Google Scholar 

  14. Dallinga-Thie GM, Kroon J, Boren J, Chapman MJ. Triglyceride-rich lipoproteins and remnants: targets for therapy? Curr Cardiol Rep. 2016;18(7):67.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sylvers-Davie KL, Davies BSJ. Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8. Am J Physiol Endocrinol Metab. 2021;321(4):E493–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Conklin D, Gilbertson D, Taft DW, Maurer MF, Whitmore TE, Smith DL, et al. Identification of a mammalian angiopoietin-related protein expressed specifically in liver. Genomics. 1999;62(3):477–82.

    Article  CAS  PubMed  Google Scholar 

  17. Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, et al. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002;30(2):151–7.

    Article  CAS  PubMed  Google Scholar 

  18. Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH, et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009;119(1):70–9.

    CAS  PubMed  Google Scholar 

  19. Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363(23):2220–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martin-Campos JM, Roig R, Mayoral C, Martinez S, Marti G, Arroyo JA, et al. Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation. Clin Chim Acta. 2012;413(5–6):552–5.

    Article  CAS  PubMed  Google Scholar 

  21. Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G, et al. Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. J Clin Endocrinol Metab. 2012;97(7):E1266–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gusarova V, Alexa CA, Wang Y, Rafique A, Kim JH, Buckler D, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56(7):1308–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res. 2015;56(7):1296–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, et al. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377(3):222–32.

    Article  CAS  PubMed  Google Scholar 

  25. Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377(3):211–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu YX, Redon V, Yu H, Querbes W, Pirruccello J, Liebow A, et al. Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol. Atherosclerosis. 2018;268:196–206.

    Article  CAS  PubMed  Google Scholar 

  27. Wang J, Zheng W, Zheng S, Yuan Y, Wen W, Cui W, et al. Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys. Mol Ther Nucleic Acids. 2023;31:68–77.

    Article  CAS  PubMed  Google Scholar 

  28. Chadwick AC, Evitt NH, Lv W, Musunuru K. Reduced blood lipid levels with in vivo CRISPR-Cas9 base editing of ANGPTL3. Circulation. 2018;137(9):975–7.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Qiu M, Glass Z, Chen J, Haas M, Jin X, Zhao X, et al. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proc Natl Acad Sci U S A. 2021;118(10):e2020401118.

  30. Adam RC, Mintah IJ, Alexa-Braun CA, Shihanian LM, Lee JS, Banerjee P, et al. Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. J Lipid Res. 2020;61(9):1271–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012;424(4):786–92.

    Article  CAS  PubMed  Google Scholar 

  32. Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci U S A. 2012;109(48):19751–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Haller JF, Mintah IJ, Shihanian LM, Stevis P, Buckler D, Alexa-Braun CA, et al. ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. J Lipid Res. 2017;58(6):1166–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, et al. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci U S A. 2013;110(40):16109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Izumi R, Kusakabe T, Noguchi M, Iwakura H, Tanaka T, Miyazawa T, et al. CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats. J Lipid Res. 2018;59(9):1575–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Balasubramaniam D, Schroeder O, Russell AM, Fitchett JR, Austin AK, Beyer TP, et al. An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif. J Lipid Res. 2022;63(5):100198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Romeo S, Pennacchio LA, Fu Y, Boerwinkle E, Tybjaerg-Hansen A, Hobbs HH, et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet. 2007;39(4):513–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Talmud PJ, Smart M, Presswood E, Cooper JA, Nicaud V, Drenos F, et al. ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk. Arterioscler Thromb Vasc Biol. 2008;28(12):2319–25.

    Article  CAS  PubMed  Google Scholar 

  39. Dewey FE, Gusarova V, O’Dushlaine C, Gottesman O, Trejos J, Hunt C, et al. Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease. N Engl J Med. 2016;374(12):1123–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Desai U, Lee EC, Chung K, Gao C, Gay J, Key B, et al. Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc Natl Acad Sci U S A. 2007;104(28):11766–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Deng M, Kutrolli E, Sadewasser A, Michel S, Joibari MM, Jaschinski F, et al. ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy. J Lipid Res. 2022;63(7):100237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020;383(8):711–20.

    Article  CAS  PubMed  Google Scholar 

  43. Banerjee P, Chan KC, Tarabocchia M, Benito-Vicente A, Alves AC, Uribe KB, et al. Functional analysis of LDLR (low-density lipoprotein receptor) variants in patient lymphocytes to assess the effect of Evinacumab in homozygous familial hypercholesterolemia patients with a spectrum of LDLR activity. Arterioscler Thromb Vasc Biol. 2019;39(11):2248–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rosenson RS, Burgess LJ, Ebenbichler CF, Baum SJ, Stroes ESG, Ali S, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med. 2020;383(24):2307–19.

    Article  CAS  PubMed  Google Scholar 

  45. Ahmad Z, Pordy R, Rader DJ, Gaudet D, Ali S, Gonzaga-Jauregui C, et al. Inhibition of angiopoietin-like protein 3 with Evinacumab in subjects with high and severe hypertriglyceridemia. J Am Coll Cardiol. 2021;78(2):193–5.

    Article  CAS  PubMed  Google Scholar 

  46. Ahmad Z, Banerjee P, Hamon S, Chan K-C, Bouzelmat A, Sasiela WJ, et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation. 2019;140(6):470–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rosenson RS, Gaudet D, Ballantyne CM, Baum SJ, Bergeron J, Kershaw EE, et al. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial. Nat Med. 2023;29(3):729–37. This publication demonstrates clearly that patients completely lacking LPL (FCS) do not respond to ANGPTL3 inhibition treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, Hurh E, Kingsbury J, Bartlett VJ, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J. 2020;41(40):3936–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bergmark BA, Marston NA, Bramson CR, Curto M, Ramos V, Jevne A, et al. Effect of Vupanorsen on non-high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol: TRANSLATE-TIMI 70. Circulation. 2022;145(18):1377–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Burks KH, Basu D, Goldberg IJ, Stitziel NO. Angiopoietin-like 3: An important protein in regulating lipoprotein levels. Best Pract Res Clin Endocrinol Metab. 2023;37(3):101688.

    Article  CAS  PubMed  Google Scholar 

  51. WaAs GF, Schwabe C, ScoA R, Gladding PA, Sullivan D, Baker J, et al. RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nat Med. 2023;29(9):2216–23.

  52. Gaudet D, Gonciarz M, Shen X, Mullins G, Leohr JK, Benichou O, et al. A first-in-human single ascending dose study of a monoclonal antibody against the ANGPTL3/8 complex in subjects with mixed hyperlipidemia. Atherosclerosis. 2022;355:12.

  53. Kawakami A, Aikawa M, Libby P, Alcaide P, Luscinskas FW, Sacks FM. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation. 2006;113(5):691–700.

    Article  CAS  PubMed  Google Scholar 

  54. Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci. 2015;36(10):675–87.

    Article  CAS  PubMed  Google Scholar 

  55. Yao Z, Wang Y. Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production. Curr Opin Lipidol. 2012;23(3):206–12.

    Article  CAS  PubMed  Google Scholar 

  56. Taskinen MR, Packard CJ, Boren J. Emerging evidence that ApoC-III inhibitors provide novel options to reduce the residual CVD. Curr Atheroscler Rep. 2019;21(8):27.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Tg, Hdl Working Group of the Exome Sequencing Project NHL, Blood I, Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22–31.

    Article  Google Scholar 

  58. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322(5908):1702–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res. 2011;52(2):189–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Maeda N, Li H, Lee D, Oliver P, Quarfordt SH, Osada J. Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J Biol Chem. 1994;269(38):23610–6.

    Article  CAS  PubMed  Google Scholar 

  61. Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112(11):1479–90.

    Article  CAS  PubMed  Google Scholar 

  62. Wong SC, Li Z, Given B, Seefeld M, Andersen A, Zhu R, et al. Personalized medicine for dyslipidemias by RNA interference-mediated reductions in apolipoprotein C3 or angiopoietin-like protein 3. J Clin Lipidol. 2019;13(3):e15.

    Article  Google Scholar 

  63. Butler AA, Price CA, Graham JL, Stanhope KL, King S, Hung YH, et al. Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference. J Lipid Res. 2019;60(4):805–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Alexander V, Gaudet D, Cheng W, Flaim J, Hughes S, Singleton W, et al. An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, very-low-density lipoprotein cholesterol and particle number, and increases high-density lipoprotein cholesterol and particle number in hypertriglyceridemic patients on a fibrate. J Am Coll Cardiol. 2014;63(12_Supplement):A1453-A.

    Article  Google Scholar 

  65. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200–6.

    Article  PubMed  Google Scholar 

  66. Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373(5):438–47.

    Article  CAS  PubMed  Google Scholar 

  67. Oral EA, Garg A, Tami J, Huang EA, O’Dea LSL, Schmidt H, et al. Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study. J Clin Lipidol. 2022;16(6):833–49.

    Article  PubMed  Google Scholar 

  68. Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021;9(5):264–75. Results of this study highlighted that ApoC-III inhibition importantly decreases TG levels in a large spectrum of hyperTG phenotypes.

    Article  CAS  PubMed  Google Scholar 

  69. Larouche M, Brisson D, Morissette MC, Gaudet D. Post-prandial analysis of fluctuations in the platelet count and platelet function in patients with the familial chylomicronemia syndrome. Orphanet J Rare Dis. 2023;18(1):167.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Gaudet D, Clifton P, Sullivan D, Baker J, Schwabe C, Thackwray S, et al. RNA interference therapy targeting apolipoprotein C-III in hypertriglyceridemia. NEJM Evid. 2023;0(0):EVIDoa2200325.

    Google Scholar 

  71. Fan W, Philip S, Granowitz C, Toth PP, Wong ND. Prevalence of US Adults with Triglycerides >/= 150 mg/dl: NHANES 2007–2014. Cardiol Ther. 2020;9(1):207–13.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Ruiz-Garcia A, Arranz-Martinez E, Lopez-Uriarte B, Rivera-Teijido M, Palacios-Martinez D, Davila-Blazquez GM, et al. Prevalence of hypertriglyceridemia in adults and related cardiometabolic factors. SIMETAP-HTG study. Clin Investig Arterioscler. 2020;32(6):242–55.

    PubMed  Google Scholar 

  73. Larouche M, Pordy R, Banerjee P, Gaudet D. Clinical trial with the ANGPTL3 monoclonal antibody evinacumab identifies a new rare chylomicronemia causing variant in the LPL gene. Canadian Journal of Cardiology. 2023;39(10):S183.

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  1. Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada

    Miriam Larouche, Etienne Khoury, Diane Brisson & Daniel Gaudet

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  1. Miriam Larouche
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DG Employer: Université de Montréal; Consultation fees: Amryt (Chiesi), Arrowhead, CRISPR Therapeutics, Eli Lilly, Ionis, Pfizer, Regeneron; Trust research/joint research funds (trials): Arrowhead, Eli Lilly, Ionis, Kowa, Pfizer, Regeneron. ML, EK, and DB have nothing to disclose.

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Larouche, M., Khoury, E., Brisson, D. et al. Inhibition of Angiopoietin-Like Protein 3 or 3/8 Complex and ApoC-III in Severe Hypertriglyceridemia. Curr Atheroscler Rep 25, 1101–1111 (2023). https://doi.org/10.1007/s11883-023-01179-y

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