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Current opinion in endocrinology, diabetes, and obesity
Feb 28, 2025;

Targeting apolipoprotein C-III: a game changer for pancreatitis prevention in severe hypertriglyceridemia.

Bram M Weijs, Reindert F Oostveen, Jordan M Kraaijenhof, Erik S G Stroes
Author Information
  1. Bram M Weijs: Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
PMID: 40012530 DOI: 10.1097/MED.0000000000000906

Abstract

PURPOSE OF REVIEW: The aim of this review is to examine recent advancements in RNA-targeted therapies for the management of severe hypertriglyceridemia (sHTG) and prevention of sHTG-associated acute pancreatitis.
RECENT FINDINGS: Recent developments in RNA-targeted therapies, aimed at inhibiting apolipoprotein C-III (apoC-III), have demonstrated substantial and sustained reductions in triglyceride levels. Novel therapies, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), such as volanesorsen, olezarsen, and plozasiran, have shown promising results in recent trials. These therapies not only effectively lower plasma triglyceride levels but also significantly reduce the incidence of acute pancreatitis.
SUMMARY: SHTG is a high-burden metabolic disorder that is associated with a significantly increased incidence and severity of acute pancreatitis. Traditional lifestyle interventions and conventional therapies, including fibrates and n-3 fatty acids, often provide only modest reductions in triglycerides and fail to prevent sHTG-associated acute pancreatitis. The emergence of novel and targeted RNA-therapies represents a potential breakthrough in the management of sHTG and acute pancreatitis prevention.

References

  1. Li C li, Jiang M, Pan C qiu, et al. The global, regional, and national burden of acute pancreatitis in 204 countries and territories. BMC Gastroenterol 2021; 21:332.
  2. Roberts SE, Morrison-Rees S, John A, et al. The incidence and aetiology of acute pancreatitis across Europe. Pancreatology 2017; 17:155–165.
  3. Jin M, Bai X, Chen X, et al. A 16-year trend of etiology in acute pancreatitis: the increasing proportion of hypertriglyceridemia-associated acute pancreatitis and its adverse effect on prognosis. J Clin Lipidol 2019; 13:947–953.e1.
  4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41:111–188.
  5. Lindkvist B, Appelros S, Regnér S, Manjer J. A prospective cohort study on risk of acute pancreatitis related to serum triglycerides, cholesterol and fasting glucose. Pancreatology 2012; 12:317–324.
  6. Valdivielso P, Ramírez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med 2014; 25:689–694.
  7. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. Can Med Assoc J 2007; 176:1113–1120.
  8. Investigators AIM-HIGH, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255–2267.
  9. HPS2-THRIVE Collaborative Group HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, prespecified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34:1279–1291.
  10. Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019; 381:531–542.
  11. Gouni-Berthold I, Alexander VJ, Yang Q, 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; 9:264–275.
  12. Alexander VJ, Karwatowska-Prokopczuk E, Prohaska TA, et al. Volanesorsen to prevent acute pancreatitis in hypertriglyceridemia. N Engl J Med 2024; 390:476–477.
  13. Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med 2024; 390:1781–1792.
  14. Watts GF, Rosenson RS, Hegele RA, et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. N Engl J Med 2024; 392:127–137.
  15. Rosenson RS, Gaudet D, Hegele RA, et al. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia. N Engl J Med 2024; 391:913–925.
  16. Rosenson RS, Gaudet D, Ballantyne CM, et al. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial. Nat Med 2023; 29:729–737.
  17. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014; 2:655–666.
  18. Hansen SEJ, Madsen CM, Varbo A, Nordestgaard BG. Low-grade inflammation in the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis: a study of more than 115000 individuals from the general population. Clin Chem 2019; 65:321–332.
  19. Toth PP, Fazio S, Wong ND, et al. Risk of cardiovascular events in patients with hypertriglyceridaemia: a review of real-world evidence. Diabetes Obes Metab 2019; 22:279–289.
  20. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014; 384:626–635.
  21. Retterstøl K, Narverud I, Selmer R, et al. Severe hypertriglyceridemia in Norway: prevalence, clinical and genetic characteristics. Lipids Health Dis 2017; 16:115.
  22. Paquette M, Bernard S. The evolving story of multifactorial chylomicronemia syndrome. Front Cardiovasc Med 2022; 9:886266.
  23. Paragh G, Németh Á, Harangi M, et al. Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia. Lipids Health Dis 2022; 21:21.
  24. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res 2011; 52:189–206.
  25. Murphy MJ, Sheng X, MacDonald TM, Wei L. Hypertriglyceridemia and acute pancreatitis. JAMA Intern Med 2013; 173:162–164.
  26. Balasubramanian S, Aggarwal P, Sharma S. Lipoprotein lipase deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2 December 2024]. http://www.ncbi.nlm.nih.gov/books/NBK560795/
  27. Gaudet D, De Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler Suppl 2010; 11:55–60.
  28. Adiamah A, Psaltis E, Crook M, Lobo DN. A systematic review of the epidemiology, pathophysiology and current management of hyperlipidaemic pancreatitis. Clin Nutr 2018; 37:1810–1822.
  29. Stefanutti C, Labbadia G, Morozzi C. Severe hypertriglyceridemia-related acute pancreatitis. Ther Apher Dial 2013; 17:130–137.
  30. Zeng Y, Wang X, Zhang W, et al. Hypertriglyceridemia aggravates ER stress and pathogenesis of acute pancreatitis. Hepatogastroenterology 2012; 59:2318–2326.
  31. Chan DC, Pang J, Romic G, Watts GF. Postprandial hypertriglyceridemia and cardiovascular disease: current and future therapies. Curr Atheroscler Rep 2013; 15:309.
  32. Carrasquilla GD, Christiansen MR, Kilpeläinen TO. The genetic basis of hypertriglyceridemia. Curr Atheroscler Rep 2021; 23:39.
  33. Paquette M, Amyot J, Fantino M, et al. Rare variants in triglycerides-related genes increase pancreatitis risk in multifactorial chylomicronemia syndrome. J Clin Endocrinol Metab 2021; 106:e3473–e3482.
  34. Szatmary P, Grammatikopoulos T, Cai W, et al. Acute pancreatitis: diagnosis and treatment. Drugs 2022; 82:1251–1276.
  35. Garg R, Rustagi T. Management of hypertriglyceridemia induced acute pancreatitis. BioMed Res Int 2018; 2018:4721357.
  36. Yang AL, McNabb-Baltar J. Hypertriglyceridemia and acute pancreatitis. Pancreatology 2020; 20:795–800.
  37. Rafiullah M, Musambil M, David SK. Effect of a very low-carbohydrate ketogenic diet vs recommended diets in patients with type 2 diabetes: a meta-analysis. Nutr Rev 2022; 80:488–502.
  38. Gouni-Berthold I, Schwarz J, Berthold HK. Updates in drug treatment of severe hypertriglyceridemia. Curr Atheroscler Rep 2023; 25:701–709.
  39. Gaudet D, Méthot J, Kastelein J. Gene therapy for lipoprotein lipase deficiency. Curr Opin Lipidol 2012; 23:310–320.
  40. Puri S, Mazza M, Roy G, et al. Evolution of nanomedicine formulations for targeted delivery and controlled release. Adv Drug Deliv Rev 2023; 200:114962.
  41. Senior M. After Glybera's withdrawal, what's next for gene therapy? Nat Biotechnol 2017; 35:491–492.
  42. Gaudet D, Stroes ES, Méthot J, et al. Long-term retrospective analysis of gene therapy with alipogene tiparvovec and its effect on lipoprotein lipase deficiency-induced pancreatitis. Hum Gene Ther 2016; 27:916–925.
  43. Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab 2018; 27:714–739.
  44. Shah M, Sharma A, Ayyad M, et al. Targeting apolipoprotein CIII for the management of severe hypertriglyceridemia: current research and future directions. Cureus 2024; 16:e67091.
  45. Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation 2010; 121:1722–1734.
  46. Tsimikas S, Ginsberg HN, Alexander VJ, et al. Differential effects of volanesorsen on apoC-III, triglycerides and pancreatitis in familial chylomicronemia syndrome diagnosed by genetic or nongenetic criteria. J Clin Lipidol 2024; S1933-2874:00299-X.
  47. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377:211–221.
  48. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014; 371:2200–2206.
Journal Article

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Created with Highcharts 10.0.0pancreatitistherapiesacutepreventionrecentRNA-targetedmanagementseverehypertriglyceridemiasHTGsHTG-associatedapolipoproteinreductionstriglyceridelevelsincludingsignificantlyincidencePURPOSEOFREVIEW:aimreviewexamineadvancementsRECENTFINDINGS:RecentdevelopmentsaimedinhibitingC-IIIapoC-IIIdemonstratedsubstantialsustainedNovelantisenseoligonucleotidesASOssmallinterferingRNAsiRNAvolanesorsenolezarsenplozasiranshownpromisingresultstrialseffectivelylowerplasmaalsoreduceSUMMARY:SHTGhigh-burdenmetabolicdisorderassociatedincreasedseverityTraditionallifestyleinterventionsconventionalfibratesn-3fattyacidsoftenprovidemodesttriglyceridesfailpreventemergencenoveltargetedRNA-therapiesrepresentspotentialbreakthroughTargetingC-III:gamechanger

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