R3i Editorial

Guidelines have long recognised that elevated triglycerides (TG) are a marker of cardiovascular risk ¹. Indeed, TG and TG-rich lipoproteins are among the atherogenic lipids and lipoproteins believed to be both causal and prognostic factors for atherosclerotic cardiovascular disease (ASCVD) ^2,3. To date, however, guideline groups provide ‘desirable TG levels’ rather than targets given limited definitive evidence from cardiovascular outcomes studies using conventional therapeutic approaches. Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA), has gained credence in the light of results from the landmark REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) study ⁴, supported by the older JELIS (Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study) ⁵. Guideline groups have now incorporated the results of REDUCE-IT in updated recommendations ^6-8. Yet it is also evident that TG-lowering alone does not explain the benefit observed in REDUCE-IT, engendering much ongoing debate.
New approaches are needed in the management of hypertriglyceridaemia. Mendelian randomization studies have been a crucial tool in the search for novel therapeutic targets. Findings have driven ongoing clinical development focused on two promising targets: apolipoprotein CIII (ApoCIII) and angiopoietin-like 3 (ANGPTL3) ^9-11. ApoCIII is a key regulator of TG-rich lipoprotein metabolism due to its inhibition of lipoprotein lipase and hepatic lipase, leading to decreased hepatic reuptake of TG-rich lipoproteins, as well as enhanced synthesis and secretion of very low-density lipoproteins (VLDL) from the liver. ANGPTL3 is exclusively expressed in the liver and inhibits TG hydrolysis by inhibiting lipoprotein lipase function. Experimental studies also provide evidence that intracellular ANGPTL3 has other potential nodes of action, including interfering with VLDL secretion, leading to a reduction in VLDL-TG ¹², although more research is needed to elucidate the intracellular function of ANGPTL3 and its impact on lipoprotein metabolism.

Several novel agents targeting these key targets are now in phase II/III trials. These include antisense oligonucleotides, gene silencing approaches, as well as monoclonal antibody therapy. At this year’s virtual European Society of Cardiology Congress, data were presented for two novel agents: ARO-ANG3, a small interfering RNA ^13,14, and vupanorsen, an N-acetyl galactosamine-conjugated ANGPTL3 antisense drug, the latter discussed in this month’s Focus ¹⁵. Both offer exciting promise in the search for new therapeutic approaches to targeting elevated TG.

Of course, the frontrunner in this field is pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα). There is good evidence that differentiates this agent from conventional fibrates (PPARα agonists), particularly with respect to its safety profile, specifically the lack of serum creatinine elevation, an issue for fenofibrate in routine clinical practice, particularly among patients with some degree of renal impairment ^16,17. The critical test is whether lowering TG with pemafibrate in high-risk statin-treated patients with hypertriglyceridaemia reduces cardiovascular events. For this we await the results of PROMINENT ¹⁸, which is crucial to answering outstanding questions regarding the role of TG-rich lipoproteins in residual cardiovascular risk.

References

1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292–2333.
2. Ganda OP, Bhatt DL, Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyderidemia management. J Am Coll Cardiol 2018;72:330–343.
3. Budoff M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am J Cardiol 2016;118:138–145.
4. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
5. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098.
6. Mach F, Baigent C Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Eur Heart J. 2020;41:111–188.
7. NLA position on the use of icosapent ethyl in high and very-high risk patients. Jacksonville, FL: National Lipid Association, 2019. https://www.lipid.org/nla/nla-position-use-icosapent-ethyl-high-and-very-high-risk-patients.
8. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: A science advisory from the American Heart Association. Circulation 2019;140:e673–e691.
9. JørgensenAB, Frikke-SchmidtR, NordestgaardBG, et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32–41.
10. TG and HDL Working Group of the Exome Sequencing Project NH, Lung, and Blood Institute Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22–31.
11. Stitziel NO, KheraAV, WangX, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054–2063.
12. Wang Y, Gusarova V, BanfiS, et al. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015;56:1296–1307.
13. Ballantyne C. RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency. ESC Congress Virtual Meeting 2020.
14. Watts G. RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia. ESC Congress Virtual Meeting 2020.
15. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ 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; doi:10.1093/eurheartj/ehaa689
16. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARα Modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep 2020;22¹:5.
17. Fruchart JC, Hermans MP, Fruchart-Najib J. Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα): new opportunities to reduce residual cardiovascular risk in chronic kidney disease? Curr Atheroscler Rep 2020;22⁸:43.
18. Pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) [NCT03071692] https://clinicaltrials.gov/ct2/show/NCT03071692