News in the treatment of dyslipidaemia

Česká verzia

Authors: Vrablík M.
Authors place of work: Centrum preventivní kardiologie, III. interní klinika 1. LF UK a VFN v Praze
Published in the journal: Kardiol Rev Int Med 2019, 21(4): 189-193

Summary

Lipid-lowering treatment is a part of the prevention and treatment of vascular diseases caused by atherosclerosis. We need new strategies for modifying plasma lipoprotein levels in light of new findings that reduce target lipid levels even further, as well as the growing population of patients for whom existing  treatments cannot be offered. The spectrum of existing drugs (new statins) is widening; pharmacological treatments (recombinant lipoprotein-bound statins) and improved forms of established drugs (selective PPARalpha receptor modulators) are coming. The new procedures include fixed combinations of established drugs improving adherence and intensifying the lipid-modifying effects (statin + ezetimibe). The portfolio of lipid-lowering therapies today also includes monoclonal antibodies against PCSK9 (PCSK9 inhibitors). The main direction of future development is biotechnology using the principle of antisense therapy, i.e. the use of specific oligonucleotide sequences blocking the translation of the selected protein. These targeted therapies targeting, for example, apolipoprotein B, apolipoprotein CIII or lipoprotein (a) are in various stages of clinical trials. A similar (but not identical) principle is the use of RNA silencing - interference with gene expression using short stretches of double-stranded RNA (e.g. inclisiran siRNA against PCSK9). Innovations in the field of hypolipidaemic pharmacotherapy in our country may also include inhibitors of microsomal triglyceride transfer protein (approved for use in homozygotes for familial hypercholesterolaemia and experimentally also for familial chylomicronaemia). The small molecule ATP citrate lyase inhibitor, bempedoic acid, decreases LDL-C by a further 20% over and above the reduction achievable by a statin. All these new directions must be directed toward the common main goal of reducing the incidence of cardiovascular and gastrointestinal complications of dyslipidaemia. Clinical research also aims to prove these effects.

Keywords:

combination therapy – PCSK9 inhibitors – new lipid lowering drugs – bempedoic acid – antisense therapy

Zdroje

1. Mach F, Baigent C, Catapano AL et al. ESC Scientific Document Group. 2019 ESC/ EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019; pii: ehz455. doi: 10.1093/ eurheartj/ ehz455.

2. Vrablík M, Piťha J, Bláha V et al. Stanovisko výboru České společnosti pro aterosklerózu k doporučením ESC/ EAS pro diagnostiku a léčbu dyslipidemií z roku 2019. AtheroRev 2019; 4(3): 126– 137.

3. Hoy SM. Pitavastatin: a review in hypercholesterolemia. Am J Cardiovasc Drugs 2017; 17(2): 157– 168. doi: 10.1007/ s40256-017-0213-8.

4. Vallejo-Vaz AJ, Kondapally Seshasai SR, Kurogi Ket al. Effect of pitavastatin on glucose, HbA1c and incident diabetes: A meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis 2015; 241(2): 409– 418. doi: 10.1016/ j.atherosclerosis.2015.06.001.

5. Widimský J et al. Doporučení pro diagnostiku a léčbu arteriální hypertenze ČSH 2017. Hypertenze a KV prevence 2018, 7 (Suppl): 1– 20.

6. Cuchel M, Meagher EA, du Toit Theron H et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open- label, phase 3 study. Lancet 2013; 381(9860): 40– 46. doi: 10.1016/ S0140-6736(12)61731-0.

7. Alonso R, Cuevas A, Mata P. Lomitapide: a review of its clinical use, efficacy, and tolerability. Core Evid 2019; 14: 19– 30. doi: 10.2147/ CE.S174169.

8. Fruchart JC, Santos RD, Aguilar-Salinas C et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol 2019; 18(1): 71. doi: 10.1186/ s12933-019-0864-7.

9. Ishibashi S, Arai H, Yokote K et al. K-877 Study Group. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: Results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol 2018; 12(1): 173– 184. doi: 10.1016/ j.jacl.2017.10.006.

10. 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(1): 11– 22. doi: 10.1056/ NEJMoa1812792.

11. Nicholls SJ, Lincoff AM, Bash D et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels’of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin Cardiol 2018; 41(10): 1281– 1288. doi: 10.1002/ clc.23055.

12. Bilen O, Ballantyne CM. Bempedoic Acid (ETC--1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep 2016; 18(10): 61. doi: 10.1007/ s11883-016-0611-4.

13. Laufs U, Banach M, Mancini GB. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 2019; 8(7): e011662. doi: 10.1161/ JAHA.118.011662.

14. Khan SU, Michos ED. Bempedoic acid and ezetimibe – better together. Eur J Prev Cardiol 2019: 2047487319864672. doi: 10.1177/ 20474873 19864672.

15. Češka R, Táborský M, Vrablík M. Společné stanovisko odborných společností k preskripci PCSK9 inhibitorů. Vnitr Lek 2019; 64(12): 1131– 1136.

16. Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372(16): 1500– 1509. doi: 10.1056/ NEJMoa1500858.

17. Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379(22): 2097– 2107. doi: 10.1056/ NEJMoa1801174.

18. Stitziel NO, Khera AV, Wang X et al. PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017; 69(16): 2054– 2063. doi: 10.1016/ j.jacc.2017.02.030.

19. Prnewswire.com. Regeneron announces positive topline results from phase 3 trial of evinacumab in patients with severe, inherited form of high cholesterol. Available at: https:/ / www.prnewswire.com/ news-releases/ regeneron-announces-positive-topline-results-from-phase-3-trial-of-evinacumab-in-patients-with-severe-inherited-form-of-high-cholesterol-300901035.html.

20. Yamamoto T, Wada F, Harada-Shiba M. Development of antisense drugs for dyslipidemia. J Atheroscler Thromb 2016; 23(9): 1011– 1025. doi: 10.5551/ jat.RV16001.

21. Ricotta DN, Frishman W. Mipomersen: a safe and effective antisense therapy adjunct to statins in patients with hypercholesterolemia. Cardiol Rev 2012; 20(2): 90– 95. doi: 10.1097/ CRD.0b013e31823424be.

22. Viney NJ, van Capelleveen JC, Geary RS et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 388(10057): 2239– 2253. doi: 10.1016/ S0140-6736(16)31009-1.

23. Warden BA, Duell PB. Volanesorsen for treatment of patients with familial chylomicronemia syndrome. Drugs Today (Barc) 2018; 54(12): 721– 735. doi: 10.1358/ dot.2018.54.12.2899384.

24. Dewey FE, Gusarova V, Dunbar et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377(3): 211– 221. doi: 10.1056/ NEJMoa1612790.

25. Ray KK, Landmesser U, Leiter LA et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017; 376(15): 1430– 1440. doi: 10.1056/ NEJMoa1615758.