Current and future trends in the treatment of dyslipidemias

Czech version

Authors: Michal Vrablík
Authors‘ workplace: Centrum preventivní kardiologie III. interní kliniky 1. LF UK a VFN v Praze
Published in: Vnitř Lék 2019; 65(10): 643-650
Category:

Overview

Lipid-lowering treatment is a part of prevention and treatment of vascular diseases caused by atherosclerosis. We need new strategies for modifying plasma lipoprotein levels in the light of new findings that reduce target lipid levels further lower, 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 lipoproteins-bound statins), improved forms of established drugs (selective PPARα receptor modulators) are coming. The new procedures include fixed combinations of established drugs improving adherence and intensifying 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 so-called antisense therapy, i.e. the use of specific oligonucleotide sequences blocking the translation of the selected protein. These novel 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 sequences of double-stranded RNA (e.g. inclisiran siRNA against PCSK9). Innovations in the field of hypolipidemic pharmacotherapy in our country may also be inhibitors of microsomal triglyceride transfer protein (approved for use in homozygotes for familial hypercholesterolemia and experimentally also for familial chylomicronemia). 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. In a broader sense, the novelty of hypolipidemic pharmacotherapy includes treatment options for some rare metabolic diseases (eg. enzyme replacement therapy for acid lysosomal lipase deficiency) manifested by lipoprotein metabolism abnormalities. All these new directions must aim at the common main goal of reducing the incidence of cardiovascular and gastrointestinal complications of dyslipidemia. Clinical research also aims to prove these effects.

Keywords:

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

Sources

Borén J, Williams KJ. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol 2016; 27(5): 473–483. Dostupné z DOI: <http://doi: 10.1097/MOL.0000000000000330>.
Hoy SM. Pitavastatin: A Review in Hypercholesterolemia. Am J Cardiovasc Drugs 2017; 17(2): 157–168. Dostupné z DOI: <http://doi: 10.1007/s40256–017–0213–8>.
Vallejo-Vaz AJ, Kondapally Seshasai SR, Kurogi K et 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. Dostupné z DOI: <http://doi: 10.1016/j.atherosclerosis.2015.06.001>.
Zhang X, Huang G. Synthetic lipoprotein as nano-material vehicle in the targeted drug delivery. Drug Deliv 2017; 24(Supl 1): 16–21. Dostupné z DOI: <http://doi: 10.1080/10717544.2017.1384518>.
Widimský J et al. Doporučení pro diagnostiku a léčbu arteriální hypertenze ČSH 2017. Hypertenze a KV prevence 2018; 7(Suppl 1): 1–20. Dostupné z WWW: <http://www.hypertension.cz/sqlcache/widimsky-1-hypertenze-kv-prevence-2018.pdf>.
Bohula EA, Morrow DA, Giugliano RP et al. Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention. J Am Coll Cardiol 2017; 69(8): 911–921. Dostupné z DOI: <http://doi: 10.1016/j.jacc.2016.11.070>.
Šatný M, Vrablík. Desatero použití ezetimibu aneb stručný průvodce jeho použitím v současnosti. AtheroRev 2019; 4(3): 161–165.
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. Dostupné z DOI: <http://doi: 10.1186/s12933–019–0864–7>.
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. Dostupné z DOI: <http://doi: 10.1016/j.jacl.2017.10.006>.
Češka R, Táborský M, Vrablík M. Společné stanovisko odborných společností k preskripci PCSK9 inhibitorů. Vnitř Lék 2019; 64(12): 1131–1136.
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: 1500–1509. Dostupné z DOI: <http://doi: 10.1056/NEJMoa1500858>.
Schwartz GG, Steg PG, Szarek M et al. [ODYSSEY OUTCOMES Committees and Investigators]. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018; 379(22): 2097–2107. Dostupné z DOI: <http://doi: 10.1056/NEJMoa1801174>.
Vrablík M, Prusíková M, Šnejdrlová M et al. Omega-3 fatty acids and cardiovascular disease risk: do we understand the relationship? Physiol Res 2009; 58(Suppl 1): S19-S26.
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. Dostupné z DOI: <http://doi: 10.1056/NEJMoa1812792>.
Catapano AL, Graham I, De Backer G et al. [ESC Scientific Document Group]. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016; 37(39): 2999–3058. Dostupné z DOI: <http://doi: 10.1093/eurheartj/ehw272>.
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. Dostupné z DOI: <http://doi: 10.1002/clc.23055>.
Yamamoto T, Wada F, Harada-Shiba M. Development of Antisense Drugs for Dyslipidemia. J Atheroscler Thromb 2016; 23(9): 1011–1025. Dostupné z DOI: <http://doi: 10.5551/jat.RV16001>.
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. Dostupné z DOI: <http://doi: 10.1097/CRD.0b013e31823424be>.
Vogt A. Lipoprotein(a)-antisense therapy. Clin Res Cardiol Suppl 2019; 14(Suppl- 1): 51–56. Dostupné z DOI: <http://doi: 10.1007/s11789–019–00096–2>.
Warden BA, Duell PB. Volanesorsen for treatment of patients with familial chylomicronemia syndrome. Drugs Today (Barc) 2018; 54(12): 721–735. Dostupné z DOI: <http://doi: 10.1358/dot.2018.54.12.2899384>.
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. Dostupné z DOI: <http://doi: 10.1056/NEJMoa1615758>.
Reiner Ž, Guardamagna O, Nair D et al. Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 2014; 235: 21–30. . Dostupné z DOI: <http://doi: 10.1016/j.atherosclerosis.2014.04.003>.
Shamburek RD, Bakker-Arkema R, Shamburek AM et al. Safety and Tolerability of ACP-501, a Recombinant Human Lecithin: Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study. Circ Res 2016; 118(1): 73–82. Dostupné z DOI: <http://doi: 10.1161/CIRCRESAHA.115.306223>.
Gaich G, Chien JY, Hu F et al. The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes. Cell Metabolism 2013; 18(3): 333–340. Dostupné z DOI: <http://doi: 10.1016/j.cmet.2013.08.005>.
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): 40–44. Dostupné z DOI: <http://doi: 10.1016/S0140–6736(12)61731–0>.
Alonso R, Cuevas A, Mata P. Lomitapide: a review of its clinical use, efficacy, and tolerability. Core Evid 2019; 14: 19–30. Dostupné z DOI: <http://doi: 10.2147/CE.S174169>.
Bilen O, Ballantyne CM. Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep 2016; 18(10): 61. Dostupné z DOI: <http://doi: 10.1007/s11883–016–0611–4>.
Laufs U, Banach M, Mancini GBJ. Efficacy and Safety of Bempedoic Acid in Patients with Hypercholesterolemia and Statin Intolerance. J Am Heart Assoc 2019; 8(7): e011662. Dostupné z DOI: <http://doi: 10.1161/JAHA.118.011662>.
Khan SU, Michos ED. Bempedoic acid and ezetimibe – better together. Eur J Prev Cardiol 2019; 2047487319864672. Dostupné z DOI: <http://doi: 10.1177/2047487319864672>. [Epub ahead of print]