The role of PCSK9-inhibitors and of lipoprotein apheresis in the treatment of homozygous and severe heterozygous familial hypercholesterolemia: A rivalry, or are things quite different?
Authors:
Vladimír Bláha 1; Milan Bláha 2; Miriam Lánská 2; Eduard Havel 1; Pavel Vyroubal 1; Zdeněk Zadák 1; Pavel Žák 2
Authors‘ workplace:
III. interní gerontometabolická klinika LF UK a FN Hradec Králové
1; IV. interní hematologická klinika LF UK a FN Hradec Králové
2
Published in:
Vnitř Lék 2018; 64(1): 43-50
Category:
Reviews
Overview
PCSK9-inhibitors belong to the new class of hypolipidemic agents. They enhance catabolism of low density lipoprotein cholesterol (LDL-C) through inhibiting activity of proprotein convertase subtilisin/kexin type 9 (PCSK9). They are monoclonal antibodies (alirocumab, evolocumab etc). Under clinical development are also other types of PCSK9-inhibitors which act at a subcellular level. The treatment with PCSK9-inhibitors can be beneficially combined with lipoprotein apheresis (LA). If such treatment using PCSK9-inhibitors is possible with regard to an individual patient’s genotype, the combination of LA and PCSK9-inhibitors leads to slowing the space of LDL-C increase between individual procedures of apheresis and enables attaining of the lowest possible values of LDL-cholesterolemia for the longest possible period of time. Due to high efficiency of PCSK9-inhibitors lowering LDL-C, but also their lower cost as compared to therapeutic LA, PCSK9-inhibitors now take precedence over the use of extracorporeal lipoprotein apheresis which, nonetheless, still remains the final method for hypolipidemic treatment of patients with severe hypercholesterolemia, who are resistant to conventional therapy while not reaching the target lipid values and at high cardiovascular risk. They belong to extracorporeal elimination methodologies which remove low density lipoprotein (LDL) cholesterol from circulating blood. LA in combination with higher doses of statins and ezetimib currently represents the most efficient method of treatment of homozygous and statin-refractory heterozygous familial hypercholesterolemia (FH). Residual cardiovascular risk in these patients still remains high, in particular because, despite the aforementioned treatment, the target values for lipids according to present recommendations cannot be reached. The combination of LA with the new drugs is promising, primarily due to its potential for further lowering of LDL-cholesterolemia between the individual apheresis procedures. Preliminary results of the ongoing studies indicate that the new hypolipidemic drugs in combination with LA, or when used separately, will substantially enrich and improve the treatment of refractory FH.
Key words:
alirocumab – atherosclerosis – evolocumab – hypercholesterolemia – cardiovascular disease – lipoprotein apheresis
Sources
1. Leebmann J, Roeseler E, Julius U et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a) – hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation 2013; 128(24): 2567–2576. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002432>.
2. Emmrich U, Hohenstein B, Julius U. Actual situation of lipoprotein apheresis in Saxony in 2013. Atheroscler Suppl 2015; 18: 215–225. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosissup.2015.02.034>.
3. Gross E, Hohenstein B, Julius U. Effects of Lipoprotein apheresis on the Lipoprotein(a) levels in the long run. Atheroscler Suppl 2015; 18: 226–232. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosissup.2015.02.033>.
4. Heigl F, Hettich R, Lotz N et al. Efficacy, safety, and tolerability of long-term lipoprotein apheresis in patients with LDL – or Lp(a) hyperlipoproteinemia: Findings gathered from more than 36,000 treatments at one center in Germany. Atheroscler Suppl 2015; 18: 154–162. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosissup.2015.02.013>.
5. Naoumova RP, Thompson GR, Soutar AK. Current management of severe homozygous hypercholesterolaemias. Curr Opin Lipidol 2004; 15(4): 413–422.
6. Gagné C, Gaudet D, Bruckert E et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002; 105(21): 2469–2475.
7. Bilheimer DW, Goldstein JL, Grundy SM et al. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 1984; 311(26): 1658–1664. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJM198412273112603>.
8. Van Craeyveld E, Jacobs F, Gordts SC et al. Gene therapy for familial hypercholesterolemia. Curr Pharm Des 2011; 17(24): 2575–2591.
9. Blaha M, Lanska M, Tomsova H et al. Apheresis data registration in WWA registry-10-year experience of our center. Transfus Apher Sci 2017; 56(5): 738–741. Dostupné z DOI: <http://dx.doi.org/10.1016/j.transci.2017.08.024>.
10. Bláha V. Inhibitory PCSK9 – zkušenosti po dvou letech praxe v ČR. Farmakoterapeutická revue 2017; 2017(2): 84–90.
11. Druce I, Abujrad H, Ooi TC. PCSK9 and triglyceride-rich lipoprotein metabolism. J Biomed Res 2015; 29. Dostupné z DOI: <http://dx.doi.org/10.7555/JBR.29.20150052>.
12. Julius U, Milton M, Stoellner D et al. Effects of lipoprotein apheresis on PCSK9 levels. Atheroscler Suppl 2015; 18: 180–186. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosissup.2015.02.028>.
13. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Incest 2002; 109(9): 1125–1131. Dostupné z DOI: <http://dx.doi.org/10.1172/JCI15593>.
14. Hori M, Ishihara M, Yuasa Y et al. Removal of Plasma Mature and Furin-Cleaved Proprotein Convertase Subtilisin/Kexin 9 by Low-Density Lipoprotein-apheresis in Familial Hypercholesterolemia: Development and Application of a New Assay for PCSK9. J Clin Endocrinol Metab 2015; 100(1): E41-E49. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2014–3066>.
15. Bruckert E, Blaha V, Stein EA et al. Trial Assessing Long-Term Use of PCSK9 Inhibition in Patients with Genetic LDL Disorders (TAUSSIG): Efficacy and Safety in Patients with Familial Hypercholesterolemia Receiving Lipid Apheresis. Circulation 2014; 130: A17016.
16. Raal FJ, Hovingh GK, Blom D et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017; 5(4): 280–290. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–8587(17)30044-X>.
17. Tavori H, Giunzioni I, Linton MF et al. Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis. Circ Res 2013; 113(12): 1290–1295. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCRESAHA.113.302655>.
18. Moriarty PM, Parhofer KG, Babirak SP et al. Alirocumab in patients with heterozygous familial hypercholesterolemia undergoing lipoprotein apheresis: Rationale and design of the ODYSSEY ESCAPE trial. J Clin Lipidol 2016; 10(3): 627–634. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacl.2016.02.003>.
19. Moriarty PM, Parhofer KG, Babirak SP et al. Alirocumab in patients with heterozygous familial hypercholesterolemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J 2016; 37(48): 3588–3595. <http://dx.doi.org/10.1093/eurheartj/ehw388>.
20. Stein EA, Sampietro T, Santos R et al. Long-term treatment with evolocumab homozygous familial hypercholesterolemia patients: Results from the trial assessing long-term use of PCSK9 inhibition in subjects with genetic LDL disorders (TAUSSIG). European Atherosclerosis Society 2016 Congress; May 31, 2016; Innsbruck, Austria. Abstrakt 146.
21. Lappegard KT, Enebakk T, Thunhaug H et al. Transition from LDL apheresis to evolocumab in heterozygous FH is equally effective in lowering LDL, without lowering HDL cholesterol. Atherosclerosis 2016; 251: 119–123. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2016.06.015>.
22. Gerald F, Watts CS. ODYSSEY ESCAPE: is PCSK9 inhibition the Trojan Horse for the use of lipoprotein apheresis in familial hypercholesterolaemia? Eur Heart J 2016; 37(48):3596–3599. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehw497>.
Labels
Diabetology Endocrinology Internal medicineArticle was published in
Internal Medicine
2018 Issue 1
Most read in this issue
- Familial combined hyperlipidemia – the most common genetic dyslipidemia in population and in patients with premature atherothrombotic cardiovascular disease
- Epidemiology of hypercholesterolemia
- Diabetic dyslipidemia and microvascular complications of diabetes
- The current position of hydrochlorothiazide among thiazide and thiazide-like diuretics