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Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels

Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels Background Lipoprotein(a) (Lp(a)) is a genetic risk factor for cardiovascular disease (CVD) and is associated with the induction and sustaining of atherosclerotic cardiovascular diseases (ASCVD). Since 2008 Lp(a) along with progressive CVD has been approved as an indication for regular lipoprotein apheresis (LA) in Germany. The German Lipoprotein Apheresis Registry (GLAR) has been initiated to provide statistical evidence for the assessment of extracorporeal procedures to treat dyslipidemia for both LDL-cholesterol (LDL-C) and Lp(a). The GLAR now allows prospective investigations over a 5-year period about annual incidence rates of cardiovascular events. Here Lp(a) patients (LDL-C < 100 mg/dl; Lp(a) > 60 mg/dl or >120 nmol/l) showed the same reduction of major coronary (83%) and non-coronary events (63%) as had been formerly shown in the Pro(a)LiFe study. However, Lp(a) is not only an apolipoprotein(a) (apo(a)) and LDL-C containing particle, which is covalently bound to a LDL-C core by a disulphide bridge. The composition of this particle, inter alia containing oxidized phospholipids, gives pro-atherosclerotic, pro-inflammatory, and pro-thrombotic properties, inducing atherosclerotic processes mainly in the arterial wall. However, recent investigations have shown that a reduction of inflammatory settings without LDL-C or Lp(a) reduction may reduce ASCVD events. Lipoprotein apheresis (LA) could not only reduce LDL-C and Lp(a) in parallel, but also different inflammatory and coagulation parameters. In summary lipoprotein apheresis is not only anti-atherosclerotic, but also anti-inflammatory and anti-thrombotic and therefore an ideal treatment option with respect to the shown reduction of major adverse coronary events (MACE) and major adverse non-coronary events (MANCE) by reducing Lp(a) levels. Keywords Lipoprotein apheresis · Lipoprotein (a) · Cardiovascular disease · Coronary artery disease · Major coronary events · Major non-coronary events · Inflammation · Prevention This article is part of the special issue “Lp(a) – Update 2018” Center for Nephrology, Hypertension, and Metabolic V. J. J. Schettler Diseases, Hanover, Germany v.schettler@nz-goe.de Medical Care Centre Kempten-Allgäu, Kempten, Germany 1 7 Center of Nephrology Göttingen GbR, An der Department of Medicine II for Nephrology, Hypertension and Lutter 24, 37075 Göttingen, Germany Vascular Risks, AGAPLESION Markus Hospital, Frankfurt, Germany BRAVE—Benefit for Research on Arterial Hypertension, Dyslipidemia and Vascular Risk and Education e. V, Scientific Institute for Nephrology (WiNe), Düsseldorf, Göttingen, Germany Germany 3 9 BioArtProducts GmbH (B.A.P.), Rostock, Germany Apheresis Research Institute, Stadtwaldgürtel 77, 50935 Cologne, Extracorporeal Treatment and Apheresis Center, Department Germany of Internal Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Medizinische Klinik und Poliklinik 4, Universität München, Dresden, Dresden, Germany Munich, Germany K 34 V. J. J. Schettler et al. Introduction Members of the German Apheresis Working Group filled the gap: LA therapy is indicated, when high Lp(a) lev- Atherosclerotic cardiovascular diseases (ASCVD) are the els (>60 mg/dl (120 nmol/l)) in combination with normal main cause of morbidity and mortality in western countries LDL-C levels (<100 mg/dl (<2.6 mmol/l)) induced untypi- [1]. Since 2009 multiple investigations have provided more cally early cardiovascular damage [12]. In addition, LA may evidence that Lp(a) is an independent risk factor [2]. This be also indicated when at a particular time the atherosclero- evidence was obtained from genetic, Mendelian random- sis process is in such an advanced state that further progress ization, and epidemiologic investigations [2, 3]. Lp(a) is will be life-threatening or fatal. In this situation LA ther- complex due to its composition of a low-density lipoprotein apy is the only therapeutic way to achieve significant Lp(a) cholesterol (LDL-C) particle, in which apolipoprotein B is reduction and a better prognosis. covalently bound to apolipoprotein(a), which contains dif- However, the Canakinumab Anti-inflammatory Throm- ferent kringles with various characteristics [4]. These struc- bosis Outcomes Study (CANTOS) has provided convincing tures are responsible for its pro-atherosclerotic, pro-inflam- evidence of interleukin-1 beta as a target, whose neutraliza- matory, and pro-thrombotic properties, inducing ASCVD tion by a selective antibody reduces major cardiovascular or calcific aortic valve stenosis (CAVS) [2]. Therefore, be- events without affecting LDL-C or Lp(a) levels [13]. This cause of the different compositions Lp(a) properties are provides strong evidence in support of the inflammation not similar or comparable to LDL. Consequently, drug-in- hypothesis and will certainly stimulate research in this area duced Lp(a) reduction might be less successful than could and open the way for novel therapy in high-risk patients fol- be shown for LDL-C. lowing myocardial infarction. Recent investigations have Until now, little is known about the effect of reducing shown that a reduction of inflammatory settings without Lp(a) and the outcomes with respect to the development and LDL-C or Lp(a) reduction may reduce ASCVD events [14]. progress of ASCVD or CAVS [2]. In the last few decades The LA procedure could not only reduce LDL-C and Lp(a) a lot of investigations could not differentiate between the in parallel, but also various inflammatory and coagulation effect of Lp(a) and LDL-C on atherosclerosis development parameters [15, 16]. due to ineffective LDL-C-lowering therapies. The demand In a recent publication of the Pro(a)LiFe study, the for a therapy is increasing because of the knowledge that 5-year prospective follow-up results confirm that LA has Lp(a) can induce early ASCVD or CAVS independently a lasting effect on prevention of cardiovascular events in of LDL-C levels [5]. Whereas statins are discussed as in- patients with increased Lp(a) levels [17]. For this issue creasing Lp(a) levels [6], some investigations showed a re- a database query of the German Lipoprotein Apheresis duction of Lp(a) induced by nicotinic acid [7]. However, Registry (GLAR) was performed to verify the findings a reduction of major cardiovascular events (MACE) could from the Pro(a)LiFe study [18]. not be shown for nicotinic acid. Due to the negative results of the Atherothrombosis Intervention in Metabolic Syn- drome with low HDL/HIGH Triglycerides (AIM-HIGH) Material and methods trial, nicotinic acid has been withdrawn from the German market [8]. Data queries and evaluation The monoclonal antibodies to proprotein convertase sub- tilisin/kexin type 9 (PCSK9) alirocumab and evolocumab The latest database query for this publication was per- reduced LDL-C by up to a mean of 60–70% from base- formed in April 2018. All data were collected in the time line, which corresponds to a reduction of MACE [9, 10]. period 2012–2017 and analyzed using the statistics soft- In addition, both PCSK9 inhibitors (PCSK9i) showed a re- ware SigmaStat (SigmaStat 4.0; Systat Software Inc., San duction of Lp(a), 20–30% in low or moderate Lp(a) levels Jose, CA, USA). <50 mg/dl (<120 nmol/l), but less than 20% in higher Lp(a) Additionally, patient data were analyzed with respect levels [11]. Although outcome studies for both PCSK9i ex- to incidence rates of major coronary events (MACE) ist, data showing a reduction of Lp(a) corresponding to and major non-coronary events (MANCE) 2 years be- MACE reduction are not available until now. fore and prospectively 2–5 years after initiation of LA Since 2008 Lp(a) accompanied by progressive cardio- treatment. This current data pattern gives the optimal sam- vascular disease has been approved as an indication for ple size for statistical evaluation. For this investigation, lipoprotein apheresis (LA) in Germany. The term “pro- a specific data term for Lp(a) patients’ selection was cre- gressive cardiovascular disease” was not clearly defined by ated: Lp(a) > 60 mg/dl (>120 nmol/l); LDL-C < 100 mg/dl the Federal Joint Committee (G-BA), the highest decision- (<2.6 mmol/l). making body of the joint self-government of physicians, MACE was defined as an outcome parameter i. e. cardio- dentists, hospitals and health insurance funds in Germany. vascular death, nonfatal myocardial infarction, coronary by- K Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels 35 Fig. 1 Seven-year course of German Lipoprotein Apheresis Registry (GLAR) data with respect to a major adverse cardiac events (MACE) or b major adverse non-cardiac events (MANCE). The database interrogation used the terms Lp(a) > 60 mg/dl (>120 nmol/l) and LDL-C < 100 mg/dl (<2.6 mmol/l) pass surgery, percutaneous coronary intervention, or stent, Discussion whereas MANCE was determined as non-cardiovascular events i. e. stroke, carotid percutaneous transluminal an- Now there is more evidence that elevated Lp(a) levels may gioplasty or carotid surgery or peripheral vascular events contribute to ASCVD and CAVS. Although Lp(a) isoform- (peripheral vascular event of lower extremities or renal ar- independent assays are available, it is still being discussed, teries with percutaneous transluminal angioplasty, stent, by- which Lp(a) measurement method is the gold standard, and pass surgery, amputation), or venous thrombotic events like consequently which units (mg/dl or nmol/l) Lp(a) should deep venous thrombosis or pulmonary embolism. be given in [5, 19]. Furthermore, a clear linear association The access, database, quality, entries, queries, and eval- of Lp(a) levels and the risk for ASCVD is missing, which uation of the German Lipoprotein Apheresis Registry could be measured in patients with different LDL-choles- (GLAR) were described previously [18]. terol (LDL-C) levels. With respect to the given uncertainty of Lp(a) measurement it may be useful that levels should not be given in metric units but in qualitative statements Results like normal level and cardiovascular risk, or high level and increased risk for ASCVD. Data of more than 26,977 LA treatments of 1632 patients However, based on interaction with genetic, epidemio- were entered into GLAR, mostly 1 to 2 treatments per quar- logical, translational, and pathophysiological insights, Lp(a) ter. All required data are available for each patient as the is established as an independent genetic, and likely causal design of the entry form requires complete data collection. risk factor for ASCVD and CAVS [20]. From 2012 to 2017, 79 German apheresis centers col- In a broad spectrum of patients these observations are lected retrospective and prospective observational data of consistent across risk factors and concomitant therapies. 1632 patients undergoing LA to treat high LDL-C levels Until now there is a huge demand for reducing Lp(a), but and/or high Lp(a) levels, who were suffering from progres- no investigations using lipid-lowering drugs had shown sive cardiovascular disease (CVD). that further cardiovascular events (CVE) could be reduced. Analog to the pattern of the Pro(a)LiFe study, Lp(a) Statins tend to increase Lp(a) levels, but it is never been patient data (Lp(a) > 60 mg/dl (>120 nmol/l); LDL-C < investigated if this effect is clinically relevant. Recently 100 mg/dl (<2.6 mmol/l) were analyzed with respect to approved proprotein convertase subtilisin/kexin-type 9 in- incidence rates of major coronary events (MACE) 2 years hibitors (PCSK9i) and mipomersen lower Lp(a) 20–30%, before and prospectively for 2–5 years undergoing chronic and RNA-targeted therapies lower Lp(a) levels >80% [21]. LA treatment. Patients with available data according to But these approaches have not been tested in clinical the query pattern in the period 2012–2017 were found to outcome trials. A current investigation demonstrates for have a reduction in MACE of 83% (Fig. 1a). The same PCSK9i again an impressive LDL-C reduction and a minor query scheme was applied for major non-coronary events Lp(a) reduction when Lp(a) > 80 mg/dl (>200 nmol/l). But (MANCE) (Fig. 1b). An average reduction rate of MANCE this persistent small decrease of Lp(a) may have contributed of 63% was observed. K 36 V. J. J. Schettler et al. gression and modulation of atherosclerosis [23, 24]. T cells that respond to autoantigenic components of LDL or Lp(a) particles orchestrate plaque development [25]. Many con- nections between the immune system and metabolism ex- ist; acute inflammation induces hypertriglyceridemia [26], whereas chronic inflammation in the arterial walls has more complex effects, like in rheumatoid arthritis [27]. Novel ap- proaches such as anti-inflammatory therapies like the CAN- TOS trial [13, 14], T-cell-based treatments or vaccination against LDL or Lp(a) [28] could potentially reduce cardio- vascular inflammation and protect against the development of atherosclerosis [29–31]. In addition cell–cell commu- nication is important to maintain the inflammatory settings [32]. Because of the human individual immune reactivity to high levels of LDL-C or Lp(a) the difference of atheroscle- rotic lesion development may be explainable, e. g. in some cases high levels of Lp(a) induce no, in other cases moder- ate Lp(a) levels fulminate ASCVD. However, it is becoming more and more evident that LA could not only reduce LDL-C or Lp(a) levels (Fig. 2). LA Fig. 2 The complex effect of lipoprotein apheresis (LA) on the athero- improves whole blood viscosity and endothelium-mediated genicity of Lp(a), which was classified in 3 categories: pro-inflam- vasodilation, and has a positive effect on the hemorheolog- matory, pro-thrombotic, and therefore pro-atherogenic [2, 41–44]. The ical composition, improving perfusion in the microcircula- given parameters are only examples, the influence of LA on blood com- ponents is far-ranging tion [33]. Recently in a randomized controlled cross-over trial in patients with refractory angina and increased Lp(a) to the observation that lipid lowering by PCSK9i did not levels, myocardial perfusion, atheroma burden, exercise ca- lead to a reduction in arterial wall inflammation [22]. pacity and symptoms were found to be improved with LA Lipoprotein apheresis (LA) therapy is with respect treatment [34]. In addition LA changes the plasma inflam- to Lp(a) levels only indicated when high Lp(a) levels matory profile and the cytokine pattern in patients with (>60 mg/dl (120 nmol/l)) in combination with normal LDL- severe dyslipidemia, which may correspond to the early C levels (<100 mg/dl (<1.8 mmol/l)) induced progressive reduction of MACE and MANCE in Lp(a) patients [15, cardiovascular damage. The acute decrease of Lp(a) levels 17, 35, 36]. Because of its assumed long circulation in the by LA is impressive, mostly more than 70% after LA arterial vessels Lp(a) contains pro-inflammatory oxidized treatment. Prevention of cardiovascular complications in phospholipids (OxPL), which induce monocyte trafficking patients with high Lp(a) and progressive cardiovascular to the arterial wall and mediate pro-inflammatory responses disease by long-term LA was shown in the Pro(a)LiFe through its OxPL content [32]. In patients undergoing reg- investigation. From the first year under chronic LA treat- ular LA decreased OxPL levels could be determined after ment the MACE and MANCE rates could be reduced treatment [37]. significantly. This early CVE reduction was not shown in Elevated Lp(a) could be also involved in atherothrom- any other lipid-lowering drug investigations with respect botic disorders. Lp(a) influences different coagulation fac- of high Lp(a) levels and ASCVD. However, the recent tors resulting in thrombus formation [38]. Patients suffer- database interrogation of GLAR using nearly the same ing from thrombophilia Lp(a) may aggravate the coagula- Pro(a)LiFe study settings confirm these important findings tion situation, leading e. g. to placenta-mediated pregnancy and showed a similar and constant reduction of MACE and complications resulting in early miscarriages [39, 40]. MANCE in Lp(a) patients undergoing regular LA for up to In summary regular LA treatment may break the vicious 5 years of treatment. circle of atherosclerosis induced by Lp(a) because of its But how could these impressive findings be explained? multifactorial influence on this pathophysiology (Fig. 2). Lp(a) can be a major pro-inflammatory, pro-thrombotic, or LA is therefore anti-atherosclerotic, anti-inflammatory, atherosclerotic risk factor [5]. Individuals might start de- anti-thrombotic, and consequently an optimal therapeutic veloping an atherosclerotic process due to other risk factors option to reduce increased Lp(a) levels. like high LDL-C levels, hypertension, smoking, or chronic Acknowledgements The authors appreciate the dedicated help and inflammatory diseases like rheumatoid arthritis. Further- time of the colleagues and members of the scientific board of GLAR, more, the immune system plays a crucial role in the pro- K Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels 37 Germany: A. Vogt (Munich), B.R. Jaeger (Mühlheim), F. van Bu- clinical outcomes in patients with cardiovascular disease. N Engl J uren (Oelpe), K.P. Mellwig (Bad Oeynhausen), H.U. Klör (Gießen), Med 376(18):1713. https://doi.org/10.1056/NEJMoa1615664 P. Grützmacher (Frankfurt), E. Roeseler (Hannover), U. Julius (Dres- 10. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, den), B. Hohenstein (Villingen-Schwenningen), F. Heigl (Kempten), Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema H. Blume (Düsseldorf), R. Klingel (Köln), and V.J.J. Schettler (Göt- JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero tingen). K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM, Committees OO, Investigators (2018) Alirocumab and cardio- Conflict of interest V.J.J. Schettler, C.L. Neumann, C. Peter, T. Zim- vascular outcomes after acute coronary syndrome. N Engl J Med mermann, U. Julius, B. Hohenstein, E. Roeseler, F. Heigl, P. Grütz- 379(22):2097–2107. https://doi.org/10.1056/NEJMoa1801174 macher, H. Blume, R. Klingel, A. Vogt declare that they have no com- 11. Toth PP, Worthy G, Gandra SR, Sattar N, Bray S, Cheng LI, Bridges peting interests. 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Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels

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Springer Journals
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Copyright © 2019 by The Author(s)
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Medicine & Public Health; Cardiology; Internal Medicine; Angiology; Cardiac Surgery; Diagnostic Radiology
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1861-0706
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10.1007/s11789-019-00094-4
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Abstract

Background Lipoprotein(a) (Lp(a)) is a genetic risk factor for cardiovascular disease (CVD) and is associated with the induction and sustaining of atherosclerotic cardiovascular diseases (ASCVD). Since 2008 Lp(a) along with progressive CVD has been approved as an indication for regular lipoprotein apheresis (LA) in Germany. The German Lipoprotein Apheresis Registry (GLAR) has been initiated to provide statistical evidence for the assessment of extracorporeal procedures to treat dyslipidemia for both LDL-cholesterol (LDL-C) and Lp(a). The GLAR now allows prospective investigations over a 5-year period about annual incidence rates of cardiovascular events. Here Lp(a) patients (LDL-C < 100 mg/dl; Lp(a) > 60 mg/dl or >120 nmol/l) showed the same reduction of major coronary (83%) and non-coronary events (63%) as had been formerly shown in the Pro(a)LiFe study. However, Lp(a) is not only an apolipoprotein(a) (apo(a)) and LDL-C containing particle, which is covalently bound to a LDL-C core by a disulphide bridge. The composition of this particle, inter alia containing oxidized phospholipids, gives pro-atherosclerotic, pro-inflammatory, and pro-thrombotic properties, inducing atherosclerotic processes mainly in the arterial wall. However, recent investigations have shown that a reduction of inflammatory settings without LDL-C or Lp(a) reduction may reduce ASCVD events. Lipoprotein apheresis (LA) could not only reduce LDL-C and Lp(a) in parallel, but also different inflammatory and coagulation parameters. In summary lipoprotein apheresis is not only anti-atherosclerotic, but also anti-inflammatory and anti-thrombotic and therefore an ideal treatment option with respect to the shown reduction of major adverse coronary events (MACE) and major adverse non-coronary events (MANCE) by reducing Lp(a) levels. Keywords Lipoprotein apheresis · Lipoprotein (a) · Cardiovascular disease · Coronary artery disease · Major coronary events · Major non-coronary events · Inflammation · Prevention This article is part of the special issue “Lp(a) – Update 2018” Center for Nephrology, Hypertension, and Metabolic V. J. J. Schettler Diseases, Hanover, Germany v.schettler@nz-goe.de Medical Care Centre Kempten-Allgäu, Kempten, Germany 1 7 Center of Nephrology Göttingen GbR, An der Department of Medicine II for Nephrology, Hypertension and Lutter 24, 37075 Göttingen, Germany Vascular Risks, AGAPLESION Markus Hospital, Frankfurt, Germany BRAVE—Benefit for Research on Arterial Hypertension, Dyslipidemia and Vascular Risk and Education e. V, Scientific Institute for Nephrology (WiNe), Düsseldorf, Göttingen, Germany Germany 3 9 BioArtProducts GmbH (B.A.P.), Rostock, Germany Apheresis Research Institute, Stadtwaldgürtel 77, 50935 Cologne, Extracorporeal Treatment and Apheresis Center, Department Germany of Internal Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Medizinische Klinik und Poliklinik 4, Universität München, Dresden, Dresden, Germany Munich, Germany K 34 V. J. J. Schettler et al. Introduction Members of the German Apheresis Working Group filled the gap: LA therapy is indicated, when high Lp(a) lev- Atherosclerotic cardiovascular diseases (ASCVD) are the els (>60 mg/dl (120 nmol/l)) in combination with normal main cause of morbidity and mortality in western countries LDL-C levels (<100 mg/dl (<2.6 mmol/l)) induced untypi- [1]. Since 2009 multiple investigations have provided more cally early cardiovascular damage [12]. In addition, LA may evidence that Lp(a) is an independent risk factor [2]. This be also indicated when at a particular time the atherosclero- evidence was obtained from genetic, Mendelian random- sis process is in such an advanced state that further progress ization, and epidemiologic investigations [2, 3]. Lp(a) is will be life-threatening or fatal. In this situation LA ther- complex due to its composition of a low-density lipoprotein apy is the only therapeutic way to achieve significant Lp(a) cholesterol (LDL-C) particle, in which apolipoprotein B is reduction and a better prognosis. covalently bound to apolipoprotein(a), which contains dif- However, the Canakinumab Anti-inflammatory Throm- ferent kringles with various characteristics [4]. These struc- bosis Outcomes Study (CANTOS) has provided convincing tures are responsible for its pro-atherosclerotic, pro-inflam- evidence of interleukin-1 beta as a target, whose neutraliza- matory, and pro-thrombotic properties, inducing ASCVD tion by a selective antibody reduces major cardiovascular or calcific aortic valve stenosis (CAVS) [2]. Therefore, be- events without affecting LDL-C or Lp(a) levels [13]. This cause of the different compositions Lp(a) properties are provides strong evidence in support of the inflammation not similar or comparable to LDL. Consequently, drug-in- hypothesis and will certainly stimulate research in this area duced Lp(a) reduction might be less successful than could and open the way for novel therapy in high-risk patients fol- be shown for LDL-C. lowing myocardial infarction. Recent investigations have Until now, little is known about the effect of reducing shown that a reduction of inflammatory settings without Lp(a) and the outcomes with respect to the development and LDL-C or Lp(a) reduction may reduce ASCVD events [14]. progress of ASCVD or CAVS [2]. In the last few decades The LA procedure could not only reduce LDL-C and Lp(a) a lot of investigations could not differentiate between the in parallel, but also various inflammatory and coagulation effect of Lp(a) and LDL-C on atherosclerosis development parameters [15, 16]. due to ineffective LDL-C-lowering therapies. The demand In a recent publication of the Pro(a)LiFe study, the for a therapy is increasing because of the knowledge that 5-year prospective follow-up results confirm that LA has Lp(a) can induce early ASCVD or CAVS independently a lasting effect on prevention of cardiovascular events in of LDL-C levels [5]. Whereas statins are discussed as in- patients with increased Lp(a) levels [17]. For this issue creasing Lp(a) levels [6], some investigations showed a re- a database query of the German Lipoprotein Apheresis duction of Lp(a) induced by nicotinic acid [7]. However, Registry (GLAR) was performed to verify the findings a reduction of major cardiovascular events (MACE) could from the Pro(a)LiFe study [18]. not be shown for nicotinic acid. Due to the negative results of the Atherothrombosis Intervention in Metabolic Syn- drome with low HDL/HIGH Triglycerides (AIM-HIGH) Material and methods trial, nicotinic acid has been withdrawn from the German market [8]. Data queries and evaluation The monoclonal antibodies to proprotein convertase sub- tilisin/kexin type 9 (PCSK9) alirocumab and evolocumab The latest database query for this publication was per- reduced LDL-C by up to a mean of 60–70% from base- formed in April 2018. All data were collected in the time line, which corresponds to a reduction of MACE [9, 10]. period 2012–2017 and analyzed using the statistics soft- In addition, both PCSK9 inhibitors (PCSK9i) showed a re- ware SigmaStat (SigmaStat 4.0; Systat Software Inc., San duction of Lp(a), 20–30% in low or moderate Lp(a) levels Jose, CA, USA). <50 mg/dl (<120 nmol/l), but less than 20% in higher Lp(a) Additionally, patient data were analyzed with respect levels [11]. Although outcome studies for both PCSK9i ex- to incidence rates of major coronary events (MACE) ist, data showing a reduction of Lp(a) corresponding to and major non-coronary events (MANCE) 2 years be- MACE reduction are not available until now. fore and prospectively 2–5 years after initiation of LA Since 2008 Lp(a) accompanied by progressive cardio- treatment. This current data pattern gives the optimal sam- vascular disease has been approved as an indication for ple size for statistical evaluation. For this investigation, lipoprotein apheresis (LA) in Germany. The term “pro- a specific data term for Lp(a) patients’ selection was cre- gressive cardiovascular disease” was not clearly defined by ated: Lp(a) > 60 mg/dl (>120 nmol/l); LDL-C < 100 mg/dl the Federal Joint Committee (G-BA), the highest decision- (<2.6 mmol/l). making body of the joint self-government of physicians, MACE was defined as an outcome parameter i. e. cardio- dentists, hospitals and health insurance funds in Germany. vascular death, nonfatal myocardial infarction, coronary by- K Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels 35 Fig. 1 Seven-year course of German Lipoprotein Apheresis Registry (GLAR) data with respect to a major adverse cardiac events (MACE) or b major adverse non-cardiac events (MANCE). The database interrogation used the terms Lp(a) > 60 mg/dl (>120 nmol/l) and LDL-C < 100 mg/dl (<2.6 mmol/l) pass surgery, percutaneous coronary intervention, or stent, Discussion whereas MANCE was determined as non-cardiovascular events i. e. stroke, carotid percutaneous transluminal an- Now there is more evidence that elevated Lp(a) levels may gioplasty or carotid surgery or peripheral vascular events contribute to ASCVD and CAVS. Although Lp(a) isoform- (peripheral vascular event of lower extremities or renal ar- independent assays are available, it is still being discussed, teries with percutaneous transluminal angioplasty, stent, by- which Lp(a) measurement method is the gold standard, and pass surgery, amputation), or venous thrombotic events like consequently which units (mg/dl or nmol/l) Lp(a) should deep venous thrombosis or pulmonary embolism. be given in [5, 19]. Furthermore, a clear linear association The access, database, quality, entries, queries, and eval- of Lp(a) levels and the risk for ASCVD is missing, which uation of the German Lipoprotein Apheresis Registry could be measured in patients with different LDL-choles- (GLAR) were described previously [18]. terol (LDL-C) levels. With respect to the given uncertainty of Lp(a) measurement it may be useful that levels should not be given in metric units but in qualitative statements Results like normal level and cardiovascular risk, or high level and increased risk for ASCVD. Data of more than 26,977 LA treatments of 1632 patients However, based on interaction with genetic, epidemio- were entered into GLAR, mostly 1 to 2 treatments per quar- logical, translational, and pathophysiological insights, Lp(a) ter. All required data are available for each patient as the is established as an independent genetic, and likely causal design of the entry form requires complete data collection. risk factor for ASCVD and CAVS [20]. From 2012 to 2017, 79 German apheresis centers col- In a broad spectrum of patients these observations are lected retrospective and prospective observational data of consistent across risk factors and concomitant therapies. 1632 patients undergoing LA to treat high LDL-C levels Until now there is a huge demand for reducing Lp(a), but and/or high Lp(a) levels, who were suffering from progres- no investigations using lipid-lowering drugs had shown sive cardiovascular disease (CVD). that further cardiovascular events (CVE) could be reduced. Analog to the pattern of the Pro(a)LiFe study, Lp(a) Statins tend to increase Lp(a) levels, but it is never been patient data (Lp(a) > 60 mg/dl (>120 nmol/l); LDL-C < investigated if this effect is clinically relevant. Recently 100 mg/dl (<2.6 mmol/l) were analyzed with respect to approved proprotein convertase subtilisin/kexin-type 9 in- incidence rates of major coronary events (MACE) 2 years hibitors (PCSK9i) and mipomersen lower Lp(a) 20–30%, before and prospectively for 2–5 years undergoing chronic and RNA-targeted therapies lower Lp(a) levels >80% [21]. LA treatment. Patients with available data according to But these approaches have not been tested in clinical the query pattern in the period 2012–2017 were found to outcome trials. A current investigation demonstrates for have a reduction in MACE of 83% (Fig. 1a). The same PCSK9i again an impressive LDL-C reduction and a minor query scheme was applied for major non-coronary events Lp(a) reduction when Lp(a) > 80 mg/dl (>200 nmol/l). But (MANCE) (Fig. 1b). An average reduction rate of MANCE this persistent small decrease of Lp(a) may have contributed of 63% was observed. K 36 V. J. J. Schettler et al. gression and modulation of atherosclerosis [23, 24]. T cells that respond to autoantigenic components of LDL or Lp(a) particles orchestrate plaque development [25]. Many con- nections between the immune system and metabolism ex- ist; acute inflammation induces hypertriglyceridemia [26], whereas chronic inflammation in the arterial walls has more complex effects, like in rheumatoid arthritis [27]. Novel ap- proaches such as anti-inflammatory therapies like the CAN- TOS trial [13, 14], T-cell-based treatments or vaccination against LDL or Lp(a) [28] could potentially reduce cardio- vascular inflammation and protect against the development of atherosclerosis [29–31]. In addition cell–cell commu- nication is important to maintain the inflammatory settings [32]. Because of the human individual immune reactivity to high levels of LDL-C or Lp(a) the difference of atheroscle- rotic lesion development may be explainable, e. g. in some cases high levels of Lp(a) induce no, in other cases moder- ate Lp(a) levels fulminate ASCVD. However, it is becoming more and more evident that LA could not only reduce LDL-C or Lp(a) levels (Fig. 2). LA Fig. 2 The complex effect of lipoprotein apheresis (LA) on the athero- improves whole blood viscosity and endothelium-mediated genicity of Lp(a), which was classified in 3 categories: pro-inflam- vasodilation, and has a positive effect on the hemorheolog- matory, pro-thrombotic, and therefore pro-atherogenic [2, 41–44]. The ical composition, improving perfusion in the microcircula- given parameters are only examples, the influence of LA on blood com- ponents is far-ranging tion [33]. Recently in a randomized controlled cross-over trial in patients with refractory angina and increased Lp(a) to the observation that lipid lowering by PCSK9i did not levels, myocardial perfusion, atheroma burden, exercise ca- lead to a reduction in arterial wall inflammation [22]. pacity and symptoms were found to be improved with LA Lipoprotein apheresis (LA) therapy is with respect treatment [34]. In addition LA changes the plasma inflam- to Lp(a) levels only indicated when high Lp(a) levels matory profile and the cytokine pattern in patients with (>60 mg/dl (120 nmol/l)) in combination with normal LDL- severe dyslipidemia, which may correspond to the early C levels (<100 mg/dl (<1.8 mmol/l)) induced progressive reduction of MACE and MANCE in Lp(a) patients [15, cardiovascular damage. The acute decrease of Lp(a) levels 17, 35, 36]. Because of its assumed long circulation in the by LA is impressive, mostly more than 70% after LA arterial vessels Lp(a) contains pro-inflammatory oxidized treatment. Prevention of cardiovascular complications in phospholipids (OxPL), which induce monocyte trafficking patients with high Lp(a) and progressive cardiovascular to the arterial wall and mediate pro-inflammatory responses disease by long-term LA was shown in the Pro(a)LiFe through its OxPL content [32]. In patients undergoing reg- investigation. From the first year under chronic LA treat- ular LA decreased OxPL levels could be determined after ment the MACE and MANCE rates could be reduced treatment [37]. significantly. This early CVE reduction was not shown in Elevated Lp(a) could be also involved in atherothrom- any other lipid-lowering drug investigations with respect botic disorders. Lp(a) influences different coagulation fac- of high Lp(a) levels and ASCVD. However, the recent tors resulting in thrombus formation [38]. Patients suffer- database interrogation of GLAR using nearly the same ing from thrombophilia Lp(a) may aggravate the coagula- Pro(a)LiFe study settings confirm these important findings tion situation, leading e. g. to placenta-mediated pregnancy and showed a similar and constant reduction of MACE and complications resulting in early miscarriages [39, 40]. MANCE in Lp(a) patients undergoing regular LA for up to In summary regular LA treatment may break the vicious 5 years of treatment. circle of atherosclerosis induced by Lp(a) because of its But how could these impressive findings be explained? multifactorial influence on this pathophysiology (Fig. 2). Lp(a) can be a major pro-inflammatory, pro-thrombotic, or LA is therefore anti-atherosclerotic, anti-inflammatory, atherosclerotic risk factor [5]. Individuals might start de- anti-thrombotic, and consequently an optimal therapeutic veloping an atherosclerotic process due to other risk factors option to reduce increased Lp(a) levels. like high LDL-C levels, hypertension, smoking, or chronic Acknowledgements The authors appreciate the dedicated help and inflammatory diseases like rheumatoid arthritis. Further- time of the colleagues and members of the scientific board of GLAR, more, the immune system plays a crucial role in the pro- K Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels 37 Germany: A. Vogt (Munich), B.R. Jaeger (Mühlheim), F. van Bu- clinical outcomes in patients with cardiovascular disease. N Engl J uren (Oelpe), K.P. Mellwig (Bad Oeynhausen), H.U. Klör (Gießen), Med 376(18):1713. https://doi.org/10.1056/NEJMoa1615664 P. Grützmacher (Frankfurt), E. Roeseler (Hannover), U. Julius (Dres- 10. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, den), B. Hohenstein (Villingen-Schwenningen), F. Heigl (Kempten), Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema H. Blume (Düsseldorf), R. Klingel (Köln), and V.J.J. Schettler (Göt- JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero tingen). K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM, Committees OO, Investigators (2018) Alirocumab and cardio- Conflict of interest V.J.J. Schettler, C.L. Neumann, C. Peter, T. Zim- vascular outcomes after acute coronary syndrome. N Engl J Med mermann, U. Julius, B. Hohenstein, E. Roeseler, F. Heigl, P. Grütz- 379(22):2097–2107. https://doi.org/10.1056/NEJMoa1801174 macher, H. Blume, R. Klingel, A. Vogt declare that they have no com- 11. Toth PP, Worthy G, Gandra SR, Sattar N, Bray S, Cheng LI, Bridges peting interests. 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