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Lipoprotein(a) and proprotein convertase subtilisin/kexin type9 inhibitors

Lipoprotein(a) and proprotein convertase subtilisin/kexin type9 inhibitors Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations. Keywords Lipoprotein(a) · LDL cholesterol · PCSK9 inhibitors · Cardiovascular events · Lipoprotein apheresis Lipoprotein(a)—synthesis, composition, The clearance of Lp(a) from the bloodstream is still not metabolism, and clinical significance fully understood. Hepatic (LDL receptor (LDLR), VLDL receptor, scavenger receptor B1, LDL receptor–related pro- Lipoprotein(a) (Lp(a)) consists of an LDL particle to which tein 1, cluster of differentiation 36 receptor (CD36), plas- an apolipoprotein(a) (apo(a)) is linked with a single disul- minogen receptor) and nonhepatic receptors are probably fide bond. The binding between apolipoprotein (B) (apoB), involved [1–4]. Renal mechanisms may also play a role. the major apolipoprotein of the LDL, and apo(a) takes place It is assumed that LDLRs only play a significant role in either in the hepatic cells, in the space of Disse, or in the Lp(a) clearance when hepatic levels of the receptor are very vascular lumen [1]. The cholesterol content of the LDL in high and LDL-C levels are low, as is the case in propro- Lp(a) varies between 30 and 45%. The Lp(a) concentra- tein convertase subtilisin/kexin type 9 (PCSK9) inhibitor tion is genetically determined. Mutations in the Lp(a) gene therapy. It is possible that apo(a) isoform length influences (LPA) and especially a variable number of LPA kringles IV clearance behavior of Lp(a) in human plasma following up- type 2 in the apo(a) have an effect. A low number of these regulation of LDLRs. kringles is associated with higher Lp(a) levels. The physiological significance of Lp(a) particles may re- late to their procoagulatory properties. Thus, wound healing could be stimulated. On the other hand, Lp(a) induces atherosclerotic lesions This article is part of the special issue “Lp(a) – Update 2018” and is supposed to promote aortic valve stenosis: a com- U. Julius bination of proatherosclerotic, proinflammatory and proco- ulrich.julius@uniklinikum-dresden.de agulatory actions seems to be responsible [5]. Data suggest that the atherogenicity of Lp(a) may be mediated in part by Lipidology and Center for Extracorporeal Treatment, proinflammatory oxidized phospholipids [6]. Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany K 46 U. Julius et al. Plasma PCSK9 is found in association with Lp(a) parti- Eec ff ts of PCSK9 inhibitors on Lp(a) concentrations cles in humans with high Lp(a) levels and in mice carrying human Lp(a) [7]. Studies using epidemiological data, Mendelian random- Meta-analysis of randomized controlled trials with ization and genome-wide associations have proven that el- PCSK9 inhibitors evated Lp(a) induce cardiovascular events (CVEs) like my- ocardial infarction (MI), stroke, occlusions of carotids or of A meta-analysis of studies using PCSK9 inhibitors (27 leg arteries [5, 8]. randomized controlled trials [RCTs] in 11,864 patients) New data obtained in the Danish population with re- documented a mean reduction of Lp(a) levels by 21.90% spect to the relationship between Lp(a) and mortality (95% CI 24.28, 19.51) [10]. Treatment modalities like have recently been published: In this study Lp(a) lev- type of PCSK9 inhibitor, duration of therapy, application els >93 mg/dl (199 nmol/l; 96th–100th percentiles) versus in patients with or without familial hypercholesterolemia, <10 mg/dl (18 nmol/l; 1st–50th percentiles) were associ- monotherapy or combination therapy, types of control ated with a hazard ratio (HR) of 1.50 (95% CI 1.28–1.76) treatment (placebo, ezetimibe), baseline Lp(a) (below 50 for cardiovascular mortality and of 1.20 (1.10–1.30) for or above 50 mg/dl), and immunoassay did not have a sig- all-cause mortality [9]. High levels of Lp(a), induced by nificant influence on this reduction. The lower the reached low LPA kringle IV type 2 number of repeats rather than LDL-C concentration was, the higher the reduction rate for through high cholesterol content, were associated with Lp(a). Attention should be paid to the fact that in the ma- increased mortality. jority of the included studies mean Lp(a) ranged between 9 Lp(a) levels in the atherothrombotic range are gener- and 40 mg/dl; however, in one investigation this value was ally accepted as >30 to 50 mg/dl or >75 to 125 nmol/l [1]. 100 (but SD 162!) mg/dl. Such levels affect 20 to 30% of the global population, with possibly higher incidence in patients with established car- Evolocumab in patients with very high Lp(a) diovascular disease and calcific aortic valve disease. concentrations In 65 patients with Lp(a) concentrations of about 200 nmol/l PCSK9 inhibitors—mode of action an injection therapy with 420 mg evolocumab once in 4 weeks reduced Lp(a) after 16 weeks by 28.0 (56.5, 9.0) PCSK9 inhibitors are human monoclonal antibodies bind- nmol/l (median, IQR), equivalent to 13.9 (19.3, 8.5) percent ing to the PCSK9 protein. This protein binds to LDLRs for (mean, 95% CI) [12]. LDL-C was decreased by 2.2 (0.8) endocytosis and lysosome degradation in the liver, result- mmol/l, corresponding to 60.7 (65.8, 55.5) percent (mean, ing in an increase in circulating LDL cholesterol (LDL-C) 95% CI). level. LDLRs usually recycle after they transported LDL Interestingly, arterial wall inflammation (most diseased particles into the cells. By inhibiting this LDLR destruc- segment target-to-background ratio (MDS TBR)) in the in- tion, the number of LDLRs at the cell surface markedly dex vessel (left carotid, right carotid, or thoracic aorta) was increases—leading to an effective removal of circulating not changed by evolocumab. The explanation of the authors LDL particles. Thus, reductions of LDL-C of more than for this lack of change is that Lp(a) levels remained high 50% can be reached. despite the rather modest reduction induced by the PCSK9 Evidently, the PCSK9 protein also exerts effects on other inhibitor. receptors like VLDL receptor, LDL receptor-related pro- tein 1 or the apolipoprotein E receptor [3]. Effect of PCSK9 inhibitors in patients undergoing It was shown that PCSK9 may increase the secretion of lipoprotein apheresis therapy apo(a) and of apoB—an inhibition of PCSK9 may counter- act these effects [10]. Thus PCSK9 inhibitors reduce Lp(a) ODYSSEY ESCAPE Study levels by both increasing clearance and reducing its synthe- sis. Alirocumab (150 mg biweekly, 2:1 allocation to verum and Lp(a) kinetics were studied using intravenous D3-leucine placebo, respectively) was given to patients (n =62) who administration, mass spectrometry, and compartmental were treated with lipoprotein apheresis (LA) in order to modeling [11]. Evolocumab monotherapy was shown to evaluate the possibility to replace LA therapy by the PCSK9 lower the plasma Lp(a) pool size by decreasing the produc- inhibitor [13]. Alirocumab reduced Lp(a) levels in those tion of Lp(a) particles. In combination with atorvastatin, patients with normal values (mean below 20 mg/dl) after evolocumab lowered the plasma Lp(a) pool size by accel- 6 weeks by 15% (placebo controlled) and after 18 weeks erating the catabolism of Lp(a) particles. by 2.7%. But in patients with high baseline Lp(a) concen- K Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors 47 ab LDL-C 1 (mmol/l) LDL-C 2 (mmol/l) LDL-C reducon Lp(a) 1 (nmol/l) Lp(a) 2 (nmol/l) Lp(a) reducon m 3.66 1.74 -53.85% mean 199.00 156.35 -20.80% sd 1.24 0.87 0.12 SD 74.29 55.49 0.13 Max 8.24 4.16 -23.79% Max 376.00 247.00 -0.46% Min 1.48 0.38 -81.42% Min 90.00 61.00 -44.35% Fig. 1 Individual percent reductions of LDL-C (a, n =41) and of Lp(a) (b, n =23) after 12 weeks of PCSK9 inhibitor application (usually biweekly) in patients on LA therapy. LDL-C LDL cholesterol, Lp(a) Lipoprotein(a) trations (mean above 90 mg/dl) the corresponding changes Lp(a) was measured in 25,096 patients [15]. The me- amounted to 13% and to +1.9% (placebo controlled). dian (IQR) baseline Lp(a) concentration was 37 (13, 165) nmol/l. In the placebo arm, patients with baseline Lp(a) Observations of the authors in the highest quartile had a higher risk of coronary heart disease (CHD) death, MI or urgent revascularization (UR) At our center we initiated PCSK9 inhibitor therapy in (adjusted HR Q4:Q1 1.22, 95% CI 1.01,1.48) independent patients undergoing LA treatment when LDL-C levels re- of LDL-C. At 48 weeks, evolocumab significantly reduced mained high despite maximally tolerated lipid-lowering Lp(a) by a median (IQR) of 26.9% (6.2, 46.7%)—equiv- therapy (drugs, LA). Fig. 1 shows clear differences be- alent to 11 nmol/l (1, 32) absolute change. It is important tween patients with respect to lowering of LDL-C and to note that in more than 30% of the patients receiving Lp(a) (12 weeks after start of the injection therapy), indi- evolocumab no reduction of Lp(a) was seen! cating that reporting mean values is of limited significance The percent change in Lp(a) and LDL-C at 48 weeks in when describing the effectiveness of PCSK9 inhibitors. evolocumab patients was moderately positively correlated. Among the 41 patients who started PCSK9 inhibitor Evolocumab reduced the risk of CHD death, MI or UR therapy, only 23 showed elevated Lp(a) levels (higher than by 23% (HR 0.77, 95% CI 0.67, 0.88) in patients with 120 nmol/l before first LA session). a baseline Lp(a) > median, and by 7% (HR 0.93, 0.80, 1.08) in those  median. Coupled with the higher baseline risk, the absolute risk reductions and number-needed-to-treat for Outcomedatainprospective controlled 3 years (NNT3y) were 2.49% and 40 vs. 0.95% and 105, PCSK9 inhibitor studies—association with respectively. the effects of these drugs on Lp(a) levels When a clinical threshold of 120 nmol/l (50 mg/dl) was applied, the absolute risk reductions and NNT3y were FOURIER Study 2.41% and 41 for those above the threshold versus 1.41% and 71 below the threshold. The randomized FOURIER (Further Cardiovascular Out- In a weighted least square linear regression analysis that comes Research with PCSK9 Inhibition in Patients with examined the association between treatment effect on CHD Elevated Risk) Study tested the effect of evolocumab on death, MI or UR and per unit decrease in Lp(a) adjusting cardiovascular outcomes versus placebo in patients with for differences in LDL-C, there was a significant relation- established atherosclerotic cardiovascular disease (median ship with a 15% relative risk reduction (95% CI 2, 26%, follow-up 2.2 years) [14]. P = 0.0199) per 25 nmol/l reduction in Lp(a). K 48 U. Julius et al. Table 1 CHD death, MI and UR beyond week 12 in dependence on Major CVEs were significantly reduced by alirocumab reached Lp(a) (median 29 nmol/l) and LDL-C (median 65 mg/dl) levels in the baseline 3rd (HR 0.79 (95% CI 0.66, 0.95)) and LDL-C > median LDL-C  median 4th quartiles (HR 0.83 (95% CI 0.70, 0.98)). Similar HRs (%) (%) were obtained after adjusting as detailed above. When the Lp(a) > median 8.52 7.09 time-weighted moving average Lp(a) change from baseline Lp(a)  median 7.33 5.86 was modeled with major CVEs or non-fatal MI significant LDL-C LDL cholesterol, Lp(a) Lipoprotein(a) reductions of events (approximately by 16%) were seen, even after adjusting for demographic variables (age, sex, The authors observed a stepwise decrease in the risk of race, region), baseline Lp(a), baseline LDL-C, change in CHD death, MI or UR for patients who achieved either LDL-C, and clinical variables (time from acute coronary an Lp(a) or LDL-C value below the achieved median with syndrome, body mass index, diabetes, smoking history). the lowest event rate observed for those who achieved lower levels of both values. Compared with patients above the me- dian achieved level for both lipid parameters, patients with Conclusions at least one level below the median had a 15% lower risk of major coronary events (adjusted HR 0.85, 95% CI 0.75, An elevation of Lp(a) is currently no accepted indication 0.97, P = 0.01) and those with both levels below their re- for PCSK9 inhibitors. Two reasons explain this situation: spective medians had a 29% lower risk of major coronary (1) comparing with the effect on LDL-C concentrations, events (adjusted HR 0.72, 95% CI 0.62, 0.83, P < 0.0001). It the decrease of Lp(a) under PCSK9 inhibitors is rather was reported that consistent results were observed when pa- small—even absent in many patients, and (2) the associ- tients were stratified by achieved values of LDL-C 70 mg/dl ation of the described reduction of Lp(a) levels by 20–30% and Lp(a) 120 nmol/l. with CVEs was unknown—new data on this topic appeared The incidence (3y KMrate, %) of the endpoint CHD only recently. death, MI and UR beyond week 12 was different depend- In two prospective controlled intervention studies with ing on whether the reached Lp(a) and LDL-C levels where both available PCSK9 inhibitors (evolocumab, alirocumab) above or below the median (Table 1;[15]). it could be shown that elevated baseline Lp(a) levels rep- resent an atherogenic risk factor, independently of baseline ODYSSEY OUTCOMES Trial LDL-C concentrations. It has to be remembered that Lp(a) levels were no in- This is a multicenter, randomized, double-blind, placebo- clusion criterion. Nonetheless, in the FOURIER Study ap- controlled trial involving 18,924 patients who had an acute proximately 33.1% of patients had a baseline concentration coronary syndrome 1 to 12 months earlier, had an LDL-C of higher than 120 nmol/l (or approximately 50 mg/dl) which at least 1.8 mmol/l (70 mg/dl), a non-high-density lipopro- is believed to be the 80th percentile in a general patient tein cholesterol level of at least 2.6 mmol/l (100 mg/dl), or population [15]. an apoB level of at least 80 mg/dl, and were receiving statin The lowering of Lp(a) with the injection therapy reduced therapy at a high-intensity dose or at the maximum tol- the rate of CVEs—with modeling an influence of base- erated dose [16]. Patients were randomly assigned to re- line values or PCSK9 inhibitor-induced changes of LDL- ceive alirocumab subcutaneously or matching placebo ev- C or other factors could be excluded. The higher the base- ery 2 weeks. line Lp(a) concentrations were, the higher the reduction of Data on Lp(a) have been presented at the ISA congress in CVEs by the PCSK9 inhibitors was. These findings clearly Toronto (2018). The median level was 21.2 mg/dl (IQR 6.7, put this new class of lipid-lowering drugs into another per- 59.6). Major CVEs occurred in the baseline 4th quartile spective. Possibly high Lp(a) levels will be taken into con- more often than in the 1st quartile (HR unadjusted 1.37; sideration when considering the use of these drugs in the adjusted (for age, sex, race, geographic region, time since future. Of course, this indication would be valid only in event, BMI, smoking history, diabetes, baseline LDL-C) patients whose Lp(a) levels really demonstrate a decrease 1.28). A similar relationship was observed for non-fatal on this injection therapy. MI. No relationship was found with stroke, cardiovascu- The missing effect of PCSK9 inhibitors on Lp(a) con- lar death, or all-cause death. In the course of the study centrations in up to 30% of patients is not yet fully under- alirocumab reduced Lp(a) levels in the mean by about stood. Reasons, discussed in the literature, are the follow- 5 mg/dl. After 4 months these reductions amounted to ing: (1) apo(a) with a low kringle IV type 2 number may less 9.8 mg/dl (median; IQR 3.18, 16.2) in the 3rd quartile and actively bind to the LDLR, and (2) because furin-cleaved to 20.2 mg/dl in the 4th quartile (median; IQR 8.0, 34.3), PCSK9 is somewhat less effective on binding to LDLRs more than in the 1st and 2nd quartiles. compared with the intact PCSK9 form, it is possible that K Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors 49 Conflict of interest U. Julius: honoraria from Aegerion, Akcea, Am- the balance between forms, as influenced by treatment with gen, Amryt, Chiesi, Sanofi, Kaneka, Diamed, Fresenius Medical Care, a PCSK9 inhibitor, also contributes to the degree of Lp(a) MSD. S. Tselmin received honoraria for lectures and consulting by reduction on therapy [1]. Amgen, Fresenius Medical Care, Kaneka, MSD, and Sanofi-Aventis. S. Fischer: honoraria from Sanofi, Amgen, MSD, Berlin-Chemie, Ab- The current therapeutic approach to improve the high- bott, Boehringer Ingelheim. U. Schatz and S. R. Bornstein declare that risk situation in patients with high Lp(a) levels is to opti- they have no competing interests. mize LDL-C below 1.8 mmol/l (70 mg/dl). Open Access This article is distributed under the terms of the Given the proposed potentiation of the CVD risk between Creative Commons Attribution 4.0 International License (http:// LDL-C and Lp(a), Verbeek et al. hypothesized in 2018 that creativecommons.org/licenses/by/4.0/), which permits unrestricted the risk associated with elevated Lp(a) levels would largely use, distribution, and reproduction in any medium, provided you give be attenuated at lower LDL-C levels [17]. They tested this appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were hypothesis in two large studies corresponding to a primary made. prevention setting: the European Prospective Investigation of Cancer (EPIC) Norfolk prospective population study and the Copenhagen City Heart Study prospective popu- References lation study. At LDL-C levels, corrected for Lp(a)-derived 1. 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Lipoprotein(a) and proprotein convertase subtilisin/kexin type9 inhibitors

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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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1861-0714
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10.1007/s11789-019-00099-z
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Abstract

Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations. Keywords Lipoprotein(a) · LDL cholesterol · PCSK9 inhibitors · Cardiovascular events · Lipoprotein apheresis Lipoprotein(a)—synthesis, composition, The clearance of Lp(a) from the bloodstream is still not metabolism, and clinical significance fully understood. Hepatic (LDL receptor (LDLR), VLDL receptor, scavenger receptor B1, LDL receptor–related pro- Lipoprotein(a) (Lp(a)) consists of an LDL particle to which tein 1, cluster of differentiation 36 receptor (CD36), plas- an apolipoprotein(a) (apo(a)) is linked with a single disul- minogen receptor) and nonhepatic receptors are probably fide bond. The binding between apolipoprotein (B) (apoB), involved [1–4]. Renal mechanisms may also play a role. the major apolipoprotein of the LDL, and apo(a) takes place It is assumed that LDLRs only play a significant role in either in the hepatic cells, in the space of Disse, or in the Lp(a) clearance when hepatic levels of the receptor are very vascular lumen [1]. The cholesterol content of the LDL in high and LDL-C levels are low, as is the case in propro- Lp(a) varies between 30 and 45%. The Lp(a) concentra- tein convertase subtilisin/kexin type 9 (PCSK9) inhibitor tion is genetically determined. Mutations in the Lp(a) gene therapy. It is possible that apo(a) isoform length influences (LPA) and especially a variable number of LPA kringles IV clearance behavior of Lp(a) in human plasma following up- type 2 in the apo(a) have an effect. A low number of these regulation of LDLRs. kringles is associated with higher Lp(a) levels. The physiological significance of Lp(a) particles may re- late to their procoagulatory properties. Thus, wound healing could be stimulated. On the other hand, Lp(a) induces atherosclerotic lesions This article is part of the special issue “Lp(a) – Update 2018” and is supposed to promote aortic valve stenosis: a com- U. Julius bination of proatherosclerotic, proinflammatory and proco- ulrich.julius@uniklinikum-dresden.de agulatory actions seems to be responsible [5]. Data suggest that the atherogenicity of Lp(a) may be mediated in part by Lipidology and Center for Extracorporeal Treatment, proinflammatory oxidized phospholipids [6]. Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany K 46 U. Julius et al. Plasma PCSK9 is found in association with Lp(a) parti- Eec ff ts of PCSK9 inhibitors on Lp(a) concentrations cles in humans with high Lp(a) levels and in mice carrying human Lp(a) [7]. Studies using epidemiological data, Mendelian random- Meta-analysis of randomized controlled trials with ization and genome-wide associations have proven that el- PCSK9 inhibitors evated Lp(a) induce cardiovascular events (CVEs) like my- ocardial infarction (MI), stroke, occlusions of carotids or of A meta-analysis of studies using PCSK9 inhibitors (27 leg arteries [5, 8]. randomized controlled trials [RCTs] in 11,864 patients) New data obtained in the Danish population with re- documented a mean reduction of Lp(a) levels by 21.90% spect to the relationship between Lp(a) and mortality (95% CI 24.28, 19.51) [10]. Treatment modalities like have recently been published: In this study Lp(a) lev- type of PCSK9 inhibitor, duration of therapy, application els >93 mg/dl (199 nmol/l; 96th–100th percentiles) versus in patients with or without familial hypercholesterolemia, <10 mg/dl (18 nmol/l; 1st–50th percentiles) were associ- monotherapy or combination therapy, types of control ated with a hazard ratio (HR) of 1.50 (95% CI 1.28–1.76) treatment (placebo, ezetimibe), baseline Lp(a) (below 50 for cardiovascular mortality and of 1.20 (1.10–1.30) for or above 50 mg/dl), and immunoassay did not have a sig- all-cause mortality [9]. High levels of Lp(a), induced by nificant influence on this reduction. The lower the reached low LPA kringle IV type 2 number of repeats rather than LDL-C concentration was, the higher the reduction rate for through high cholesterol content, were associated with Lp(a). Attention should be paid to the fact that in the ma- increased mortality. jority of the included studies mean Lp(a) ranged between 9 Lp(a) levels in the atherothrombotic range are gener- and 40 mg/dl; however, in one investigation this value was ally accepted as >30 to 50 mg/dl or >75 to 125 nmol/l [1]. 100 (but SD 162!) mg/dl. Such levels affect 20 to 30% of the global population, with possibly higher incidence in patients with established car- Evolocumab in patients with very high Lp(a) diovascular disease and calcific aortic valve disease. concentrations In 65 patients with Lp(a) concentrations of about 200 nmol/l PCSK9 inhibitors—mode of action an injection therapy with 420 mg evolocumab once in 4 weeks reduced Lp(a) after 16 weeks by 28.0 (56.5, 9.0) PCSK9 inhibitors are human monoclonal antibodies bind- nmol/l (median, IQR), equivalent to 13.9 (19.3, 8.5) percent ing to the PCSK9 protein. This protein binds to LDLRs for (mean, 95% CI) [12]. LDL-C was decreased by 2.2 (0.8) endocytosis and lysosome degradation in the liver, result- mmol/l, corresponding to 60.7 (65.8, 55.5) percent (mean, ing in an increase in circulating LDL cholesterol (LDL-C) 95% CI). level. LDLRs usually recycle after they transported LDL Interestingly, arterial wall inflammation (most diseased particles into the cells. By inhibiting this LDLR destruc- segment target-to-background ratio (MDS TBR)) in the in- tion, the number of LDLRs at the cell surface markedly dex vessel (left carotid, right carotid, or thoracic aorta) was increases—leading to an effective removal of circulating not changed by evolocumab. The explanation of the authors LDL particles. Thus, reductions of LDL-C of more than for this lack of change is that Lp(a) levels remained high 50% can be reached. despite the rather modest reduction induced by the PCSK9 Evidently, the PCSK9 protein also exerts effects on other inhibitor. receptors like VLDL receptor, LDL receptor-related pro- tein 1 or the apolipoprotein E receptor [3]. Effect of PCSK9 inhibitors in patients undergoing It was shown that PCSK9 may increase the secretion of lipoprotein apheresis therapy apo(a) and of apoB—an inhibition of PCSK9 may counter- act these effects [10]. Thus PCSK9 inhibitors reduce Lp(a) ODYSSEY ESCAPE Study levels by both increasing clearance and reducing its synthe- sis. Alirocumab (150 mg biweekly, 2:1 allocation to verum and Lp(a) kinetics were studied using intravenous D3-leucine placebo, respectively) was given to patients (n =62) who administration, mass spectrometry, and compartmental were treated with lipoprotein apheresis (LA) in order to modeling [11]. Evolocumab monotherapy was shown to evaluate the possibility to replace LA therapy by the PCSK9 lower the plasma Lp(a) pool size by decreasing the produc- inhibitor [13]. Alirocumab reduced Lp(a) levels in those tion of Lp(a) particles. In combination with atorvastatin, patients with normal values (mean below 20 mg/dl) after evolocumab lowered the plasma Lp(a) pool size by accel- 6 weeks by 15% (placebo controlled) and after 18 weeks erating the catabolism of Lp(a) particles. by 2.7%. But in patients with high baseline Lp(a) concen- K Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors 47 ab LDL-C 1 (mmol/l) LDL-C 2 (mmol/l) LDL-C reducon Lp(a) 1 (nmol/l) Lp(a) 2 (nmol/l) Lp(a) reducon m 3.66 1.74 -53.85% mean 199.00 156.35 -20.80% sd 1.24 0.87 0.12 SD 74.29 55.49 0.13 Max 8.24 4.16 -23.79% Max 376.00 247.00 -0.46% Min 1.48 0.38 -81.42% Min 90.00 61.00 -44.35% Fig. 1 Individual percent reductions of LDL-C (a, n =41) and of Lp(a) (b, n =23) after 12 weeks of PCSK9 inhibitor application (usually biweekly) in patients on LA therapy. LDL-C LDL cholesterol, Lp(a) Lipoprotein(a) trations (mean above 90 mg/dl) the corresponding changes Lp(a) was measured in 25,096 patients [15]. The me- amounted to 13% and to +1.9% (placebo controlled). dian (IQR) baseline Lp(a) concentration was 37 (13, 165) nmol/l. In the placebo arm, patients with baseline Lp(a) Observations of the authors in the highest quartile had a higher risk of coronary heart disease (CHD) death, MI or urgent revascularization (UR) At our center we initiated PCSK9 inhibitor therapy in (adjusted HR Q4:Q1 1.22, 95% CI 1.01,1.48) independent patients undergoing LA treatment when LDL-C levels re- of LDL-C. At 48 weeks, evolocumab significantly reduced mained high despite maximally tolerated lipid-lowering Lp(a) by a median (IQR) of 26.9% (6.2, 46.7%)—equiv- therapy (drugs, LA). Fig. 1 shows clear differences be- alent to 11 nmol/l (1, 32) absolute change. It is important tween patients with respect to lowering of LDL-C and to note that in more than 30% of the patients receiving Lp(a) (12 weeks after start of the injection therapy), indi- evolocumab no reduction of Lp(a) was seen! cating that reporting mean values is of limited significance The percent change in Lp(a) and LDL-C at 48 weeks in when describing the effectiveness of PCSK9 inhibitors. evolocumab patients was moderately positively correlated. Among the 41 patients who started PCSK9 inhibitor Evolocumab reduced the risk of CHD death, MI or UR therapy, only 23 showed elevated Lp(a) levels (higher than by 23% (HR 0.77, 95% CI 0.67, 0.88) in patients with 120 nmol/l before first LA session). a baseline Lp(a) > median, and by 7% (HR 0.93, 0.80, 1.08) in those  median. Coupled with the higher baseline risk, the absolute risk reductions and number-needed-to-treat for Outcomedatainprospective controlled 3 years (NNT3y) were 2.49% and 40 vs. 0.95% and 105, PCSK9 inhibitor studies—association with respectively. the effects of these drugs on Lp(a) levels When a clinical threshold of 120 nmol/l (50 mg/dl) was applied, the absolute risk reductions and NNT3y were FOURIER Study 2.41% and 41 for those above the threshold versus 1.41% and 71 below the threshold. The randomized FOURIER (Further Cardiovascular Out- In a weighted least square linear regression analysis that comes Research with PCSK9 Inhibition in Patients with examined the association between treatment effect on CHD Elevated Risk) Study tested the effect of evolocumab on death, MI or UR and per unit decrease in Lp(a) adjusting cardiovascular outcomes versus placebo in patients with for differences in LDL-C, there was a significant relation- established atherosclerotic cardiovascular disease (median ship with a 15% relative risk reduction (95% CI 2, 26%, follow-up 2.2 years) [14]. P = 0.0199) per 25 nmol/l reduction in Lp(a). K 48 U. Julius et al. Table 1 CHD death, MI and UR beyond week 12 in dependence on Major CVEs were significantly reduced by alirocumab reached Lp(a) (median 29 nmol/l) and LDL-C (median 65 mg/dl) levels in the baseline 3rd (HR 0.79 (95% CI 0.66, 0.95)) and LDL-C > median LDL-C  median 4th quartiles (HR 0.83 (95% CI 0.70, 0.98)). Similar HRs (%) (%) were obtained after adjusting as detailed above. When the Lp(a) > median 8.52 7.09 time-weighted moving average Lp(a) change from baseline Lp(a)  median 7.33 5.86 was modeled with major CVEs or non-fatal MI significant LDL-C LDL cholesterol, Lp(a) Lipoprotein(a) reductions of events (approximately by 16%) were seen, even after adjusting for demographic variables (age, sex, The authors observed a stepwise decrease in the risk of race, region), baseline Lp(a), baseline LDL-C, change in CHD death, MI or UR for patients who achieved either LDL-C, and clinical variables (time from acute coronary an Lp(a) or LDL-C value below the achieved median with syndrome, body mass index, diabetes, smoking history). the lowest event rate observed for those who achieved lower levels of both values. Compared with patients above the me- dian achieved level for both lipid parameters, patients with Conclusions at least one level below the median had a 15% lower risk of major coronary events (adjusted HR 0.85, 95% CI 0.75, An elevation of Lp(a) is currently no accepted indication 0.97, P = 0.01) and those with both levels below their re- for PCSK9 inhibitors. Two reasons explain this situation: spective medians had a 29% lower risk of major coronary (1) comparing with the effect on LDL-C concentrations, events (adjusted HR 0.72, 95% CI 0.62, 0.83, P < 0.0001). It the decrease of Lp(a) under PCSK9 inhibitors is rather was reported that consistent results were observed when pa- small—even absent in many patients, and (2) the associ- tients were stratified by achieved values of LDL-C 70 mg/dl ation of the described reduction of Lp(a) levels by 20–30% and Lp(a) 120 nmol/l. with CVEs was unknown—new data on this topic appeared The incidence (3y KMrate, %) of the endpoint CHD only recently. death, MI and UR beyond week 12 was different depend- In two prospective controlled intervention studies with ing on whether the reached Lp(a) and LDL-C levels where both available PCSK9 inhibitors (evolocumab, alirocumab) above or below the median (Table 1;[15]). it could be shown that elevated baseline Lp(a) levels rep- resent an atherogenic risk factor, independently of baseline ODYSSEY OUTCOMES Trial LDL-C concentrations. It has to be remembered that Lp(a) levels were no in- This is a multicenter, randomized, double-blind, placebo- clusion criterion. Nonetheless, in the FOURIER Study ap- controlled trial involving 18,924 patients who had an acute proximately 33.1% of patients had a baseline concentration coronary syndrome 1 to 12 months earlier, had an LDL-C of higher than 120 nmol/l (or approximately 50 mg/dl) which at least 1.8 mmol/l (70 mg/dl), a non-high-density lipopro- is believed to be the 80th percentile in a general patient tein cholesterol level of at least 2.6 mmol/l (100 mg/dl), or population [15]. an apoB level of at least 80 mg/dl, and were receiving statin The lowering of Lp(a) with the injection therapy reduced therapy at a high-intensity dose or at the maximum tol- the rate of CVEs—with modeling an influence of base- erated dose [16]. Patients were randomly assigned to re- line values or PCSK9 inhibitor-induced changes of LDL- ceive alirocumab subcutaneously or matching placebo ev- C or other factors could be excluded. The higher the base- ery 2 weeks. line Lp(a) concentrations were, the higher the reduction of Data on Lp(a) have been presented at the ISA congress in CVEs by the PCSK9 inhibitors was. These findings clearly Toronto (2018). The median level was 21.2 mg/dl (IQR 6.7, put this new class of lipid-lowering drugs into another per- 59.6). Major CVEs occurred in the baseline 4th quartile spective. Possibly high Lp(a) levels will be taken into con- more often than in the 1st quartile (HR unadjusted 1.37; sideration when considering the use of these drugs in the adjusted (for age, sex, race, geographic region, time since future. Of course, this indication would be valid only in event, BMI, smoking history, diabetes, baseline LDL-C) patients whose Lp(a) levels really demonstrate a decrease 1.28). A similar relationship was observed for non-fatal on this injection therapy. MI. No relationship was found with stroke, cardiovascu- The missing effect of PCSK9 inhibitors on Lp(a) con- lar death, or all-cause death. In the course of the study centrations in up to 30% of patients is not yet fully under- alirocumab reduced Lp(a) levels in the mean by about stood. Reasons, discussed in the literature, are the follow- 5 mg/dl. After 4 months these reductions amounted to ing: (1) apo(a) with a low kringle IV type 2 number may less 9.8 mg/dl (median; IQR 3.18, 16.2) in the 3rd quartile and actively bind to the LDLR, and (2) because furin-cleaved to 20.2 mg/dl in the 4th quartile (median; IQR 8.0, 34.3), PCSK9 is somewhat less effective on binding to LDLRs more than in the 1st and 2nd quartiles. compared with the intact PCSK9 form, it is possible that K Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors 49 Conflict of interest U. Julius: honoraria from Aegerion, Akcea, Am- the balance between forms, as influenced by treatment with gen, Amryt, Chiesi, Sanofi, Kaneka, Diamed, Fresenius Medical Care, a PCSK9 inhibitor, also contributes to the degree of Lp(a) MSD. S. Tselmin received honoraria for lectures and consulting by reduction on therapy [1]. Amgen, Fresenius Medical Care, Kaneka, MSD, and Sanofi-Aventis. S. Fischer: honoraria from Sanofi, Amgen, MSD, Berlin-Chemie, Ab- The current therapeutic approach to improve the high- bott, Boehringer Ingelheim. U. Schatz and S. R. Bornstein declare that risk situation in patients with high Lp(a) levels is to opti- they have no competing interests. mize LDL-C below 1.8 mmol/l (70 mg/dl). Open Access This article is distributed under the terms of the Given the proposed potentiation of the CVD risk between Creative Commons Attribution 4.0 International License (http:// LDL-C and Lp(a), Verbeek et al. hypothesized in 2018 that creativecommons.org/licenses/by/4.0/), which permits unrestricted the risk associated with elevated Lp(a) levels would largely use, distribution, and reproduction in any medium, provided you give be attenuated at lower LDL-C levels [17]. They tested this appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were hypothesis in two large studies corresponding to a primary made. prevention setting: the European Prospective Investigation of Cancer (EPIC) Norfolk prospective population study and the Copenhagen City Heart Study prospective popu- References lation study. At LDL-C levels, corrected for Lp(a)-derived 1. 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Journal

Clinical Research in Cardiology SupplementsSpringer Journals

Published: Mar 5, 2019

References