PCSK9 inhibitors: Ratification of the role of LDL cholesterol in cardiovascular prevention. Towards a convergence of European and North American prevention guidelines?

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Towards a convergence of European and North American prevention guidelines?" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2898 "Ancho" => 2162 "Tamanyo" => 219886 ] ] "descripcion" => array:1 [ "es" => "Número de pacientes necesarios a tratar (NNT) para evitar un evento cardiovascular en diferentes niveles de riesgo absoluto y c-LDL de partida en pacientes en tratamiento máximo con estatinas. La estimación del beneficio clínico del tratamiento hipolipidemiante en función del riesgo vascular y niveles de c-LDL se muestra en forma de NNT (NNT durante 5 años) para una intervención que reduce el c-LDL un 20% (panel A, efecto aproximado de ezetimiba) y del 50% (panel B, efecto aproximado de inhibidores de PCSK9). Los cálculos se han realizado asumiendo una reducción de riesgo relativo del 21% para cada reducción de 1 mmol/l (38,7mg/dl) de c-LDL. NNT: 1/reducción de riesgo absoluto×100. Reducción de riesgo absoluto: reducción de riesgo relativo×riesgo absoluto basal. El NNT da una aproximación al beneficio de la intervención en cada grupo de pacientes y del coste del tratamiento farmacológico asociado. Adaptado a partir de Robinson et al.<a class="elsevierStyleCrossRef" href="#bib0575">55</a>." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Guijarro, M. Camafort" "autores" => array:2 [ 0 => array:2 [ "nombre" => "C." 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(A) Artery of healthy model. (B) Artery with hypo-anechoic plaque (crosses) in the posterior wall of the bulb in a patient with hypercholesterolemia. Abbreviations: CCA, common carotid artery; ECA, external carotid artery; ICA, internal carotid artery." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L.M. Beltrán, E. Rodilla" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L.M." "apellidos" => "Beltrán" ] 1 => array:2 [ "nombre" => "E." 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Towards a convergence of European and North American prevention guidelines?" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "374" "paginaFinal" => "382" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "C. Guijarro, M. Camafort" "autores" => array:2 [ 0 => array:4 [ "nombre" => "C." "apellidos" => "Guijarro" "email" => array:1 [ 0 => "cguijarro@fhalcorcon.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Camafort" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Medicina Interna, Hospital Universitario Fundación Alcorcón, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos Alcorcón, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Interna General, ICMiD Hospital Clínic-IDIBAPS, Universidad de Barcelona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Inhibidores de PCSK9: ratificación del papel del colesterol LDL en prevención cardiovascular. ¿Hacia la convergencia en las guías de prevención europeas y norteamericanas?" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Ference et al.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> and Ference et al.<a class="elsevierStyleCrossRef" href="#bib0380">16</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 736 "Ancho" => 2500 "Tamanyo" => 136179 ] ] "descripcion" => array:1 [ "en" => "Effect of reducing low-density lipoprotein cholesterol (LDL-C) on coronary events according to the mechanism of reduction. Panel A: combination of various genetic scores for genes associated with changes in cholesterol levels and incidence of coronary artery disease adjusted for a reduction of 10mg/dL in LDL-C. Panel B: cardiovascular protective effect of various drug treatments that act on the previously mentioned genetic variants adjusted for a reduction of 38.7mg/dL in randomized clinical trials. The results show that the effect of the changes in LDL-C of genetic origin on the risk of vascular events is approximately the same for each unit change in LDL-C performed through an upregulation of LDL receptor. Similarly, the cardiovascular protective effect of statins, ezetimibe and PCSK9 inhibitors is similar for equivalent changes in LDL-C. Note that the protective effect of genetic changes (that act over the course of a lifetime) is approximately 4 times greater than that of drug treatments (typical duration of 4–5 years). The effect of bempedoic acid has not yet been evaluated in randomized clinical trials. There are no drugs that act directly on LDL receptor expression. Abbreviations: ACLY, ATP citrate lyase; bempedoic A., bempedoic acid; CI, confidence interval; LDLR, LDL receptor; NPC1L1, Niemann-Pick C1-Like 1 protein; (i) PCSK9 (inhibitors of) convertase subtilisin/kexin type 9 proprotein; OR, odds ratio." ] ] ] "textoCompleto" => "Low-density lipoprotein cholesterol and arteriosclerosisThe epidemiological association between high cholesterol levels and the development of atherosclerotic cardiovascular disease, in particular ischemic heart disease, has been overwhelmingly confirmed.<a class="elsevierStyleCrossRefs" href="#bib0305">1,2</a> In recent decades, a considerable number of randomized clinical trials have shown that lipid-lowering therapy targeted mainly at reducing low-density lipoprotein cholesterol (LDL-C) translates into significant reductions in cardiovascular morbidity and mortality.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> Although not exclusively, the most consistent evidence has been gained from studies with statins. Meta-analyses of the Cholesterol Treatment Trialists' CTT Collaboration have consistently shown that an absolute reduction of 1mmol/L (38.7mg/dL) in LDL-C is associated with a 20–25% reduction in cardiovascular complications.<a class="elsevierStyleCrossRefs" href="#bib0315">3,4</a> The cardiovascular protective effect is not restricted to ischemic heart disease, but rather extends to atherosclerotic cerebrovascular disease. Additionally, lipid-lowering therapy is associated with a reduction in cardiovascular and overall mortality, with no increase in mortality by cancer or other causes. Although statin therapy is associated with a slightly increased risk of developing diabetes, this risk has been clearly outweighed by a higher qualitative and quantitative benefit in cardiovascular risk prevention.<a class="elsevierStyleCrossRef" href="#bib0325">5</a> Studies have not found a threshold below which the protective effect of lipid-lowering therapy is attenuated or disappears, which has translated into the expression “the lower, the better”.Although lipid-lowering therapy is perhaps one of the most important therapeutic contributors to reducing cardiovascular mortality in Western countries,<a class="elsevierStyleCrossRef" href="#bib0330">6</a> cardiovascular mortality continues to be the leading cause of avoidable death in our setting.<a class="elsevierStyleCrossRef" href="#bib0335">7</a> The approximately 30% risk reduction for cardiovascular events in clinical trials has focused attention on the other patients (70%) who apparently do not benefit from lipid-lowering therapy, resulting in the concept of “residual risk”. Although this term has become widespread, it is questionable to consider such a high percentage as “residual”. A more appropriate term would be “persistent risk”.<a class="elsevierStyleCrossRef" href="#bib0340">8</a>Although it is illusory to assume that a multifactorial disease such as arteriosclerosis can be controlled with a single-factor approach, it is reasonable to ask how the control of dyslipidemia can be improved.<a class="elsevierStyleCrossRef" href="#bib0345">9</a> Trials primarily targeting the increase in high-density lipoprotein cholesterol (HDL-C) have resulted in notable failures.<a class="elsevierStyleCrossRef" href="#bib0350">10</a> Recent Mendelian randomization studies have questioned the role reduced c-HDL as a causal agent of arteriosclerosis.<a class="elsevierStyleCrossRef" href="#bib0355">11</a> In contrast, genetic studies have supported a role for triglyceride-rich lipoproteins as causal agents of vascular injury.<a class="elsevierStyleCrossRef" href="#bib0360">12</a> Thus, modulating the activity of lipoprotein lipase, the main enzyme involved in degrading triglyceride-rich lipoproteins (e.g., through angiopoietin-like proteins), takes on a new role.<a class="elsevierStyleCrossRef" href="#bib0365">13</a> The REDUCE-IT study recently supported the role of high doses of omega 3 fatty acids in reducing cardiovascular complications in patients with hypertriglyceridemia.<a class="elsevierStyleCrossRef" href="#bib0370">14</a> Nevertheless, an analysis of the revival of hypertriglyceridemia as a therapeutic target clearly exceeds the objectives of this review.Reducing low-density lipoprotein cholesterol: beyond statinsThe success of statins paradoxically led to their consideration as a per se cardiovascular protective drug, to the point of ignoring the relevance of cholesterol as a factor. Thus, the 2013 US guidelines proposed the use of statins at varying intensities based on the patients’ vascular risk, considering unnecessary the measurement of cholesterol levels during follow-up.<a class="elsevierStyleCrossRef" href="#bib0375">15</a> These recommendations cast doubt on the possible benefit of reducing LDL-C, particularly with non statin therapies. It has recently been shown that various genetic polymorphisms that reduce the action of ATP citrate lyase (ACLY, an enzyme involved in cholesterol synthesis upstream from HMG-CoA reductase) are associated with a reduction in LDL-C and reduced cardiovascular complications.<a class="elsevierStyleCrossRef" href="#bib0380">16</a> Bempedoic acid, a selective inhibitor of ACLY, produces modest reductions in circulating cholesterol, even in patients treated with statins.<a class="elsevierStyleCrossRef" href="#bib0385">17</a> The possible cardiovascular protective effect of this new cholesterol synthesis inhibitor is being evaluated in clinical trials.The IMPROVE-IT study showed that treatment with ezetimibe, an inhibitor of intestinal cholesterol absorption, provided cardiovascular benefits to patients in secondary prevention already treated with statins, extending the lipid-lowering benefits to achieved LDL-C levels of approximately 55mg/dL.<a class="elsevierStyleCrossRef" href="#bib0390">18</a> Mendelian randomization studies have confirmed that changes in cholesterol absorption through genetic variants in the NPCL1 protein (ezetimibe’s target of action) are also associated wtih changes in the incidence of coronary heart disease, closing the pathophysiological circle (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0310">2</a> Other recent studies<a class="elsevierStyleCrossRefs" href="#bib0395">19,20</a> have confirmed that reducing LDL-C through statins to levels of approximately 50mg/dL continues to offer cardiovascular benefits.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Although statins and ezetimibe have different primary mechanisms of action (cholesterol synthesis inhibition and cholesterol absorption inhibition, respectively), both actions involve reducing the intracellular cholesterol pool. As a result, an increase in LDL receptor expression and cell uptake of circulating cholesterol takes place. This secondary response is the main mechanism responsible for the reduction in circulating cholesterol for both drugs. It is therefore interesting to consider the possible beneficial effect of a more direct modulation of the LDL receptor.Proprotein convertase subtilisin/kexin type 9, lipid effects and arteriosclerosisJust about 15 years ago, a study described a family who showed a phenotype similar to familial hypercholesterolemia: marked increase in LDL-C and increased cardiovascular morbidity, with an autosomal dominant inheritance pattern in the absence of mutations of the LDL receptor or apolipoprotein B-100 (17). Genetic studies showed that these patients exhibited increased expression of a protein: proprotein convertase subtilisin/kexin type 9 (PCSK9). The role of PCSK9 in regulating cholesterol has been widely evaluated in recent years.<a class="elsevierStyleCrossRef" href="#bib0405">21</a> PCSK9 is expressed in a variety of tissues but predominantly in the liver. The PCSK9 protein binds to the LDL receptor. Once LDL binds to its receptor, the complex is internalized in the cell, providing its lipid cargo for cell metabolism. In the presence of PCSK9, the LDL receptor is subjected to degradation in the lysosome. In the absence of PCSK9, the receptor is “recycled” and transported to the cell membrane, where it can continue to uptake LDL particles.Inversely, mutations with defective PCSK9 synthesis have been reported, which present an opposite phenotype to that of familial hypercholesterolemia: reduced circulating cholesterol levels and a marked reduction in the incidence of ischemic heart disease.<a class="elsevierStyleCrossRef" href="#bib0410">22</a> A few individuals who were homozygous or double heterozygous for null alleles of PCSK9 have been reported, with undetectable PCSK9 levels.<a class="elsevierStyleCrossRef" href="#bib0415">23</a> These patients show dramatically low LDL-C levels but present normal development and no clinical consequences other than protection against developing arteriosclerosis. This natural experiment suggests that we can in some manner cancel the function of PCSK9 to reduce LDL-C levels and protect against the development of arteriosclerosis with no apparent risk of complications. Reductions in cholesterol levels associated with genetic profiles with cholesterol synthesis inhibition (HMG-CoA reductase, ATP citrate lyase), cholesterol absorption (NPC1-L1) and LDL receptor degradation (PCSK9) result in reductions in the rate of ischemic heart disease proportional to the reduction in LDL-C by any of the above mechanisms.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> If we have drugs that can inhibit cholesterol synthesis (statins, bempedoic acid), absorption (ezetimibe) and degradation of the LDL receptor (PCSK9), with no adverse effects (“off target”), we can expect reductions in the incidence rate of atherosclerotic vascular disease directly proportional to the reduction in LDL-C levels (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0340">8</a>Various methods have been developed to reduce LDL-C levels via PCSK9, one of which is the administration of interference ribonucleic acid (RNAi) which blocks the expression of PCSK9. This RNAi conjugated with N-acetylgalactosamine (inclisiran) is administered parenterally and taken up by the liver, leading to selective prevention of the hepatic synthesis of PCSK9. Clinical studies in early phases have shown that injection of inclisiran every 3-6 months is associated with LDL-C reductions of 50% lasting up to 6 months, with no apparent adverse effects.<a class="elsevierStyleCrossRef" href="#bib0420">24</a> As of this time, ongoing clinical studies in advanced phases are evaluating whether the treatment of patients with hypercholesterolemia translates effectively into a reduction of cardiovascular complications with no relevant adverse effects.Inhibition of proprotein convertase subtilisin/kexin type 9 and cardiovascular protection: FOURIER and ODYSSEY OUTCOMES studiesThe most advanced clinical procedure for blocking the action of PCSK9 is the use of monoclonal antibodies against PCSK9.<a class="elsevierStyleCrossRef" href="#bib0425">25</a> Three monoclonal antibodies have been developed: bococizumab, alirocumab and evolocumab. Bococizumab is a humanized monoclonal antibody that loses efficacy due the development of antibodies against bococizumab. Although the clinical development of bococizumab has been stopped for this reason, the results of the Spire studies have already demonstrated cardiovascular protective effects.<a class="elsevierStyleCrossRefs" href="#bib0430">26,27</a>The fully human antibodies alirocumab and evolocumab have completed a notable clinical development culminated by 2 randomized clinical trials whose main outcome was a combined variable of major cardiovascular events.The FOURIER study<a class="elsevierStyleCrossRef" href="#bib0440">28</a> assessed the effect of evolocumab versus placebo in 27,654 patients between 40 and 85 years of age with a prior history of cardiovascular disease (acute myocardial infarction, ischemic stroke or peripheral arterial disease) and an additional cardiovascular risk factor. The patients presented an LDL-C level >70mg/dL and a base lipid-lowering therapy with statins (high intensity in 69%). Approximately 5% of the patients were concomitantly treated with ezetimibe. Evolocumab was administered bi-weekly (140mg subcutaneously) or monthly (420mg subcutaneously), with a median follow-up of 2.2 years. Treatment with evolocumab was associated with an intense lipid-lowering effect (LDL-C reduction of 56mg/dL [59%], sustained over time). Treatment with evolocumab was also associated with a 15% reduction (hazard ratio [HR], 0.85; 95% CI 0.79–0.92; p<.0001) in the combined primary endpoint (cardiovascular death, acute myocardial infarction, stroke, hospitalization for unstable angina or revascularization). This effect was slightly higher for the key secondary endpoint (cardiovascular death, acute myocardial infarction, stroke), with a 20% reduction (HR, 0.8; 95% CI 0.73–0.88). There were no differences in adverse effects (including the development of diabetes or cognitive problems) between the placebo and intervention groups, except for an increased rate of local reactions at the injection site with evolocumab (2.1% vs. 1.6%). The cardiovascular protective effect might seem modest when compared with the marked reduction in LDL-C, but we should consider the limited duration of the study (2.2 years) compared with the typical duration of studies with statins (approximately 5 years). Similar to the results of studies with statins, the risk reduction was lower in the first year (12%, 95% CI 3–20) than in the second year of follow-up (19%, 95% CI 11–27), both of which are consistent with the expected benefit according to the absolute reduction in LDL-C levels and treatment duration. The results were consistent for all analyzed subgroups, including a similar protective effect for patients with the lowest starting levels of LDL, with no loss of effect or increase in adverse effects up to LDL levels of approximately 30mg/dL.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> It is important to note that given the fact that the action of PCSK9 inhibitors for reducing cholesterol is to promote cell uptake of PCSK9 via the LDL receptor, toxic cell effects are not expected simply due to the reduction in circulating LDL-C.<a class="elsevierStyleCrossRef" href="#bib0450">30</a>The ODYSSEY OUTCOMES study<a class="elsevierStyleCrossRef" href="#bib0455">31</a> is consistent with and complementary to the FOURIER trial. Unlike the FOURIER study, the ODYSSEY OUTCOMES study required the presence of a recent acute coronary syndrome between 1 and 12 months prior to the study, as well as similar lipid levels (LDL-C >70mg/dL, non-HDL cholesterol >100mg/dL or apolipoprotein B >80mg/dL). A total of 18,924 patients were randomly assigned to receive placebo or alirocumab 75/mg subcutaneously bi-weekly in a blinded manner. The patients in the ODYSSEY OUTCOMES study underwent intensive lipid-lowering therapy (more than 95% with statins, 89% with high-intensity statins and 2.9% with ezetimibe). Unlike the FOURIER study with fixed doses of evolocumab, the alirocumab doses were titrated upwards or downwards to achieve an LDL-C level between 25 and 50mg/dL, suppressing the treatment with alirocumab if levels below 15mg/dL were reached. The patients assigned to alirocumab showed a reduction in LDL-C at 4 weeks of 53mg/dL (57%), which was attenuated to a reduction of 37mg/dL at 4 years (in the intent-to-treat analysis).Treatment with alirocumab was associated with a 15% reduction (HR, 0.85; 95% CI 0.78–0.93; p<.001) in the combined primary endpoint (cardiovascular death, acute myocardial infarction, stroke or angina that required hospitalization) after a median follow-up of 2.8 years. Once again, treatment with alirocumab was not associated with an increased incidence of adverse effects except for the presence of local irritation at the injection site (3.8% vs. 2.1%). It is worth noting that, unlike the FOURIER study, treatment with alirocumab was associated with a reduction in overall mortality (3.5% vs. 4.1%; HR, 0.85; 95% CI 0.73–0.98; nominal p=.026). Although the nominal p was significant according to conventional limits (<.05), this result should be interpreted with caution, because there was no reduction in mortality of cardiovascular origin, a variable that was required to be significant in a hierarchycal evaluation of the secondary outcome variables prior to the evaluation of the overall mortality. Nevertheless, noncardiovascular mortality increased in the patients who presented a previous nonfatal cardiovascular event, suggesting that some “noncardiovascular” deaths could have a certain relationship with the severity of the cardiovascular disease partially prevented by alirocumab.A subgroup analysis showed that the entire cardiovascular benefit for the patients in the ODYSSEY OUTCOMES study was concentrated in the patients who started with LDL-C levels >100mg/dL. In this subgroup of patients, treatment with alirocumab was associated with a significant reduction in cardiovascular mortality (HR, 0.72; 95% CI 0.53–0.98) and overall mortality (HR, 0.71; 95% CI 0.56–0.90). The loss of the protective effect by the treatment with alirocumab for patients with LDL-C levels <100mg/dL in the ODYSSEY OUTCOMES study contrasts with the persistence of this effect in the FOURIER study.<a class="elsevierStyleCrossRefs" href="#bib0440">28,31</a> It is possible that the design of the ODYSSEY OUTCOMES study, unlike that of the FOURIER study, with the option of reducing the alirocumab regimen (and including its suppression if LDL levels were sufficiently low) could have limited the effects in a conventional intent-to-treat analysis. Studies have very recently reported that the reduction in mortality achieved with alirocumab extends to LDL cholesterol levels of approximately 30mg/dL.These results are consistent with previous studies showing that reductions in cardiovascular complications are still achieved when reaching cholesterol levels between 25 and 30mg/dL.<a class="elsevierStyleCrossRefs" href="#bib0460">32,33</a>In any case, both studies confirm that treatment with PCSK9 inhibitors in patients with atherosclerotic vascular disease and LDL-C levels >70mg/dL reduces cardiovascular complications with a good safety profile. Recent studies, such as the one described in this issue, confirm the lipid-lowering efficacy and safety of PCSK9 inhibitors in actual clinical practice.<a class="elsevierStyleCrossRefs" href="#bib0470">34,35</a>It has therefore been demonstrated that LDL-C reduction using statins, ezetimibe or PCSK9 inhibitors can offer cardiovascular protective effects well beyond the levels that, until recently, have been considered optimal.<a class="elsevierStyleCrossRef" href="#bib0480">36</a>Cardiovascular risk prevention guidelines: towards a new convergenceThe 2013 US guidelines on hypercholesterolemia<a class="elsevierStyleCrossRef" href="#bib0370">14</a> granted statins the leading role, indicating that treatment with statins of high or moderate intensity is warranted by the overall vascular risk situation. Unlike the preceding US guidelines (NCEPIII)<a class="elsevierStyleCrossRef" href="#bib0485">37</a> and the European guidelines, the objectives of LDL-C control were removed, and even the need to measure the lipid-lowering treatment response was left out.<a class="elsevierStyleCrossRef" href="#bib0490">38</a> However, within the US scientific community, an expert group of the American College of Cardiology<a class="elsevierStyleCrossRefs" href="#bib0495">39,40</a> continued to consider as highly relevant the measurement of cholesterol levels and options for lipid-lowering therapy complementary to statins. The recent US guidelines<a class="elsevierStyleCrossRef" href="#bib0505">41</a> have reinstated (at least partially) the advisability of achieving lipid objectives (LDL <70mg/dL) in secondary prevention, considering the use of ezetimibe or iPCSK9 reasonable for patients who do not reach these levels.The use of ezetimibe is recommended as a priority option given the evidence of long-term safety studies, maintaining PCSK9 inhibitors as an alternative if reductions in LDL-C unattainable with ezetimibe are necessary (>25% reductions).<a class="elsevierStyleCrossRefs" href="#bib0495">39,41</a>Thus, the recent US hypercholesterolemia guidelines have gone beyond the monoculture of statins as the lipid-lowering therapy in cardiovascular risk prevention, realigning to a significant extent with the European guidelines.The use of statins and ezetimibe is also favored given the fact that they are generic drugs with acceptable costs, are easy to administer and have been demonstrated safe after decades of clinical use in hundreds of thousands of patients. In contrast, the cost of PCSK9 inhibitors is very high, and there are no data on their long-term safety and efficacy.<a class="elsevierStyleCrossRefs" href="#bib0505">41–43</a> These considerations justify the selective use of PCSK9 inhibitors in patients most likely to benefit from using these drugs. The Spanish and European Societies of Arteriosclerosis and Cardiology have issued specific recommendations for the use of PCSK9 inhibitors after the recent approval for the use of both drugs for treating difficult-to-control hypercholesterolemia.<a class="elsevierStyleCrossRefs" href="#bib0520">44–47</a> The initial guidelines were developed based on the lipid-lowering action of PCSK9 inhibitors before the publication of the pivotal FOURIER and ODYSSEY OUTCOMES studies, based on the potential but still undemonstrated cardiovascular benefits in randomized clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0540">48,49</a> After the recent findings, the European Medicines Agency approved the indication of evolocumab and alirocumab for preventing atherosclerotic cardiovascular disease.<a class="elsevierStyleCrossRefs" href="#bib0550">50,51</a> A reassessment of the role of PCSK9 inhibitors in the spectrum of cardiovascular risk prevention is therefore expected. Given that PCSK9 inhibitors are highly expensive drugs, the issue translates mainly to a cost/benefit analysis, the subject of wide debate at present.<a class="elsevierStyleCrossRefs" href="#bib0560">52–54</a>Recent publications have explicitly advocated for a comprehensive approach that addresses the absolute risk of cardiovascular disease and the expected benefit of reducing LDL-C.<a class="elsevierStyleCrossRef" href="#bib0575">55</a> Determining the clinical benefit of the main lipid-lowering therapies available (statins, ezetimibe, PCSK9 inhibitors) has shown extraordinary consistency in the benefit derived from the absolute reduction from starting LDL-C levels.<a class="elsevierStyleCrossRefs" href="#bib0310">2,4,16</a> Thus, the benefit in reducing the risk of vascular events is proportional to the starting LDL-C level and the proportional reduction achievable with each treatment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Paradoxically, cardiovascular risk stratification in secondary prevention has not achieved a generalized consensus. A number of scientific societies, such as the American Society of Clinical Endocrinologists, have proposed the new vascular risk category “extreme”,<a class="elsevierStyleCrossRef" href="#bib0580">56</a> which includes patients in secondary prevention who present any of the following characteristics: (a) recurrence of ischemia despite LDL-C levels <70mg/dL; (b) diabetes mellitus; (c) chronic renal failure (stages 3/4); (d) familial hypercholesterolemia; and (e) early cardiovascular disease. Subgroup studies of the clinical trials with PCSK9 inhibitors have also identified other groups at especially high risk who can obtain a greater absolute benefit from the therapy, such as those with a recent acute coronary syndrome, extensive atherosclerosis (involvement of multiple territories, especially with symptomatic peripheral arterial disease) and an increase in lipoprotein (a) levels.<a class="elsevierStyleCrossRefs" href="#bib0440">28,31,57–59</a> The Spanish Society of Arteriosclerosis has developed updated guidelines with usage recommendations based on these principles.<a class="elsevierStyleCrossRef" href="#bib0600">60</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>In summary, the results of cardiovascular risk prevention trials with PCSK9 inhibitors, combined with genetic studies and intervention with statins and inhibitors of cholesterol absorption, confirm the etiological role of LDL-C in the development of arteriosclerosis. Therapy with drugs that reduce LDL-C levels (if their safety is demonstrated in clinical trials) can offer a benefit proportional to the reduction in LDL-C to previously unsuspected levels, much lower than the “ambitious” therapeutic objectives of most current guidelines on cardiovascular risk prevention. The main challenge for clinicians is the correct identification of patients with “extreme” vascular risk who could benefit from a particularly intensive lipid-lowering therapy.Conflicts of interestCarlos Guijarro declares having been reimbursed for talks, training and consulting by AMGEN, Esteve, MSD, Sanofi." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1471356" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1340022" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1471357" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1340021" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Low-density lipoprotein cholesterol and arteriosclerosis" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Reducing low-density lipoprotein cholesterol: beyond statins" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Proprotein convertase subtilisin/kexin type 9, lipid effects and arteriosclerosis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Inhibition of proprotein convertase subtilisin/kexin type 9 and cardiovascular protection: FOURIER and ODYSSEY OUTCOMES studies" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Cardiovascular risk prevention guidelines: towards a new convergence" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-04-22" "fechaAceptado" => "2019-05-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1340022" "palabras" => array:9 [ 0 => "Cholesterol" 1 => "Low density lipoprotein" 2 => "Clinical guidelines" 3 => "Mendelian randomization analysis" 4 => "Hydroxymethylglutaryl-CoA reductase inhibitors" 5 => "Ezetimibe" 6 => "Proprotein convertase subtilisin kexin 9 inhibitors" 7 => "Cost-effectiveness analysis" 8 => "Numbers needed to treat" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1340021" "palabras" => array:10 [ 0 => "Colesterol" 1 => "Lipoproteínas de baja densidad" 2 => "Prevención cardiovascular" 3 => "Aleatorización mendeliana" 4 => "Guías clínicas" 5 => "Inhibidores hidroximetilglutaril coenzima A reductasa" 6 => "Inhibidores de proproteína convertasa subtilisina kexina 9" 7 => "Ezetimiba" 8 => "Análisis de coste-efectividad" 9 => "Número necesario a tratar" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The epidemiological association of cholesterol associated with low density lipoproteins (LDL-c) levels and the development of atherosclerotic vascular disease has been ratified by mendelian randomization studies. Paradoxically, the success of statins led to the underestimation of other lipid-lowering therapies and even the measurement of LDL-c. Recent studies show that the reduction of LDL-c to extraordinarily low levels through absorption inhibition, and, in a particularly intensive manner, with monoclonal antibodies against pro-protein convertase subtilisine kexine 9 (PCSK9) continues to offer cardiovascular protection. However, the high cost and limited experience with PCSK-9 inhibitors advised a prudent use of them. An appropriate selection of patients most likely to benefit from treatment with PCSK9 inhibitors emerges as the basis for a consensus of international guidelines: the combination of a high absolute vascular risk and a greater expected benefit by the starting LDL-c levels." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La asociación epidemiológica entre los niveles de colesterol asociado a lipoproteínas de baja densidad (c-LDL) y el desarrollo de enfermedad vascular aterosclerosa ha sido ratificada mediante estudios de aleatorización mendeliana. Paradójicamente, el éxito de las estatinas condujo a minusvalorar otros tratamientos hipolipidemiantes e incluso la medición del c-LDL. Estudios recientes muestran que la reducción del c-LDL hasta niveles extraordinariamente bajos mediante inhibidores de la absorción y, de modo especialmente intenso, con los anticuerpos monoclonales anti proproteína convertasa subtilisina kexina 9 (PCSK9) continúa ofreciendo protección cardiovascular. Sin embargo, el elevado coste y la limitada experiencia con los inhibidores de PCSK-9 aconsejan un uso prudente de los mismos. Una selección adecuada de los pacientes que más se pueden beneficiar del tratamiento con inhibidores de vPCSK9 emerge como base de consenso de las guías internacionales: la combinación de un elevado riesgo vascular absoluto y un mayor beneficio esperable por los niveles de c-LDL de partida." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Guijarro C, Camafort M. PCSK9 inhibitors: Ratification of the role of LDL cholesterol in cardiovascular prevention. Towards a convergence of European and North American prevention guidelines? Rev Clin Esp. 2020;220:374–382." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Ference et al.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> and Ference et al.<a class="elsevierStyleCrossRef" href="#bib0380">16</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 736 "Ancho" => 2500 "Tamanyo" => 136179 ] ] "descripcion" => array:1 [ "en" => "Effect of reducing low-density lipoprotein cholesterol (LDL-C) on coronary events according to the mechanism of reduction. Panel A: combination of various genetic scores for genes associated with changes in cholesterol levels and incidence of coronary artery disease adjusted for a reduction of 10mg/dL in LDL-C. Panel B: cardiovascular protective effect of various drug treatments that act on the previously mentioned genetic variants adjusted for a reduction of 38.7mg/dL in randomized clinical trials. The results show that the effect of the changes in LDL-C of genetic origin on the risk of vascular events is approximately the same for each unit change in LDL-C performed through an upregulation of LDL receptor. Similarly, the cardiovascular protective effect of statins, ezetimibe and PCSK9 inhibitors is similar for equivalent changes in LDL-C. Note that the protective effect of genetic changes (that act over the course of a lifetime) is approximately 4 times greater than that of drug treatments (typical duration of 4–5 years). The effect of bempedoic acid has not yet been evaluated in randomized clinical trials. There are no drugs that act directly on LDL receptor expression. Abbreviations: ACLY, ATP citrate lyase; bempedoic A., bempedoic acid; CI, confidence interval; LDLR, LDL receptor; NPC1L1, Niemann-Pick C1-Like 1 protein; (i) PCSK9 (inhibitors of) convertase subtilisin/kexin type 9 proprotein; OR, odds ratio." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Robinson et al.<a class="elsevierStyleCrossRef" href="#bib0575">55</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2898 "Ancho" => 2161 "Tamanyo" => 263486 ] ] "descripcion" => array:1 [ "en" => "Number of patients needed to treat (NNT) to prevent a cardiovascular event at various levels of absolute risk and starting LDL-C levels in patients undergoing maximum treatment with statins. The estimate of the clinical benefit of lipid-lowering treatment according to the vascular risk and LDL-C levels is shown in NNT form (NNT for 5 years) for an intervention that reduces LDL-C by 20% (panel A, approximate effect of ezetimibe) and by 50% (panel B, approximate effect of PCSK9 inhibitors). The calculations were performed assuming a 21% reduction in relative risk for each 1mmol/L (38.7mg/dL) reduction in LDL-C. NNT: 1/reduction of absolute risk×100. Absolute risk reduction: relative risk reduction×baseline absolute risk. 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