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which has translated into the expression &#8220;the lower&#44; the better&#8221;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Although lipid-lowering therapy is perhaps one of the most important therapeutic contributors to reducing cardiovascular mortality in Western countries&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> cardiovascular mortality continues to be the leading cause of avoidable death in our setting&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a> The approximately 30&#37; risk reduction for cardiovascular events in clinical trials has focused attention on the other patients &#40;70&#37;&#41; who apparently do not benefit from lipid-lowering therapy&#44; resulting in the concept of &#8220;residual risk&#8221;&#46; Although this term has become widespread&#44; it is questionable to consider such a high percentage as &#8220;residual&#8221;&#46; A more appropriate term would be &#8220;persistent risk&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Although it is illusory to assume that a multifactorial disease such as arteriosclerosis can be controlled with a single-factor approach&#44; it is reasonable to ask how the control of dyslipidemia can be improved&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Trials primarily targeting the increase in high-density lipoprotein cholesterol &#40;HDL-C&#41; have resulted in notable failures&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> Recent Mendelian randomization studies have questioned the role reduced c-HDL as a causal agent of arteriosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> In contrast&#44; genetic studies have supported a role for triglyceride-rich lipoproteins as causal agents of vascular injury&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a> Thus&#44; modulating the activity of lipoprotein lipase&#44; the main enzyme involved in degrading triglyceride-rich lipoproteins &#40;e&#46;g&#46;&#44; through angiopoietin-like proteins&#41;&#44; takes on a new role&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></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&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> Nevertheless&#44; an analysis of the revival of hypertriglyceridemia as a therapeutic target clearly exceeds the objectives of this review&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Reducing low-density lipoprotein cholesterol&#58; beyond statins</span><p id="par0020" class="elsevierStylePara elsevierViewall">The success of statins paradoxically led to their consideration as a <span class="elsevierStyleItalic">per se</span> cardiovascular protective drug&#44; to the point of ignoring the relevance of cholesterol as a factor&#46; Thus&#44; the 2013 US guidelines proposed the use of statins at varying intensities based on the patients&#8217; vascular risk&#44; considering unnecessary the measurement of cholesterol levels during follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> These recommendations cast doubt on the possible benefit of reducing LDL-C&#44; particularly with non statin therapies&#46; It has recently been shown that various genetic polymorphisms that reduce the action of ATP citrate lyase &#40;ACLY&#44; an enzyme involved in cholesterol synthesis upstream from HMG-CoA reductase&#41; are associated with a reduction in LDL-C and reduced cardiovascular complications&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> Bempedoic acid&#44; a selective inhibitor of ACLY&#44; produces modest reductions in circulating cholesterol&#44; even in patients treated with statins&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a> The possible cardiovascular protective effect of this new cholesterol synthesis inhibitor is being evaluated in clinical trials&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The IMPROVE-IT study showed that treatment with ezetimibe&#44; an inhibitor of intestinal cholesterol absorption&#44; provided cardiovascular benefits to patients in secondary prevention already treated with statins&#44; extending the lipid-lowering benefits to achieved LDL-C levels of approximately 55<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a> Mendelian randomization studies have confirmed that changes in cholesterol absorption through genetic variants in the NPCL1 protein &#40;ezetimibe&#8217;s target of action&#41; are also associated wtih changes in the incidence of coronary heart disease&#44; closing the pathophysiological circle &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> Other recent studies<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">19&#44;20</span></a> have confirmed that reducing LDL-C through statins to levels of approximately 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dL continues to offer cardiovascular benefits&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Although statins and ezetimibe have different primary mechanisms of action &#40;cholesterol synthesis inhibition and cholesterol absorption inhibition&#44; respectively&#41;&#44; both actions involve reducing the intracellular cholesterol pool&#46; As a result&#44; an increase in LDL receptor expression and cell uptake of circulating cholesterol takes place&#46; This secondary response is the main mechanism responsible for the reduction in circulating cholesterol for both drugs&#46; It is therefore interesting to consider the possible beneficial effect of a more direct modulation of the LDL receptor&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Proprotein convertase subtilisin&#47;kexin type 9&#44; lipid effects and arteriosclerosis</span><p id="par0035" class="elsevierStylePara elsevierViewall">Just about 15 years ago&#44; a study described a family who showed a phenotype similar to familial hypercholesterolemia&#58; marked increase in LDL-C and increased cardiovascular morbidity&#44; with an autosomal dominant inheritance pattern in the absence of mutations of the LDL receptor or apolipoprotein B-100 &#40;17&#41;&#46; Genetic studies showed that these patients exhibited increased expression of a protein&#58; proprotein convertase subtilisin&#47;kexin type 9 &#40;PCSK9&#41;&#46; The role of PCSK9 in regulating cholesterol has been widely evaluated in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> PCSK9 is expressed in a variety of tissues but predominantly in the liver&#46; The PCSK9 protein binds to the LDL receptor&#46; Once LDL binds to its receptor&#44; the complex is internalized in the cell&#44; providing its lipid cargo for cell metabolism&#46; In the presence of PCSK9&#44; the LDL receptor is subjected to degradation in the lysosome&#46; In the absence of PCSK9&#44; the receptor is &#8220;recycled&#8221; and transported to the cell membrane&#44; where it can continue to uptake LDL particles&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Inversely&#44; mutations with defective PCSK9 synthesis have been reported&#44; which present an opposite phenotype to that of familial hypercholesterolemia&#58; reduced circulating cholesterol levels and a marked reduction in the incidence of ischemic heart disease&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> A few individuals who were homozygous or double heterozygous for null alleles of PCSK9 have been reported&#44; with undetectable PCSK9 levels&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> These patients show dramatically low LDL-C levels but present normal development and no clinical consequences other than protection against developing arteriosclerosis&#46; 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&#46; Reductions in cholesterol levels associated with genetic profiles with cholesterol synthesis inhibition &#40;HMG-CoA reductase&#44; ATP citrate lyase&#41;&#44; cholesterol absorption &#40;NPC1-L1&#41; and LDL receptor degradation &#40;PCSK9&#41; result in reductions in the rate of ischemic heart disease proportional to the reduction in LDL-C by any of the above mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> If we have drugs that can inhibit cholesterol synthesis &#40;statins&#44; bempedoic acid&#41;&#44; absorption &#40;ezetimibe&#41; and degradation of the LDL receptor &#40;PCSK9&#41;&#44; with no adverse effects &#40;&#8220;off target&#8221;&#41;&#44; we can expect reductions in the incidence rate of atherosclerotic vascular disease directly proportional to the reduction in LDL-C levels &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Various methods have been developed to reduce LDL-C levels via PCSK9&#44; one of which is the administration of interference ribonucleic acid &#40;RNAi&#41; which blocks the expression of PCSK9&#46; This RNAi conjugated with N-acetylgalactosamine &#40;inclisiran&#41; is administered parenterally and taken up by the liver&#44; leading to selective prevention of the hepatic synthesis of PCSK9&#46; Clinical studies in early phases have shown that injection of inclisiran every 3-6 months is associated with LDL-C reductions of 50&#37; lasting up to 6 months&#44; with no apparent adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a> As of this time&#44; 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&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Inhibition of proprotein convertase subtilisin&#47;kexin type 9 and cardiovascular protection&#58; FOURIER and ODYSSEY OUTCOMES studies</span><p id="par0050" class="elsevierStylePara elsevierViewall">The most advanced clinical procedure for blocking the action of PCSK9 is the use of monoclonal antibodies against PCSK9&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> Three monoclonal antibodies have been developed&#58; bococizumab&#44; alirocumab and evolocumab&#46; Bococizumab is a humanized monoclonal antibody that loses efficacy due the development of antibodies against bococizumab&#46; Although the clinical development of bococizumab has been stopped for this reason&#44; the results of the Spire studies have already demonstrated cardiovascular protective effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">26&#44;27</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">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&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The FOURIER study<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> assessed the effect of evolocumab versus placebo in 27&#44;654 patients between 40 and 85 years of age with a prior history of cardiovascular disease &#40;acute myocardial infarction&#44; ischemic stroke or peripheral arterial disease&#41; and an additional cardiovascular risk factor&#46; The patients presented an LDL-C level &#62;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and a base lipid-lowering therapy with statins &#40;high intensity in 69&#37;&#41;&#46; Approximately 5&#37; of the patients were concomitantly treated with ezetimibe&#46; Evolocumab was administered bi-weekly &#40;140<span class="elsevierStyleHsp" style=""></span>mg subcutaneously&#41; or monthly &#40;420<span class="elsevierStyleHsp" style=""></span>mg subcutaneously&#41;&#44; with a median follow-up of 2&#46;2 years&#46; Treatment with evolocumab was associated with an intense lipid-lowering effect &#40;LDL-C reduction of 56<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#91;59&#37;&#93;&#44; sustained over time&#41;&#46; Treatment with evolocumab was also associated with a 15&#37; reduction &#40;hazard ratio &#91;HR&#93;&#44; 0&#46;85&#59; 95&#37; CI 0&#46;79&#8211;0&#46;92&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41; in the combined primary endpoint &#40;cardiovascular death&#44; acute myocardial infarction&#44; stroke&#44; hospitalization for unstable angina or revascularization&#41;&#46; This effect was slightly higher for the key secondary endpoint &#40;cardiovascular death&#44; acute myocardial infarction&#44; stroke&#41;&#44; with a 20&#37; reduction &#40;HR&#44; 0&#46;8&#59; 95&#37; CI 0&#46;73&#8211;0&#46;88&#41;&#46; There were no differences in adverse effects &#40;including the development of diabetes or cognitive problems&#41; between the placebo and intervention groups&#44; except for an increased rate of local reactions at the injection site with evolocumab &#40;2&#46;1&#37; vs&#46; 1&#46;6&#37;&#41;&#46; The cardiovascular protective effect might seem modest when compared with the marked reduction in LDL-C&#44; but we should consider the limited duration of the study &#40;2&#46;2 years&#41; compared with the typical duration of studies with statins &#40;approximately 5 years&#41;&#46; Similar to the results of studies with statins&#44; the risk reduction was lower in the first year &#40;12&#37;&#44; 95&#37; CI 3&#8211;20&#41; than in the second year of follow-up &#40;19&#37;&#44; 95&#37; CI 11&#8211;27&#41;&#44; both of which are consistent with the expected benefit according to the absolute reduction in LDL-C levels and treatment duration&#46; The results were consistent for all analyzed subgroups&#44; including a similar protective effect for patients with the lowest starting levels of LDL&#44; with no loss of effect or increase in adverse effects up to LDL levels of approximately 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></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&#44; toxic cell effects are not expected simply due to the reduction in circulating LDL-C&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The ODYSSEY OUTCOMES study<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> is consistent with and complementary to the FOURIER trial&#46; Unlike the FOURIER study&#44; the ODYSSEY OUTCOMES study required the presence of a recent acute coronary syndrome between 1 and 12 months prior to the study&#44; as well as similar lipid levels &#40;LDL-C &#62;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; non-HDL cholesterol &#62;100<span class="elsevierStyleHsp" style=""></span>mg&#47;dL or apolipoprotein B &#62;80<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46; A total of 18&#44;924 patients were randomly assigned to receive placebo or alirocumab 75&#47;mg subcutaneously bi-weekly in a blinded manner&#46; The patients in the ODYSSEY OUTCOMES study underwent intensive lipid-lowering therapy &#40;more than 95&#37; with statins&#44; 89&#37; with high-intensity statins and 2&#46;9&#37; with ezetimibe&#41;&#46; Unlike the FOURIER study with fixed doses of evolocumab&#44; the alirocumab doses were titrated upwards or downwards to achieve an LDL-C level between 25 and 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; suppressing the treatment with alirocumab if levels below 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dL were reached&#46; The patients assigned to alirocumab showed a reduction in LDL-C at 4 weeks of 53<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;57&#37;&#41;&#44; which was attenuated to a reduction of 37<span class="elsevierStyleHsp" style=""></span>mg&#47;dL at 4 years &#40;in the intent-to-treat analysis&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Treatment with alirocumab was associated with a 15&#37; reduction &#40;HR&#44; 0&#46;85&#59; 95&#37; CI 0&#46;78&#8211;0&#46;93&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; in the combined primary endpoint &#40;cardiovascular death&#44; acute myocardial infarction&#44; stroke or angina that required hospitalization&#41; after a median follow-up of 2&#46;8 years&#46; Once again&#44; treatment with alirocumab was not associated with an increased incidence of adverse effects except for the presence of local irritation at the injection site &#40;3&#46;8&#37; vs&#46; 2&#46;1&#37;&#41;&#46; It is worth noting that&#44; unlike the FOURIER study&#44; treatment with alirocumab was associated with a reduction in overall mortality &#40;3&#46;5&#37; vs&#46; 4&#46;1&#37;&#59; HR&#44; 0&#46;85&#59; 95&#37; CI 0&#46;73&#8211;0&#46;98&#59; nominal <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;026&#41;&#46; Although the nominal p was significant according to conventional limits &#40;&#60;&#46;05&#41;&#44; this result should be interpreted with caution&#44; because there was no reduction in mortality of cardiovascular origin&#44; 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&#46; Nevertheless&#44; noncardiovascular mortality increased in the patients who presented a previous nonfatal cardiovascular event&#44; suggesting that some &#8220;noncardiovascular&#8221; deaths could have a certain relationship with the severity of the cardiovascular disease partially prevented by alirocumab&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">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 &#62;100<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; In this subgroup of patients&#44; treatment with alirocumab was associated with a significant reduction in cardiovascular mortality &#40;HR&#44; 0&#46;72&#59; 95&#37; CI 0&#46;53&#8211;0&#46;98&#41; and overall mortality &#40;HR&#44; 0&#46;71&#59; 95&#37; CI 0&#46;56&#8211;0&#46;90&#41;&#46; The loss of the protective effect by the treatment with alirocumab for patients with LDL-C levels &#60;100<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in the ODYSSEY OUTCOMES study contrasts with the persistence of this effect in the FOURIER study&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">28&#44;31</span></a> It is possible that the design of the ODYSSEY OUTCOMES study&#44; unlike that of the FOURIER study&#44; with the option of reducing the alirocumab regimen &#40;and including its suppression if LDL levels were sufficiently low&#41; could have limited the effects in a conventional intent-to-treat analysis&#46; Studies have very recently reported that the reduction in mortality achieved with alirocumab extends to LDL cholesterol levels of approximately 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;These results are consistent with previous studies showing that reductions in cardiovascular complications are still achieved when reaching cholesterol levels between 25 and 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32&#44;33</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In any case&#44; both studies confirm that treatment with PCSK9 inhibitors in patients with atherosclerotic vascular disease and LDL-C levels &#62;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dL reduces cardiovascular complications with a good safety profile&#46; Recent studies&#44; such as the one described in this issue&#44; confirm the lipid-lowering efficacy and safety of PCSK9 inhibitors in actual clinical practice&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">It has therefore been demonstrated that LDL-C reduction using statins&#44; ezetimibe or PCSK9 inhibitors can offer cardiovascular protective effects well beyond the levels that&#44; until recently&#44; have been considered optimal&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Cardiovascular risk prevention guidelines&#58; towards a new convergence</span><p id="par0090" class="elsevierStylePara elsevierViewall">The 2013 US guidelines on hypercholesterolemia<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> granted statins the leading role&#44; indicating that treatment with statins of high or moderate intensity is warranted by the overall vascular risk situation&#46; Unlike the preceding US guidelines &#40;NCEPIII&#41;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> and the European guidelines&#44; the objectives of LDL-C control were removed&#44; and even the need to measure the lipid-lowering treatment response was left out&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> However&#44; within the US scientific community&#44; an expert group of the American College of Cardiology<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">39&#44;40</span></a> continued to consider as highly relevant the measurement of cholesterol levels and options for lipid-lowering therapy complementary to statins&#46; The recent US guidelines<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> have reinstated &#40;at least partially&#41; the advisability of achieving lipid objectives &#40;LDL &#60;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; in secondary prevention&#44; considering the use of ezetimibe or iPCSK9 reasonable for patients who do not reach these levels&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The use of ezetimibe is recommended as a priority option given the evidence of long-term safety studies&#44; maintaining PCSK9 inhibitors as an alternative if reductions in LDL-C unattainable with ezetimibe are necessary &#40;&#62;25&#37; reductions&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">39&#44;41</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Thus&#44; the recent US hypercholesterolemia guidelines have gone beyond the monoculture of statins as the lipid-lowering therapy in cardiovascular risk prevention&#44; realigning to a significant extent with the European guidelines&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The use of statins and ezetimibe is also favored given the fact that they are generic drugs with acceptable costs&#44; are easy to administer and have been demonstrated safe after decades of clinical use in hundreds of thousands of patients&#46; In contrast&#44; the cost of PCSK9 inhibitors is very high&#44; and there are no data on their long-term safety and efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">41&#8211;43</span></a> These considerations justify the selective use of PCSK9 inhibitors in patients most likely to benefit from using these drugs&#46; 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&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">44&#8211;47</span></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&#44; based on the potential but still undemonstrated cardiovascular benefits in randomized clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">48&#44;49</span></a> After the recent findings&#44; the European Medicines Agency approved the indication of evolocumab and alirocumab for preventing atherosclerotic cardiovascular disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">50&#44;51</span></a> A reassessment of the role of PCSK9 inhibitors in the spectrum of cardiovascular risk prevention is therefore expected&#46; Given that PCSK9 inhibitors are highly expensive drugs&#44; the issue translates mainly to a cost&#47;benefit analysis&#44; the subject of wide debate at present&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">52&#8211;54</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">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&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a> Determining the clinical benefit of the main lipid-lowering therapies available &#40;statins&#44; ezetimibe&#44; PCSK9 inhibitors&#41; has shown extraordinary consistency in the benefit derived from the absolute reduction from starting LDL-C levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2&#44;4&#44;16</span></a> Thus&#44; 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 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Paradoxically&#44; cardiovascular risk stratification in secondary prevention has not achieved a generalized consensus&#46; A number of scientific societies&#44; such as the American Society of Clinical Endocrinologists&#44; have proposed the new vascular risk category &#8220;extreme&#8221;&#44;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a> which includes patients in secondary prevention who present any of the following characteristics&#58; &#40;a&#41; recurrence of ischemia despite LDL-C levels &#60;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; &#40;b&#41; diabetes mellitus&#59; &#40;c&#41; chronic renal failure &#40;stages 3&#47;4&#41;&#59; &#40;d&#41; familial hypercholesterolemia&#59; and &#40;e&#41; early cardiovascular disease&#46; 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&#44; such as those with a recent acute coronary syndrome&#44; extensive atherosclerosis &#40;involvement of multiple territories&#44; especially with symptomatic peripheral arterial disease&#41; and an increase in lipoprotein &#40;a&#41; levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">28&#44;31&#44;57&#8211;59</span></a> The Spanish Society of Arteriosclerosis has developed updated guidelines with usage recommendations based on these principles&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">In summary&#44; the results of cardiovascular risk prevention trials with PCSK9 inhibitors&#44; combined with genetic studies and intervention with statins and inhibitors of cholesterol absorption&#44; confirm the etiological role of LDL-C in the development of arteriosclerosis&#46; Therapy with drugs that reduce LDL-C levels &#40;if their safety is demonstrated in clinical trials&#41; can offer a benefit proportional to the reduction in LDL-C to previously unsuspected levels&#44; much lower than the &#8220;ambitious&#8221; therapeutic objectives of most current guidelines on cardiovascular risk prevention&#46; The main challenge for clinicians is the correct identification of patients with &#8220;extreme&#8221; vascular risk who could benefit from a particularly intensive lipid-lowering therapy&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">Carlos Guijarro declares having been reimbursed for talks&#44; training and consulting by AMGEN&#44; Esteve&#44; MSD&#44; Sanofi&#46;</p></span></span>"
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          "titulo" => "Low-density lipoprotein cholesterol and arteriosclerosis"
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          "titulo" => "Reducing low-density lipoprotein cholesterol&#58; beyond statins"
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          "titulo" => "Proprotein convertase subtilisin&#47;kexin type 9&#44; lipid effects and arteriosclerosis"
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          "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 => "Lipoprote&#237;nas de baja densidad"
            2 => "Prevenci&#243;n cardiovascular"
            3 => "Aleatorizaci&#243;n mendeliana"
            4 => "Gu&#237;as cl&#237;nicas"
            5 => "Inhibidores hidroximetilglutaril coenzima A reductasa"
            6 => "Inhibidores de proprote&#237;na convertasa subtilisina kexina 9"
            7 => "Ezetimiba"
            8 => "An&#225;lisis de coste-efectividad"
            9 => "N&#250;mero necesario a tratar"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The epidemiological association of cholesterol associated with low density lipoproteins &#40;LDL-c&#41; levels and the development of atherosclerotic vascular disease has been ratified by mendelian randomization studies&#46; Paradoxically&#44; the success of statins led to the underestimation of other lipid-lowering therapies and even the measurement of LDL-c&#46; Recent studies show that the reduction of LDL-c to extraordinarily low levels through absorption inhibition&#44; and&#44; in a particularly intensive manner&#44; with monoclonal antibodies against pro-protein convertase subtilisine kexine 9 &#40;PCSK9&#41; continues to offer cardiovascular protection&#46; However&#44; the high cost and limited experience with PCSK-9 inhibitors advised a prudent use of them&#46; An appropriate selection of patients most likely to benefit from treatment with PCSK9 inhibitors emerges as the basis for a consensus of international guidelines&#58; the combination of a high absolute vascular risk and a greater expected benefit by the starting LDL-c levels&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La asociaci&#243;n epidemiol&#243;gica entre los niveles de colesterol asociado a lipoprote&#237;nas de baja densidad &#40;c-LDL&#41; y el desarrollo de enfermedad vascular aterosclerosa ha sido ratificada mediante estudios de aleatorizaci&#243;n mendeliana&#46; Parad&#243;jicamente&#44; el &#233;xito de las estatinas condujo a minusvalorar otros tratamientos hipolipidemiantes e incluso la medici&#243;n del c-LDL&#46; Estudios recientes muestran que la reducci&#243;n del c-LDL hasta niveles extraordinariamente bajos mediante inhibidores de la absorci&#243;n y&#44; de modo especialmente intenso&#44; con los anticuerpos monoclonales anti proprote&#237;na convertasa subtilisina kexina 9 &#40;PCSK9&#41; contin&#250;a ofreciendo protecci&#243;n cardiovascular&#46; Sin embargo&#44; el elevado coste y la limitada experiencia con los inhibidores de PCSK-9 aconsejan un uso prudente de los mismos&#46; Una selecci&#243;n adecuada de los pacientes que m&#225;s se pueden beneficiar del tratamiento con inhibidores de vPCSK9 emerge como base de consenso de las gu&#237;as internacionales&#58; la combinaci&#243;n de un elevado riesgo vascular absoluto y un mayor beneficio esperable por los niveles de c-LDL de partida&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Guijarro C&#44; Camafort M&#46; PCSK9 inhibitors&#58; Ratification of the role of LDL cholesterol in cardiovascular prevention&#46; Towards a convergence of European and North American prevention guidelines&#63; Rev Clin Esp&#46; 2020&#59;220&#58;374&#8211;382&#46;</p>"
      ]
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      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Ference et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> and Ference et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Effect of reducing low-density lipoprotein cholesterol &#40;LDL-C&#41; on coronary events according to the mechanism of reduction&#46; Panel A&#58; combination of various genetic scores for genes associated with changes in cholesterol levels and incidence of coronary artery disease adjusted for a reduction of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in LDL-C&#46; Panel B&#58; cardiovascular protective effect of various drug treatments that act on the previously mentioned genetic variants adjusted for a reduction of 38&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in randomized clinical trials&#46; 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&#46; Similarly&#44; the cardiovascular protective effect of statins&#44; ezetimibe and PCSK9 inhibitors is similar for equivalent changes in LDL-C&#46; Note that the protective effect of genetic changes &#40;that act over the course of a lifetime&#41; is approximately 4 times greater than that of drug treatments &#40;typical duration of 4&#8211;5 years&#41;&#46; The effect of bempedoic acid has not yet been evaluated in randomized clinical trials&#46; There are no drugs that act directly on LDL receptor expression&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; ACLY&#44; ATP citrate lyase&#59; bempedoic A&#46;&#44; bempedoic acid&#59; CI&#44; confidence interval&#59; LDLR&#44; LDL receptor&#59; NPC1L1&#44; Niemann-Pick C1-Like 1 protein&#59; &#40;i&#41; PCSK9 &#40;inhibitors of&#41; convertase subtilisin&#47;kexin type 9 proprotein&#59; OR&#44; odds ratio&#46;</p>"
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        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Robinson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Number of patients needed to treat &#40;NNT&#41; to prevent a cardiovascular event at various levels of absolute risk and starting LDL-C levels in patients undergoing maximum treatment with statins&#46; The estimate of the clinical benefit of lipid-lowering treatment according to the vascular risk and LDL-C levels is shown in NNT form &#40;NNT for 5 years&#41; for an intervention that reduces LDL-C by 20&#37; &#40;panel A&#44; approximate effect of ezetimibe&#41; and by 50&#37; &#40;panel B&#44; approximate effect of PCSK9 inhibitors&#41;&#46; The calculations were performed assuming a 21&#37; reduction in relative risk for each 1<span class="elsevierStyleHsp" style=""></span>mmol&#47;L &#40;38&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; reduction in LDL-C&#46; NNT&#58; 1&#47;reduction of absolute risk<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>100&#46; Absolute risk reduction&#58; relative risk reduction<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>baseline absolute risk&#46; The NNT provides an approach to the intervention&#39;s benefit in each patient group and the cost of the associated drug treatment&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:60 [
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                          "colaboracion" => "Cholesterol Treatment Trialists&#8217; CTT Collaboration"
                          "etal" => false
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "C&#46; Guijarro"
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                        0 => array:2 [
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                            0 => "B&#46;F&#46; Voight"
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                            3 => "R&#46; Frikke-Schmidt"
                            4 => "M&#46; Barbalic"
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                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                            0 => "B&#46;A&#46; Ference"
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Review
PCSK9 inhibitors: Ratification of the role of LDL cholesterol in cardiovascular prevention. Towards a convergence of European and North American prevention guidelines?
Inhibidores de PCSK9: ratificación del papel del colesterol LDL en prevención cardiovascular. ¿Hacia la convergencia en las guías de prevención europeas y norteamericanas?
C. Guijarroa,
Corresponding author
cguijarro@fhalcorcon.es

Corresponding author.
, M. Camafortb
a Unidad de Medicina Interna, Hospital Universitario Fundación Alcorcón, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos Alcorcón, Madrid, Spain
b Servicio de Medicina Interna General, ICMiD Hospital Clínic-IDIBAPS, Universidad de Barcelona, Barcelona, Spain

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