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Lipoprotein(a) lowering and cardiovascular risk reduction by PCSK9 inhibitors

      Keywords

      1. Introduction

      Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition augments recirculation of the low-density lipoprotein (LDL) receptor to the hepatocyte surface [
      • Seidah N.G.
      • Benjannet S.
      • Wickham L.
      • et al.
      The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.
      ], thereby lowering atherogenic particles through accelerated clearance of circulating LDL cholesterol (LDL-C). This observation led to several strategies to inhibit PCSK9, including monoclonal antibodies (evolocumab and alirocumab), small-molecule inhibitors specific to PCSK9, small interfering RNA (siRNA) molecules (inclisiran), antisense oligonucleotides, immunotherapy with a PCSK9 peptide vaccine, and CRISPR/Cas9 editing of PCSK9. In placebo-controlled trials of patients on a maximally tolerated lipid-lowering regimen, PCSK9 monoclonal antibodies resulted in a significant LDL-C lowering and a ∼20% relative risk reduction in atherosclerotic cardiovascular disease (ASCVD) events [
      • Talasaz A.H.
      • Ho A.J.
      • Bhatty F.
      • et al.
      Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD.
      ]. A notable finding in these trials was a 15%–35% reduction in lipoprotein(a) (Lp(a)) levels in the treatment arm. Proposed mechanisms of Lp(a) lowering through PCSK9 inhibition include decreased Lp(a) synthesis due to reduced intracellular formation of apoprotein B, reduced availability of apolipoprotein(a), as well as increased Lp(a) clearance by the LDL-, very low density lipoprotein (VLDL)- and plasminogen-receptor mediated pathways [
      • Watts G.F.
      • Chan D.C.
      • Somaratne R.
      • et al.
      Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics.
      ].

      2. Effect of PCSK9 inhibition on Lp(a) mediated risk

      The Lp(a) lowering effect of PCSK9 inhibitors raises the question as to what extent the beneficial outcomes of PCSK9 inhibition are mediated by reduction of Lp(a) levels. In this issue of Atherosclerosis, De Marchis et al. [
      • De Marchis G.M.
      • Dittrich T.D.
      • Malik R.
      • et al.
      Genetic proxies for PCSK9 inhibition associate with lipoprotein(a): effects on coronary artery disease and ischemic stroke.
      ] attempted to address this question using Mendelian randomization (MR) and mediation analysis in the following series of steps (Fig. 1): 1) identify genetic proxies for PCSK9 inhibition in 188,577 individuals from the Global Lipids Genetics Consortium; 2) establish variants associated with low LDL cholesterol and PCSK9 levels in protein quantitative trait loci analysis of 35,559 individuals from the Icelandic Cancer Project/deCODE dataset; 3) perform association testing between genetic proxies for PCSK9 inhibitors and Lp(a) levels in 310,020 UK Biobank participants; 4) identify genetic proxies for Lp(a) levels in the CHD Exome + Consortium dataset of 48,333 individuals; and finally, 5) explore associations of the genetic proxies for PCSK9 inhibitors and Lp(a) levels with coronary heart disease (CHD) and stroke in 245,106 individuals from the CARDIoGRAMplusC4D and 514,791 individuals from the MEGASTROKE consortia, who were not on a statin.
      Fig. 1
      Fig. 1Schematic of the approach used by De Marchis et al. [
      • De Marchis G.M.
      • Dittrich T.D.
      • Malik R.
      • et al.
      Genetic proxies for PCSK9 inhibition associate with lipoprotein(a): effects on coronary artery disease and ischemic stroke.
      ] to analyze the effects of PCSK9 mediated Lp(a)-lowering on adverse cardiovascular events.
      LDL-C = low-density lipoprotein cholesterol, Lp(a) = lipoprotein(a), MR = mendelian randomization.
      The authors demonstrated that a 1-standard deviation (SD) decrease in PCSK9 levels through genetically mediated PCSK9 inhibition corresponded to a 4% reduction in log-Lp(a) levels (equal to 0.5 mg/dL in absolute Lp(a) reduction) and a 7% (21 mg/dL) reduction in LDL-C levels, resulting in a 0.8% and 0.5% reduction in the likelihood of CHD and stroke, respectively. The reduction in CHD risk per 1-SD decrement in PCSK9 levels was 18%, of which 4% risk reduction was mediated by Lp(a), a very modest effect.

      3. Clinical implications

      In patients treated with statins, including those with LDL-C below 70 mg/dL, residual risk of ASCVD is in part mediated by elevated Lp(a) levels [
      • Wei W.Q.
      • Li X.
      • Feng Q.
      • et al.
      LPA variants are associated with residual cardiovascular risk in patients receiving statins.
      ,
      • Safarova M.S.
      • Ezhov M.V.
      • Afanasieva O.I.
      • et al.
      Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography.
      ,
      • Schwartz G.G.
      • Szarek M.
      • Bittner V.A.
      • et al.
      Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol.
      ,
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      ]. In a post-hoc analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial, each doubling in Lp(a) levels was associated with ∼8% higher risk of CHD death, myocardial infarction, or urgent coronary revascularization [
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ]. Selective Lp(a) apheresis on the background of statin therapy led to 70% reduction in Lp(a) on average and significantly reduced coronary atherosclerosis burden as compared to the control group [
      • Safarova M.S.
      • Ezhov M.V.
      • Afanasieva O.I.
      • et al.
      Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography.
      ]. The findings of De Marchis et al. [
      • De Marchis G.M.
      • Dittrich T.D.
      • Malik R.
      • et al.
      Genetic proxies for PCSK9 inhibition associate with lipoprotein(a): effects on coronary artery disease and ischemic stroke.
      ] suggest that clinically significant reduction in the CHD risk of 12% and in large artery stroke of 7.5% would be expected with a 60% reduction in Lp(a) levels, reinforcing the need for potent Lp(a) lowering therapies. Currently, three novel Lp(a) targeting therapies that reduce Lp(a) levels by over 70% are being evaluated in clinical trials (ClinicalTrials.gov NCT04023552; NCT04270760; NCT04606602).

      4. Insights from Mendelian randomization analyses

      In MR analyses, genetic variants are used as an instrument to determine whether an association between a risk factor/marker and an outcome is causal in nature [
      • Smith G.D.
      • Ebrahim S.
      'Mendelian randomization'
      Can genetic epidemiology contribute to understanding environmental determinants of disease?.
      ]. Two common challenges in MR studies are low power due to a weak genetic instrument and the possibility of genetic variants having pleiotropic effects [
      • Safarova M.S.
      • Satterfield B.A.
      • Fan X.
      • et al.
      A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR.
      ], making it difficult to delineate the pathways that influence the outcome of interest [
      • Verbanck M.
      • Chen C.Y.
      • Neale B.
      • et al.
      Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.
      ,
      • Hemani G.
      • Bowden J.
      • Davey Smith G.
      Evaluating the potential role of pleiotropy in Mendelian randomization studies.
      ]. To increase the strength of their genetic instrument for LDL-C and Lp(a), the authors combined 10 PSCSK9 variants with a resulting beta coefficient (the degree of change in the outcome variable for every 1-unit of change in the predictor variable) of 0.12 and 0.07 in LDL-C and Lp(a) reduction, respectively. To address pleiotropy (PCSK9 variants being associated with both lower LDL-C and Lp(a) levels), the authors used two-step mediation MR analyses to tease out the separate contributions of Lp(a)-lowering and LDL-C lowering, towards ASCVD risk reduction due to PCSK9 inhibition.
      There are several caveats to the results reported by De Marchis et al. [
      • De Marchis G.M.
      • Dittrich T.D.
      • Malik R.
      • et al.
      Genetic proxies for PCSK9 inhibition associate with lipoprotein(a): effects on coronary artery disease and ischemic stroke.
      ] First, high estimated LDL-C may be partly due to elevated Lp(a) levels, affecting the accuracy of the genetic instrument chosen for the MR analyses. Second, while monoclonal antibodies to PCSK9 reduced Lp(a) levels by 14% per 1-SD decrement in LDL cholesterol [
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      ], MR analysis by the authors suggested a reduction in Lp(a) of 7% per 1-SD reduction in LDL-C, raising the possibility of additional mechanisms through which pharmacological PCSK9 inhibition may lower Lp(a) levels. Therefore, the Lp(a)-mediated reduction in adverse cardiovascular outcomes may be greater than that suggested by the MR analyses performed by the authors. Third, Lp(a) levels differ by race and ethnicity. Black individuals have highest average levels, followed by Asian, Hispanic, and White individuals; and race was found to be a modifying variable in Lp(a)-related risk of ASCVD events [
      • Satterfield B.A.
      • Dikilitas O.
      • Safarova M.S.
      • et al.
      Associations of Genetically Predicted Lipoprotein (A) Levels with Cardiovascular Traits in Individuals of European and African Ancestry.
      ,
      • Steffen B.T.
      • Thanassoulis G.
      • Duprez D.
      • et al.
      Race-based differences in lipoprotein(a)-associated risk of carotid atherosclerosis.
      ,
      • Forbang N.I.
      • Criqui M.H.
      • Allison M.A.
      • et al.
      Sex and ethnic differences in the associations between lipoprotein(a) and peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis.
      ]. This study used datasets of predominantly European ancestry individuals, limiting the generalizability of the findings. However, the approach utilized by the authors could be adapted to diverse cohorts in the future.
      In conclusion, the MR and mediation analysis by De Marchis et al. [
      • De Marchis G.M.
      • Dittrich T.D.
      • Malik R.
      • et al.
      Genetic proxies for PCSK9 inhibition associate with lipoprotein(a): effects on coronary artery disease and ischemic stroke.
      ] suggests that Lp(a) reduction by genetic proxies of PCSK9 inhibition is modest as is the downstream reduction in ASCVD risk due to Lp(a) lowering. The study provides insights into the contribution of Lp(a)-lowering to the reduction in ASCVD risk in patients treated with PCSK9 inhibitors. Further studies of selective and substantially more potent Lp(a) lowering strategies are underway and will provide more definitive answers regarding the effect of such lowering on clinical outcomes.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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