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      Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk : Insights From the FOURIER Trial

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          Abstract

          Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined.

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          Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

          Nicholas Viney, Julian C van Capelleveen, Richard S Geary … (2016)
          Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations.
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            Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies

            Joanna M M Howson, Stephen Burgess, Brian A Ference … (2018)
            Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures Coronary heart disease. Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10 −37 ), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10 −12 ). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
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              Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

              Paul Elliott, Hugh Watkins, Heribert Schunkert … (2009)
              Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. To investigate association of genetic loci with CRP levels and risk of coronary heart disease. We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. Risk of coronary heart disease. Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.
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                Author and article information

                Journal
                Title: Circulation
                Abbreviated Title: Circulation
                Publisher: Ovid Technologies (Wolters Kluwer Health)
                ISSN (Print): 0009-7322
                ISSN (Electronic): 1524-4539
                Publication date Created: March 19 2019
                Publication date (Print): March 19 2019
                Volume: 139
                Issue: 12
                Pages: 1483-1492
                Affiliations
                [1 ]TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.L.O., R.P.G., E.K., K.A.I., M.S.S.).
                [2 ]Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health &amp; Science University, Portland (S.F.).
                [3 ]Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (E.S.G.S.).
                [4 ]Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Germany (I.G.-B.).
                [5 ]Amgen, Thousand Oaks, CA (A.L.P., S.M.W.).
                [6 ]Center for Preventive Cardiology, 3rd Internal Medicine Clinic, University General Hospital and Charles University 1st Medical Faculty, Prague, Czech Republic (R.C.).
                [7 ]National Cardiology Research Center, Moscow, Russia (M.V.E.).
                [8 ]Department of Cardiology, Leiden University Medical Center, The Netherlands (J.W.J.).
                [9 ]Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Health, Aarhus University, Denmark (H.K.J.).
                [10 ]Cardiovascular Division, Hacettepe University, Ankara, Turkey (S.L.T.).
                [11 ]Cardiology Division, University of Geneva, Switzerland (F.M.).
                [12 ]3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminenhospital and Sigmund Freud University, Medical Faculty, Vienna, Austria (K.H.).
                [13 ]Imperial College London, UK (P.S.S.).
                [14 ]Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia (A.C.K.).
                [15 ]Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Norway (T.R.P.).
                Article
                DOI: 10.1161/CIRCULATIONAHA.118.037184
                PubMed ID: 30586750
                SO-VID: 4e17819e-6ede-49b5-9acc-160a2c85a1b4
                Copyright © © 2019
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