Achieved LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia: A model that explores the efficacy of conventional and novel lipid-lowering therapy

Published:April 18, 2018DOI:https://doi.org/10.1016/j.jacl.2018.04.002

      Highlights

      • Treatment target achievement was assessed in a large cohort of general FH patients.
      • We modeled the proportion of patients reaching target with different therapies.
      • Less than 10% with and 50% without CHD reach goal with maximal statin therapy.
      • These percentages increase on addition of ezetimibe, CETP or PCSK9 inhibition.
      • Considering published adherence data, these percentages might be lower in real life.

      Background

      A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL).

      Objective

      We set out to model which proportion of patients reach targets using conventional and novel therapies.

      Methods

      We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2. We applied 100% adherence rates and literature-based adherence rates from 62% to 80%.

      Results

      We included 1,059 heFH patients with and 9,420 heFH patients without coronary heart disease (CHD). With maximal dose statin, 8.3% and 48.1% of patients with and without CHD would reach their recommended LDL-c targets, respectively. This increases to 54.3% and 93.2% when ezetimibe is added. Addition of CETPi increases these numbers to 95.7% and 99.7%, whereas adding PCSK9i would result in 99.8% and 100% goal attainment. Using literature-based adherence rates, these numbers decrease to 3.8% and 27.3% for maximal dose statin, 5.8% and 38.9% combined with ezetimibe, 31.4% and 81.2% when adding CETPi, and 40.3% and 87.1% for addition of PCSK9i.

      Conclusions

      Less than 10% with and 50% of heFH patients without CHD would reach treatment targets with maximal dose statin, but this substantially increases on addition of ezetimibe, CETPi, or PCSK9i. However, considering recently published adherence data, this might be lower in real life, especially in heFH patients with CHD.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sjouke B.
        • Kusters D.M.
        • Kindt I.
        • et al.
        Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.
        Eur Heart J. 2015; 36: 560-565
        • Benn M.
        • Watts G.F.
        • Tybjaerg-Hansen A.
        • Nordestgaard B.G.
        Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen general population study estimated a prevalence of 1 in 217.
        Eur Heart J. 2016; 37: 1384-1394
        • Huijgen R.
        • Kindt I.
        • Defesche J.C.
        • Kastelein J.J.
        Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.
        Eur Heart J. 2012; 33: 2325-2330
        • Benn M.
        • Watts G.F.
        • Tybjaerg-Hansen A.
        • Nordestgaard B.G.
        Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
        J Clin Endocrinol Metab. 2012; 97: 3956-3964
        • Khera A.V.
        • Won H.H.
        • Peloso G.M.
        • et al.
        Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
        J Am Coll Cardiol. 2016; 67: 2578-2589
        • Catapano A.L.
        • Graham I.
        • De Backer G.
        • et al.
        2016 ESC/EAS guidelines for the management of dyslipidaemias.
        Eur Heart J. 2016; 37: 2999-3058
        • Pijlman A.H.
        • Huijgen R.
        • Verhagen S.N.
        • et al.
        Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands.
        Atherosclerosis. 2010; 209: 189-194
        • Beliard S.
        • Carreau V.
        • Carrié A.
        • et al.
        Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects.
        Atherosclerosis. 2014; 234: 136-141
        • Kastelein J.J.
        • Besseling J.
        • Shah S.
        • et al.
        Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study.
        Lancet. 2015; 385: 2153-2161
        • Kenilworh N.J.
        (Available at:)
        • Raal F.
        • Scott R.
        • Somaratne R.
        • et al.
        Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial.
        Circulation. 2012; 126: 2408-2417
        • Raal F.J.
        • Stein E.A.
        • Dufour R.
        • et al.
        PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2015; 385: 331-340
        • Kastelein J.J.
        • Ginsberg H.N.
        • Langslet G.
        • et al.
        ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
        Eur Heart J. 2015; 36: 2996-3003
        • Ginsberg H.N.
        • Rader D.J.
        • Raal F.J.
        • et al.
        Efficacy and Safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher.
        Cardiovasc Drugs Ther. 2016; 30: 473-483
        • Ohsfeldt R.L.
        • Gandhi S.K.
        • Fox K.M.
        • Stacy T.A.
        • McKenney J.M.
        Effectiveness and cost-effectiveness of rosuvastatin, atorvastatin, and simvastatin among high-risk patients in usual clinical practice.
        Am J Manag Care. 2006; 12: S412-S423
        • Frolkis J.P.
        • Pearce G.L.
        • Nambi V.
        • Minor S.
        • Sprecher D.L.
        Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.
        Am J Med. 2002; 113: 625-629
        • Huijgen R.
        • Kindt I.
        • Verhoeven S.B.
        • et al.
        Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal.
        PLoS One. 2010; 5: e9220
        • Volpp K.G.
        • Troxel A.B.
        • Mehta S.J.
        • et al.
        Effect of electronic reminders, financial incentives, and social support on outcomes after myocardial infarction: the heartstrong randomized clinical trial.
        JAMA Intern Med. 2017; 177: 1093-1101
        • Umans-Eckenhausen M.A.
        • Defesche J.C.
        • Sijbrands E.J.
        • Scheerder R.L.
        • Kastelein J.J.
        Review of first 5 years of screening for familial hypercholesterolaemia in The Netherlands.
        Lancet. 2001; 357: 165-168
        • Besseling J.
        • Kastelein J.J.
        • Defesche J.C.
        • Hutten B.A.
        • Hovingh G.K.
        Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.
        JAMA. 2015; 313: 1029-1036
        • Cobbaert C.
        • Boerma G.J.
        • Lindemans J.
        Evaluation of the cholestech L.D.X. desktop analyser for cholesterol, HDL-cholesterol, and triacylglycerols in heparinized venous blood.
        Eur J Clin Chem Clin Biochem. 1994; 32: 391-394
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Besseling J.
        • Kindt I.
        • Hof M.
        • et al.
        Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.
        Atherosclerosis. 2014; 233: 219-223
        • Fouchier S.W.
        • Defesche J.C.
        • Umans-Eckenhausen M.W.
        • Kastelein J.P.
        The molecular basis of familial hypercholesterolemia in The Netherlands.
        Hum Genet. 2001; 109: 602-615
        • Lombardi M.P.
        • Redeker E.J.
        • Defesche J.C.
        • et al.
        Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.
        Clin Genet. 2000; 57: 116-124
        • Reiner Z.
        • Catapano A.L.
        • De Backer G.
        • et al.
        • European Association for Cardiovascular, Prevention & Rehabilitation
        ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European society of cardiology (ESC) and the European atherosclerosis society (EAS).
        Eur Heart J. 2011; 32: 1769-1818
        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • et al.
        2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American college of cardiology/American heart association task force on practice guidelines.
        J Am Coll Cardiol. 2014; 63: 2889-2934
        • Fox K.M.
        • Gandhi S.K.
        • Ohsfeldt R.L.
        • Blasetto J.W.
        • Davidson M.H.
        Effectiveness of statins in Medicare-eligible patients and patients <65 years using clinical practice data.
        Int J Clin Pract. 2007; 61: 1634-1642
        • Hines D.
        • Rane P.
        • Patel J.
        • Harrison D.
        • Wade R.
        Persistence and adherence with proprotein convertase subtilisin/kexin type 9 inhibitors in clinical practice.
        J Am Coll Cardiol. 2017; 69: 159
        • Catapano J.S.
        • Chapman A.J.
        • Horner L.P.
        • et al.
        Pre-injury polypharmacy predicts mortality in isolated severe traumatic brain injury patients.
        Am J Surg. 2017; 213: 1104-1108
        • Huijgen R.
        • Hutten B.A.
        • Kindt I.
        • Vissers M.N.
        • Kastelein J.J.
        Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH.
        Circ Cardiovasc Genet. 2012; 5: 354-359
        • Farnier M.
        • Colhoun H.M.
        • Sasiela W.J.
        • et al.
        Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years.
        J Clin Lipidol. 2017; 11: 986-997
        • Kim M.C.
        • Cho J.Y.
        • Jeong H.C.
        • et al.
        Impact of postdischarge statin withdrawal on long-term outcomes in patients with acute myocardial infarction.
        Am J Cardiol. 2015; 115: 1-7
        • Ray K.K.
        • Landmesser U.
        • Leiter L.A.
        • et al.
        Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol.
        N Engl J Med. 2017; 376: 1430-1440
        • Landlinger C.
        • Pouwer M.G.
        • Juno C.
        • et al.
        The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice.
        Eur Heart J. 2017; 38: 2499-2507
        • Huijgen R.
        • Vissers M.N.
        • Kindt I.
        • et al.
        Assessment of carotid atherosclerosis in normocholesterolemic individuals with proven mutations in the low-density lipoprotein receptor or apolipoprotein B genes.
        Circ Cardiovasc Genet. 2011; 4: 413-417
        • Robinson J.G.
        • Huijgen R.
        • Ray K.
        • et al.
        Determining when to add nonstatin therapy: a quantitative approach.
        J Am Coll Cardiol. 2016; 68: 2412-2421
        • Besseling J.
        • Hovingh G.K.
        • Huijgen R.
        • Kastelein J.J.
        • Hutten B.A.
        Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality.
        J Am Coll Cardiol. 2016; 68: 252-260
        • Baigent C.
        • Keech A.
        • Kearney P.M.
        • et al.
        Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
        Lancet. 2005; 366: 1267-1278
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        • Cholesterol Treatment Trialists, (CTT) Collaboration
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Bowman L.
        • Hopewell J.C.
        • Chen F.
        • et al.
        • Group, H. T. R. C.
        Effects of anacetrapib in patients with atherosclerotic vascular disease.
        N Engl J Med. 2017; 377: 1217-1227
        • Ference B.A.
        • Kastelein J.J.P.
        • Ginsberg H.N.
        • et al.
        Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk.
        JAMA. 2017; 318: 947-956
        • Merck Provides Update on Anacetrapib Development Program
        (Available at:)
        • Cupido A.J.
        • Reeskamp L.F.
        • Kastelein J.J.P.
        Novel lipid modifying drugs to lower LDL cholesterol.
        Curr Opin Lipidol. 2017; 28: 367-373
        • Galema-Boers A.M.H.
        • Lenzen M.J.
        • Sijbrands E.J.
        • Roeters van Lennep J.E.
        Proprotein convertase subtilisin/kexin 9 inhibition in patients with familial hypercholesterolemia: initial clinical experience.
        J Clin Lipidol. 2017; 11: 674-681
        • Boekholdt S.M.
        • Hovingh G.K.
        • Mora S.
        • et al.
        Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
        J Am Coll Cardiol. 2014; 64: 485-494
        • Ridker P.M.
        • Revkin J.
        • Amarenco P.
        • et al.
        Cardiovascular efficacy and safety of Bococizumab in high-risk patients.
        N Engl J Med. 2017; 376: 1527-1539