Treatment of drug-resistant hypercholesterolemia
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Section Editor — Lipids
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
- Sarah D de Ferranti, MD, MPH
Sarah D de Ferranti, MD, MPH
- Director, Preventive Cardiology Clinic
- Department of Cardiology
- Boston Children's Hospital
- Paul Durrington, MD
Paul Durrington, MD
- Professor of Medicine
- Physician to Manchester Royal Infirmary
- University of Manchester
Hypercholesterolemia, and in particular, an elevated level of serum (or plasma) low density lipoprotein cholesterol (LDL-C), is associated with an increased risk of adverse cardiovascular events. Lipid lowering drug therapy, particularly with statins, is indicated to decrease the risk of cardiovascular events in most individuals with established atherosclerotic cardiovascular disease and in many who are at high risk. (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Summary and recommendations' and "Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention", section on 'Summary and recommendations'.)
Statins are the preferred therapy for most patients requiring treatment of dyslipidemia and in particular those with an elevated LDL-C. The goals of therapy are discussed elsewhere. (See "Intensity of lipid lowering therapy in secondary prevention of cardiovascular disease".)
If after treatment with the maximal tolerated dose of statin the patient has not achieved the LDL-C goal, a number of other agents are available with varying levels of evidence for clinical benefits. These agents include nicotinic acid (niacin), bile acid sequestrants, and ezetimibe and their use is discussed elsewhere. (See "Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".)
However, some patients, including young individuals with severe hypercholesterolemia such as occurs in familial hypercholesterolemia, are unable to sufficiently lower their LDL-C to values with the use of these drugs. These individuals remain at high risk for cardiovascular events.
This topic will discuss therapeutic options for these individuals, including low density lipoprotein (LDL) apheresis, lomitapide, mipomersen, as well as a number of procedures that are rarely performed such as partial ileal bypass surgery, liver transplantation, and portocaval shunting. Gene therapy is a possible future alternative in selected patients such as those with familial hypercholesterolemia (FH), some of who have a defect in the LDL receptor. (See "Inherited disorders of LDL-cholesterol metabolism", section on 'Familial hypercholesterolemia'.)
- Gordon BR, Stein E, Jones P, Illingworth DR. Indications for low-density lipoprotein apheresis. Am J Cardiol 1994; 74:1109.
- Thompson GR, Catapano A, Saheb S, et al. Severe hypercholesterolaemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol 2010; 21:492.
- Thompson GR, HEART-UK LDL Apheresis Working Group. Recommendations for the use of LDL apheresis. Atherosclerosis 2008; 198:247.
- Hemphill LC. Familial hypercholesterolemia: current treatment options and patient selection for low-density lipoprotein apheresis. J Clin Lipidol 2010; 4:346.
- Pfohl M, Naoumova RP, Klass C, et al. Acute and chronic effects on cholesterol biosynthesis of LDL-apheresis with or without concomitant HMG-CoA reductase inhibitor therapy. J Lipid Res 1994; 35:1946.
- Ito MK, McGowan MP, Moriarty PM, National Lipid Association Expert Panel on Familial Hypercholesterolemia. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5:S38.
- Mabuchi H, Koizumi J, Shimizu M, et al. Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia. Hokuriku-FH-LDL-Apheresis Study Group. Am J Cardiol 1998; 82:1489.
- Thompson GR. LDL apheresis. Atherosclerosis 2003; 167:1.
- Thompson GR, Maher VM, Matthews S, et al. Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis. Lancet 1995; 345:811.
- Kroon AA, Aengevaeren WR, van der Werf T, et al. LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation 1996; 93:1826.
- Aengevaeren WR, Kroon AA, Stalenhoef AF, et al. Low density lipoprotein apheresis improves regional myocardial perfusion in patients with hypercholesterolemia and extensive coronary artery disease. LDL-Apheresis Atherosclerosis Regression Study (LAARS). J Am Coll Cardiol 1996; 28:1696.
- Tamai O, Matsuoka H, Itabe H, et al. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation 1997; 95:76.
- Igarashi K, Tsuji M, Nishimura M, Horimoto M. Improvement of endothelium-dependent coronary vasodilation after a single LDL apheresis in patients with hypercholesterolemia. J Clin Apher 2004; 19:11.
- Sato M, Amano I. Changes in oxidative stress and microcirculation by low-density lipoprotein apheresis. Ther Apher Dial 2003; 7:419.
- Kobayashi K, Yamashita K, Tasaki H, et al. Evaluation of improved coronary flow velocity reserve using transthoracic Doppler echocardiography after single LDL apheresis. Ther Apher Dial 2004; 8:383.
- Stefanutti C, Vivenzio A, Di Giacomo S, et al. Aorta and coronary angiographic follow-up of children with severe hypercholesterolemia treated with low-density lipoprotein apheresis. Transfusion 2009; 49:1461.
- Authors/Task Force Members:, Catapano AL, Graham I, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016; 253:281.
- Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report National Cholesterol Education Program. NIH Publication No. 02-5215, National Heart, Lung, and Blood Institute, National Institutes of Health; 2002.
- Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011; 128 Suppl 5:S213.
- Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5:S1.
- Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990; 323:946.
- Buchwald H, Matts JP, Fitch LL, et al. Changes in sequential coronary arteriograms and subsequent coronary events. Surgical Control of the Hyperlipidemias (POSCH) Group. JAMA 1992; 268:1429.
- Buchwald H, Varco RL, Boen JR, et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med 1998; 158:1253.
- Bilheimer DW, Goldstein JL, Grundy SM, et al. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 1984; 311:1658.
- Valdivielso P, Escolar JL, Cuervas-Mons V, et al. Lipids and lipoprotein changes after heart and liver transplantation in a patient with homozygous familial hypercholesterolemia. Ann Intern Med 1988; 108:204.
- Kakaei F, Nikeghbalian S, Kazemi K, et al. Liver transplantation for homozygous familial hypercholesterolemia: two case reports. Transplant Proc 2009; 41:2939.
- Maiorana A, Nobili V, Calandra S, et al. Preemptive liver transplantation in a child with familial hypercholesterolemia. Pediatr Transplant 2011; 15:E25.
- Bilheimer DW, Goldstein JL, Grundy SM, Brown MS. Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia. J Clin Invest 1975; 56:1420.
- Starzl TE, Putnam CW, Koep LJ. Portacaval shunt and hyperlipidemia. Arch Surg 1978; 113:71.
- Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007; 356:148.
- Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2008; 5:497.
- Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381:40.
- Lomitapide capsules. US Food & Drug Administration (FDA) approved product information. Revised August, 2014. US national Library of medicine. Available at: http://www.dailymed.nlm.nih.gov/ (Accessed on November 06, 2014).
- Kastelein JJ, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 2006; 114:1729.
- Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol 2010; 55:1611.
- Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375:998.
- Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 2012; 126:2283.
- Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J 2012; 33:1142.
- Thomas GS, Cromwell WC, Ali S, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2013; 62:2178.
- Oka K, Pastore L, Kim IH, et al. Long-term stable correction of low-density lipoprotein receptor-deficient mice with a helper-dependent adenoviral vector expressing the very low-density lipoprotein receptor. Circulation 2001; 103:1274.
- Grossman M, Rader DJ, Muller DW, et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1995; 1:1148.
- Van Craeyveld E, Jacobs F, Gordts SC, De Geest B. Gene therapy for familial hypercholesterolemia. Curr Pharm Des 2011; 17:2575.
- Kastelein JJ, 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.
- Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 2015; 386:452.
- Melone M, Wilsie L, Palyha O, et al. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J Am Coll Cardiol 2012; 59:1697.
- Pinkosky SL, Filippov S, Srivastava RA, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res 2013; 54:134.
- Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol 2013; 62:1154.
- LDL-C GOALS
- REFERRAL TO A SPECIALIST
- PCSK9 ANTIBODIES
- LDL APHERESIS
- Efficacy and safety
- Clinical use
- Recommendations of others
- PARTIAL ILEAL BYPASS SURGERY
- LIVER TRANSPLANTATION
- PORTOCAVAL SHUNT
- POTENTIAL FUTURE APPROACHES
- Gene therapy
- CETP inhibition
- Antibody removal of resistin
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS