Managing recalcitrant hypercholesterolemia in patients on current best standard of care: efficacy and safety of novel pharmacotherapies

References

• Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 112(22), 3375–3383 (2005).
   Google Scholar
• Watts GF, Gidding S, Wierzbicki AS et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int. J. Cardiol. 171(3), 309–325 (2014). •• A comprehensive review describing the latest guidelines for the identification and management of familial hypercholesterolemia (FH).
   Google Scholar
• Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur. Heart J. 34(45), 3478–3490 (2013). •• A comprehensive review describing the latest guidelines for the identification and management of FH.
   Google Scholar
• WHO. Familial hypercholesterolaemia: report of a WHO consultation. WHO, Paris, France (1997).
   Google Scholar
• Fahed AC, Nemer GM. Familial hypercholesterolemia: the lipids or the genes? Nutr. Metab. (Lond.) 8(1), 23 (2011).
   Google Scholar
• Neefjes LA, Ten Kate GJ, Rossi A et al. CT coronary plaque burden in asymptomatic patients with familial hypercholesterolaemia. Heart 97(14), 1151–1157 (2011).
   Google Scholar
• Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am. J. Cardiol. 81(5), 582–587 (1998).
   Google Scholar
• Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J. Am. Coll. Cardiol. 46(8), 1411–1416 (2005).
   Google Scholar
• Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J. Am. Coll. Cardiol. 57(16), 1666–1675 (2011).
   Google Scholar
• Choumerianou DM, Dedoussis GV. Familial hypercholesterolemia and response to statin therapy according to LDLR genetic background. Clin. Chem. Lab. Med. 43(8), 793–801 (2005).
   Google Scholar
• Pijlman AH, Huijgen R, Verhagen SN et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 209(1), 189–194 (2010).
   Google Scholar
• Versmissen J, Oosterveer DM, Yazdanpanah M et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337, a2423 (2008).
   Google Scholar
• Neil A, Cooper J, Betteridge J et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur. Heart J. 29(21), 2625–2633 (2008).
   Google Scholar
• Harada-Shiba M, Sugisawa T, Makino H et al. Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. J. Atheroscler. Thromb. 17(7), 667–674 (2010).
   Google Scholar
• Raal FJ, Pilcher GJ, Panz VR et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 124(20), 2202–2207 (2011).
   Google Scholar
• Elis A, Zhou R, Stein EA. Effect of lipid-lowering treatment on natural history of heterozygous familial hypercholesterolemia in past three decades. Am. J. Cardiol. 108(2), 223–226 (2011).
   Google Scholar
• Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am. J. Cardiol. 102(10 Suppl.), 1K–34K (2008).
   Google Scholar
• Bell DS, Dinicolantonio JJ, O’Keefe JH. Is statin-induced diabetes clinically relevant? A comprehensive review of the literature. Diabetes Obes. Metab. doi:10.1111/dom.12254 (2013) (Epub ahead of print).
   Google Scholar
• Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr. Opin. Lipidol. 18(4), 401–408 (2007).
   Google Scholar
• Artenstein AW, Opal SM. Proprotein convertases in health and disease. N. Engl. J. Med. 365(26), 2507–2518 (2011).
   Google Scholar
• Abifadel M, Varret M, Rabes JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34(2), 154–156 (2003).
   Google Scholar
• Dowdall M. Highlighting the future potential of PCSK9-targeted therapeutics. Clin. Lipidol. 7(6), 599–601 (2012).
   Google Scholar
• Rhainds D, Arsenault BJ, Tardif JC. PCSK9 inhibition and LDL cholesterol lowering: the biology of an attractive therapeutic target and critical review of the latest clinical trials. Clin. Lipidol. 7(6), 621–640 (2012).
   Google Scholar
• Garber K. Biologics inch toward cholesterol-lowering market. Nat. Biotechnol. 30(4), 302–304 (2012).
   Google Scholar
• Dias CS, Shaywitz AJ, Wasserman SM et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose Phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J. Am. Coll. Cardiol. 60(19), 1888–1898 (2012).
   Google Scholar
• Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128(19), 2113–2120 (2013).
   Google Scholar
• 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 126(20), 2408–2417 (2012).
   Google Scholar
• Stein EA, Mellis S, Yancopoulos GD et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366(12), 1108–1118 (2012).
   Google Scholar
• Stein EA, Gipe D, Bergeron J et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a Phase 2 randomised controlled trial. Lancet 380(9836), 29–36 (2012).
   Google Scholar
• Sullivan D, Olsson AG, Scott R et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 308(23), 2497–2506 (2012).
   Google Scholar
• Giugliano RP, Desai NR, Kohli P et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, Phase 2 study. Lancet 380(9858), 2007–2017 (2012).
   Google Scholar
• Koren MJ, Scott R, Kim JB et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, Phase 2 study. Lancet 380(9858), 1995–2006 (2012).
   Google Scholar
• Koren MJ, Giugliano RP, Raal FJ et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the open-label study of long-term evaluation against LDL-C (OSLER) randomized trial. Circulation 129(2), 234–243 (2013). •• A phase III trial with evolocumab.
   Google Scholar
• Roth EM, Mckenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med. 367(20), 1891–1900 (2012).
   Google Scholar
• AHA. Effects of 12 Weeks of Treatment with RN316 (PF-04950615), a Humanized IgG2Δa Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects on High and Maximal Dose Statins. http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_446310.pdf
   Google Scholar
• Gumbiner B, Udata C, Joh T et al. The effects of multiple dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects. Circulation 126, A13524 (2012).
   Google Scholar
• Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, Phase 1 trial. Lancet 383(9911), 60–68 (2014).
   Google Scholar
• Crooke RM, Baker BF, Wedel M. Cardiovascular Therapeutic Applications in Antisense Drug Technology; Principles, Strategies and Applications (2nd Edition). CRC Press, FL, USA, 601–639 (2007).
   Google Scholar
• Kohli P, Cannon CP. A new approach to managing the ‘statin-intolerant’ patient? Eur. Heart J. 33(9), 1040–1043 (2012).
   Google Scholar
• Akdim F, Visser ME, Tribble DL et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am. J. Cardiol. 105(10), 1413–1419 (2010).
   Google Scholar
• 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 375(9719), 998–1006 (2010).
   Google Scholar
• 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 114(16), 1729–1735 (2006).
   Google Scholar
• 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. 55(15), 1611–1618 (2010).
   Google Scholar
• Akdim F, Tribble DL, Flaim JD et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur. Heart J. 32(21), 2650–2659 (2011).
   Google Scholar
• 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. 33(9), 1142–1149 (2012).
   Google Scholar
• Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. 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. 62(23), 2178–2184 (2013). •• A phase III trial with evolocumab.
   Google Scholar
• Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in ApoB-lipoprotein assembly. J. Lipid Res. 44(1), 22–32 (2003).
   Google Scholar
• Sankatsing RR, Fouchier SW, De Haan S et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler. Thromb. Vasc. Biol. 25(9), 1979–1984 (2005).
   Google Scholar
• Joy TR. Novel therapeutic agents for lowering low density lipoprotein cholesterol. Pharmacol. Ther. 135(1), 31–43 (2012).
   Google Scholar
• Cuchel M, Bloedon LT, Szapary PO et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356(2), 148–156 (2007).
   Google Scholar
• 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 381(9860), 40–46 (2013). •• A phase III trial with evolocumab.
   Google Scholar
• Samaha FF, Mckenney J, Bloedon LT, Sasiela WJ, Rader DJ. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat. Clin. Pract. Cardiovasc. Med. 5(8), 497–505 (2008).
   Google Scholar
• Durrington PN. Hyperlipidaemia Diagnosis and Management (3rd Edition). Hodder Arnold, London, UK (2008).
   Google Scholar
• Bishop BM. Systematic review of CETP inhibitors for increasing high-density lipoprotein cholesterol: where do these agents stand in the approval process? Am. J. Ther. doi:10.1097/MJT.0b013e31828b8463 (2013) (Epub ahead of print).
   Google Scholar
• Krishna R, Anderson MS, Bergman AJ et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled Phase I studies. Lancet 370(9603), 1907–1914 (2007).
   Google Scholar
• Cannon CP, Shah S, Dansky HM et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363(25), 2406–2415 (2010).
   Google Scholar
• Bloomfield D, Carlson GL, Sapre A et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am. Heart J. 157(2), 352–360.e352 (2009).
   Google Scholar
• Teramoto T, Shirakawa M, Kikuchi M, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidaemia. Atherosclerosis 230(1), 52–60 (2013).
   Google Scholar
• Gotto AM Jr, Cannon CP, Li XS et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am. J. Cardiol. 113(1), 76–83 (2014).
   Google Scholar
• Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 306(19), 2099–2109 (2011).
   Google Scholar
• Gotto AM Jr, Cannon CP, Li XS et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am. J. Cardiol. 113(1), 76–83 (2014).
   Google Scholar
• Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin. Ther. 35(8), 1082–1098 (2013).
   Google Scholar
• Sahebkar A1, Watts GF. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect?. Cardiovasc. Drugs Ther. 27(6), 559–567 (2013).
   Google Scholar
• Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J. Am. Coll. Cardiol. 44(3), 720–732 (2004).
   Google Scholar
• Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr. Opin. Lipidol. 18(4), 401–408 (2007).
   Google Scholar
• Nielsen LB. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis 143(2), 229–243 (1999).
   Google Scholar
• Tsimikas S, Brilakis ES, Miller ER et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 353(1), 46–57 (2005).
   Google Scholar
• Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J. Am. Coll. Cardiol. 60(8), 716–721 (2012).
   Google Scholar
• Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301(22), 2331–2339 (2009).
   Google Scholar
• Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31(23), 2844–2853 (2010).
   Google Scholar
• Jansen AC, Van Aalst-Cohen ES, Tanck MW et al. The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. Int. J. Med. 256(6), 482–490 (2004). • Indicates the important role of lipoprotein(a) in determining the risk of cardiovascular disease in FH patients.
   Google Scholar
• Alagona P Jr. Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy. Am. J. Manag. Care 15(3 Suppl.), S65–S73 (2009).
   Google Scholar
• Le NA, Walter MF. The role of hypertriglyceridemia in atherosclerosis. Curr. Atheroscler. Rep. 9(2), 110–115 (2007).
   Google Scholar
• Nakaya N. Hypertriglyceridemia as a cause of atherosclerosis. Nihon Rinsho 60(5), 860–867 (2002).
   Google Scholar
• Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 9, 14 (2012).
   Google Scholar