PERSPECTIVE
METABOLIC SYNDROME AND RELATED DISORDERS Volume 13, Number 3, 2015 Mary Ann Liebert, Inc. Pp. 99–101 DOI: 10.1089/met.2015.1503
PCSK9 Inhibitors: The Next Frontier in Low-Density Lipoprotein Lowering Ishwarlal Jialal, MD, PhD, DABCL, FRCPATH,1 and Shailendra B. Patel, BM, ChB, DPhil, FRCP 2
Abstract
The discovery and elucidation of the role of the low-density lipoprotein receptor (LDL-R) in familial hypercholesterolemia (FH) ushered in the statin group of drugs. These drugs, in addition to lowering low-density lipoprotein cholesterol (LDL-C), result in a significant reduction in cardiovascular events (CVE) and mortality. Recently, a gain-of-function mutation in another protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), was reported to result in a FH phenotype by promoting degradation of the LDL-R. More importantly, loss-offunction mutations in the same gene resulted in low LDL-C and a reduction in CVE, making this an enticing target for drug development. Numerous strategies have been developed to target PCSK9, the most successful being monoclonal antibodies (mAbs) that bind PCSK9. These mAbs have been shown to reduce LDL-C around 50% as either monotherapy with diet or in combination with statin therapy. In this short perspective, we discuss the biochemistry and biology of PCSK9 in relation to lipid metabolism and the promising studies in humans demonstrating a substantial reduction in LDL-C with relative good short-term safety of PCSK9 mAbs.
F
regulated convertase 1 (NARC-1) and was highly expressed in liver and intestine,7 with expression also detected in kidneys and brain. Remarkably, genetic screening of some subjects with low plasma LDL-C ( < 58 mg/dL) exhibited clear loss-of-function mutations in PCSK9.8 The majority of these subjects were African American, and the two mutations identified collectively had a prevalence of *2% in this community.9 Loss of function mutations were confirmed in other populations and like in the initial studies were associated with a reduction in cardiovascular events. The suspicion that PCSK9 regulated LDL-R trafficking was soon confirmed by several groups: PCSK9 regulates LDL-R degradation,10 and the gain-of-function mutations increased receptor turnover, leading to reduced LDL-C clearance, whereas loss of function leads to increased LDL-R activity. It appears that the major mechanism of action of PCSK9 is via binding to the epidermal growth factor–like repeat A domain of the LDL-R in the extracellular space, promoting its degradation. Interestingly, PCSK9 is also regulated by sterol regulatory element-binding protein 2 (SREBP2): Statins upregulate LDL-R in the liver,11 but also increase PCSK9, suggesting PCSK9 acts to dampen the increased LDL-R activity.12 A consequence of this is that the potential statin-mediated LDL-C lowering is attenuated by the
amilial hypercholesterolemia (FH) is a very classical disease, and its contribution to not only medicine but science cannot be under-stated. It is an autosomal dominantly inherited disease caused by loss-of-function mutations affecting the low-density lipoprotein receptor (LDL-R). Elucidation of the disease pathophysiology led to the awarding of a Nobel prize for receptor endocytosis and disease,1 the discovery and use of agents that inhibited cholesterol synthesis (statins),2,3 and the elegant regulatory mechanisms operative in the liver that control intracellular cholesterol balance as well as plasma low-density lipoprotein cholesterol (LDL-C).2 FH, caused by mutations in the LDL-R, remains the commonest condition, but there were families that showed an autosomal dominant inheritance pattern yet did not map to the LDL-R locus (chromosome 19p13.3), suggesting other genetic loci were out there. The first of these identified was a defect involving the LDL-R ligand, apolipoprotein B (chromosome 2p23), preventing binding of the LDL particle to the LDL-R.3 However, yet another locus causing autosomal dominant FH had been mapped to the 1p34.1–p32 region,4,5 and elucidation of this led to a very novel protein,6 proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease, where a gain-of-function mutation led to increased LDL-C. PCSK9 had been identified independently as neural apoptosis 1
Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento, California. Clement J. Zablocki VAMC and Division of Endocrinology, Diabetes, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin. 2
99
100
increase in PCSK9, and if we can negate this latter aspect, then statins may be even more effective in lowering LDLC.11,12 Identification and characterization of subjects with no PCSK9 protein (homozygous null subjects) showed they had very low LDL-C, yet were otherwise healthy,13 making PCSK9 a good pharmaceutical target. As discussed in the section above, the rationale of targeting PCSK9 is clear and scientifically plausible. Various strategies have been employed to target PCSK9, including antisense oligonucleotides (now discontinued because of adverse reactions), small interfering (si) RNA, adnectins (genetically engineered proteins that bind to antigens), and monoclonal antibodies (mAbs). The strategy using mAbs that bind PCSK9 has advanced the farthest clinically, spanning phases 1 to 3 clinical trials, as reviewed recently by various groups.13–16 With respect to alirocumab, clinical trials showed substantial reductions (*50%) in LDL-C. This benefit was seen in patients with heterozygotic FH and non-FH patients, in combination with statin and ezetimibe therapy as well as monotherapy on diet. In these studies, alirocumab was administered subcutaneously either every 2 or 4 weeks. It appears the best dosing is 150 mg every 2 weeks. Not surprising there were parallel reductions in both non-HDL-C and apolipoprotein B and a modest reduction in triglycerides (TGs).13–16 However, in contrast to statin therapy there was also a significant reduction in lipoprotein (a) [Lp(a)] levels.13–16 As with alirocumab, evolocumab demonstrated significant and potent LDL-C reductions in phases 1 to 3 trials. These benefits were seen with monotherapy (with diet) and in combination with a statin or ezetimibe, and again in both FH and non-FH patients. Furthermore, commensurate reductions in non-HDL-C, apolipoprotein B, and TGs were reported.13–16 The reduction in Lp(a) appears to be a class effect, as it was also demonstrated with evolocumab therapy.13–16 Most importantly, in the GAUSS study,17 evolocumab therapy administered every 4 weeks was tested in statin-intolerant patients (due to muscle-related side effects) and was both efficacious and well-tolerated, with a low prevalence of myalgia reported (7.5%) in this predisposed cohort. Another important therapeutic advance with evolocumab was the demonstration of significant LDL-C reduction in a small pilot study of eight patients with homozygous FH due to a defective LDL-R.18 This is very important because it is very difficult to get a 50% reduction in LDL-C in these patients. Not surprisingly, patients bearing two null receptor defects and therefore having no LDL-R expression did not benefit. There are two other mAbs to PCSK9, bococizumab and LY3015014. However full published reports in peer-reviewed journals are sparse compared to alirocumab and evolocumab.14 The major concern with any new class of drugs is always adverse reactions. In the published studies to date, the majority with a duration of 12 weeks, it appears that the commonest side effects were minor injection site reactions, nasopharyngitis, and upper respiratory tract infections. In one patient on alirocumab, an episode of leukocytoclastic vasculitis was documented that resolved with appropriate treatment. Furthermore, two studies19,20 of evolocumab therapy, with a duration of 52 weeks, have been reported, one of which was an open-label study.20 In both of these studies, the durability of the reduction in LDL-C and safety was most encouraging. With mAb therapy, the issue of neutralizing antibodies abrogating biological effects always needs to be considered. However, to date, including the 52-week studies, this has not emerged as an
JIALAL AND PATEL
issue. Animal studies targeting PCSK9 suggest the potential for abnormal glucose tolerance, increased visceral adiposity, immune dysregulation, and increased susceptibility to hepatic viruses.14 PCSK9 is expressed in nonhepatic organs, thus longer-term vigilance will be mandatory regarding these aspects, and attention to these concerns needs to be carefully recorded in the ongoing large clinical trials. With the advent of this class of drugs, the reliability of the Friedewald calculation to report LDL-C levels < 70 mg/dL is a major concern because there is a significant underestimation. This major issue will need to be addressed soon.21 Whereas the majority of drugs that lower LDL-C have been shown to reduce CVE, this level of evidence may not be required for the PCSK9 mAbs given the precedent of the introduction of statin therapy without clinical trials demonstrating a reduction in CVE and the large residual risk that remains, including the issue of statin-intolerant patients and inadequate management of patients with FH. However cardiovascular safety will need to be monitored for at least 2 years if regulatory bodies approve these drugs prior to trials with CVE end points. Nonetheless large studies of duration of 5 years (alirocumab, ODYSSEY Outcomes; evolocumab, MACE-FOURIER; and bococizumab, SPIRE 1 and 2) are in progress to determine the effect of these drugs on CVE as the primary end point and are also addressing the issue of longterm safety.14 There is much promise and excitement that this journey, which was initiated in 2003 with the identification of PCSK9 in lipid regulation, will translate to substantial reduction in atherosclerotic cardiovascular morbidity and mortality.
Author Disclosure Statement Dr. I. Jialal serves on the Pfizer Advisory Board.
References 1. Goldstein JL, Brown MS. Familial hypercholesterolemia: Pathogenesis of a receptor disease. Johns Hopkins Med J 1978;143:8–16. 2. Brown MS, Goldstein JL., Cholesterol feedback: From Schoenheimer’s bottle to Scap’s MELADL. J Lipid Re 2009; 50(Suppl):S15–S27. 3. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: :ow density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987;84:6919–6923. 4. Varret M, Rabes JP, Saint-Jore B, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1–p32. Am J Hum Genet 1999;64:1378–1387. 5. Hunt SC, Hopkins PN, Bulka K, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol 2000;20:1089–1093. 6. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–156. 7. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003;100:928–933. 8. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161–165.
PCSK9 INHIBITORS
9. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–1272. 10. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a postendoplasmic reticulum compartment. Proc Natl Acad Sci USA 2005;102:2069–2074. 11. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454–1459. 12. Attie AD, Seidah NG. Dual regulation of the LDL receptor—some clarity and new questions. Cell Metab 2005;1: 290–292. 13. Abifadel M, Elbitar S, El Khoury P, et al. Living the PCSK9 adventure: From the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr Atheroscler Rep 2014;16:439–438. 14. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9inhibitors. Nat Rev Cardiol 2014;11:563–575. 15. Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis 2014:107;58–66. 16. Stein EA, Raal F. Reduction in low-density lipoprotein cholesterol by monoclonal antibody inhibition of PSCK9. Annu Rev Med 2014;65:417–431. 17. Sullivan D, Olsson AG, Scott R, et al. Effect of monoclocal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin intolerant patients. JAMA 2012;308:2497–2506 18. Stein EA, Honarpour N, Wasserman SM, et al. Effect of PCSK9 monoclonal antibody, AMG145, in homozygous familial hypercholesterolemia. Circulation 2013;128:2113–2120.
101
19. Blom DJ, Hala T, Bolognese M, et al.; DESCARTES Investigators. A 52 week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809–1819. 20. Koren MJ, Giugliano RP, Raal FJ, et al.; OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab in patients with hypercholesterolemia. Circulation 2014:129:234–243 21. Jialal I. What is the role of the clinical laboratory in the new ACC/AHA Guidelines for the treatment of blood cholesterol in adult. Am J Clin Pathol 2014;141:772–773.
Address correspondence to: Ishwarlal Jialal, MD, PhD, DABCL, FRCPATH Director, Laboratory for Atherosclerosis and Metabolic Research University of California Davis Medical Center 4635 2nd Avenue, Research I Building, Room 3000 Sacramento, CA 95817 E-mail: [email protected] Shailendra B. Patel, BM, ChB, DPhil, FRCP Clement J. Zablocki VAMC and Division of Endocrinology, Diabetes, and Clinical Nutrition Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 E-mail: [email protected]
METABOLIC SYNDROME AND RELATED DISORDERS Volume 13, Number 3, 2015 Mary Ann Liebert, Inc. Pp. 99–101 DOI: 10.1089/met.2015.1503
PCSK9 Inhibitors: The Next Frontier in Low-Density Lipoprotein Lowering Ishwarlal Jialal, MD, PhD, DABCL, FRCPATH,1 and Shailendra B. Patel, BM, ChB, DPhil, FRCP 2
Abstract
The discovery and elucidation of the role of the low-density lipoprotein receptor (LDL-R) in familial hypercholesterolemia (FH) ushered in the statin group of drugs. These drugs, in addition to lowering low-density lipoprotein cholesterol (LDL-C), result in a significant reduction in cardiovascular events (CVE) and mortality. Recently, a gain-of-function mutation in another protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), was reported to result in a FH phenotype by promoting degradation of the LDL-R. More importantly, loss-offunction mutations in the same gene resulted in low LDL-C and a reduction in CVE, making this an enticing target for drug development. Numerous strategies have been developed to target PCSK9, the most successful being monoclonal antibodies (mAbs) that bind PCSK9. These mAbs have been shown to reduce LDL-C around 50% as either monotherapy with diet or in combination with statin therapy. In this short perspective, we discuss the biochemistry and biology of PCSK9 in relation to lipid metabolism and the promising studies in humans demonstrating a substantial reduction in LDL-C with relative good short-term safety of PCSK9 mAbs.
F
regulated convertase 1 (NARC-1) and was highly expressed in liver and intestine,7 with expression also detected in kidneys and brain. Remarkably, genetic screening of some subjects with low plasma LDL-C ( < 58 mg/dL) exhibited clear loss-of-function mutations in PCSK9.8 The majority of these subjects were African American, and the two mutations identified collectively had a prevalence of *2% in this community.9 Loss of function mutations were confirmed in other populations and like in the initial studies were associated with a reduction in cardiovascular events. The suspicion that PCSK9 regulated LDL-R trafficking was soon confirmed by several groups: PCSK9 regulates LDL-R degradation,10 and the gain-of-function mutations increased receptor turnover, leading to reduced LDL-C clearance, whereas loss of function leads to increased LDL-R activity. It appears that the major mechanism of action of PCSK9 is via binding to the epidermal growth factor–like repeat A domain of the LDL-R in the extracellular space, promoting its degradation. Interestingly, PCSK9 is also regulated by sterol regulatory element-binding protein 2 (SREBP2): Statins upregulate LDL-R in the liver,11 but also increase PCSK9, suggesting PCSK9 acts to dampen the increased LDL-R activity.12 A consequence of this is that the potential statin-mediated LDL-C lowering is attenuated by the
amilial hypercholesterolemia (FH) is a very classical disease, and its contribution to not only medicine but science cannot be under-stated. It is an autosomal dominantly inherited disease caused by loss-of-function mutations affecting the low-density lipoprotein receptor (LDL-R). Elucidation of the disease pathophysiology led to the awarding of a Nobel prize for receptor endocytosis and disease,1 the discovery and use of agents that inhibited cholesterol synthesis (statins),2,3 and the elegant regulatory mechanisms operative in the liver that control intracellular cholesterol balance as well as plasma low-density lipoprotein cholesterol (LDL-C).2 FH, caused by mutations in the LDL-R, remains the commonest condition, but there were families that showed an autosomal dominant inheritance pattern yet did not map to the LDL-R locus (chromosome 19p13.3), suggesting other genetic loci were out there. The first of these identified was a defect involving the LDL-R ligand, apolipoprotein B (chromosome 2p23), preventing binding of the LDL particle to the LDL-R.3 However, yet another locus causing autosomal dominant FH had been mapped to the 1p34.1–p32 region,4,5 and elucidation of this led to a very novel protein,6 proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease, where a gain-of-function mutation led to increased LDL-C. PCSK9 had been identified independently as neural apoptosis 1
Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento, California. Clement J. Zablocki VAMC and Division of Endocrinology, Diabetes, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin. 2
99
100
increase in PCSK9, and if we can negate this latter aspect, then statins may be even more effective in lowering LDLC.11,12 Identification and characterization of subjects with no PCSK9 protein (homozygous null subjects) showed they had very low LDL-C, yet were otherwise healthy,13 making PCSK9 a good pharmaceutical target. As discussed in the section above, the rationale of targeting PCSK9 is clear and scientifically plausible. Various strategies have been employed to target PCSK9, including antisense oligonucleotides (now discontinued because of adverse reactions), small interfering (si) RNA, adnectins (genetically engineered proteins that bind to antigens), and monoclonal antibodies (mAbs). The strategy using mAbs that bind PCSK9 has advanced the farthest clinically, spanning phases 1 to 3 clinical trials, as reviewed recently by various groups.13–16 With respect to alirocumab, clinical trials showed substantial reductions (*50%) in LDL-C. This benefit was seen in patients with heterozygotic FH and non-FH patients, in combination with statin and ezetimibe therapy as well as monotherapy on diet. In these studies, alirocumab was administered subcutaneously either every 2 or 4 weeks. It appears the best dosing is 150 mg every 2 weeks. Not surprising there were parallel reductions in both non-HDL-C and apolipoprotein B and a modest reduction in triglycerides (TGs).13–16 However, in contrast to statin therapy there was also a significant reduction in lipoprotein (a) [Lp(a)] levels.13–16 As with alirocumab, evolocumab demonstrated significant and potent LDL-C reductions in phases 1 to 3 trials. These benefits were seen with monotherapy (with diet) and in combination with a statin or ezetimibe, and again in both FH and non-FH patients. Furthermore, commensurate reductions in non-HDL-C, apolipoprotein B, and TGs were reported.13–16 The reduction in Lp(a) appears to be a class effect, as it was also demonstrated with evolocumab therapy.13–16 Most importantly, in the GAUSS study,17 evolocumab therapy administered every 4 weeks was tested in statin-intolerant patients (due to muscle-related side effects) and was both efficacious and well-tolerated, with a low prevalence of myalgia reported (7.5%) in this predisposed cohort. Another important therapeutic advance with evolocumab was the demonstration of significant LDL-C reduction in a small pilot study of eight patients with homozygous FH due to a defective LDL-R.18 This is very important because it is very difficult to get a 50% reduction in LDL-C in these patients. Not surprisingly, patients bearing two null receptor defects and therefore having no LDL-R expression did not benefit. There are two other mAbs to PCSK9, bococizumab and LY3015014. However full published reports in peer-reviewed journals are sparse compared to alirocumab and evolocumab.14 The major concern with any new class of drugs is always adverse reactions. In the published studies to date, the majority with a duration of 12 weeks, it appears that the commonest side effects were minor injection site reactions, nasopharyngitis, and upper respiratory tract infections. In one patient on alirocumab, an episode of leukocytoclastic vasculitis was documented that resolved with appropriate treatment. Furthermore, two studies19,20 of evolocumab therapy, with a duration of 52 weeks, have been reported, one of which was an open-label study.20 In both of these studies, the durability of the reduction in LDL-C and safety was most encouraging. With mAb therapy, the issue of neutralizing antibodies abrogating biological effects always needs to be considered. However, to date, including the 52-week studies, this has not emerged as an
JIALAL AND PATEL
issue. Animal studies targeting PCSK9 suggest the potential for abnormal glucose tolerance, increased visceral adiposity, immune dysregulation, and increased susceptibility to hepatic viruses.14 PCSK9 is expressed in nonhepatic organs, thus longer-term vigilance will be mandatory regarding these aspects, and attention to these concerns needs to be carefully recorded in the ongoing large clinical trials. With the advent of this class of drugs, the reliability of the Friedewald calculation to report LDL-C levels < 70 mg/dL is a major concern because there is a significant underestimation. This major issue will need to be addressed soon.21 Whereas the majority of drugs that lower LDL-C have been shown to reduce CVE, this level of evidence may not be required for the PCSK9 mAbs given the precedent of the introduction of statin therapy without clinical trials demonstrating a reduction in CVE and the large residual risk that remains, including the issue of statin-intolerant patients and inadequate management of patients with FH. However cardiovascular safety will need to be monitored for at least 2 years if regulatory bodies approve these drugs prior to trials with CVE end points. Nonetheless large studies of duration of 5 years (alirocumab, ODYSSEY Outcomes; evolocumab, MACE-FOURIER; and bococizumab, SPIRE 1 and 2) are in progress to determine the effect of these drugs on CVE as the primary end point and are also addressing the issue of longterm safety.14 There is much promise and excitement that this journey, which was initiated in 2003 with the identification of PCSK9 in lipid regulation, will translate to substantial reduction in atherosclerotic cardiovascular morbidity and mortality.
Author Disclosure Statement Dr. I. Jialal serves on the Pfizer Advisory Board.
References 1. Goldstein JL, Brown MS. Familial hypercholesterolemia: Pathogenesis of a receptor disease. Johns Hopkins Med J 1978;143:8–16. 2. Brown MS, Goldstein JL., Cholesterol feedback: From Schoenheimer’s bottle to Scap’s MELADL. J Lipid Re 2009; 50(Suppl):S15–S27. 3. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: :ow density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987;84:6919–6923. 4. Varret M, Rabes JP, Saint-Jore B, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1–p32. Am J Hum Genet 1999;64:1378–1387. 5. Hunt SC, Hopkins PN, Bulka K, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol 2000;20:1089–1093. 6. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–156. 7. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003;100:928–933. 8. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161–165.
PCSK9 INHIBITORS
9. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–1272. 10. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a postendoplasmic reticulum compartment. Proc Natl Acad Sci USA 2005;102:2069–2074. 11. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454–1459. 12. Attie AD, Seidah NG. Dual regulation of the LDL receptor—some clarity and new questions. Cell Metab 2005;1: 290–292. 13. Abifadel M, Elbitar S, El Khoury P, et al. Living the PCSK9 adventure: From the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr Atheroscler Rep 2014;16:439–438. 14. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9inhibitors. Nat Rev Cardiol 2014;11:563–575. 15. Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis 2014:107;58–66. 16. Stein EA, Raal F. Reduction in low-density lipoprotein cholesterol by monoclonal antibody inhibition of PSCK9. Annu Rev Med 2014;65:417–431. 17. Sullivan D, Olsson AG, Scott R, et al. Effect of monoclocal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin intolerant patients. JAMA 2012;308:2497–2506 18. Stein EA, Honarpour N, Wasserman SM, et al. Effect of PCSK9 monoclonal antibody, AMG145, in homozygous familial hypercholesterolemia. Circulation 2013;128:2113–2120.
101
19. Blom DJ, Hala T, Bolognese M, et al.; DESCARTES Investigators. A 52 week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809–1819. 20. Koren MJ, Giugliano RP, Raal FJ, et al.; OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab in patients with hypercholesterolemia. Circulation 2014:129:234–243 21. Jialal I. What is the role of the clinical laboratory in the new ACC/AHA Guidelines for the treatment of blood cholesterol in adult. Am J Clin Pathol 2014;141:772–773.
Address correspondence to: Ishwarlal Jialal, MD, PhD, DABCL, FRCPATH Director, Laboratory for Atherosclerosis and Metabolic Research University of California Davis Medical Center 4635 2nd Avenue, Research I Building, Room 3000 Sacramento, CA 95817 E-mail: [email protected] Shailendra B. Patel, BM, ChB, DPhil, FRCP Clement J. Zablocki VAMC and Division of Endocrinology, Diabetes, and Clinical Nutrition Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 E-mail: [email protected]
