The efficacy and safety of PCSK9 inhibitor on hypercholesteremia: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

ZHAO Zinan ^1,2,3,4 , ZHANG Yatong ^1,2,3,4 , LI Kexin ⁵ , QI Wenyuan ⁵ ,  HU Xin ^1,2,3,4

1. Department of Pharmacy, Beijing Hospital, Beijing 100730, P.R.China;
2. Assessment of Clinical Drugs Risk and Individual Application Key Laboratory, Beijing Hospital, Beijing 100730, P.R.China;
3. National Center of Gerontology, Beijing 100730, P.R.China;
4. Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, P.R.China;
5. Beijing Hospital Clinical Trial Center, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, P.R.China;

Corresponding author：

HU Xin, Email: huxinbjyy@126.com

Keywords：

PCSK9 inhibitor; Hypercholesteremia; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202003096

Video：

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Objectives To systematically review the efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on hypercholesteremia.Methods Databases including The Cochrane Library, PubMed, EMbase, CNKI, WanFang Data and CBM were searched electronically for randomized controlled trials (RCTs) of PCSK9 inhibitor on the treatment of hypercholesteremia from inception to June 2019. Two reviewers independently screened literatures, extracted data, and assessed risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software.Results A total of 42 RCTs involving 90 058 patients were included. Alirocumab, evolocumab, bococizumab and LY3015014 were retrieved. Placebo, statin or ezetimibe were used to treat the patient in the control group. The efficacy results showed that there were significant differences between alirocumab combined statin and placebo combined statin (MD=−49.89, 95%CI −56.34 to −43.44, P<0.00001) or evolocumab combined statin and placebo combined statin (MD=−56.54, 95%CI −61.09 to −52.00, P<0.00001) in reducing LDL-C levels. There was significant difference between alirocumab combined statin and ezetimibe combined statin (MD=−29.41, 95%CI −36.08 to −22.75, P<0.00001) in reducing LDL-C levels. The results of Safety showed that there were no significant differences between alirocumab and placebo (RR=0.99, 95%CI 0.97 to 1.01, P=0.37) or evolocumab and placebo (RR=1.05, 95%CI 1.00 to 1.10, P=0.07) in the incidence of adverse events (AEs). There was significant difference between bococizumab and placebo (RR=1.09, 95%CI 1.01 to 1.18, P=0.03) in the incidence of AEs. There was significant difference between evolocumab and ezetimibe (RR=0.89, 95%CI 0.80 to 0.99, P=0.04) in the incidence of AEs. There was no significant difference between alirocumab and statin (RR=0.93, 95%CI 0.84 to 1.03, P=0.90) in the incidence of AEs.Conclusions PCSK9 inhibitor can reduce LDL-C levels in patients with hypercholesterolemia and has good safety. Due to the limitation of the quantity and quality of the included studies, the above conclusions are needed to be verified by more high quality studies.

Citation： ZHAO Zinan, ZHANG Yatong, LI Kexin, QI Wenyuan, HU Xin. The efficacy and safety of PCSK9 inhibitor on hypercholesteremia: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2020, 20(11): 1284-1294. doi: 10.7507/1672-2531.202003096 Copy

1.	Nicholls SJ, Brandrup-Wognsen G, Palmer M, et al. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol, 2010, 105(1): 69-76.
2.	Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis, 2012, 220(2): 381-386.
3.	Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat a of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem, 2007, 282(25): 18602-18612.
4.	Chaudhary R, Garg J, Shah N, et al. PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol, 2017, 9(2): 76-91.
5.	Kazi DS, Penko J, Coxson PG, et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA, 2017, 318(8): 748-750.
6.	陈文文, 李振山, 刘妍妍, 等. PCSK9抑制剂依洛尤单抗在降低心血管事件风险中的研究进展. 中国医院药学杂志, 2020, 40(3): 344-348.
7.	Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from: www.training.cochrane.org/handbook.
8.	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, 2012, 380(9836): 29-36.
9.	McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol, 2012, 59(25): 2344-2353.
10.	Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med, 2012, 367(20): 1891-1900.
11.	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, 2012, 308(23): 2497-2506.
12.	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, 2012, 380(9858): 2007-2017.
13.	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, 2012, 380(9858): 1995-2006.
14.	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(20): 2408-2417.
15.	Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol, 2014, 176(1): 55-61.
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20.	Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. Circ J, 2014, 78(5): 1073-1082.
21.	Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol, 2015, 9(6): 758-769.
22.	Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J, 2015, 169(6): 906-915.
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25.	Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab, 2015, 100(8): 3140-3148.
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27.	Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965): 341-350.
28.	Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol, 2015, 115(9): 1212-1221.
29.	Roth EM, Moriarty PM, Bergeron J, et al. A phase Ⅲ randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis, 2016, 254: 254-262.
30.	Stroes E, Guyton JR, Lepor N, et al. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: the ODYSSEY CHOICE Ⅱ study. J Am Heart Assoc, 2016, 5(9): e003421.
31.	Ginsberg HN, Rader DJ, Raal FJ, 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(5): 473-483.
32.	Teramoto T, Kobayashi M, Tasaki H, et al. Efficacy and safety of alirocumab in Japanese patients with heterozygous familial hypercholesterolemia or at high cardiovascular risk with hypercholesterolemia not adequately controlled with statins-ODYSSEY JAPAN randomized controlled trial. Circ J, 2016, 80(9): 1980-1987.
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36.	Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol, 2014, 63(23): 2541-2548.
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1. Nicholls SJ, Brandrup-Wognsen G, Palmer M, et al. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol, 2010, 105(1): 69-76.
2. Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis, 2012, 220(2): 381-386.
3. Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat a of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem, 2007, 282(25): 18602-18612.
4. Chaudhary R, Garg J, Shah N, et al. PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol, 2017, 9(2): 76-91.
5. Kazi DS, Penko J, Coxson PG, et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA, 2017, 318(8): 748-750.
6. 陈文文, 李振山, 刘妍妍, 等. PCSK9抑制剂依洛尤单抗在降低心血管事件风险中的研究进展. 中国医院药学杂志, 2020, 40(3): 344-348.
7. Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from: www.training.cochrane.org/handbook.
8. 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, 2012, 380(9836): 29-36.
9. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol, 2012, 59(25): 2344-2353.
10. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med, 2012, 367(20): 1891-1900.
11. 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, 2012, 308(23): 2497-2506.
12. 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, 2012, 380(9858): 2007-2017.
13. 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, 2012, 380(9858): 1995-2006.
14. 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(20): 2408-2417.
15. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol, 2014, 176(1): 55-61.
16. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J, 2014, 168(5): 682-689.
17. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med, 2014, 370(19): 1809-1819.
18. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA, 2014, 311(18): 1870-1882.
19. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase Ⅲ clinical trial of evolocumab. J Am Coll Cardiol, 2014, 63(23): 2531-2540.
20. Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. Circ J, 2014, 78(5): 1073-1082.
21. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol, 2015, 9(6): 758-769.
22. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J, 2015, 169(6): 906-915.
23. Kastelein JJ, Ginsberg HN, 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(43): 2996-3003.
24. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med, 2015, 372(16): 1489-1499.
25. Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab, 2015, 100(8): 3140-3148.
26. Raal FJ, Stein EA, 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(9965): 331-340.
27. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965): 341-350.
28. Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol, 2015, 115(9): 1212-1221.
29. Roth EM, Moriarty PM, Bergeron J, et al. A phase Ⅲ randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis, 2016, 254: 254-262.
30. Stroes E, Guyton JR, Lepor N, et al. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: the ODYSSEY CHOICE Ⅱ study. J Am Heart Assoc, 2016, 5(9): e003421.
31. Ginsberg HN, Rader DJ, Raal FJ, 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(5): 473-483.
32. Teramoto T, Kobayashi M, Tasaki H, et al. Efficacy and safety of alirocumab in Japanese patients with heterozygous familial hypercholesterolemia or at high cardiovascular risk with hypercholesterolemia not adequately controlled with statins-ODYSSEY JAPAN randomized controlled trial. Circ J, 2016, 80(9): 1980-1987.
33. Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS Ⅱ randomized trial. Atherosclerosis, 2016, 244: 138-146.
34. Teramoto T, Kobayashi M, Uno K, et al. Efficacy and safety of alirocumab in Japanese subjects (phase 1 and 2 studies). Am J Cardiol, 2016, 118(1): 56-63.
35. Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J, 2016, 37(48): 3588-3595.
36. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol, 2014, 63(23): 2541-2548.
37. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA, 2016, 315(15): 1580-1590.
38. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA, 2016, 316(22): 2373-2384.
39. Kiyosue A, Honarpour N, Kurtz C, et al. A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol, 2016, 117(1): 40-47.
40. Kastelein JJ, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. Eur Heart J, 2016, 37(17): 1360-1369.
41. Leiter LA, Cariou B, Müller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab, 2017, 19(12): 1781-1792.
42. Koh KK, Nam CW, Chao TH, et al. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). J Clin Lipidol, 2018, 12(1): 162-172.
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