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Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies in Regard to Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials

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Abstract

Background

Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Objective

The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes.

Methods and Results

Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints. Twenty-three studies including 65,957 participants were identified. Compared with controls, PCSK9-mAb treatment was not associated with the adverse event of diabetes (RR 0.97, 95% CI 0.91–1.02; p = 0.22). When we analysed the trials in terms of PCSK9-mAb type, alirocumab was associated with a significant reduction in the risk of diabetes (RR 0.91, 95% CI 0.85–0.98; p = 0.01), whereas no significant reduction was observed in participants receiving evolocumab or bococizumab. Interestingly, compared with ezetimibe, which was actively used as lipid-modifying therapy in the control group, PCSK9-mAbs seem to have a lower risk of incident diabetes (RR 0.60, 95% CI 0.37–0.99; p = 0.04). This meta-analysis also revealed a noticeable increase in the risk of incident diabetes in the evolocumab and alirocumab pool (RR 2.14, 95% CI 1.12–4.07; p = 0.02) when the use of statins was equivalent between the experimental and active comparator arms.

Conclusion

Compared with placebo or any other comparator, PCSK9-mAb treatment was not associated with the adverse event of diabetes. However, evolocumab and alirocumab show high risk of incident diabetes when there is no interference from unbalanced use of statins. The imbalance in background lipid modifying therapy or different comparators used in the control arms of the studies might have masked the effect of PCSK9-mAb therapy on diabetes.

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References

  1. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.

    CAS  PubMed  Google Scholar 

  3. Casula M, Mozzanica F, Scotti L, Tragni E, Pirillo A, Corrao G, et al. Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Nutr Metab Cardiovasc Dis. 2017;27(5):396–406.

    CAS  PubMed  Google Scholar 

  4. Erqou S, Lee CC, Adler AI. Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia. 2014;57(12):2444–52.

    CAS  PubMed  Google Scholar 

  5. Bardini G, Giannini S, Rotella CM, Pala L, Cresci B, Mannucci E. Lower and higher-potency statins on glycemic control in type 2 diabetes: a retrospective cohort study. Diabetes Res Clin Pract. 2016;120:104–10.

    CAS  PubMed  Google Scholar 

  6. Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA. 2016;316(13):1383–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Fall T, Xie W, Poon W, Yaghootkar H, Magi R, Knowles JW, et al. Using genetic variants to assess the relationship between circulating lipids and type 2 diabetes. Diabetes. 2015;64(7):2676–84.

    CAS  PubMed  Google Scholar 

  8. Li S, Li JJ. PCSK9: a key factor modulating atherosclerosis. J Atheroscler Thromb. 2015;22(3):221–30.

    PubMed  Google Scholar 

  9. Li S, Zhang Y, Xu RX, Guo YL, Zhu CG, Wu NQ, et al. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease. Ann Med. 2015;47(5):386–93.

    PubMed  Google Scholar 

  10. Li C, Lin L, Zhang W, Zhou L, Wang H, Luo X, et al. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials. J Am Heart Assoc. 2015;4(6):e001937.

    PubMed  PubMed Central  Google Scholar 

  11. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40–51.

    PubMed  Google Scholar 

  12. Zhang XL, Zhu QQ, Zhu L, Chen JZ, Chen QH, Li GN, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med. 2015;13:123.

    PubMed  PubMed Central  Google Scholar 

  13. Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T, Baker NC, et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016;37(6):536–45.

    CAS  PubMed  Google Scholar 

  14. Sattar N, Preiss D, Robinson JG, Djedjos CS, Elliott M, Somaratne R, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016;4(5):403–10.

    CAS  PubMed  Google Scholar 

  15. Schmidt AF, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017;4:CD011748.

    PubMed  Google Scholar 

  16. Navarese EP, Kolodziejczak M, Petrescu A, Wernly B, Lichtenauer M, Lauten A, et al. Role of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with coronary artery disease undergoing percutaneous coronary intervention. Expert Rev Cardiovasc Ther. 2018;16(6):419–29.

    CAS  PubMed  Google Scholar 

  17. Stein EA, Giugliano RP, Koren MJ, Raal FJ, Roth EM, Weiss R, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J. 2014;35(33):2249–59.

    CAS  PubMed  Google Scholar 

  18. Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, Direk K, et al. Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol. 2017;5(7):534–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mbikay M, Sirois F, Mayne J, Wang GS, Chen A, Dewpura T, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 2010;584(4):701–6.

    CAS  PubMed  Google Scholar 

  20. Langhi C, Le May C, Gmyr V, Vandewalle B, Kerr-Conte J, Krempf M, et al. PCSK9 is expressed in pancreatic δ-cells and does not alter insulin secretion. Biochem Biophys Res Commun. 2009;390(4):1288–93.

    CAS  PubMed  Google Scholar 

  21. Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375(22):2144–53.

    CAS  PubMed  Google Scholar 

  22. Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5(2):97–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Colhoun HM, Ginsberg HN, Robinson JG, Leiter LA, Müller-Wieland D, Henry RR, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY phase 3 studies. Eur Heart J. 2016;37(39):2981–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sattar N, Toth PP, Blom DJ, Koren MJ, Soran H, Uhart M, et al. Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus. Am J Cardiol. 2017;120(9):1521–7.

    CAS  PubMed  Google Scholar 

  25. Monami M, Sesti G, Mannucci E. PCSK9 inhibitor therapy: a systematic review and meta-analysis of metabolic and cardiovascular outcomes in patients with diabetes. Diabetes Obes Metab. 2018. https://doi.org/10.1111/dom.13599(Epub 28 Nov 2018).

    Article  PubMed  Google Scholar 

  26. Cao YX, Liu HH, Dong QT, Li S, Li JJ. Effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies on new-onset diabetes mellitus and glucose metabolism: a systematic review and meta-analysis. Diabetes Obes Metab. 2018;20(6):1391–8.

    CAS  PubMed  Google Scholar 

  27. Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50.

    CAS  PubMed  Google Scholar 

  28. Ginsberg HN, Farnier M, Robinson JG, Cannon CP, Sattar N, Baccara-Dinet MT, et al. Efficacy and safety of alirocumab in individuals with diabetes mellitus: pooled analyses from five placebo-controlled phase 3 studies. Diabetes Ther. 2018;9(3):1317–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. de Carvalho LSF, Campos AM, Sposito AC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incident type 2 diabetes: a systematic review and meta-analysis with over 96,000 patient-years. Diabetes Care. 2018;41(2):364–7.

    PubMed  Google Scholar 

  30. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–84.

    CAS  PubMed  Google Scholar 

  31. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clin Res Ed). 2009;339:b2700.

    Google Scholar 

  32. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, 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.

    CAS  PubMed  Google Scholar 

  33. Bays H, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni-Berthold I, 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):3140–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99.

    CAS  PubMed  Google Scholar 

  36. Farnier M, Jones P, Severance R, Averna M, Steinhagen-Thiessen E, Colhoun HM, 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;244:138–46.

    CAS  PubMed  Google Scholar 

  37. Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, 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):473–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol. 2016;117(1):40–7.

    CAS  PubMed  Google Scholar 

  39. Roth EM, Moriarty PM, Bergeron J, Langslet G, Manvelian G, Zhao 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;254:254–62.

    CAS  PubMed  Google Scholar 

  40. Teramoto T, Kobayashi M, Tasaki H, Yagyu H, Higashikata T, Takagi Y, 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):1980–7.

    CAS  PubMed  Google Scholar 

  41. Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, 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.

    PubMed  Google Scholar 

  42. Koh KK, Nam CW, Chao TH, Liu ME, Wu CJ, Kim DS, 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):162–72.

    PubMed  Google Scholar 

  43. Leiter LA, Zamorano JL, Bujas-Bobanovic M, Louie MJ, Lecorps G, Cannon CP, et al. Lipid-lowering efficacy and safety of alirocumab in patients with or without diabetes: a sub-analysis of ODYSSEY COMBO II. Diabetes Obes Metab. 2017;19(7):989–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376(16):1527–39.

    CAS  PubMed  Google Scholar 

  45. Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017;376(16):1517–26.

    CAS  PubMed  Google Scholar 

  46. Lorenzatti AJ, Eliaschewitz FG, Chen Y, Fialkow J, Lu J, Baass A, et al. Rationale and design of a randomized study to assess the efficacy and safety of evolocumab in patients with diabetes and dyslipidemia: the BERSON clinical trial. Clin Cardiol. 2018;41(9):1117–22.

    PubMed  PubMed Central  Google Scholar 

  47. Ray KK, Leiter LA, Muller-Wieland D, Cariou B, Colhoun HM, Henry RR, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: the ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab. 2018;20(6):1479–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107.

    CAS  PubMed  Google Scholar 

  49. Paseban M, Butler AE, Sahebkar A. Mechanisms of statin-induced new-onset diabetes. J Cell Physiol. 2019;234(8):12551–61.

    CAS  PubMed  Google Scholar 

  50. Cai R, Yuan Y, Zhou Y, Xia W, Wang P, Sun H, et al. Lower intensified target LDL-c level of statin therapy results in a higher risk of incident diabetes: a meta-analysis. PLoS One. 2014;9(8):e104922.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the help of Zhongbai Zhang (The Medical University of Chinese People’s Armed Police Force), Zhiyun Yan (The Medical University of Chinese People’s Armed Police Force), and Rundu Chen (The Affiliated Hospital Medical University of Chinese People’s Armed Police Force) for the language modification and help with the statistical techniques.

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Authors and Affiliations

  1. Department of Cardiology, Tianjin University of Traditional Chinese Medicine, 220 Chenglin Rd, Dongli District, Tianjin, 300162, China

    Qiwen Chen, Xueting Qin & Rui Liu

  2. Department of Cardiology, The Affiliated Hospital Medical University of Chinese People’s Armed Police Force, 220 Chenglin Rd, Dongli District, Tianjin, 300162, China

    Guodong Wu, Chuang Li & Mei Zhang

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  1. Qiwen Chen
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  2. Guodong Wu
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  3. Chuang Li
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Contributions

MZ and QC contributed to the conception of this work; MZ, QC, CL, XQ, RL, and GW contributed to the design of the work; QC, CL, XQ, RL, and GW contributed to the acquisition, analysis, and interpretation of the data; and QC drafted the manuscript. All authors critically revised the manuscript, gave final approval for publication of this work, and agree to be accountable for all aspects of the work, ensuring integrity and accuracy.

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Correspondence to Mei Zhang.

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No external funding was used in the preparation of this work.

Conflict of Interest

Qiwen Chen, Guodong Wu, Chuang Li, Xueting Qin, Rui Liu, and Mei Zhang declare they have no potential conflicts of interest that might be relevant to the contents of this systematic review.

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Chen, Q., Wu, G., Li, C. et al. Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies in Regard to Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Am J Cardiovasc Drugs 20, 343–353 (2020). https://doi.org/10.1007/s40256-019-00386-w

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