Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis
Autoři:
Arrigo F. G. Cicero aff001; Federica Fogacci aff001; Adrian V. Hernandez aff002; Maciej Banach aff004;
Působiště autorů:
Hypertension and Cardiovascular Risk Factors Research Group, Department of Medicine and Surgery Sciences, University of Bologna, Bologna, Italy
aff001; Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut/Hartford Hospital Evidence-based Practice Center, Hartford, Connecticut, United States of America
aff002; Vicerrectorado de Investigacion, Universidad San Ignacio de Loyola, Lima, Peru
aff003; Chair of Nephrology and Hypertension, Department of Hypertension, Medical University of Lodz, Lodz, Poland
aff004; Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
aff005; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
aff006
Vyšlo v časopise:
Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis. PLoS Med 17(7): e32767. doi:10.1371/journal.pmed.1003121
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pmed.1003121
Souhrn
Background
Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile.
Methods and findings
We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD −14.94%; 95% CI −17.31%, −12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD −18.17%; 95% CI −21.14%, −15.19%; p < 0.001), low-density lipoprotein cholesterol (MD −22.94%; 95% CI −26.63%, −19.25%; p < 0.001), low-density lipoprotein particle number (MD −20.67%; 95% CI −23.84%, −17.48%; p < 0.001), apolipoprotein B (MD −15.18%; 95% CI −17.41%, −12.95%; p < 0.001), high-density lipoprotein cholesterol (MD −5.83%; 95% CI −6.14%, −5.52%; p < 0.001), high-density lipoprotein particle number (MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049), and hsCRP (MD −27.03%; 95% CI −31.42%, −22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length.
Conclusions
Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.
Klíčová slova:
Database searching – Cholesterol – Lipids – Lipoproteins – Metaanalysis – Plasma proteins – Publication ethics – Statins
Zdroje
1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–322. doi: 10.1161/CIR.0000000000000152 25520374
2. Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60:2631–9. doi: 10.1016/j.jacc.2012.09.017 23083789
3. Strilchuk L, Fogacci F, Cicero AF. Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data. Expert Opin Drug Saf. 2019;18:611–21. doi: 10.1080/14740338.2019.1620730 31100030
4. Ruscica M, Banach M, Sahebkar A, Corsini A, Sirtori CR. ETC-1002 (bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials. Expert Opin Pharmacother. 2019;20:791–803. doi: 10.1080/14656566.2019.1583209 30810432
5. Beigneux AP, Kosinski C, Gavino B, Horton JD, Skarnes WC, Young SG. ATP-citrate lyase deficiency in the mouse. J Biol Chem. 2004;279:9557–64. doi: 10.1074/jbc.M310512200 14662765
6. Berkhout TA, Havekes LM, Pearce NJ, Groot PH. The effect of (-)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2. Biochem J. 1990;272:181–6. doi: 10.1042/bj2720181 2176080
7. Saeed A, Ballantyne CM. Bempedoic acid (ETC-1002): a current review. Cardiol Clin. 2018;36:257–64. doi: 10.1016/j.ccl.2017.12.007 29609755
8. Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457. doi: 10.1038/ncomms13457 27892461
9. Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8:e011662. doi: 10.1161/JAHA.118.011662 30922146
10. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. doi: 10.1136/bmj.b2535 19622551
11. Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions. Chichester (UK): John Wiley & Sons; 2008.
12. Sahebkar A, Pirro M, Banach M, Mikhailidis DP, Atkin SL, Cicero AFG. Lipid-lowering activity of artichoke extracts: a systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2018;58:2549–56. doi: 10.1080/10408398.2017.1332572 28609140
13. Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive meta-analysis. Version 3. Englewood (NJ): Biostat; 2013.
14. Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45:769–73. doi: 10.1016/0895-4356(92)90054-q 1619456
15. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. doi: 10.1186/1471-2288-14-135 25524443
16. Melsen WG, Bootsma MC, Rovers MM, Bonten MJ. The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses. Clin Microbiol Infect. 2014;20:123–9. doi: 10.1111/1469-0691.12494 24320992
17. Haenszel W, Hon NB. Statistical approaches to the study of cancer with particular reference to case registers. J Chronic Dis. 1956;4:589–99. doi: 10.1016/0021-9681(56)90049-2 13376690
18. Fogacci F, Banach M, Cicero AF. Resveratrol effect on patients with non-alcoholic fatty liver disease: a matter of dose and treatment length. Diabetes Obes Metab. 2018;20:1798–9. doi: 10.1111/dom.13324 29656521
19. Sahebkar A, Pirro M, Reiner Ž, Cicero A, Ferretti G, Simental-Mendía M, et al. A systematic review and meta-analysis of controlled trials on the effects of statin and fibrate therapies on plasma homocysteine levels. Curr Med Chem. 2016;23:4490–503. doi: 10.2174/0929867323666161007155310 27748179
20. Duval S, Tweedie R. Trim and fill: a simple funnel‐plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–63. doi: 10.1111/j.0006-341x.2000.00455.x 10877304
21. Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27:593–603. doi: 10.1177/2047487319864671 31357887
22. Lalwani ND, Hanselman JC, MacDougal DE, Sterling LR, Cramer CT. Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: a randomized placebo-controlled trial. J Clin Lipidol. 2019;13:568–79. doi: 10.1016/j.jacl.2019.05.003 31202641
23. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022–32. doi: 10.1056/NEJMoa1803917 30865796
24. Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195–203. doi: 10.1016/j.atherosclerosis.2018.06.002 29910030
25. Ballantyne CM, McKenney JM, MacDougall DE, Margulies JR, Robinson PL, Hanselman JC, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol. 2016;117:1928–33. doi: 10.1016/j.amjcard.2016.03.043 27138185
26. Thompson PD, MacDougall DE, Newton RS, Margulies JR, Hanselman JC, Orloff DG, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10:556–67. doi: 10.1016/j.jacl.2015.12.025 27206943
27. Gutierrez MJ, Rosenberg NL, Macdougall DE, Hanselman JC, Margulies JR, Strange P, et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2014;34:676–83. doi: 10.1161/ATVBAHA.113.302677 24385236
28. Thompson PD, Rubino J, Janik MJ, MacDougall DE, McBride SJ, Margulies JR, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015;9:295–304. doi: 10.1016/j.jacl.2015.03.003 26073387
29. Ballantyne CM, Davidson MH, Macdougall DE, Bays HE, Dicarlo LA, Rosenberg NL, 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;62:1154–62. doi: 10.1016/j.jacc.2013.05.050 23770179
30. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81. doi: 10.1016/S0140-6736(10)61350-5 21067804
31. Gitt AK, Lautsch D, Ferrieres J, Kastelein J, Drexel H, et al. Low-density lipoprotein cholesterol in a global cohort of 57,885 statin-treated patients. Atherosclerosis. 2016;255:200–9. doi: 10.1016/j.atherosclerosis.2016.09.004 27667299
32. Ferrieres J, De Ferrari GM, Hermans MP, Elisaf M, Toth PP, Horack M, et al. Predictors of LDL-cholesterol target value attainment differ in acute and chronic coronary heart disease patients: Results from DYSIS II Europe. Eur J Prev Cardiol. 2018;25(18):1966–76. doi: 10.1177/2047487318806359 30335504
33. Lemstra M, Blackburn D, Crawley A, Fung R. Proportion and risk indicators of nonadherence to statin therapy: a meta-analysis. Can J Cardiol. 2012; 28:574–80. doi: 10.1016/j.cjca.2012.05.007 22884278
34. Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7:472–83. doi: 10.1016/j.jacl.2013.03.001 24079289
35. Taylor BA, Thompson PD. Statin-associated muscle disease: advances in diagnosis and management. Neurotherapeutics. 2018;15:1006–17. doi: 10.1007/s13311-018-0670-z 30251222
36. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et al. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society consensus panel statement on assessment. Aetiology and management. Eur Heart J. 2015;36:1012–22. doi: 10.1093/eurheartj/ehv043 25694464
37. 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;375:735–42. doi: 10.1016/S0140-6736(09)61965-6 20167359
38. Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J. 2016;37:908–16. doi: 10.1093/eurheartj/ehv641 26643266
39. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97. doi: 10.1056/NEJMoa1410489 26039521
40. Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database Syst Rev. 2018;11:CD012502. doi: 10.1002/14651858.CD012502.pub2 30480766
41. De Ferrari GM, Perna GP, Nicosia A, Guasti L, Casu G, et al. Available oral lipid-lowering agents could bring most high-risk patients to target: an estimate based on the Dyslipidemia International Study II—Italy. J Cardiovasc Med. 2018;19:485–90.
42. Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev. 2015;10:CD009580.
43. Cicero AFG, Landolfo M, Ventura F, Borghi C. Current pharmacotherapeutic options for primary dyslipidemia in adults. Expert Opin Pharmacother. 2019;20:1277–88. doi: 10.1080/14656566.2019.1604687 31059312
44. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;41:111–88. doi: 10.1093/eurheartj/ehz455 31504418
45. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease—executive summary. Endocr Pract. 2017;23(4):479–97. doi: 10.4158/EP171764.GL 28156151
46. Pucci G, Cicero AF, Borghi C, Schillaci G. Emerging biologic therapies for hypercholesterolaemia. Expert Opin Biol Ther. 2017;17:1077–87. doi: 10.1080/14712598.2017.1341485 28617192
47. Wang X, Luo S, Gan X, He C, Huang R. Safety and efficacy of ETC-1002 in hypercholesterolaemic patients: a meta-analysis of randomised controlled trials. Kardiol Pol. 2019;77:207–16. doi: 10.5603/KP.a2019.0013 30740643
48. Ruscica M, Reiner Z, Sirtori CR. Can we further optimize statin therapy to increase tolerability? Expert Opin Drug Discov. 2019;14(9):843–7. doi: 10.1080/17460441.2019.1615436 31096808
49. Evaluation of major cardiovascular events in patients with, or at high risk for, cardiovascular disease who are statin intolerant treated with bempedoic acid (ETC-1002) or placebo (CLEAR Outcomes). NCT02993406. ClinicalTrials.gov. 2016 Dec 15 [cited 2020 Jun 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT02993406.
Článek vyšel v časopise
PLOS Medicine
2020 Číslo 7
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Je libo čepici místo mozkového implantátu?
- Pomůže v budoucnu s triáží na pohotovostech umělá inteligence?
- AI může chirurgům poskytnout cenná data i zpětnou vazbu v reálném čase
- Nová metoda odlišení nádorové tkáně může zpřesnit resekci glioblastomů
Nejčtenější v tomto čísle
- Obesity, clinical, and genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: A cohort study using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank
- Participation in adherence clubs and on-time drug pickup among HIV-infected adults in Zambia: A matched-pair cluster randomized trial
- Estimation of SARS-CoV-2 mortality during the early stages of an epidemic: A modeling study in Hubei, China, and six regions in Europe
- Neonatal outcome in 29 pregnant women with COVID-19: A retrospective study in Wuhan, China
