Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics

被引：91

作者：

Bovijn, Jonas ^{[1
,2
]}

Krebs, Kristi ^{[3
]}

Chen, Chia-Yen ^{[4
,5
,6
,16
]}

Boxall, Ruth ^{[7
,8
,9
]}

Censin, Jenny C. ^{[1
,2
]}

Ferreira, Teresa ^{[1
]}

Pulit, Sara L. ^{[1
,10
,11
,17
]}

Glastonbury, Craig A. ^{[1
,18
]}

Laber, Samantha ^{[1
,2
]}

Millwood, Iona Y. ^{[7
,8
,9
]}

Lin, Kuang ^{[7
,8
]}

Li, Liming ^{[12
]}

Chen, Zhengming ^{[7
,8
]}

Milani, Lili ^{[3
]}

Smith, George Davey ^{[13
,14
]}

Walters, Robin G. ^{[7
,8
,9
]}

Magi, Reedik ^{[3
]}

Neale, Benjamin M. ^{[4
,6
]}

Lindgren, Cecilia M. ^{[1
,2
,10
,15
]}

Holmes, Michael, V ^{[1
,7
,8
,9
,15
]}

机构：

[1] Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Big Data Inst, Oxford OX3 7FZ, England

[2] Univ Oxford, Wellcome Ctr Human Genet, Oxford OX3 7BN, England

[3] Univ Tartu, Estonian Genome Ctr, Inst Genom, EE-51010 Tartu, Estonia

[4] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[6] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[7] Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England

[8] Univ Oxford, Epidemiol Studies Unit CTSU, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England

[9] Univ Oxford, Med Res Council, Populat Hlth Res Unit MRC PHRU, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England

[10] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[11] Univ Med Ctr Utrecht, Dept Genet, NL-3584 CX Utrecht, Netherlands

[12] Peking Univ, Hlth Sci Ctr, Dept Epidemiol & Biostat, Beijing 100191, Peoples R China

[13] Univ Bristol, Integrat Epidemiol Unit, Med Res Council, Bristol BS8 2BN, Avon, England

[14] Univ Bristol, Populat Hlth Sci, Bristol Med Sch, Barley House, Bristol BS8 2BN, Avon, England

[15] Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford OX3 9DU, England

[16] Biogen, Cambridge, MA 02142 USA

[17] Vertex Pharmaceut, Abingdon OX14 4RW, Oxon, England

[18] BenevolentAl, London W1T 5HD, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 549期

基金：

英国惠康基金; 中国国家自然科学基金; 英国医学研究理事会;

关键词：

BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; MENDELIAN RANDOMIZATION; AORTIC CALCIFICATION; OSTEOPOROSIS; ROMOSOZUMAB; DISEASE; VARIANTS; RISK; ASSOCIATION;

D O I：

10.1126/scitranslmed.aay6570

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

引用

页数：21

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