Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.
Jonas Bovijn,Kristi Krebs,Chia-Yen Chen,Chia-Yen Chen,Ruth Boxall,Ruth Boxall,Jenny C Censin,Teresa Ferreira,Sara L. Pulit,Sara L. Pulit,Sara L. Pulit,Craig A. Glastonbury,Samantha Laber,Iona Y Millwood,Iona Y Millwood,Kuang Lin,Liming Li,Zhengming Chen,Lili Milani,George Davey Smith,Robin G. Walters,Robin G. Walters,Reedik Mägi,Benjamin M. Neale,Benjamin M. Neale,Cecilia M. Lindgren,Michael V. Holmes +26 more
Reads0
Chats0
TLDR
It is indicated that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerOSTin inhibitors.Abstract:
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 Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with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.read more
Citations
More filters
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Anubha Mahajan,Daniel Taliun,Matthias Thurner,Neil R. Robertson,Jason M. Torres,N. William Rayner,Anthony Payne,Valgerdur Steinthorsdottir,Robert A. Scott,Niels Grarup,James P. Cook,Ellen M. Schmidt,Matthias Wuttke,Chloé Sarnowski,Reedik Magill,Jana Nano,Christian Gieger,Stella Trompet,Cécile Lecoeur,Michael Preuss,Bram P. Prins,Xiuqing Guo,Lawrence F. Bielak,Jennifer E. Below,Donald W. Bowden,John C. Chambers,Young-Jin Kim,Maggie C.Y. Ng,Lauren E. Petty,Xueling Sim,Weihua Zhang,Amanda J. Bennett,Jette Bork-Jensen,Chad M. Brummett,Mickaël Canouil,Kai-Uwe Ec Kardt,Krista Fischer,Sharon L.R. Kardia,Florian Kronenberg,Kristi Läll,Ching-Ti Liu,Adam E. Locke,Jian'an Luan,Loanna Ntalla,Vibe Nylander,Sebastian Schoenherr,Claudia Schurmann,Loic Yengo,Erwin P. Bottinger,Ivan Brandslund,Cramer Christensen,George Dedoussis,Jose C. Florez,Ian Ford,Timothy M. Frayling,Vilmantas Giedraitis,Sophie Hackinger,Andrew T. Hattersley,Christian Herder,M. Arfan Ikram,Martin Ingelsson,Marit E. Jørgensen,Torben Jørgensen,Jennifer Kriebel,Johanna Kuusisto,Symen Ligthart,Cecilia M. Lindgren,Allan Linneberg,Valeriya Lyssenko,Vasiliki Mamakou,Thomas Meitinger,Karen L. Mohlke,Andrew D. Morris,Girish N. Nadkarni,James S. Pankow,Annette Peters,Naveed Sattar,Alena Stančáková,Konstantin Strauch,Kent D. Taylor,Barbara Thorand,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Jaakko Tuomilehto,Daniel R. Witte,Josée Dupuis,Patricia A. Peyser,Eleftheria Zeggini,Ruth J. F. Loos,Philippe Froguel,Erik Ingelsson,Lars Lind,Leif Groop,Markku Laakso,Francis S. Collins,J. Wouter Jukema,Colin N. A. Palmer,Harald Grallert,Andres Metspalu,Abbas Dehghan,Anna Koettgen,Gonçalo R. Abecasis,James B. Meigs,Rotter, Jerome, I,Jonathan Marchini,Oluf Pedersen,Torben Hansen,Claudia Langenberg,Nicholas J. Wareham,Kari Stefansson,Anna L. Gloyn,Andrew P. Morris,Michael Boehnke,McCarthy, Mark, I +113 more
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.
Journal ArticleDOI
Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development.
Michael V. Holmes,Tom G. Richardson,Brian A. Ference,Neil M Davies,Neil M Davies,George Davey Smith +5 more
TL;DR: This Review compares and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits and explains how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.
Journal ArticleDOI
Chronic kidney disease—mineral and bone disorders: pathogenesis and management
Jorge B. Cannata-Andía,Beatriz Martín-Carro,Julia Martín-Vírgala,Javier Rodríguez-Carrio,Javier Rodríguez-Carrio,José Joaquín Bande-Fernández,Cristina Alonso-Montes,Natalia Carrillo-López +7 more
TL;DR: The knowledge of the mineral and bone disorders in CKD and the increased variety of efficacious therapies should lead to a better prevention and management of CKD-MBD.
Journal ArticleDOI
Anti-Sclerostin Antibodies in Osteoporosis and Other Bone Diseases
TL;DR: Romosozumab was recently approved in several countries for the treatment of severe osteoporosis in postmenopausal women with high fracture risk and without a history of heart attack, myocardial infarction or stroke.
Journal ArticleDOI
Glutamine Metabolism in Osteoprogenitors Is Required for Bone Mass Accrual and PTH-Induced Bone Anabolism in Male Mice.
Steve Stegen,Claire-Sophie Devignes,Sophie Torrekens,Riet Van Looveren,Peter Carmeliet,Peter Carmeliet,Geert Carmeliet +6 more
TL;DR: GLS1‐mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production, and glutamine‐derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability.
References
More filters
Journal ArticleDOI
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
TL;DR: Moher et al. as mentioned in this paper introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses, which is used in this paper.
Journal Article
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.
TL;DR: The QUOROM Statement (QUality Of Reporting Of Meta-analyses) as mentioned in this paper was developed to address the suboptimal reporting of systematic reviews and meta-analysis of randomized controlled trials.
Journal ArticleDOI
Conducting Meta-Analyses in R with the metafor Package
TL;DR: The metafor package provides functions for conducting meta-analyses in R and includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models.
Journal ArticleDOI
RoB 2: a revised tool for assessing risk of bias in randomised trials.
Jonathan A C Sterne,Jelena Savović,Jelena Savović,Matthew J. Page,Roy G Elbers,Natalie S Blencowe,Isabelle Boutron,Isabelle Boutron,Isabelle Boutron,Christopher J Cates,Hung-Yuan Cheng,Mark Corbett,Sandra Eldridge,Jonathan Emberson,Miguel A. Hernán,Sally Hopewell,Asbjørn Hróbjartsson,Asbjørn Hróbjartsson,Daniela R Junqueira,Peter Jüni,Jamie J Kirkham,Toby J Lasserson,Tianjing Li,Alexandra McAleenan,Barnaby C Reeves,Sasha Shepperd,Ian Shrier,Lesley A. Stewart,Kate Tilling,Ian R. White,Penny Whiting,Penny Whiting,Julian P T Higgins,Julian P T Higgins +33 more
TL;DR: The Cochrane risk-of-bias tool has been updated to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
Related Papers (5)
Romosozumab Treatment in Postmenopausal Women with Osteoporosis.
Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein
Romosozumab in Postmenopausal Women with Low Bone Mineral Density
Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)
Wendy Balemans,Martin Ebeling,N Patel,E Van Hul,P Olson,M Dioszegi,C Lacza,Wim Wuyts,J Van den Ende,Patrick Willems,AF Paes-Alves,Suvimol Hill,Manuel Bueno,Feliciano J. Ramos,Paolo Tacconi,Frederik G. Dikkers,Constantine A. Stratakis,Klaus Lindpaintner,B Vickery,Dorothee Foernzler,W. Van Hul +20 more