Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors

Monika R Frysz; Ingrid Gergei; H Scharnagi; George Davey Smith; Jie Zheng; Debbie A Lawlor; M Herrman; Winfried Maerz; Jonathan H Tobias

doi:10.1002/jbmr.4467

Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors

Monika R Frysz^*, Ingrid Gergei, H Scharnagi, George Davey Smith, Jie Zheng, Debbie A Lawlor, M Herrman, Winfried Maerz, Jonathan H Tobias

^*Corresponding author for this work

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Abstract

Romososumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterise relationships between sclerostin and CVD and related risk factors in more detail, by examining these in two large cohorts, LURIC (34% female, mean 63.0 years) and ALSPAC mothers (mean 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analysed, adjusted for age, sex (LURIC), BMI, smoking, social deprivation and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) [1.25 (1.12, 1.37)], risk of elevated fasting glucose [1.15 (1.04, 1.26)], and triglyceride levels [0.03 (0.00, 0.06)]. Conversely, higher sclerostin was associated with lower eGFR [-0.20 (-0.38, -0.02)], HDL cholesterol [-0.05 (-0.10, -0.01)], and Apolopoprotein A-I [-0.05 (-0.08, -0.02)] (odds ratio/ difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow up [HR 1.13 (1.03, 1.23)], and with severity of coronary artery disease on angiogram as reflected by Friesinger score [0.05 (0.01, 0.09)]. Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR and Apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with CAD severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors.

Original language	English
Journal	Journal of Bone and Mineral Research
Early online date	5 Nov 2021
DOIs	https://doi.org/10.1002/jbmr.4467
Publication status	E-pub ahead of print - 5 Nov 2021

Bibliographical note

Funding Information:
MF receives salary funding from Wellcome Trust (project grant ref 209233). GDS, JZ, DAL, and JHT work in or are affiliated with a unit that receives funding from the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/16). DAL is a National Institute of Health Research Senior Investigator (NF‐0616‐10102) and BHF Chair of Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003). IG reports employment with Boehringer Ingelheim International GmbH, outside the submitted work. WM reports employment with Synlab Holding Deutschland GmbH, received grants from Abbott Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from AstraZeneca, grants and personal fees from BASF, grants and personal fees from Danone Research, personal fees from MSD, grants and personal fees from Sanofi, grants and personal fees from Siemens Diagnostics, and personal fees from Synageva, all outside the submitted work.

Funding Information:
The UK Medical Research Council and Wellcome (grant ref 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grant funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This research was specifically funded by the British Heart Foundation (grant ref SP/07/008/24066).

Publisher Copyright:
© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords

LURIC
ALSPAC
CVD
sclerostin
Diabetes Mellitus
HDL cholesterol

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title = "Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors",

abstract = "Romososumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterise relationships between sclerostin and CVD and related risk factors in more detail, by examining these in two large cohorts, LURIC (34% female, mean 63.0 years) and ALSPAC mothers (mean 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analysed, adjusted for age, sex (LURIC), BMI, smoking, social deprivation and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) [1.25 (1.12, 1.37)], risk of elevated fasting glucose [1.15 (1.04, 1.26)], and triglyceride levels [0.03 (0.00, 0.06)]. Conversely, higher sclerostin was associated with lower eGFR [-0.20 (-0.38, -0.02)], HDL cholesterol [-0.05 (-0.10, -0.01)], and Apolopoprotein A-I [-0.05 (-0.08, -0.02)] (odds ratio/ difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow up [HR 1.13 (1.03, 1.23)], and with severity of coronary artery disease on angiogram as reflected by Friesinger score [0.05 (0.01, 0.09)]. Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR and Apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with CAD severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors.",

keywords = "LURIC, ALSPAC, CVD, sclerostin, Diabetes Mellitus, HDL cholesterol",

author = "Frysz, {Monika R} and Ingrid Gergei and H Scharnagi and {Davey Smith}, George and Jie Zheng and Lawlor, {Debbie A} and M Herrman and Winfried Maerz and Tobias, {Jonathan H}",

note = "Funding Information: MF receives salary funding from Wellcome Trust (project grant ref 209233). GDS, JZ, DAL, and JHT work in or are affiliated with a unit that receives funding from the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/16). DAL is a National Institute of Health Research Senior Investigator (NF‐0616‐10102) and BHF Chair of Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003). IG reports employment with Boehringer Ingelheim International GmbH, outside the submitted work. WM reports employment with Synlab Holding Deutschland GmbH, received grants from Abbott Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from AstraZeneca, grants and personal fees from BASF, grants and personal fees from Danone Research, personal fees from MSD, grants and personal fees from Sanofi, grants and personal fees from Siemens Diagnostics, and personal fees from Synageva, all outside the submitted work. Funding Information: The UK Medical Research Council and Wellcome (grant ref 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grant funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This research was specifically funded by the British Heart Foundation (grant ref SP/07/008/24066). Publisher Copyright: {\textcopyright} 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).",

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T1 - Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors

AU - Frysz, Monika R

AU - Gergei, Ingrid

AU - Scharnagi, H

AU - Davey Smith, George

AU - Zheng, Jie

AU - Lawlor, Debbie A

AU - Herrman, M

AU - Maerz, Winfried

AU - Tobias, Jonathan H

N1 - Funding Information: MF receives salary funding from Wellcome Trust (project grant ref 209233). GDS, JZ, DAL, and JHT work in or are affiliated with a unit that receives funding from the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/16). DAL is a National Institute of Health Research Senior Investigator (NF‐0616‐10102) and BHF Chair of Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003). IG reports employment with Boehringer Ingelheim International GmbH, outside the submitted work. WM reports employment with Synlab Holding Deutschland GmbH, received grants from Abbott Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from AstraZeneca, grants and personal fees from BASF, grants and personal fees from Danone Research, personal fees from MSD, grants and personal fees from Sanofi, grants and personal fees from Siemens Diagnostics, and personal fees from Synageva, all outside the submitted work. Funding Information: The UK Medical Research Council and Wellcome (grant ref 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grant funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This research was specifically funded by the British Heart Foundation (grant ref SP/07/008/24066). Publisher Copyright: © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

PY - 2021/11/5

Y1 - 2021/11/5

N2 - Romososumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterise relationships between sclerostin and CVD and related risk factors in more detail, by examining these in two large cohorts, LURIC (34% female, mean 63.0 years) and ALSPAC mothers (mean 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analysed, adjusted for age, sex (LURIC), BMI, smoking, social deprivation and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) [1.25 (1.12, 1.37)], risk of elevated fasting glucose [1.15 (1.04, 1.26)], and triglyceride levels [0.03 (0.00, 0.06)]. Conversely, higher sclerostin was associated with lower eGFR [-0.20 (-0.38, -0.02)], HDL cholesterol [-0.05 (-0.10, -0.01)], and Apolopoprotein A-I [-0.05 (-0.08, -0.02)] (odds ratio/ difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow up [HR 1.13 (1.03, 1.23)], and with severity of coronary artery disease on angiogram as reflected by Friesinger score [0.05 (0.01, 0.09)]. Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR and Apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with CAD severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors.

AB - Romososumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterise relationships between sclerostin and CVD and related risk factors in more detail, by examining these in two large cohorts, LURIC (34% female, mean 63.0 years) and ALSPAC mothers (mean 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analysed, adjusted for age, sex (LURIC), BMI, smoking, social deprivation and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) [1.25 (1.12, 1.37)], risk of elevated fasting glucose [1.15 (1.04, 1.26)], and triglyceride levels [0.03 (0.00, 0.06)]. Conversely, higher sclerostin was associated with lower eGFR [-0.20 (-0.38, -0.02)], HDL cholesterol [-0.05 (-0.10, -0.01)], and Apolopoprotein A-I [-0.05 (-0.08, -0.02)] (odds ratio/ difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow up [HR 1.13 (1.03, 1.23)], and with severity of coronary artery disease on angiogram as reflected by Friesinger score [0.05 (0.01, 0.09)]. Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR and Apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with CAD severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors.

KW - LURIC

KW - ALSPAC

KW - CVD

KW - sclerostin

KW - Diabetes Mellitus

KW - HDL cholesterol

U2 - 10.1002/jbmr.4467

DO - 10.1002/jbmr.4467

M3 - Article (Academic Journal)

C2 - 34738659

SN - 0884-0431

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

ER -

Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors

Abstract

Bibliographical note

Keywords

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

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