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Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial

Nikolaus Marx Orcid Logo, John E. Deanfield, Johannes F.E. Mann, Rosario Arechavaleta, Steve Bain Orcid Logo, Harpreet S. Bajaj Orcid Logo, Katrine Bayer Tanggaard, Andreas L. Birkenfeld Orcid Logo, John B. Buse Orcid Logo, Zaklina Davicevic-Elez, Cyrus Desouza Orcid Logo, Scott S. Emerson, Mads D.M. Engelmann, G. Kees Hovingh, Silvio E. Inzucchi Orcid Logo, Pardeep S. Jhund Orcid Logo, Sharon L. Mulvagh Orcid Logo, Rodica Pop-Busui Orcid Logo, Neil R. Poulter Orcid Logo, Søren Rasmussen, Shih-Te Tu, Darren K. McGuire Orcid Logo

Circulation, Volume: 151, Issue: 23, Pages: 1639 - 1650

Swansea University Author: Steve Bain Orcid Logo

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DOI (Published version): 10.1161/circulationaha.125.074545

Abstract

Background: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) improve cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) and CV or chronic kidney disease (CKD). However, there are limited data about the effect of combinin...

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Published in: Circulation
ISSN: 0009-7322 1524-4539
Published: Wolters Kluwer Health, Inc. 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa69195
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2025-06-10T15:35:27.9164558</datestamp><bib-version>v2</bib-version><id>69195</id><entry>2025-04-01</entry><title>Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial</title><swanseaauthors><author><sid>5399f4c6e6a70f3608a084ddb938511a</sid><ORCID>0000-0001-8519-4964</ORCID><firstname>Steve</firstname><surname>Bain</surname><name>Steve Bain</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2025-04-01</date><deptcode>MEDS</deptcode><abstract>Background: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) improve cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) and CV or chronic kidney disease (CKD). However, there are limited data about the effect of combining these agents on CV and safety outcomes.Methods: The SOUL trial (NCT03914326) randomised 9650 participants with T2D and atherosclerotic CV disease and/or CKD to oral semaglutide or placebo. As prespecified, participants were analysed according to baseline use of SGLT2i (Yes: n=2596, No: n=7054) and, subsequently for any use of SGLT2i during the trial (Yes: n=4718, No: n=4932). The primary outcome was time to first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. Safety was evaluated by comparing the incidence of serious adverse events.Results: Over a mean follow-up of 47.5&#xB1;10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide vs placebo (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.77; 0.96). In those taking SGLT2i at baseline, there were 143/1296 (semaglutide) versus 158/1300 (placebo) primary outcome events (HR 0.89; 95% CI 0.71; 1.11); and 436/3529 versus 510/3525, respectively, in participants not taking SGLT2i at baseline (HR 0.84; 95% CI 0.74; 0.95; P-interaction 0.66). An analysis of MACE by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar.Conclusions: Oral semaglutide reduced MACE outcomes independently of concomitant SGLT2i treatment and this combination appeared to be safe.</abstract><type>Journal Article</type><journal>Circulation</journal><volume>151</volume><journalNumber>23</journalNumber><paginationStart>1639</paginationStart><paginationEnd>1650</paginationEnd><publisher>Wolters Kluwer Health, Inc.</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0009-7322</issnPrint><issnElectronic>1524-4539</issnElectronic><keywords>cardiovascular diseases; cardiovascular system; diabetes mellitus, type 2; glucagon-like peptide-1 receptor agonists; renal insufficiency, chronic; semaglutide; sodium-glucose transporter 2 inhibitors</keywords><publishedDay>10</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-06-10</publishedDate><doi>10.1161/circulationaha.125.074545</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>The SOUL trial was funded by Novo Nordisk A/S.</funders><projectreference/><lastEdited>2025-06-10T15:35:27.9164558</lastEdited><Created>2025-04-01T09:40:52.4178045</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Nikolaus</firstname><surname>Marx</surname><orcid>0000-0001-6141-634x</orcid><order>1</order></author><author><firstname>John E.</firstname><surname>Deanfield</surname><order>2</order></author><author><firstname>Johannes F.E.</firstname><surname>Mann</surname><order>3</order></author><author><firstname>Rosario</firstname><surname>Arechavaleta</surname><order>4</order></author><author><firstname>Steve</firstname><surname>Bain</surname><orcid>0000-0001-8519-4964</orcid><order>5</order></author><author><firstname>Harpreet S.</firstname><surname>Bajaj</surname><orcid>0000-0002-1461-1465</orcid><order>6</order></author><author><firstname>Katrine Bayer</firstname><surname>Tanggaard</surname><order>7</order></author><author><firstname>Andreas L.</firstname><surname>Birkenfeld</surname><orcid>0000-0003-1407-9023</orcid><order>8</order></author><author><firstname>John B.</firstname><surname>Buse</surname><orcid>0000-0002-9723-3876</orcid><order>9</order></author><author><firstname>Zaklina</firstname><surname>Davicevic-Elez</surname><order>10</order></author><author><firstname>Cyrus</firstname><surname>Desouza</surname><orcid>0000-0001-6660-0568</orcid><order>11</order></author><author><firstname>Scott S.</firstname><surname>Emerson</surname><order>12</order></author><author><firstname>Mads D.M.</firstname><surname>Engelmann</surname><order>13</order></author><author><firstname>G. Kees</firstname><surname>Hovingh</surname><order>14</order></author><author><firstname>Silvio E.</firstname><surname>Inzucchi</surname><orcid>0000-0003-1254-6636</orcid><order>15</order></author><author><firstname>Pardeep S.</firstname><surname>Jhund</surname><orcid>0000-0003-4306-5317</orcid><order>16</order></author><author><firstname>Sharon L.</firstname><surname>Mulvagh</surname><orcid>0000-0002-7377-4053</orcid><order>17</order></author><author><firstname>Rodica</firstname><surname>Pop-Busui</surname><orcid>0000-0002-2042-1350</orcid><order>18</order></author><author><firstname>Neil R.</firstname><surname>Poulter</surname><orcid>0000-0002-6292-997x</orcid><order>19</order></author><author><firstname>S&#xF8;ren</firstname><surname>Rasmussen</surname><order>20</order></author><author><firstname>Shih-Te</firstname><surname>Tu</surname><order>21</order></author><author><firstname>Darren K.</firstname><surname>McGuire</surname><orcid>0000-0002-6412-7989</orcid><order>22</order></author></authors><documents><document><filename>69195__34454__c4bd09f72a8a43f78a57b73af30fd582.pdf</filename><originalFilename>69195.VOR.pdf</originalFilename><uploaded>2025-06-10T15:28:08.3596691</uploaded><type>Output</type><contentLength>466857</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2025 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by-nc-nd/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling 2025-06-10T15:35:27.9164558 v2 69195 2025-04-01 Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial 5399f4c6e6a70f3608a084ddb938511a 0000-0001-8519-4964 Steve Bain Steve Bain true false 2025-04-01 MEDS Background: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) improve cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) and CV or chronic kidney disease (CKD). However, there are limited data about the effect of combining these agents on CV and safety outcomes.Methods: The SOUL trial (NCT03914326) randomised 9650 participants with T2D and atherosclerotic CV disease and/or CKD to oral semaglutide or placebo. As prespecified, participants were analysed according to baseline use of SGLT2i (Yes: n=2596, No: n=7054) and, subsequently for any use of SGLT2i during the trial (Yes: n=4718, No: n=4932). The primary outcome was time to first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. Safety was evaluated by comparing the incidence of serious adverse events.Results: Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide vs placebo (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.77; 0.96). In those taking SGLT2i at baseline, there were 143/1296 (semaglutide) versus 158/1300 (placebo) primary outcome events (HR 0.89; 95% CI 0.71; 1.11); and 436/3529 versus 510/3525, respectively, in participants not taking SGLT2i at baseline (HR 0.84; 95% CI 0.74; 0.95; P-interaction 0.66). An analysis of MACE by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar.Conclusions: Oral semaglutide reduced MACE outcomes independently of concomitant SGLT2i treatment and this combination appeared to be safe. Journal Article Circulation 151 23 1639 1650 Wolters Kluwer Health, Inc. 0009-7322 1524-4539 cardiovascular diseases; cardiovascular system; diabetes mellitus, type 2; glucagon-like peptide-1 receptor agonists; renal insufficiency, chronic; semaglutide; sodium-glucose transporter 2 inhibitors 10 6 2025 2025-06-10 10.1161/circulationaha.125.074545 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee The SOUL trial was funded by Novo Nordisk A/S. 2025-06-10T15:35:27.9164558 2025-04-01T09:40:52.4178045 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Nikolaus Marx 0000-0001-6141-634x 1 John E. Deanfield 2 Johannes F.E. Mann 3 Rosario Arechavaleta 4 Steve Bain 0000-0001-8519-4964 5 Harpreet S. Bajaj 0000-0002-1461-1465 6 Katrine Bayer Tanggaard 7 Andreas L. Birkenfeld 0000-0003-1407-9023 8 John B. Buse 0000-0002-9723-3876 9 Zaklina Davicevic-Elez 10 Cyrus Desouza 0000-0001-6660-0568 11 Scott S. Emerson 12 Mads D.M. Engelmann 13 G. Kees Hovingh 14 Silvio E. Inzucchi 0000-0003-1254-6636 15 Pardeep S. Jhund 0000-0003-4306-5317 16 Sharon L. Mulvagh 0000-0002-7377-4053 17 Rodica Pop-Busui 0000-0002-2042-1350 18 Neil R. Poulter 0000-0002-6292-997x 19 Søren Rasmussen 20 Shih-Te Tu 21 Darren K. McGuire 0000-0002-6412-7989 22 69195__34454__c4bd09f72a8a43f78a57b73af30fd582.pdf 69195.VOR.pdf 2025-06-10T15:28:08.3596691 Output 466857 application/pdf Version of Record true © 2025 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License. true eng https://creativecommons.org/licenses/by-nc-nd/4.0/
title Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
spellingShingle Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
Steve Bain
title_short Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
title_full Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
title_fullStr Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
title_full_unstemmed Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
title_sort Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial
author_id_str_mv 5399f4c6e6a70f3608a084ddb938511a
author_id_fullname_str_mv 5399f4c6e6a70f3608a084ddb938511a_***_Steve Bain
author Steve Bain
author2 Nikolaus Marx
John E. Deanfield
Johannes F.E. Mann
Rosario Arechavaleta
Steve Bain
Harpreet S. Bajaj
Katrine Bayer Tanggaard
Andreas L. Birkenfeld
John B. Buse
Zaklina Davicevic-Elez
Cyrus Desouza
Scott S. Emerson
Mads D.M. Engelmann
G. Kees Hovingh
Silvio E. Inzucchi
Pardeep S. Jhund
Sharon L. Mulvagh
Rodica Pop-Busui
Neil R. Poulter
Søren Rasmussen
Shih-Te Tu
Darren K. McGuire
format Journal article
container_title Circulation
container_volume 151
container_issue 23
container_start_page 1639
publishDate 2025
institution Swansea University
issn 0009-7322
1524-4539
doi_str_mv 10.1161/circulationaha.125.074545
publisher Wolters Kluwer Health, Inc.
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description Background: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) improve cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) and CV or chronic kidney disease (CKD). However, there are limited data about the effect of combining these agents on CV and safety outcomes.Methods: The SOUL trial (NCT03914326) randomised 9650 participants with T2D and atherosclerotic CV disease and/or CKD to oral semaglutide or placebo. As prespecified, participants were analysed according to baseline use of SGLT2i (Yes: n=2596, No: n=7054) and, subsequently for any use of SGLT2i during the trial (Yes: n=4718, No: n=4932). The primary outcome was time to first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. Safety was evaluated by comparing the incidence of serious adverse events.Results: Over a mean follow-up of 47.5±10.9 months, the risk of the primary outcome in the overall trial population was 14% lower for oral semaglutide vs placebo (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.77; 0.96). In those taking SGLT2i at baseline, there were 143/1296 (semaglutide) versus 158/1300 (placebo) primary outcome events (HR 0.89; 95% CI 0.71; 1.11); and 436/3529 versus 510/3525, respectively, in participants not taking SGLT2i at baseline (HR 0.84; 95% CI 0.74; 0.95; P-interaction 0.66). An analysis of MACE by any in-trial SGLT2i use versus no use also showed no evidence of heterogeneity in the effects of oral semaglutide. The adverse event profiles of oral semaglutide with or without concomitant SGLT2i were similar.Conclusions: Oral semaglutide reduced MACE outcomes independently of concomitant SGLT2i treatment and this combination appeared to be safe.
published_date 2025-06-10T05:26:17Z
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score 11.089572

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