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Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial

Sharon L. Mulvagh, Silvio E. Inzucchi, Nikolaus Marx, Neil R. Poulter, John E. Deanfield, Rodica Pop-Busui, Scott S. Emerson, Johannes F. E. Mann, Mads D. M. Engelmann, G. Kees Hovingh, Kabirdev Mandavya, Zaklina Davicevic-Elez, Ole Kleist Jeppesen, Alberto Lorenzatti, Aytekin Oguz, Boris Mankovsky, Chaicharn Deerochanawong, , Juan J. Gorgojo-Martinez, Linong Ji, Steve Bain Orcid Logo, Darren K. McGuire, John B. Buse

JAMA Cardiology

Swansea University Author: Steve Bain Orcid Logo

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DOI (Published version): 10.1001/jamacardio.2026.0245

Abstract

Importance: Individuals with type 2 diabetes (T2D) are at high risk of atherosclerotic cardiovascular disease (ASCVD). In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chr...

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Published in: JAMA Cardiology
ISSN: 2380-6583 2380-6591
Published: American Medical Association 2026
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URI: https://cronfa.swan.ac.uk/Record/cronfa71266
first_indexed 2026-01-19T10:11:28Z
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In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chronic kidney disease (CKD) receiving standard of care (SoC); however, whether oral semaglutide modifies recognized CV risk factors in the long term is unclear. Objective: To investigate whether treatment with oral semaglutide was associated with changes in ASCVD risk factors vs placebo. Design, Setting, and Participants: This secondary analysis comprises post hoc intention-to-treat analyses of the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes) double-blind multicenter randomized clinical trial (randomization 1:1 to oral semaglutide or placebo) among adults with T2D and ASCVD and/or CKD receiving SoC. Participants underwent randomization from June 2019 to March 2021, with a mean (SD) of 47.5 (10.9) months of follow-up, and data were analyzed from February to December 2025. Intervention(s): Participants were treated with either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard care. Main Outcomes and Measures: The primary outcome was the association of oral semaglutide vs placebo with glycated hemoglobin (HbA1c), body weight, and blood pressure (BP) using estimated treatment differences (ETDs) and with high-sensitivity C-reactive protein (hsCRP) and lipid plasma levels using estimated treatment ratios (ETRs). Results: Of 9650 randomized participants (mean [SD] age, 66.1 (7.6) years; 2790 female participants [28.9%]), 9495 participants (98.4%) completed the trial. Early (13 weeks) improvements in HbA1c (&#x2212;0.87 percentage points), body weight (&#x2212;2.54%), systolic BP (SBP, &#x2212;3.84 mm Hg), pulse pressure (&#x2212;3.81 mm Hg), hsCRP (&#x2212;18.08%), total cholesterol (TC, &#x2212;7.00%), non&#x2013;high-density lipoprotein cholesterol (non&#x2013;HDL-C, &#x2212;8.02%), HDL-C (&#x2212;4.49%), and triglycerides (&#x2212;8.15%) were observed with oral semaglutide vs placebo and sustained over the trial duration. Body weight reductions were gradual across both groups. At week 156, in favor of oral semaglutide were ETDs for HbA1c (&#x2212;0.47 percentage points; 95% CI, &#x2212;0.52 to &#x2212;0.42), body weight (&#x2212;3.26 percentage points; 95% CI, &#x2212;3.55 to &#x2212;2.98), SBP (&#x2212;1.83 mm Hg; 95% CI, &#x2212;2.47 to &#x2212;1.18), and pulse pressure (&#x2212;2.17 mm Hg; 95% CI, &#x2212;2.72 to &#x2212;1.61) and ETRs for hsCRP (0.77; 95% CI, 0.74-0.81), TC (0.99; 95% CI, 0.98-1.00), non&#x2013;HDL-C (0.98; 95% CI, 0.97-0.99), HDL-C (1.01; 95% CI, 1.01-1.02), and triglycerides (0.94; 95% CI, 0.93-0.96). No significant treatment differences were observed for low-density lipoprotein cholesterol or diastolic BP. Conclusions and Relevance: In this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with early and sustained improvements vs placebo in multiple ASCVD risk factors in high-risk participants with T2D and ASCVD and/or CKD, incremental to SoC. 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Kees</firstname><surname>Hovingh</surname><order>10</order></author><author><firstname>Kabirdev</firstname><surname>Mandavya</surname><order>11</order></author><author><firstname>Zaklina</firstname><surname>Davicevic-Elez</surname><order>12</order></author><author><firstname>Ole Kleist</firstname><surname>Jeppesen</surname><order>13</order></author><author><firstname>Alberto</firstname><surname>Lorenzatti</surname><order>14</order></author><author><firstname>Aytekin</firstname><surname>Oguz</surname><order>15</order></author><author><firstname>Boris</firstname><surname>Mankovsky</surname><order>16</order></author><author><firstname>Chaicharn Deerochanawong,</firstname><surname/><order>17</order></author><author><firstname>Juan J.</firstname><surname>Gorgojo-Martinez</surname><order>18</order></author><author><firstname>Linong</firstname><surname>Ji</surname><order>19</order></author><author><firstname>Steve</firstname><surname>Bain</surname><orcid>0000-0001-8519-4964</orcid><order>20</order></author><author><firstname>Darren K.</firstname><surname>McGuire</surname><order>21</order></author><author><firstname>John B.</firstname><surname>Buse</surname><order>22</order></author></authors><documents><document><filename>71266__36627__a2ef97a59c3c4d20abed75220425198f.pdf</filename><originalFilename>71266.VOR.pdf</originalFilename><uploaded>2026-04-28T16:27:23.4545540</uploaded><type>Output</type><contentLength>496029</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2026 Mulvagh SL et al. 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spelling 2026-04-28T16:31:46.2624261 v2 71266 2026-01-19 Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial 5399f4c6e6a70f3608a084ddb938511a 0000-0001-8519-4964 Steve Bain Steve Bain true false 2026-01-19 MEDS Importance: Individuals with type 2 diabetes (T2D) are at high risk of atherosclerotic cardiovascular disease (ASCVD). In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chronic kidney disease (CKD) receiving standard of care (SoC); however, whether oral semaglutide modifies recognized CV risk factors in the long term is unclear. Objective: To investigate whether treatment with oral semaglutide was associated with changes in ASCVD risk factors vs placebo. Design, Setting, and Participants: This secondary analysis comprises post hoc intention-to-treat analyses of the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes) double-blind multicenter randomized clinical trial (randomization 1:1 to oral semaglutide or placebo) among adults with T2D and ASCVD and/or CKD receiving SoC. Participants underwent randomization from June 2019 to March 2021, with a mean (SD) of 47.5 (10.9) months of follow-up, and data were analyzed from February to December 2025. Intervention(s): Participants were treated with either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard care. Main Outcomes and Measures: The primary outcome was the association of oral semaglutide vs placebo with glycated hemoglobin (HbA1c), body weight, and blood pressure (BP) using estimated treatment differences (ETDs) and with high-sensitivity C-reactive protein (hsCRP) and lipid plasma levels using estimated treatment ratios (ETRs). Results: Of 9650 randomized participants (mean [SD] age, 66.1 (7.6) years; 2790 female participants [28.9%]), 9495 participants (98.4%) completed the trial. Early (13 weeks) improvements in HbA1c (−0.87 percentage points), body weight (−2.54%), systolic BP (SBP, −3.84 mm Hg), pulse pressure (−3.81 mm Hg), hsCRP (−18.08%), total cholesterol (TC, −7.00%), non–high-density lipoprotein cholesterol (non–HDL-C, −8.02%), HDL-C (−4.49%), and triglycerides (−8.15%) were observed with oral semaglutide vs placebo and sustained over the trial duration. Body weight reductions were gradual across both groups. At week 156, in favor of oral semaglutide were ETDs for HbA1c (−0.47 percentage points; 95% CI, −0.52 to −0.42), body weight (−3.26 percentage points; 95% CI, −3.55 to −2.98), SBP (−1.83 mm Hg; 95% CI, −2.47 to −1.18), and pulse pressure (−2.17 mm Hg; 95% CI, −2.72 to −1.61) and ETRs for hsCRP (0.77; 95% CI, 0.74-0.81), TC (0.99; 95% CI, 0.98-1.00), non–HDL-C (0.98; 95% CI, 0.97-0.99), HDL-C (1.01; 95% CI, 1.01-1.02), and triglycerides (0.94; 95% CI, 0.93-0.96). No significant treatment differences were observed for low-density lipoprotein cholesterol or diastolic BP. Conclusions and Relevance: In this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with early and sustained improvements vs placebo in multiple ASCVD risk factors in high-risk participants with T2D and ASCVD and/or CKD, incremental to SoC. Trial Registration: ClinicalTrials.gov Identifier: NCT03914326. Journal Article JAMA Cardiology 0 American Medical Association 2380-6583 2380-6591 25 3 2026 2026-03-25 10.1001/jamacardio.2026.0245 Original Investigation COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) The SOUL trial and the open access fee were funded by Novo Nordisk A/S. 2026-04-28T16:31:46.2624261 2026-01-19T10:00:28.6567293 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Sharon L. Mulvagh 1 Silvio E. Inzucchi 2 Nikolaus Marx 3 Neil R. Poulter 4 John E. Deanfield 5 Rodica Pop-Busui 6 Scott S. Emerson 7 Johannes F. E. Mann 8 Mads D. M. Engelmann 9 G. Kees Hovingh 10 Kabirdev Mandavya 11 Zaklina Davicevic-Elez 12 Ole Kleist Jeppesen 13 Alberto Lorenzatti 14 Aytekin Oguz 15 Boris Mankovsky 16 Chaicharn Deerochanawong, 17 Juan J. Gorgojo-Martinez 18 Linong Ji 19 Steve Bain 0000-0001-8519-4964 20 Darren K. McGuire 21 John B. Buse 22 71266__36627__a2ef97a59c3c4d20abed75220425198f.pdf 71266.VOR.pdf 2026-04-28T16:27:23.4545540 Output 496029 application/pdf Version of Record true © 2026 Mulvagh SL et al. This is an open access article distributed under the terms of the CC-BY-NC-ND License. true eng https://jamanetwork.com/pages/cc-by-nc-nd-license-permissions
title Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
spellingShingle Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
Steve Bain
title_short Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
title_full Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
title_fullStr Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
title_full_unstemmed Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
title_sort Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial
author_id_str_mv 5399f4c6e6a70f3608a084ddb938511a
author_id_fullname_str_mv 5399f4c6e6a70f3608a084ddb938511a_***_Steve Bain
author Steve Bain
author2 Sharon L. Mulvagh
Silvio E. Inzucchi
Nikolaus Marx
Neil R. Poulter
John E. Deanfield
Rodica Pop-Busui
Scott S. Emerson
Johannes F. E. Mann
Mads D. M. Engelmann
G. Kees Hovingh
Kabirdev Mandavya
Zaklina Davicevic-Elez
Ole Kleist Jeppesen
Alberto Lorenzatti
Aytekin Oguz
Boris Mankovsky
Chaicharn Deerochanawong,
Juan J. Gorgojo-Martinez
Linong Ji
Steve Bain
Darren K. McGuire
John B. Buse
format Journal article
container_title JAMA Cardiology
container_volume 0
publishDate 2026
institution Swansea University
issn 2380-6583
2380-6591
doi_str_mv 10.1001/jamacardio.2026.0245
publisher American Medical Association
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 Importance: Individuals with type 2 diabetes (T2D) are at high risk of atherosclerotic cardiovascular disease (ASCVD). In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chronic kidney disease (CKD) receiving standard of care (SoC); however, whether oral semaglutide modifies recognized CV risk factors in the long term is unclear. Objective: To investigate whether treatment with oral semaglutide was associated with changes in ASCVD risk factors vs placebo. Design, Setting, and Participants: This secondary analysis comprises post hoc intention-to-treat analyses of the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes) double-blind multicenter randomized clinical trial (randomization 1:1 to oral semaglutide or placebo) among adults with T2D and ASCVD and/or CKD receiving SoC. Participants underwent randomization from June 2019 to March 2021, with a mean (SD) of 47.5 (10.9) months of follow-up, and data were analyzed from February to December 2025. Intervention(s): Participants were treated with either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard care. Main Outcomes and Measures: The primary outcome was the association of oral semaglutide vs placebo with glycated hemoglobin (HbA1c), body weight, and blood pressure (BP) using estimated treatment differences (ETDs) and with high-sensitivity C-reactive protein (hsCRP) and lipid plasma levels using estimated treatment ratios (ETRs). Results: Of 9650 randomized participants (mean [SD] age, 66.1 (7.6) years; 2790 female participants [28.9%]), 9495 participants (98.4%) completed the trial. Early (13 weeks) improvements in HbA1c (−0.87 percentage points), body weight (−2.54%), systolic BP (SBP, −3.84 mm Hg), pulse pressure (−3.81 mm Hg), hsCRP (−18.08%), total cholesterol (TC, −7.00%), non–high-density lipoprotein cholesterol (non–HDL-C, −8.02%), HDL-C (−4.49%), and triglycerides (−8.15%) were observed with oral semaglutide vs placebo and sustained over the trial duration. Body weight reductions were gradual across both groups. At week 156, in favor of oral semaglutide were ETDs for HbA1c (−0.47 percentage points; 95% CI, −0.52 to −0.42), body weight (−3.26 percentage points; 95% CI, −3.55 to −2.98), SBP (−1.83 mm Hg; 95% CI, −2.47 to −1.18), and pulse pressure (−2.17 mm Hg; 95% CI, −2.72 to −1.61) and ETRs for hsCRP (0.77; 95% CI, 0.74-0.81), TC (0.99; 95% CI, 0.98-1.00), non–HDL-C (0.98; 95% CI, 0.97-0.99), HDL-C (1.01; 95% CI, 1.01-1.02), and triglycerides (0.94; 95% CI, 0.93-0.96). No significant treatment differences were observed for low-density lipoprotein cholesterol or diastolic BP. Conclusions and Relevance: In this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with early and sustained improvements vs placebo in multiple ASCVD risk factors in high-risk participants with T2D and ASCVD and/or CKD, incremental to SoC. Trial Registration: ClinicalTrials.gov Identifier: NCT03914326.
published_date 2026-03-25T05:35:45Z
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