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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 
,
Darren K. McGuire,
John B. Buse,
(SOUL Study Group)
,
Darren K. McGuire,
John B. Buse,
(SOUL Study Group)
JAMA Cardiology
Swansea University Author:
Steve Bain
-
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© 2026 Mulvagh SL et al. This is an open access article distributed under the terms of the CC-BY-NC-ND License.
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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...
| Published in: | JAMA Cardiology |
|---|---|
| ISSN: | 2380-6583 2380-6591 |
| Published: |
American Medical Association (AMA)
2026
|
| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa71781 |
| first_indexed |
2026-04-22T14:43:51Z |
|---|---|
| last_indexed |
2026-05-12T08:38:14Z |
| id |
cronfa71781 |
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SURis |
| fullrecord |
<?xml version="1.0"?><rfc1807><datestamp>2026-05-11T15:41:26.4498843</datestamp><bib-version>v2</bib-version><id>71781</id><entry>2026-04-22</entry><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</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>2026-04-22</date><deptcode>MEDS</deptcode><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 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. 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2026-05-11T15:41:26.4498843 v2 71781 2026-04-22 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 2026-04-22 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 (AMA) 2380-6583 2380-6591 25 3 2026 2026-03-25 10.1001/jamacardio.2026.0245 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. 2026-05-11T15:41:26.4498843 2026-04-22T15:41:24.2084193 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 (SOUL Study Group) 23 71781__36703__11047d23b9e14e679d3422dc816f6609.pdf 71781.VOR.pdf 2026-05-11T15:32:04.1226143 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 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| 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 |
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5399f4c6e6a70f3608a084ddb938511a |
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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 (SOUL Study Group) |
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JAMA Cardiology |
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2026 |
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2380-6583 2380-6591 |
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10.1001/jamacardio.2026.0245 |
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American Medical Association (AMA) |
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Faculty of Medicine, Health and Life Sciences |
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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 |
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2026-03-25T12:57:49Z |
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11.106326 |