Sharon L. Mulvagh, S. E. Inzucchi, Nikolaus Marx, Neil R Poulter, J Deanfield, Rodica Pop-Busui, Scott S. Emerson, Johannes F. E. Mann, Mads D. M. Engelmann, G. Kees Hovingh, Kabirdev Mandavya, Žaklina Davicevic-Elez, Ole Kleist Jeppesen, Alberto Lorenzatti, Aytekin Oğuz, Boris Mankovsky, Chaicharn Deerochanawong, Juan J. Gorgojo-Martinez, Li Li Ji, Stephen C. Bain, Darren K. McGuire, John B. Buse, SOUL Study Group, Andreas L. Birkenfeld, Kim A. Connelly, Martin Haluzik, Matthew A. Cavender, Monika Kellerer, Pardeep S. Jhund, Søren Gregersen, Carolyn S. P. Lam, P Schelde, Aslam Amod, Borys Mankovsky, Cyrus Desouza, Juan J. Gorgojo-Martinez, Rosario Arechavaleta, Shih‐Te Tu, José Francisco, Robinson Sánchez García, Francis Chun Chung Chow, Hirotaka Watada, Kun Ho Yoon, Federico Pérez Manghi, José M Pozzi, Alberto Lorenzatti, Virginia Esther Visco, Daniel Piskorz, Lucrecia Nardone, Mariano I. Chahin, Miguel Bustamante Labarta, Cecilia Luquez, Ignacio J. MacKinnon, Thomas Pieber, R. Prager, Evelyn Fließer-Görzer, Christoph Ebenbichler, Peter Fasching, Chantal Mathieu, Christophe De Block, Francis Duyck, Ellen Heyns, Bruno Lapauw, Luiz A. A. Turatti, DENISE FRANCO, Rosângela Rogisnki Réa, Hugo Lisboa, João Eduardo Nunes Salles, José F. K. Saraiva, Alberto G. T. Fonseca, Maria H. Vidotti, Silmara Oliveira Leite, Naresh Aggarwal, Harpreet Bajaj, Robert Schlosser, Luis Noronha, SUE PEDERSEN, Guy Tellier, John Weisnagel, Sorin Beca, Hani Alasaad, Zubin Punthakee, John G. B. Mancini, Richard Tytus, Thomas Ransom, Mansoor Husain, Michael Tsoukas, Li Li Ji, Jun Liu, Guoyue Yuan, Xinhua Ye, XIAOLIN DONG, Fang Bian, A. Angelo Cadena Bonfanti, Ivan D. Hernandez Erazo, Eder A. Hernández Ruiz, Juan E. Gómez Mesa, Silvija Canecki-Varzic, Jelena Vučak Lončar, Vesna Simegi-Djekic
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.