{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:10:32Z","timestamp":1790097032436,"version":"4.0.1"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: There has been a prominent rise in the use of GLP-1 RAs recently, particularly semaglutide, for the treatment of T2DM with or without obesity. Subcutaneous injections of semaglutide have demonstrated beneficial effects on cardiovascular risk factors. However, several factors hinder the use of subcutaneous administration. Therefore, the oral route is preferred; yet, it remains unclear whether oral semaglutide provides cardiovascular protection comparable to its subcutaneous counterpart. Methods: A systematic review in line with the PRISMA guidelines was performed based on eight databases (Scopus, Proquest, Science Direct, PubMed, Google Scholar, EBSCOHost, Clinical Key, and The Cochrane Library) to identify clinical studies that assessed the effects of oral semaglutide on cardiovascular risk factors, especially blood pressure and lipid or cholesterol profile in T2DM patients. Inclusion criteria included studies that used oral semaglutide on top of a mainstay treatment for T2DM compared to the placebo control group, assessed cardiovascular risk factors, and were conducted prospectively or in an RCT design. Case reports, ongoing studies with incomplete results, reviews, animal studies, and retrospective studies were excluded. The Newcastle-Ottawa scale and Jadad scale were used to assess the risk of bias in the included studies. Data extracted from the selected studies included patient characteristics, study design, research methodology, intervention regimen, and cardiovascular risk factors: SBP, DBP, TC, HDL, LDL, and TG. Data were presented in a table format to compare and synthesize the results of each study. Results: Five clinical studies were selected (two were randomized trials and three were observational, prospective studies). All five studies reported a consistent trend in the reduction in SBP (ranging from \u22122.60 to \u221212.74 mmHg) after oral semaglutide treatment. However, its effect on DBP was found to be less consistent. Lipid profile results show the most consistent trend in total cholesterol reduction (\u22128.80 to \u221222.19 mg\/dL). Four studies reported a favorable reduction in LDL cholesterol (\u22127.6 to \u221218.0 mg\/dL) and triglycerides (\u221211.00 to \u221240.13 mg\/dL). HDL cholesterol shows the least consistent findings where three studies reported an increasing trend, yet this was not statistically significant; one study reported a mild increase in HDL (+0.90 \u00b1 0.12; p &lt; 0.0001); and one study reported a slight reduction in HDL (55.6 \u00b1 2.5 to 51.6 \u00b1 2.2; p &lt; 0.05). Conclusions: Once-daily oral semaglutide is a promising add-on therapy for the treatment of T2DM with or without obesity in reducing cardiovascular risk factors, potentially lowering cardiovascular-related mortality. Thus, once-daily oral semaglutide may offer cardiovascular benefits comparable to the subcutaneous form, with the advantage of improved adherence.<\/jats:p>","DOI":"10.3390\/jcm14072239","type":"journal-article","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T12:18:52Z","timestamp":1742905132000},"page":"2239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Effect of Oral Semaglutide on Cardiovascular Risk Factors in Patients with Type 2 Diabetes: A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-1886","authenticated-orcid":false,"given":"Stanislaus Ivanovich","family":"Krishnanda","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Cipto Mangunkusumo National General Hospital, University of Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Christabelle","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Cipto Mangunkusumo National General Hospital, University of Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver Emmanuel","family":"Yausep","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Cipto Mangunkusumo National General Hospital, University of Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5858-2217","authenticated-orcid":false,"given":"Caroline","family":"Sugiharto","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Pelita Harapan, Tangerang 15810, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2124-2597","authenticated-orcid":false,"given":"Leroy David","family":"Vincent","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Cipto Mangunkusumo National General Hospital, University of Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4045-2784","authenticated-orcid":false,"given":"Raksheeth","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Internal Medicine at Jacobi Medical Center\/Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Damara","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Weiss Memorial Hospital, Chicago, IL 60640, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante Saksono","family":"Harbuwono","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Cipto Mangunkusumo National General Hospital, University of Indonesia, Jakarta 10430, Indonesia"},{"name":"Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/XCE.0000000000000116","article-title":"Epidemiology in Diabetes Mellitus and Cardiovascular Disease","volume":"6","author":"Fan","year":"2017","journal-title":"Cardiovasc. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1161\/CIRCULATIONAHA.118.038868","article-title":"Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus","volume":"139","author":"Zelniker","year":"2019","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1053\/j.gastro.2007.03.054","article-title":"Biology of Incretins: GLP-1 and GIP","volume":"132","author":"Baggio","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1056\/NEJMoa1607141","article-title":"Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1056\/NEJMoa1612917","article-title":"Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes","volume":"377","author":"Holman","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1603827","article-title":"Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/S0140-6736(18)32261-X","article-title":"Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (Harmony Outcomes): A Double-Blind, Randomised Placebo-Controlled Trial","volume":"392","author":"Hernandez","year":"2018","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0140-6736(19)31149-3","article-title":"Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): A Double-Blind, Randomised Placebo-Controlled Trial","volume":"394","author":"Gerstein","year":"2019","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.2337\/dc24-0764","article-title":"Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT","volume":"47","author":"Lingvay","year":"2024","journal-title":"Diabetes Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"403","DOI":"10.2147\/DMSO.S141235","article-title":"Reasons for Discontinuation of GLP1 Receptor Agonists: Data from a Real-World Cross-Sectional Survey of Physicians and Their Patients with Type 2 Diabetes","volume":"10","author":"Sikirica","year":"2017","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1007\/s13300-024-01551-4","article-title":"Real-World Use of Oral and Subcutaneous Semaglutide in Routine Clinical Practice in the UK: A Single-Centre, Retrospective Observational Study","volume":"15","author":"Sadouki","year":"2024","journal-title":"Diabetes Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2337\/ds20-0016","article-title":"Optimizing Therapeutic Outcomes With Oral Semaglutide: A Patient-Centered Approach","volume":"34","author":"Isaacs","year":"2021","journal-title":"Diabetes Spectrum."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gallwitz, B., and Giorgino, F. (2021). Clinical Perspectives on the Use of Subcutaneous and Oral Formulations of Semaglutide. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.645507"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1111\/jdi.14265","article-title":"Adherence and Treatment Discontinuation of Oral Semaglutide and Once-weekly Semaglutide Injection at 12 Month Follow-up: Japanese Real-world Data","volume":"15","author":"Horii","year":"2024","journal-title":"J. Diabetes Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.2147\/DDDT.S470826","article-title":"Clinical Pharmacokinetics of Semaglutide: A Systematic Review","volume":"18","author":"Yang","year":"2024","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1056\/NEJMoa1901118","article-title":"Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"381","author":"Husain","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pantanetti, P., Ronconi, V., Sguanci, M., Palomares, S.M., Mancin, S., Tartaglia, F.C., Cangelosi, G., and Petrelli, F. (2024). Oral Semaglutide in Type 2 Diabetes: Clinical\u2013Metabolic Outcomes and Quality of Life in Real-World Practice. J. Clin. Med., 13.","DOI":"10.3390\/jcm13164752"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0140-6736(23)01127-3","article-title":"Efficacy and Safety of Once-Daily Oral Semaglutide 25 Mg and 50 Mg Compared with 14 Mg in Adults with Type 2 Diabetes (PIONEER PLUS): A Multicentre, Randomised, Phase 3b Trial","volume":"402","author":"Aroda","year":"2023","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Volpe, S., Lisco, G., Fanelli, M., Racaniello, D., Colaianni, V., Lavarra, V., Triggiani, D., Crudele, L., Triggiani, V., and Sabb\u00e0, C. (2023). Oral Semaglutide Improves Body Composition and Preserves Lean Mass in Patients with Type 2 Diabetes: A 26-Week Prospective Real-Life Study. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1240263"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107040","DOI":"10.1016\/j.phrs.2023.107040","article-title":"Type 2 Diabetes Mellitus Pharmacological Remission with Dapagliflozin plus Oral Semaglutide","volume":"199","author":"Lunati","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1161\/CIRCULATIONAHA.121.057687","article-title":"Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium","volume":"145","author":"Kandzari","year":"2022","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s40256-020-00423-z","article-title":"Blood Pressure-Lowering Effect of Newer Antihyperglycemic Agents (SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors)","volume":"21","author":"Liakos","year":"2021","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102355","DOI":"10.1016\/j.coph.2023.102355","article-title":"The Blood Pressure Lowering Effects of Glucagon-like Peptide-1 Receptor Agonists: A Mini-Review of the Potential Mechanisms","volume":"69","author":"Tavares","year":"2023","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rowlands, J., Heng, J., Newsholme, P., and Carlessi, R. (2018). Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00672"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/s12933-021-01417-0","article-title":"Oral GLP-1 Analogue: Perspectives and Impact on Atherosclerosis in Type 2 Diabetic Patients","volume":"20","author":"Saraiva","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Le, R., Nguyen, M.T., Allahwala, M.A., Psaltis, J.P., Marathe, C.S., Marathe, J.A., and Psaltis, P.J. (2024). Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs. J. Clin. Med., 13.","DOI":"10.3390\/jcm13164674"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1007\/s00125-005-0126-y","article-title":"Glucagon-like Peptide 1 Abolishes the Postprandial Rise in Triglyceride Concentrations and Lowers Levels of Non-Esterified Fatty Acids in Humans","volume":"49","author":"Meier","year":"2006","journal-title":"Diabetologia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","article-title":"Glucagon-like Peptide-1 Receptor: Mechanisms and Advances in Therapy","volume":"9","author":"Zheng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Katsuyama, H., Hakoshima, M., Kaji, E., Mino, M., Kakazu, E., Iida, S., Adachi, H., Kanto, T., and Yanai, H. (2024). Effects of Once-Weekly Semaglutide on Cardiovascular Risk Factors and Metabolic Dysfunction-Associated Steatotic Liver Disease in Japanese Patients with Type 2 Diabetes: A Retrospective Longitudinal Study Based on Real-World Data. Biomedicines, 12.","DOI":"10.3390\/biomedicines12051001"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/dom.13120","article-title":"Semaglutide Improves Postprandial Glucose and Lipid Metabolism, and Delays First-hour Gastric Emptying in Subjects with Obesity","volume":"20","author":"Hjerpsted","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-Weekly Semaglutide in Adults with Overweight or Obesity","volume":"384","author":"Wilding","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S2213-8587(21)00203-5","article-title":"Cardiovascular, Mortality, and Kidney Outcomes with GLP-1 Receptor Agonists in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Trials","volume":"9","author":"Sattar","year":"2021","journal-title":"Lancet Diabetes Endocrinol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/7\/2239\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:00:06Z","timestamp":1760029206000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/7\/2239"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["jcm14072239"],"URL":"https:\/\/doi.org\/10.3390\/jcm14072239","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,25]]}}}