Investigation of clinical outcomes on the oral or injectable use of semaglutide and cardiovascular risks: a systematic review

Abstract

Introduction: In the context of GLP-1 analogs and cardiovascular risks, both subcutaneous and oral formulations of semaglutide have undergone extensive phase 3 clinical trials. Objective: It was to analyze, through a systematic review, the main clinical findings of the oral or injectable use of semaglutide and its relationship with cardiovascular risks. Methods: The systematic review rules of the PRISMA Platform were followed. The search was conducted from November 2024 to January 2025 in the Scopus, Embase, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 132 articles were found. A total of 35 articles were fully evaluated and 25 articles were included. According to the GRADE instrument, most of the studies presented homogeneity in their results, with X² = 87.5%> 50%. It was concluded that subcutaneous injection is more likely to result in endocrine-related adverse events. Oral administration is more likely to induce gastrointestinal adverse events. Furthermore, it significantly accelerates the onset of adverse reactions. As one of the newer agents in the class, the safety of semaglutide in both subcutaneous and oral formulations has been examined in phase 3 and CVOT programs. However, no major safety concerns have emerged to date, although definitive conclusions for pancreatic cancer, thyroid cancer, and complications of polycystic kidney disease cannot be drawn at this time. Compared with the beneficial effects of these drugs on glucose metabolism, blood pressure, body weight, and cardiovascular (and potentially even renal) outcomes, these agents have an overall beneficial risk/benefit profile for treating patients with T2DM. GLP-1RAs are safe, well tolerated, and improve cardiovascular outcomes, largely independent of their antihyperglycemic properties, but they remain underutilized by cardiologists and require therapy management in patients with T2DM and established atherosclerotic cardiovascular disease or high risk for established atherosclerotic cardiovascular disease.