Oral Semaglutide Shows Real-World Heart Protection in Diabetes Patients with Cardiovascular Disease

People living with type 2 diabetes who also carry a diagnosis of atherosclerotic cardiovascular disease face some of the highest cardiovascular risks in modern medicine, and a new large-scale analysis suggests that a pill may help change that trajectory. A retrospective cohort study published in Diabetes Therapy examined tens of thousands of adults in the United States who had recently started oral semaglutide, the first approved oral glucagon-like peptide-1 receptor agonist, and compared their cardiovascular outcomes against those starting other noninsulin glucose-lowering therapies. The result: new users of oral semaglutide experienced significantly lower risks of major adverse cardiovascular events, ischemic stroke, and all-cause death than comparable patients taking other common diabetes pills, offering some of the first real-world confirmation of the benefits suggested by clinical trials.

The study drew on administrative claims data from Optum’s deidentified Clinformatics Data Mart Database, which captures health records from large commercial and Medicare Advantage plans spanning all 50 US states. Researchers identified adults with confirmed diagnoses of both type 2 diabetes and established atherosclerotic cardiovascular disease who initiated oral semaglutide or another noninsulin glucose-lowering therapy between October 2019 and April 2024. After propensity score matching to balance baseline characteristics, the analysis compared 10,878 new users of oral semaglutide against 28,639 users of other noninsulin therapies, and conducted additional matched comparisons against specific drug classes, including dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors. An as-treated approach was the primary analysis, with intention-to-treat sensitivity analyses confirming robustness.

The investigators assessed a battery of cardiovascular endpoints, ranging from the classic 3-point definition of major adverse cardiovascular events—ischemic stroke, myocardial infarction, and cardiovascular-related death—to broader composites that add hospitalization for unstable angina and heart failure, as well as modified versions that substitute all-cause death. Death was categorized as cardiovascular-related when claims showed a cardiovascular primary diagnosis within 30 days before death, while other events required an inpatient claim with a qualifying ICD-10-CM diagnosis code in the primary position. This multi-layered endpoint strategy matters because composite measures aggregate more events than their individual components, providing greater statistical power to detect treatment differences in a real-world population where follow-up periods are often short.

The headline finding was striking. Compared with users of other noninsulin glucose-lowering therapies, new users of oral semaglutide had a 17 percent lower risk of 3-point major adverse cardiovascular events and a 21 percent lower risk of the modified 3-point version. The benefits extended across the endpoint spectrum: oral semaglutide initiation was associated with a 26 percent lower risk of 5-point major adverse cardiovascular events, a 27 percent lower risk of the modified 5-point measure, and a 16 percent lower risk of 2-point events. Individually, oral semaglutide users experienced 23 percent lower risk of ischemic stroke and 29 percent lower risk of all-cause death, though the differences in myocardial infarction and cardiovascular-related death did not reach statistical significance in this dataset.

The class-specific comparisons sharpened the picture. Against matched users of dipeptidyl peptidase 4 inhibitors, each group comprising 7,218 patients, oral semaglutide users had a 22 percent lower risk of 3-point major adverse cardiovascular events, a 24 percent lower risk of the modified version, a 39 percent lower risk of ischemic stroke, and a 36 percent lower risk of all-cause death. Against sodium-glucose cotransporter 2 inhibitor users, the comparison was somewhat narrower, with 7,491 oral semaglutide users matched against 21,572 SGLT2 inhibitor users, yet oral semaglutide still delivered a 21 percent lower risk of 3-point events, a 22 percent lower risk of modified 3-point events, and significant reductions across the broader 5-point and 2-point composites. These are notable gains considering SGLT2 inhibitors themselves carry established cardiovascular benefits, meaning oral semaglutide outperformed an already cardioprotective comparator.

The economic implications were also meaningful. Oral semaglutide users accumulated fewer hospitalizations and lower overall medical costs than their counterparts on other therapies. Specifically, they had 19 percent fewer all-cause inpatient visits, 19 percent lower all-cause inpatient costs, and roughly $2,927 lower all-cause medical costs per patient per year compared with users of other noninsulin therapies. Against dipeptidyl peptidase 4 inhibitors, the savings were larger: 31 percent fewer all-cause inpatient visits and nearly $4,972 lower annual all-cause medical costs. Emergency room visits and costs were the notable exception, showing no significant differences in most comparisons, suggesting the cost advantages concentrate in inpatient and outpatient care rather than acute unscheduled visits.

The findings dovetail with the SOUL randomized clinical trial, which demonstrated that oral semaglutide was superior to placebo in reducing cardiovascular events among people with type 2 diabetes and established cardiovascular disease or chronic kidney disease, showing a 14 percent reduction in 3-point major adverse cardiovascular events. The real-world cohort had a slightly older average age than the trial population, a higher proportion of women, and broader representation of race, ethnicity, and geography, making it a useful complement to the trial’s controlled conditions. The US Food and Drug Administration has since approved oral semaglutide for cardiovascular risk reduction in adults with type 2 diabetes at high risk, including those without prior cardiovascular events, expanding its potential reach.

What makes oral semaglutide scientifically interesting is the chemistry behind the pill. Peptides like semaglutide are normally destroyed by digestive enzymes and cannot cross the intestinal wall, which is why GLP-1 receptor agonists have historically required injection. Oral semaglutide overcomes this by co-formulation with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, known as SNAC, an absorption enhancer that enables localized uptake of the peptide through the stomach lining without disrupting absorption of other molecules. This technological achievement matters clinically because injection aversion remains a real barrier for many patients, and an oral option with comparable cardiovascular protection could help combat therapeutic inertia in diabetes management.

The authors caution that the observational design cannot fully establish causation, and that claims data lack clinical granularity on kidney function, blood pressure, lipids, smoking, and lifestyle factors that may influence cardiovascular risk. Negative-control analyses examining outcomes theoretically unrelated to the drugs, such as breast or prostate cancer and arm or shoulder fractures, found no differences between groups, providing some reassurance against unmeasured confounding. Follow-up was relatively short, averaging roughly nine to ten months, and the study population was limited to the US health care setting. Still, the consistency of the results with the SOUL trial, combined with prior real-world evidence showing cardiovascular benefits of once-weekly injectable semaglutide, builds a coherent case that this class of drugs genuinely protects the heart in high-risk patients, whether delivered by needle or by pill.

Subject of Research: Real-world cardiovascular outcomes of oral semaglutide in adults with type 2 diabetes and atherosclerotic cardiovascular disease.

Article Title: Comparing Cardiovascular Outcomes in New Users of Oral Semaglutide Versus Other Noninsulin Glucose-Lowering Therapies Among Adults with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

Article References: Tan, X., Liang, Y., Zhong, C., Xie, L., Guevarra, M., Swift, C., & de Havenon, A. (2026). Comparing Cardiovascular Outcomes in New Users of Oral Semaglutide Versus Other Noninsulin Glucose-Lowering Therapies Among Adults with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. Diabetes Therapy. https://doi.org/10.1007/s13300-026-01919-8

Image Credits: AI Generated

DOI: 10.1007/s13300-026-01919-8

Keywords: oral semaglutide, type 2 diabetes, cardiovascular outcomes, major adverse cardiovascular events, GLP-1 receptor agonist, DPP4 inhibitors, SGLT2 inhibitors, ischemic stroke, real-world evidence, SNAC absorption, Diabetes Therapy, comparative effectiveness