Oral Semaglutide 25 mg Shows Cardiometabolic Benefits Beyond Weight Loss in OASIS 4 Analysis

Investigational oral semaglutide 25 mg improved glycemic parameters and cardiovascular risk factors across multiple categories of weight loss in adults with overweight or obesity, according to post hoc analyses from the OASIS 4 phase 3 trial presented at ObesityWeek 2025 in Atlanta.

In the overall OASIS 4 trial population, a greater proportion of participants with prediabetes at baseline (71.1%) achieved normoglycemia at week 64 with oral semaglutide compared with those receiving placebo (33.3%). Participants treated with oral semaglutide 25 mg were more likely to achieve body weight reduction of 15% or more compared with placebo, and those who reached this threshold demonstrated greater improvements in blood pressure, inflammatory markers, and lipid profiles.

Cardiometabolic Markers Improved

The cardiometabolic analysis examined how the magnitude of weight loss affected glycemic control and cardiovascular risk factors. Participants achieving ≥15% body weight reduction showed larger reductions in systolic blood pressure (−10.1 mmHg versus −4.1 mmHg in those with <15% weight loss) and diastolic blood pressure (−4.3 mmHg versus −1.1 mmHg). C-reactive protein levels decreased more substantially in the higher weight loss group (ratio to baseline: 0.34 versus 0.74), as did non-HDL cholesterol (0.90 versus 0.96) and triglycerides (0.73 versus 0.87).

"It's exciting to see these new results from the cardiometabolic post hoc analysis, which showed that while benefits were most pronounced in people who achieved greater than 15% weight loss, clear improvements in glycemic parameters and CV risk factors were observed in patients taking [semaglutide], regardless of how much weight was lost, based on the groups observed," Domenica Rubino, MD, trial investigator and Director of the Washington Center for Weight Management and Research in Washington, DC, said in a statement.

Comparable Efficacy to Injectable Formulation

An indirect treatment comparison between oral semaglutide in the OASIS 4 and injectable semaglutide in the STEP 1 trial demonstrated comparable outcomes. Key endpoints including the proportion of patients achieving 5% or more, 10% or more, 15% or more, and 20% or more reductions in body weight, changes in cardiometabolic markers, and quality of life scores were similar across the formulations in their respective trials.

A pooled analysis of OASIS 4 and STEP trials showed consistent weight loss efficacy regardless of menopausal status. Pre-menopausal women lost an average of 18.2% body weight over 64 weeks, while peri-menopausal and post-menopausal women lost 15.0% and 15.7%, respectively. The percentage achieving >15% weight loss ranged from 53.4% to 58.1% across menopausal stages.

Improved Physical Function

In participants who self-reported low physical function at baseline using the Patient Global Impressions of Status questionnaire, 77.3% taking oral semaglutide 25 mg achieved meaningful improvement in physical function scores at 64 weeks versus 42.9% taking placebo.

Consistent Safety Profile

The safety and tolerability profile of the oral GLP-1 formulation aligned with that of injectable semaglutide. Gastrointestinal adverse events were generally mild to moderate in severity and transient. Nausea occurred in 46.6% of patients on oral semaglutide versus 18.6% on placebo, while vomiting affected 30.9% versus 5.9%. Adverse events leading to permanent discontinuation occurred in 6.9% of patients on oral semaglutide and 5.9% on placebo. Serious adverse events were about half as common among the participants taking oral semaglutide (3.9%) as in the group taking placebo (8.8%), according to Novo Nordisk.

"The OASIS 4 results that we are sharing at this important meeting build on existing clinical trial evidence for oral semaglutide and extend findings beyond weight loss to suggested improvements in overall health," Martin Holst Lange, chief scientific officer and executive vice president of Research & Development at Novo Nordisk, said in the statement.

The OASIS 4 trial enrolled 307 participants with BMI of 30 kg/m² or greater or BMI of 27 kg/m² or greater with weight-related comorbidities, excluding those with diabetes. Participants were randomly assigned to once-daily oral semaglutide 25 mg or placebo, alongside lifestyle intervention for 64 weeks. Several of the analyses presented at ObesityWeek 2025 were exploratory post hoc evaluations that require further validation.

Novo Nordisk submitted a New Drug Application to the FDA in May 2025 for oral semaglutide 25 mg. The agency's review is expected to be completed by the end of 2025. If approved, this would be the first oral GLP-1 receptor agonist for chronic weight management.

FDA accepts filing application for oral semaglutide 25 mg, which if approved, would be the first oral GLP-1 treatment for obesity. News release. Novo Nordisk. May 2, 2025. Accessed November 6, 2025. https://www.prnewswire.com/news-releases/fda-accepts-filing-application-for-oral-semaglutide-25-mg-which-if-approved-would-be-the-first-oral-glp-1-treatment-for-obesity-302445232.html