In addition to significant weight reduction, those taking oral semaglutide 25 mg experienced improvements in daily physical function, including activities such as bending, walking, standing, and overall mobility, along with better cardiovascular risk profiles. Novo Nordisk has submitted the treatment to the US Food and Drug Administration (FDA) as the first oral GLP-1 therapy for long-term weight management.2 Production of the medication is already underway at the company's facilities in the United States.

Landmark Study Published in The New England Journal of Medicine

The OASIS 4 phase 3 trial, published in The New England Journal of Medicine, marks a major advance in Novo Nordisk's effort to expand obesity treatment options. Conducted over 64 weeks, the study compared once-daily oral semaglutide 25 mg plus lifestyle changes with a placebo in 307 adults who were obese or overweight and had at least one weight-related condition, but did not have diabetes.

Participants who consistently adhered to treatment achieved an average weight loss of 16.6% versus 2.7% for those taking placebo. Over one-third (34.4%) lost at least 20% of their body weight compared with 2.9% in the placebo group. These outcomes were similar to previous results with injectable Wegovy.

When measured regardless of treatment adherence, average weight loss was 13.6% for the semaglutide group compared with 2.2% for placebo. In this group, nearly 30% (29.7%) of participants still lost 20% or more of their weight, compared with 3.3% for placebo. The study also confirmed improvements in cardiovascular risk markers and physical activity levels consistent with the injectable version.

Expert Perspectives on Efficacy and Potential Impact

"The oral semaglutide 25 mg data show compelling efficacy for an oral weight management medication with 16.6% weight loss and a safety and tolerability profile consistent with injectable Wegovy," said Martin Holst Lange, chief scientific officer and executive vice president of Research & Development at Novo Nordisk. "Currently, less than 2% of individuals with obesity in the US receive obesity medication and Wegovy in a pill may also address patient preference for oral treatment. Pending FDA approval, ample supply will be available to meet the expected US demand as we hope to set a new treatment benchmark for oral weight loss medications for people with overweight or obesity."

The OASIS 4 trial reported that gastrointestinal side effects with the oral medication were generally mild to moderate and temporary. The most common were nausea (46.6% compared with 18.6% for placebo) and vomiting (30.9% compared with 5.9% for placebo). Adverse events leading to permanent discontinuation occurred in 6.9% of participants on semaglutide and 5.9% of those on placebo. Serious adverse events were less frequent among those taking the medication (3.9%) compared with placebo (8.8%).

These findings reinforce the established safety and tolerability record of semaglutide, supported by more than 37 million patient-years of use worldwide.

Advancing Obesity Care Through Innovation

"The OASIS 4 trial results further underscore the significant impact that semaglutide can have in achieving sustainable weight loss and broader health benefits," said Sean Wharton, lead study author and medical director of the Wharton Medical Clinic. "Oral semaglutide 25 mg builds on the proven efficacy and established safety and tolerability profile of semaglutide and represents a significant advancement in obesity treatment. People with overweight or obesity have individual preferences, and with oral semaglutide as a potential new treatment option, more of those who are not on treatment today may consider starting GLP-1 treatment."

Novo Nordisk submitted a New Drug Application (NDA) for the once-daily Wegovy® pill to the FDA in February. The review is expected to be completed by the end of 2025.5 Currently, there are no oral GLP-1 therapies approved for weight management. If authorized, the new pill will be manufactured entirely in the United States, where production is already underway at Novo Nordisk's expanded facility.

Inside the OASIS 4 Clinical Trial

OASIS 4 was a 64-week, randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of once-daily oral semaglutide 25 mg in 307 adults with obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity. People with diabetes were not included.

The study included a 12-week dose escalation phase, a 52-week treatment period, and a 7-week follow-up after treatment ended. Participants were assigned in a 2:1 ratio to either semaglutide or placebo, combined with lifestyle counseling and diet modification for the duration of the trial.

Understanding Obesity as a Chronic Condition

Obesity is a complex, chronic, and progressive disease that requires long-term management. A common misconception is that it results solely from a lack of willpower, when in reality, biological, genetic, social, and environmental factors all contribute to the difficulty of losing and maintaining weight.

About Wegovy and Its Existing Uses

Wegovy is the brand name for semaglutide 2.4 mg, which is currently available as an injection. In the European Union, Wegovy is approved as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adults with obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) who have at least one weight-related condition. It is also approved for adolescents aged 12 and older with obesity and a body weight above 60 kg.

The label includes clinical data showing reductions in major cardiovascular events (MACE), improvements in symptoms related to heart failure with preserved ejection fraction (HFpEF), enhanced physical function, and less pain associated with knee osteoarthritis.

In the United States, Wegovy (semaglutide) injection 2.4 mg is approved for adults and children aged 12 and older with obesity, or adults with overweight and a related medical condition, to help reduce excess body weight and maintain weight loss. It is also indicated to lower the risk of major cardiovascular events such as death, heart attack, or stroke in adults with obesity or overweight and established heart disease.

Semaglutide injection 2.4 mg carries a Boxed Warning for possible thyroid tumors, including cancer, and should not be used by individuals with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Oral semaglutide 25 mg (Wegovy in a pill) is not yet approved in the US or Europe.

"I'm really excited about the translational potential of this work," said Dr. Anna Orr, the Nan and Stephen Swid Associate Professor of Frontotemporal Dementia Research in the Feil Family Brain and Mind Research Institute and member of the Appel Alzheimer's Disease Research Institute at Weill Cornell, who co-led the study. "We can now target specific mechanisms and go after the exact sites that are relevant for disease."

How Mitochondria and Free Radicals Affect the Brain

The research focused on mitochondria, the cell's energy-producing structures that convert food into usable energy. In the process, mitochondria release reactive oxygen species (ROS) -- molecules commonly known as free radicals. At normal levels, ROS help regulate essential cell functions, but excessive or poorly timed production can damage cells.

"Decades of research implicate mitochondrial ROS in neurodegenerative diseases," said Dr. Adam Orr, an assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell, who co-led the work.

Because of this connection, scientists have long tested antioxidants as a potential way to neutralize ROS and slow neurodegeneration. However, these clinical trials have largely failed. "That lack of success might be related to the inability of antioxidants to block ROS at their source and do so selectively without altering cell metabolism," Dr. Adam Orr explained.

A New Way to Stop Harmful Free Radicals

As a postdoctoral researcher, Dr. Orr developed a drug discovery platform designed to find molecules that specifically suppress ROS at individual mitochondrial sites while leaving normal functions intact. Through this approach, the team identified a group of compounds called S3QELs ("sequels"), which showed potential to block harmful ROS activity.

The researchers focused on Complex III, a mitochondrial site known for producing ROS that can leak into the rest of the cell, potentially causing damage. To their surprise, the excess ROS did not originate from neurons, but from astrocytes -- non-neuronal cells that provide structural and metabolic support to neurons.

"When we added S3QELs, we found significant neuronal protection but only in the presence of astrocytes," said Daniel Barnett, a graduate student in the Orr lab and the study's lead author. "This suggested that ROS coming from Complex III caused at least some of the neuronal pathology."

Further experiments showed that when astrocytes were exposed to disease-related factors such as inflammatory molecules or proteins linked to dementia (including amyloid-beta), their mitochondrial ROS production increased dramatically. Treatment with S3QELs suppressed much of this rise, while blocking other ROS sources did not have the same effect.

Barnett discovered that ROS oxidized certain immune and metabolic proteins involved in neurological disease, altering the activity of thousands of genes tied to inflammation and dementia.

"The precision of these mechanisms had not been previously appreciated, especially not in brain cells," said Dr. Anna Orr. "This suggests a very nuanced process in which specific triggers induce ROS from specific mitochondrial sites to affect specific targets."

Promising Results in Animal Models

When the team administered the S3QEL compound to mice engineered to model frontotemporal dementia, they observed reduced astrocyte activation, lower levels of inflammatory gene expression, and a decrease in a tau modification linked to dementia. Remarkably, these effects appeared even when treatment began after symptoms had already started.

Extended treatment improved lifespan, was well tolerated, and produced no significant side effects. Dr. Anna Orr attributes this to the compound's highly targeted action.

The team plans to continue developing the S3QEL compounds in collaboration with medicinal chemist Dr. Subhash Sinha, professor of research in neuroscience in the Brain and Mind Research Institute and member of the Appel Alzheimer's Disease Research Institute at Weill Cornell.

They also intend to investigate how disease-associated genes influence ROS production and whether certain genetic variants that raise or lower dementia risk might do so by altering mitochondrial ROS activity.

Changing How Scientists Think About Free Radicals

"The study has really changed our thinking about free radicals and opened up many new avenues of investigation," said Dr. Adam Orr. The potential of these findings to open new research approaches to inflammation and neurodegeneration is highlighted in the journal.