By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv
Oral semaglutide: who responds quickly to treatment?
Oral semaglutide at a dose of 25 mg, known as the Wegovy pill, is at the center of the debate about the new obesity pills. At the European Congress on Obesity, ECO 2026, held in Istanbul in May 2026, researchers presented new data on patients defined as “early responders.” These are people who responded quickly, already in the first weeks of treatment. The data come from a post hoc analysis of the OASIS 4 trial.
According to the data presented at the congress, the researchers defined early responders as those who lost at least 10% of their body weight by week 16. Of the patients, 28.8% met this definition. In other words, almost one in three patients responded quickly and substantially.
A 21.6% weight loss in early responders
The early responders kept showing impressive results later on. By week 16, they had lost an average of 13.2% of their body weight. By week 64, at the end of the trial, they reached an average weight loss of 21.6%.
However, those who didn’t respond early also lost a meaningful amount of weight. In this group, weight dropped by an average of 11.5% by the end of the trial. This is still a figure with medical and metabolic value. So a slow response in the first months doesn’t mean that treatment has failed. I wrote about the reasons people respond differently in my article on why weight loss injections don’t work for everyone.
Not just weight: better function and quality of life
The researchers also looked at physical function. Among patients who had a physical limitation at the start of the trial, 77.3% of those on the pill achieved a meaningful improvement in their function score. In the placebo group, by contrast, the rate was 42.9%. The improvement included walking, standing for a long time, bending and physical activity.
The key message is that the response in the first months may become an important tool in personalized medicine. Identifying early responders will help tailor treatment precisely, boost motivation and estimate the chance of long-term success.
Are the side effects of oral semaglutide the reason for the weight loss?
Many patients worry that their weight loss simply comes from nausea. At the congress, researchers presented another poster on the digestive tolerability of the semaglutide pill and its link to weight loss. According to the researchers, most digestive side effects appeared during dose escalation and then gradually faded. In addition, most were mild to moderate.
What’s more, the analysis showed that most of the drug’s effect on weight does not depend on digestive side effects. In other words, the drug works through biological mechanisms of hunger, fullness, reward in the brain and energy balance. It doesn’t cause weight loss just because of temporary discomfort. Still, it’s important to know that in the original OASIS 4 trial, digestive side effects occurred in 74.0% of patients on the pill, compared with 42.2% on placebo. That’s why gradual dose increases, eating slowly and medical follow-up matter so much.
Oral semaglutide in the OASIS 4 trial
The OASIS 4 trial included 307 adults with obesity or overweight and without diabetes. After 64 weeks, patients on the pill lost an average of 13.6% of their body weight, compared with 2.2% on placebo. In addition, the researchers found a significant improvement in the physical function score.
Further analyses of the trial also looked at metabolic targets: BMI, waist-to-height ratio, blood sugar, blood pressure and blood lipids. The overall picture is consistent. People who reached their weight and waist targets often reached normal blood sugar and triglyceride levels as well. In other words, weight loss is only part of the story. I answer common questions about the Wegovy pill in my article on weight loss pills.
Oral semaglutide vs. orforglipron: the ORION analysis
The market for obesity drugs is changing at a dramatic pace. After the era of injections, the focus is gradually shifting to pills as well. Two drugs are at the center today: oral semaglutide 25 mg and orforglipron, sold as Foundayo. Both are intended for obesity, and both activate the GLP-1 receptor.
Because there is still no head-to-head trial in obesity, researchers ran an indirect comparison called ORION. It set OASIS 4 against ATTAIN-1, the phase 3 trial of orforglipron. The researchers matched the populations by starting weight, sex and blood sugar status.
According to the results, oral semaglutide led to greater weight loss than orforglipron 36 mg. The gap was 3.2 percentage points in the analysis that included all patients, even those who stopped treatment. In the analysis that assumed everyone stayed on treatment, the gap was 3.0 percentage points. The difference was statistically significant. The data were first presented at the Obesity Medicine Association (OMA) meeting in April 2026, and then at ECO 2026.
Tolerability and stopping treatment
One of the most notable findings in ORION concerned tolerability. Orforglipron 36 mg was linked to 4.1 times higher odds of stopping treatment because of any side effect. The odds of stopping because of digestive side effects were 13.9 times higher. In absolute numbers, in ATTAIN-1, 5.3% to 10.3% of patients on orforglipron stopped treatment because of side effects, compared with 2.7% on placebo.
These findings matter, because staying on treatment is one of the most important factors for long-term success. However, the number of events was relatively small. So we should interpret the size of the differences with caution.
Patient preferences: the OPTIC study
At the same time, researchers presented the OPTIC study, which examined patient preferences. It included 800 adults in the United States with obesity or overweight. Participants chose between treatment profiles based on the clinical trials of the two drugs. Of them, 84% preferred the profile similar to oral semaglutide. In addition, 65% said that taking a pill on an empty stomach and waiting 30 minutes before a meal would not disrupt their routine.
This figure is interesting, because one criticism of the semaglutide pill is the need to take it fasting and then wait. Keep in mind that the study tested preferences based on profiles, not real experience with the drugs.
Not every pill works the same way
Both drugs act on the same receptor, but they are completely different molecules. Semaglutide is a peptide that resembles a natural hormone in the body. Orforglipron, on the other hand, is a small molecule that is not a peptide. These differences affect absorption, tolerability and how you take the drug. For example, according to Lilly, you can take Foundayo at any time of day, with no food or water restrictions.
In addition, in type 2 diabetes there is already a direct trial. The ACHIEVE-3 trial compared orforglipron 36 mg with oral semaglutide 14 mg, the Rybelsus dose. After 52 weeks, weight dropped by 9.2% with orforglipron, compared with 5.3% with semaglutide. On the other hand, 9.7% stopped orforglipron because of side effects, compared with 4.9% on semaglutide. In other words, the picture depends on the population and the dose. You’ll find a broader comparison in my article on Foundayo vs. the semaglutide pill.
Limits of the comparison and approval status
Despite the results, ORION is an indirect comparison, not a head-to-head trial. The researchers themselves note that some of the differences may stem from differences between the trial populations. Also, Novo Nordisk, the maker of Wegovy, presented the analysis.
And what about approvals? The FDA approved the Wegovy pill in December 2025, and the European Union approved it in July 2026. In Israel, it is expected to arrive at the end of 2026. The FDA approved Foundayo in April 2026, and it has been available in Israel since mid-September 2026.
The bottom line on oral semaglutide
The race between obesity pills is no longer only about weight loss. It also includes persistence, quality of life, tolerability and convenience. Oral semaglutide enters the field with strong data, especially in early responders. At the same time, orforglipron has the advantage of being taken without restrictions. In the end, you and your doctor make the right choice together, based on your goals, routine and health.
This article provides general information and is not a substitute for personal medical advice.
References
ECO2026: Novo says one in three adults respond early to Wegovy pill, double mobility results
Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity
Indirect Analysis Suggests Greater Weight Loss With Oral Semaglutide vs Orforglipron
Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment
Novo Nordisk A/S: Wegovy pill approved in the US as first oral GLP-1 for weight management
Novo Nordisk funded the OASIS 4 trial and also presented the ORION and OPTIC analyses. Lilly funded the ATTAIN-1 and ACHIEVE-3 trials.
