The search for effective and practical obesity treatments continues to evolve. Three major studies recently published in The New England Journal of Medicine highlight progress with oral GLP-1 therapies. These include oral semaglutide at 25 mg daily (OASIS-4 trial) and orforglipron, a small-molecule GLP-1 receptor agonist, studied in both obesity without diabetes (ATTAIN-1 trial) and type 2 diabetes (ACHIEVE-1 trial). Together, they broaden the conversation on oral options that may complement or rival existing therapies such as Rybelsus 14 mg, the currently approved oral semaglutide.
#1 Oral Semaglutide 25 mg: OASIS-4 Trial
The OASIS-4 trial tested once-daily oral semaglutide 25 mg in 205 adults with obesity or overweight plus comorbidities, but without diabetes. Participants also received lifestyle interventions.
- Weight loss results: At 64 weeks, average weight reduction reached −14% with semaglutide 25 mg versus −2% with placebo. Nearly half of patients achieved at least 15% body-weight reduction. Quality-of-life scores also improved.
- Safety: Gastrointestinal effects such as nausea and diarrhea were more common, with nearly three-quarters of participants experiencing them. Still, the profile resembled other GLP-1 therapies.
These findings suggest the 25 mg oral dose approaches the efficacy of injectable semaglutide (Wegovy 2.4 mg), though the head-to-head comparison is not available.
#2 Orforglipron in Obesity: ATTAIN-1 Trial
The largest of the three studies, ATTAIN-1 enrolled over 3,100 adults with obesity but no diabetes. Participants received placebo or orforglipron at doses up to 36 mg daily for 72 weeks.
- Weight loss outcomes: At the highest dose, average weight reduction was −11% compared with −2% for placebo.
More than half of participants achieved ≥10% weight loss, over one-third achieved ≥15%, and nearly one-fifth reached ≥20%.
- Metabolic improvements: Waist size, triglycerides, non-HDL cholesterol, and blood pressure all improved.
- Safety: GI events were the most common reason for discontinuation, affecting 5–10% of participants.
These findings confirm orforglipron’s place as a credible oral option for obesity treatment.
#3 Orforglipron in Type 2 Diabetes: ACHIEVE-1 Trial
Orforglipron is structurally distinct, as a non-peptide, small-molecule GLP-1 receptor agonist. Unlike semaglutide, it does not require refrigeration or fasting dosing, which could improve patient adherence.
In ACHIEVE-1, 559 adults with early type 2 diabetes received placebo or orforglipron at multiple doses, with the maximum studied dose being 36 mg daily.
- Glycemic control: HbA1c reductions were robust, averaging −1.5% at the 36 mg dose, compared with −0.4% with placebo.
- Weight reduction: Weight loss reached −8% at 36 mg, versus −2% for placebo.
- Tolerability: Side effects were again mostly gastrointestinal. Discontinuation rates remained under 8%.
This positions orforglipron as a potentially valuable dual agent for weight and glucose control in early diabetes.
Comparison With Rybelsus 14 mg
Rybelsus (oral semaglutide 14 mg) is already FDA-approved for type 2 diabetes and sometimes used off-label for weight management. However, weight loss averages 4–6% at 14 mg, significantly lower than seen with newer trials.
- Semaglutide 25 mg: In OASIS-4, weight loss reached −14%, nearly triple the Rybelsus 14 mg effect.
- Orforglipron 36 mg: In ATTAIN-1, −11% weight loss was achieved, again well above Rybelsus outcomes.
- Clinical relevance: These data suggest that both orforglipron and higher-dose oral semaglutide (25 mg) may soon offer oral alternatives that match injectable GLP-1s in efficacy. This could reshape prescribing patterns for obesity and diabetes, especially for patients reluctant to use injections.
Patient Case Variations
- Sleep Apnea: A 42-year-old woman with BMI 34 and obstructive sleep apnea struggles with daily injections. Oral semaglutide 25 mg may provide an effective alternative, with weight loss exceeding 13%.
- Diabetes: A 58-year-old man with early type 2 diabetes and BMI 30 prefers pill-based therapy. Orforglipron 36 mg could improve his HbA1c by more than 1% while reducing body weight by 7%.
- PCOS A 35-year-old woman with BMI 38 and polycystic ovary syndrome may benefit from orforglipron 36 mg, with expected weight loss over 10% and metabolic improvements.
- CVD Risk: A 65-year-old man with BMI 32 and cardiovascular risk factors tried Rybelsus 14 mg with modest results. Transitioning to semaglutide 25 mg or orforglipron may provide stronger weight reduction and improve lipid and blood pressure control.
- Fatty Liver: A 50-year-old woman with BMI 29 and fatty liver disease could benefit from either oral option, with weight loss above 10% possibly reducing liver fat and inflammation.
Summary Table
| Trial | Oral Therapy | Max Dose Studied | Population | Duration | Mean Weight Loss | Key Points |
|---|---|---|---|---|---|---|
| OASIS-4 | Semaglutide | 25 mg/day | Obesity without diabetes | 64 wks | −14% | Stronger efficacy than Rybelsus 14 mg; GI side effects common |
| ATTAIN-1 | Orforglipron | 36 mg/day | Obesity without diabetes | 72 wks | −11% | Over half achieved ≥10% weight loss; improved metabolic markers |
| ACHIEVE-1 | Orforglipron | 36 mg/day | Early type 2 diabetes | 40 wks | −8% | Also reduced HbA1c by −1.5%; good option in diabetes care |
Key Takeaways
The landscape of oral GLP-1 therapies is shifting quickly. Oral semaglutide 25 mg and orforglipron both achieved double-digit weight loss in clinical trials, with results that approach the success of injectable therapies. Compared with Rybelsus 14 mg, these next-generation orals delivered far greater weight reduction.
For patients who prefer pill-based treatments, or who struggle with injections, these findings represent important progress. Gastrointestinal side effects remain the main limitation, though tolerability is consistent with other GLP-1s.
At our practice in Montgomery County, Maryland, we follow these research developments closely. By combining advanced therapies with personalized, holistic care, we aim to give patients practical, effective, and thoughtful options for long-term weight and metabolic health.
References:
- Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity. Wharton S, Lingvay I, Bogdanski P, et al. The New England Journal of Medicine. 2025;393(11):1077-1087. doi:10.1056/NEJMoa2500969.
- Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. Wharton S, Aronne LJ, Stefanski A, et al. The New England Journal of Medicine. 2025;393(24):2368-2379. doi:10.1056/NEJMoa2511774.
- Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. Rosenstock J, Hsia S, Nevarez Ruiz L, et al. The New England Journal of Medicine. 2025;393(19):1860-1873. doi:10.1056/NEJMoa2505669.
- Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. Wharton S, Blevins T, Connery L, et al. The New England Journal of Medicine. 2023;389(10):877-888. doi:10.1056/NEJMoa2302392.
- Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. McGuire DK, Marx N, Mulvagh SL, et al. The New England Journal of Medicine. 2025;392(20):2001-2012. doi:10.1056/NEJMoa2501006.
About Dr. Gerti Tashko, MD
Dr. Gerti Tashko, MD, is an endocrinologist in Montgomery County, Maryland. He is uniquely quadruple board-certified in endocrinology, lipidology, hypertension, and obesity medicine. His practice delivers root-cause-focused metabolic and endocrine care, available virtually and in person. He uses advanced diagnostics, personalized nutrition, and preventive medicine to improve long-term health.
