How does oral semaglutide work and what does the evidence show?

Oral semaglutide is a GLP-1 receptor agonist formulated with an absorption enhancer (SNAC) so a small amount can cross the stomach lining. In the Phase 3 OASIS-4 trial, 25 mg daily led to about 13–16% weight loss over 64 weeks in adults with overweight or obesity.

How does oral semaglutide compare with injectable semaglutide?

Both forms have similar GI side effects and safety warnings. Injectables (2.4 mg weekly) showed ~14.9% mean weight loss at 68 weeks in STEP-1. Oral 25 mg daily showed ~13–16% weight loss at 64 weeks in OASIS-4. No direct head-to-head trials exist.

If Rybelsus already exists, why another oral version?

Rybelsus is approved for type 2 diabetes at 3–14 mg, too low for meaningful weight loss. Obesity trials use 25 mg daily to achieve drug exposure similar to injections.

Why might FDA approval improve access compared to compounded oral semaglutide?

Compounded oral doses are often too low or cost-prohibitive at effective strengths, and quality can vary. FDA approval would standardize dosing, ensure manufacturing quality, and may encourage insurance coverage, making effective oral therapy safer and more affordable.

Who might qualify for oral semaglutide if approved?

Likely adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related condition. Insurance coverage would probably mirror Wegovy’s, depending on payer and state.

Oral Semaglutide 25 mg: Efficacy, Safety, and What FDA Review Means for Weight Loss

Creator: Dr. Joshua Silva, MD
Published: 2025-09-25

Joshua Silva, MD
Oct 30
4 min read

In 2025, oral semaglutide is on the brink of a major shift: the FDA has accepted a New Drug Application (NDA) for a daily 25 mg pill version of Wegovy (semaglutide) for weight management. If approved, this would be the first oral GLP-1 medication intended for chronic obesity care.

But before we get ahead of ourselves, here’s what patients should know about efficacy, dosing challenges, safety, and how this might change access to GLP-1 therapy.

Note: This article does not reference data from the ATTAIN-1 trial, which is ongoing and evaluating oral semaglutide for adults with overweight or obesity and type 2 diabetes.

The Challenge of Oral Versions of Semaglutide

Oral peptides face absorption hurdles — food, gastric pH, and gastric emptying all impact absorption. Oral semaglutide is absorbed very poorly, leading to low bioavailability. Only 1% of Rybelsus® (the currently FDA-approved oral form for type 2 diabetes) actually reaches the bloodstream.

In contrast, the bioavailability of injectable semaglutide (Ozempic® & Wegovy®) is about 89%.

How Oral Semaglutide Compares With Injectable Wegovy® (Dose, Frequency, Results)

Semaglutide is a GLP-1 receptor agonist. Injected forms already approved for diabetes (Ozempic®) and obesity (Wegovy®) are given as once-weekly subcutaneous injections.

To improve absorption, oral semaglutide is formulated with an absorption enhancer (SNAC), allowing it to cross the stomach lining more efficiently and enter the bloodstream.

The STEP-1 clinical trial showed that once-weekly 2.4 mg injectable semaglutide produced an average 14.9% weight loss over 68 weeks.
In the Phase 3 OASIS-4 trial, adults taking 25 mg oral semaglutide daily achieved an average 13.6% weight loss over 64 weeks.

Table comparing injectable versus oral semaglutide for weight loss: STEP-1 trial (2.4 mg weekly injection, 14.9% weight loss at 68 weeks) vs OASIS-4 trial (25 mg daily oral, 13.6% weight loss at 64 weeks).

If Rybelsus® (oral semaglutide) Already Exists, Why Do We Need Another Oral Version?

Rybelsus® is FDA-approved oral semaglutide for type 2 diabetes at doses too low to produce significant weight loss (3 mg, 7 mg, and 14 mg) and is not approved for obesity. For weight management, clinical trials have tested higher daily doses (e.g., 25 mg) to achieve drug exposure levels closer to those of injectable semaglutide.

Where Does Compounded Oral Semaglutide Fall Short—and How Could FDA Approval Help?

You may have noticed that compounded oral semaglutide is already offered by various online distributors. However, the dosing is usually far too low to be effective for weight loss. For example, one site lists availability of 3 mg, 6 mg, and 9 mg oral capsules, while another pharmacy sells a liquid form with concentrations ranging from 1.25 to 7.5 mg per mL in 4 mL vials. Providing a patient with enough medication to reach an effective therapeutic dose quickly becomes cost-prohibitive.

Future FDA approval of an oral semaglutide product could help standardize dosing to effective yet safe amounts and make treatment more affordable for patients who cannot tolerate injections or commercial preparations.

How Do Side Effects Compare Between Oral and Injectable Semaglutide?

No head-to-head trials have directly compared the two methods of administration, so no firm statistical conclusions can be made.

However, they have very similar gastrointestinal side-effect profiles, including nausea, diarrhea, vomiting, constipation, abdominal pain, and decreased appetite.

Serious risks and warnings are also shared: a boxed warning for thyroid C-cell tumors, as well as risks of pancreatitis, gallbladder disease, acute kidney injury (usually related to dehydration), and worsening diabetic retinopathy in some populations.

Who might qualify for oral semalgutide (if FDA approved)?

Clinically Qualifications:

This will likely include Adults with obesity (BMI ≥30) or overweight (BMI ≥27) with a weight-related comorbidity—mirroring obesity indications used for injectable semaglutide and reflected in oral-dose obesity trials (e.g., OASIS-4 enrolled adults with overweight/obesity without diabetes). Final criteria will depend on FDA labeling if approved.

Insurance Qualifications:

Coverage usually follows the FDA indication plus each plan’s criteria (BMI thresholds, comorbidities, prior authorization). If approved, expect patterns similar to Wegovy’s coverage, with variability by payer and state.

Disclaimer: This article is for educational purposes only and is not a substitute for professional medical advice.

Interested in learning more about oral or injectable semaglutide? Book a consultation at Potere Health MD in St. George or Cedar City, Utah today.

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About the Author

Dr. Joshua Silva, MD, is a licensed physician and Medical Director of Potere Health MD. He completed residency training in Occupational and Environmental Medicine from the University of Utah and now specializes in evidence-based weight management, including GLP-1/GIP therapies (semaglutide, tirzepatide). Dr. Silva provides in-person and virtual care for patients throughout Utah.

Sources:

PR Newswire. FDA Accepts Filing Application for Oral Semaglutide 25 mg, Which if Approved Would Be the First Oral GLP-1 Treatment for Obesity. Available at: 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
Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine. 2021;384:989-1002. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
OASIS-4 Investigators. Oral Semaglutide 25 mg for Weight Management in Adults with Overweight or Obesity. New England Journal of Medicine. 2025. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2500969
FDA Clinical Pharmacology Review for Oral Semaglutide (Rybelsus). NDA 213051. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213051Orig1s000ClinPharmR.pdf
Granhall C, et al. Oral Semaglutide: A Review of the First Oral GLP-1 Receptor Agonist. Diabetes Ther.2020;11(6):1347-1362. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC7364672/
FDA Prescribing Information (Rybelsus®). 2024 update. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213051s018lbl.pdf
FDA Prescribing Information (Wegovy®). 2023 update. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215256s007lbl.pdf