Written By: Divyanjali Godage BPharm
Reviewed By: Pharmacally Editorial Team
The OASIS-4 phase 3 trial conducted by Novo Nordisk and published in the New England Journal of Medicine shows that once-daily oral semaglutide 25 mg produces clinically significant weight loss (mean weight loss 13.6% vs −2.2% with placebo at week 64). This degree of weight loss, Semaglutide has already shown in the pivotal STEP trials of once-weekly subcutaneous 2.4 mg dosage (about 14.9% at 68 weeks). The data suggest oral semaglutide 25 mg could be a viable alternative for many patients, but it is not an uncomplicated one-to-one substitute. Important differences in dosing, pharmacology, trial context, tolerability and real-world adherence mean doctors should weigh these differences and wait for more approval and real-world data before treating them as the same.
OASIS-4 Trial
OASIS-4 was a randomized, double-blind, placebo-controlled phase 3 trial of 71 weeks with co-primary analysis at week 64. Trial enrolled adults without diabetes who had BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity. Participants received once-daily oral Semaglutide 25 mg or placebo, combined with lifestyle intervention. Co-primary endpoints were percent change in body weight and the proportion achieving ≥ 5% weight loss; secondary endpoints included higher responder thresholds (≥10%, ≥15%, ≥20%) and a quality-of-life physical function score.
Main efficacy results
A total of 205 participants were randomized to the oral semaglutide group, while 102 were assigned to the placebo group.
Mean weight change at week 64: −13.6% with oral semaglutide 25 mg vs −2.2% with placebo (estimated difference-11.4 percentage points)
Responder rates: Oral semaglutide significantly increased the proportions achieving ≥5%, ≥10%, and ≥15% and ≥20% weight loss versus placebo.
Safety: gastrointestinal adverse events were common with oral semaglutide (74.0% vs 42.2% with placebo) and drove many discontinuations; overall serious adverse events were uncommon but must be reviewed in full text for details
OASIS-4 Trial (25 mg) x STEP Trial (2.4 mg)
The STEP trials that formed the evidence base for the once-weekly subcutaneous semaglutide 2.4 mg (Wegovy) showed mean weight reductions in the range of around 14.9% to 17% at 68 weeks in adults without diabetes. On the other hand Semaglutide oral form shows weight loss around 13.6 % at 64 week. This result place the oral semaglutide in the same basket with once weekly injection form. This mean percent weight loss after 1 year is comparable between the oral 25 mg data from OASIS-4 and the STEP results for 2.4 mg weekly, at least in the controlled trial setting.
Important pharmacologic and practical differences
Route and formulation / absorption issues
Since semaglutide is a peptide, it can be broken down in the stomach by proteolytic enzymes, which limits its natural bioavailability. To overcome this, the oral tablet is combined with an absorption enhancer (SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate) that helps enough of the drug to reach the bloodstream. This co-formulation means the pill has to be taken in a specific way and the amount absorbed can vary more than with the injection. In practice, oral semaglutide must be taken on an empty stomach with a small amount of water and patients must wait (normally more than 30 minutes) before eating or taking other oral medications that schedule can reduce convenience and affect adherence.
Dosing frequency and adherence patterns
Daily pills and weekly injections have pros and cons. For some patients, a daily routine pill improves adherence; however a weekly injection reduces the daily burden and removes strict timing constraints like no fasting requirement and wait for 30 min after dose. Real-world adherence and persistence often differ from trials and will matter for long-term outcomes.
Tolerability profile
Both formulations cause gastrointestinal side effects (nausea, vomiting, diarrhea, constipation), but the incidence and pattern may differ. In OASIS-4, gastrointestinal side effects were reported in about 74% of participants taking oral semaglutide, compared with 42% in the placebo group.
Bioavailability variability and drug interactions
Oral peptide absorption can vary by gastric pH, gastric emptying, and co-medications. The injectable formulation bypasses the gut and gives more predictable pharmacokinetics. This matters especially in patients on multiple oral drugs or with GI conditions. Regulatory labels for oral semaglutide already instruct specific fasting/timing rules for similar oral formulations.
So can the oral 25 mg substitute the weekly 2.4 mg?
For people who prefer pills or find injections difficult, oral semaglutide 25 mg could be a good option if it gets approved and is affordable. The weight loss seen in OASIS-4 was close to the results from the STEP trials with the weekly injection, so patients who take the pill as directed may expect similar benefits.
Reasons to avoid automatic substitution
Head-to-head data are limited. OASIS-4 compared oral semaglutide to placebo; it did not randomize participants against the injectable 2.4 mg formulation in the same trial.
Oral dosing requires fasting and has higher variability in exposure; some patients may get less benefit or more GI side effects in real life.
Individual tolerability and adherence will determine which route works best for a given patient. Some patients do better with weekly injections because they avoid daily GI triggers and timing burdens. Others prefer pills and accept the fasting rule.
Final summary
The OASIS-4 NEJM study establishes that oral semaglutide 25 mg produces significant and clinically important weight loss. This result is almost as strong as those seen with the once-weekly 2.4 mg injection in clinical trials. For many patients the oral semaglutide option will be convenient and evidence-backed alternative but practical differences in absorption, dosing logistics, tolerability and the absence of direct head-to-head trial make two formulations not yet substitutable for every patient. Physician should personalize the therapy and counsel patients on administration and side effects before prescribing them.
References
Sean Wharton, Ildiko Lingvay, Pawel Bogdanski, et al, Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity, N Engl J Med 2025;393:1077-1087 DOI: 10.1056/NEJMoa2500969
Aroda VR, Blonde L, Pratley RE. A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes. Rev Endocr Metab Disord. 2022 Oct; 23(5):979-994. Doi: 10.1007/s11154-022-09735-8. Epub 2022 Jul 15. PMID: 35838946; PMCID: PMC9515042.
Highlights of prescribing information, RYBELSUS (semaglutide) tablets, for oral use
Novo’s Wegovy pill close to matching injectable version in weight-loss trial, 18 September 2025, Financial Times, https://www.ft.com/content/44ceb964-cb6a-44b4-817e-d3c2a26d4ba4
Colin IM, Gérard KM. Once-weekly 2.4 mg Semaglutide for Weight Management in Obesity: A Game Changer? touchREV Endocrinol. 2022 Jun;18(1):35-42. Doi: 10.17925/EE.2022.18.1.35. Epub 2022 Jun 15. PMID: 35949360; PMCID: PMC9354513.