PMID-40934115 — OASIS 4: Oral Semaglutide 25 mg in Overweight/Obesity (Phase 3)

[DRAFT — authored 2026-04-19. Citation verified against PubMed/NEJM 2026-04-19.]

Citation

Wharton S, Lingvay I, Bogdanski P, Duque do Vale R, Jacob S, Karlsson T, Shaji C, Rubino D, Garvey WT; OASIS 4 Study Group. 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. PMID: 40934115. NCT05564117.

External URL: PubMed

Study Design

Design: Phase 3, 71-week, double-blind, randomized, placebo-controlled trial
Setting: 22 sites in 4 countries
Population: Adults without diabetes; BMI ≥30 kg/m² OR BMI ≥27 with ≥1 obesity-related complication
N: 307 (sem 25 mg: 205; placebo: 102) — 79% women, 92% White, mean age 48 years
Intervention: Oral semaglutide 25 mg once daily (12-week dose escalation) vs placebo; 64 weeks on therapy + 7-week off-treatment follow-up
Adjunct: Lifestyle interventions (diet + physical activity)
Primary endpoint: Percent change in body weight from baseline to week 64

Key Findings

Body weight change at week 64

Oral semaglutide 25 mg: Estimated mean change −13.6% (treatment-policy estimand)
Placebo: −2.2%
Treatment difference: −11.4 percentage points (95% CI −13.2 to −9.6, P<0.001)
With full treatment adherence (trial-product estimand): Oral sem 25 mg produced −16.6% mean weight loss vs −2.7% placebo

Categorical weight-loss outcomes

Proportion achieving ≥5%, ≥10%, ≥15%, ≥20% weight loss: all significantly higher with oral sem 25 mg vs placebo (all P<0.001)

Secondary endpoints

Physical function: Improvements vs placebo
Cardiometabolic risk factors: Improvements in waist circumference, BP, lipids, glucose

Safety

GI adverse events most common; dose-dependent; consistent with class
No new safety signals specific to the 25 mg oral dose
No unexpected hepatic, cardiovascular, or other safety concerns

Clinical Relevance

OASIS 4 is the pivotal Phase 3 trial supporting FDA approval of oral semaglutide 25 mg for chronic weight management (oral Wegovy). Core teaching points:

Oral sem 25 mg weight-loss magnitude approaches injectable sem 2.4 mg — OASIS 4 achieved −13.6% (treatment-policy) / −16.6% (adherent) weight loss at 64 weeks, comparable to STEP 1's −14.9% at 68 weeks for injectable sem 2.4 mg.
Addresses the injection-averse population — provides a pill alternative for patients declining weekly injections; major access/equity implication.
Not equivalent to injectable Wegovy — different PK, different food/water timing requirements (must be taken on empty stomach with ≤120 mL water, 30-min fast before next food/drink), less weight-loss-maximum than injectable 2.4 mg.
Complements OASIS 1 (PMID: 37385278) — OASIS 1 was 50 mg oral sem for obesity. OASIS 4 establishes 25 mg as the clinically preferred dose for chronic weight management balancing tolerability and efficacy.
FDA approval: August 2025 FDA approval of oral Wegovy for chronic weight management follows OASIS 4 publication.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (oral formulation section; oral Wegovy narrative)
Lesson 5.4 — Oral pharmacotherapy options

Related Studies

PMID-37385279 – PIONEER PLUS Aroda Oral Semaglutide 25mg 50mg T2D — PIONEER PLUS in T2D population
PMID-37385278 – OASIS 1 Oral Semaglutide 50mg for Obesity — OASIS 1 predecessor
PMID-40162642 – SOUL Oral Semaglutide CV Outcomes — oral sem 14 mg CV outcomes

PMID-40934115 – OASIS 4 Wharton Oral Semaglutide 25mg Obesity