OASIS 4 Trial: Oral Semaglutide 25mg Delivers 13.6% Weight Loss

OASIS 4 (NCT05564117) is a Phase 3b randomized, double-blind, placebo-controlled trial of oral semaglutide 25 mg once daily in adults with overweight or obesity without type 2 diabetes. The trial was sponsored by Novo Nordisk and enrolled 307 participants across sites in the United States, Canada, and Europe. Participants were randomized 2:1 to receive oral semaglutide 25 mg or matching placebo, with both arms receiving concurrent lifestyle intervention.

The 64 week trial duration included a 16 week dose-escalation phase and a 48 week maintenance phase. The primary endpoint was percentage change in body weight from baseline to week 64 and the proportion of participants achieving at least 5 percent weight reduction. The trial was designed to evaluate whether the 25 mg oral dose could approach the efficacy of subcutaneous semaglutide 2.4 mg (Wegovy) from the STEP program.

The primary endpoint was met with statistical significance. Participants randomized to oral semaglutide 25 mg achieved a mean body weight reduction of 13.6 percent from baseline at week 64, compared with 2.2 percent in the placebo arm. The estimated treatment difference of 11.4 percentage points (95 percent confidence interval 10.1 to 12.7) was highly statistically significant.

This result is notable because it represents the first oral GLP-1 therapy to achieve weight reductions in the same efficacy tier as subcutaneous injectable GLP-1 and GLP-1/GIP agonists. Prior oral semaglutide formulations at 14 mg have typically produced 4 to 6 percent weight reduction in non-diabetic obesity populations, so the 25 mg dose represents a meaningful efficacy step increase.

The coprimary responder endpoint showed that 79.2 percent of participants randomized to oral semaglutide 25 mg achieved at least a 5 percent reduction in body weight by week 64, compared with 31.1 percent in the placebo arm. Additionally, 64.8 percent achieved at least 10 percent weight reduction, 49.5 percent achieved at least 15 percent, and 24.1 percent achieved at least 20 percent weight reduction.

Secondary endpoints including waist circumference, systolic blood pressure, fasting plasma glucose, HbA1c, C-reactive protein, and fasting lipid profile all improved in a manner consistent with the STEP program data for subcutaneous semaglutide 2.4 mg. Patient-reported outcomes measured by the IWQOL-Lite-CT instrument showed significant improvements in physical function.

Oral semaglutide is formulated with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, commonly referred to as SNAC. SNAC acts as a permeation enhancer in the stomach by transiently and locally increasing the pH and forming a protective microenvironment around the peptide, which protects semaglutide from gastric degradation and promotes its transcellular absorption through the gastric epithelium.

The absolute oral bioavailability of semaglutide delivered via SNAC-based tablets is approximately 0.4 to 1 percent. Because absorption is highly sensitive to stomach contents and fluid volume, the product labeling requires administration with no more than 120 mL of plain water, at least 30 minutes before the first food, beverage, or other oral medication of the day. Deviation from this protocol can reduce systemic exposure by 30 to 40 percent.

In OASIS 4 the dose-escalation schedule was 3 mg for 4 weeks, 7 mg for 4 weeks, 14 mg for 4 weeks, then 25 mg for the remaining 52 weeks, consistent with the Novo Nordisk dose-titration approach used to mitigate gastrointestinal adverse events. The escalation strategy is intended to allow gradual adaptation of gastric emptying and gastrointestinal motility to GLP-1 receptor stimulation.

Participants were instructed to take the tablet immediately upon waking with no more than 120 mL of water and to wait at least 30 minutes before consuming food, beverages, or other oral medications. Adherence to this protocol was monitored through structured electronic diary entries.

Adverse events were consistent with the established class profile of GLP-1 receptor agonists. Nausea was reported by 35.4 percent of participants on the 25 mg dose versus 10.7 percent on placebo, diarrhea by 24.2 percent versus 9.7 percent, constipation by 22.9 percent versus 11.7 percent, and vomiting by 17.9 percent versus 2.9 percent. Most gastrointestinal events were mild to moderate in severity and occurred during dose escalation.

Serious adverse events occurred in 5.9 percent of participants on oral semaglutide versus 3.9 percent on placebo. Adverse event-related discontinuations were 7.4 percent versus 2.9 percent respectively. No new safety signals were identified compared with the established semaglutide safety profile across the SUSTAIN, PIONEER, STEP, and SELECT programs.

The OASIS program comprises OASIS 1 (50 mg oral semaglutide in obesity), OASIS 2 (50 mg in East Asian population), OASIS 3 (50 mg 68-week data), and OASIS 4 (25 mg dose). OASIS 1 reported in 2023 that oral semaglutide 50 mg produced 15.1 percent mean weight reduction at 68 weeks, establishing the proof of concept that very high oral doses could approximate subcutaneous efficacy.

OASIS 4 was designed to identify the minimum effective dose that achieves clinically meaningful weight reduction while preserving a manageable tolerability profile and acceptable tablet size. The 25 mg dose emerged as the regulatory submission dose for the obesity indication, while the 14 mg dose remains the diabetes-indicated dose.

Based on the OASIS program data, the U.S. Food and Drug Administration approved oral semaglutide 25 mg for chronic weight management in December 2025 under the trade name Wegovy (oral). Commercial availability in the United States began in January 2026, positioning Novo Nordisk as the first company to market a high-dose oral GLP-1 therapy for obesity.

Novo Nordisk announced that the oral Wegovy formulation would be sold in parallel with the subcutaneous Wegovy 2.4 mg injection and with Rybelsus 14 mg for diabetes. The company positioned the oral option primarily for patients with injection aversion or for whom subcutaneous administration presents adherence or logistical barriers. The 2026 launch preceded the expected approval of Eli Lilly orforglipron (Foundayo) by approximately five months.

The OASIS 4 data establish that peptide GLP-1 agonists can achieve injectable-tier efficacy via oral administration when SNAC-enhanced formulations are dosed at 25 mg or higher. This is a material scientific and commercial result even in the context of emerging non-peptide oral GLP-1 agonists such as orforglipron, because it preserves the full pharmacology of semaglutide including established cardiovascular outcomes data from SELECT and FLOW.

From a research peptide perspective, OASIS 4 also validates high-dose SNAC formulations as a viable delivery platform for other peptide therapeutics and may accelerate oral formulation development for amylin analogs, GIP agonists, and dual- and triple-agonist peptides currently in clinical development.