Oral semaglutide 25 mg once daily was associated with significant weight loss vs. placebo, comparable with that seen with the 50 mg oral dose and with the subcutaneous (SC) injectable version of the drug, according to new results from the phase 3 OASIS 4 trial, published Sept. 17 in NEJM.

Sean Wharton, MD, et al., randomly assigned 307 patients (79% women; 92% White; mean age, 48 years) without diabetes and with overweight or obesity to oral semaglutide 25 mg (n=205) or placebo (n=102) once daily, plus lifestyle interventions. The trial included a 12-week dose escalation and a seven-week off-treatment follow-up, spanning 71 weeks with 64 weeks on therapy.

Results showed that the primary endpoint of estimated mean change in body weight at week 64 was significantly greater with oral semaglutide 25 mg vs. placebo (−14% vs. −2%; p<0.001). Weight loss was similar across baseline BMI subgroups.

Notably, the reduction in body weight was similar with that seen in OASIS 1 where it was 12.7 percentage points more with oral semaglutide 50 mg than placebo and with STEP 1 where it was 12.4 percentage points more with 2.4 mg subcutaneous semaglutide weekly than placebo.

In the present study, body weight reductions of ≥5%, ≥10%, ≥15% and ≥20% were significantly more likely in the oral semaglutide group vs. placebo (p<0.001 for all comparisons). Notably, 30% of the oral semaglutide group achieved ≥20% weight loss vs. 3% of the placebo group.

Findings also revealed that physical function, measured by Impact of Weight on Quality of Life–Lite Clinical Trials (IWQOL-Lite-CT) Version Physical Function score, significantly improved with oral semaglutide vs. placebo (16 points vs. 8 points; p<0.001). Cardiometabolic risk factors such as BMI, waist circumference, glycated hemoglobin levels, lipids and C-reactive protein improved as well.

The safety profile was consistent with other GLP-1 medications. The most frequent adverse events were gastrointestinal (74% with oral semaglutide vs. 42% with placebo) and were typically mild to moderate and transient. Adverse events leading to discontinuation occurred in 7% of the oral semaglutide group vs. 6% of the placebo group.

Wharton and colleagues write that "oral semaglutide at a dose of 25 mg may enhance the flexibility of the treatment strategy for overweight and obesity by providing an alternative dose for the oral molecule as well as an alternative to subcutaneous semaglutide at a dose of 2.4 mg."