Higher dose oral semaglutide shown to produce remarkable weight loss and/or reduce Hba1c levels in overweight and obese patients with or without type 2 diabetes

Semaglutide is a GLP-1 analogue peptide which has been used and approved to treat overweight, obesity or type 2 diabetes for many years as a once weekly subcutaneous injections. The oral formulation of semaglutide (Rybelsius) is also now available and currently approved at a maximum dose of 14 mg/day. In a previous phase 2 dose ranging studies however, additional weight loss was observed at doses higher than 14 mg/day. Two trials—the OASIS, in patients with overweight or obesity without type 2 diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were therefore conducted to evaluate the efficacy and safety of higher doses of oral semglutide at 25 and 50 mg/day to induce weight loss and improvement of other metabolic parameters. Both phase-3 studies were presented at the American Diabetes Association (ADA) 83rd Scientific Sessions and simultaneously published in The Lancet. OASIS-1^[1] showed that oral semaglutide 50 mg produced a mean % weight reduction of 15.1% compared with −2.4% with placebo. Adverse events were marginally more frequent with oral semaglutide, driven by largely gastrointestinal side effects (80% with oral semaglutide vs. 46% with placebo) and gall bladder and biliary related disorders (11.1% with oral semaglutide vs. 3.6% with placebo). The PIONEER PLUS trial^[2] meanwhile showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 and 50 mg) compared with the currently [highest] approved 14-mg dose. Hba1c reduction was reduced by −1.5%, −1.8% and −2.0% with oral semaglutide 14, 25 and 50 mg, respectively. These two studies therefore showed the safety and efficacy of oral semaglutide to treat obesity and type 2 diabetes, with results comparable to the use of injectable semaglutide 2.4 mg once weekly. Due to the lack of availability of injectable semaglutide worldwide, it is thought that availability of an efficacious ‘pill’ might have a larger global reach and increase access to care as well as provide opportunities to individualized care especially for individuals who struggle with the use of injectable therapies. However, its effect on reducing cardiovascular outcomes remains unclear. Studies are ongoing to clarify this important clinical and research question.