For both diabetes and obesity, semaglutide was more effective at higher doses.

The oral formulation of the glucagon-like peptide-1 (GLP-1) inhibitor semaglutide is approved by the US Food and Drug Administration at doses as high as 14 mg daily for treating patients with type 2 diabetes. But unlike the subcutaneous form, the oral form is not approved for treating obesity in patients without diabetes. In two recent manufacturer-sponsored trials, researchers examined higher doses of oral semaglutide for diabetes and obesity.

In one study, researchers randomised 1600 patients with glycosylated haemoglobin (HbA_1c) of 8.0% to 10.5% (64 to 91mmol/mol) and body mass index (BMI) 25kg/m² or higher (mean BMI, 34 kg/m²) to receive oral semaglutide – 14 mg, 25 mg or 50 mg daily – in addition to their previous oral antidiabetic medications; patients who used insulin were excluded. After 52 weeks, mean changes in HbA_1c in the three groups were −1.5%, −1.8% and −2.0%, respectively; mean percentage changes in body weight were −4.7%, −7.3% and −8.5%, respectively.

The other study involved only patients without diabetes. Researchers randomised 600 patients with BMI 30 kg/m² or higher, or BMI 27 kg/m² or higher plus weight-related complications other than diabetes, to receive oral semaglutide (escalated to 50 mg daily) or placebo, in addition to lifestyle intervention. At baseline, mean BMI was 38kg/m². After 68 weeks, mean changes in body weight were −15% and −2% with semaglutide and placebo, respectively; 54% of patients who took semaglutide, compared with 6% of those who took placebo, lost 15% or more of their baseline body weight.

In both studies, the most frequent adverse effects were mild-to-moderate nausea, vomiting, and diarrhoea, primarily during dose escalation. 

Comment: Doses of oral semaglutide higher than those currently approved appear to be tolerated reasonably well and to be increasingly effective for short-term management of both diabetes and obesity as dosages increase. Notably, weight loss was substantially greater in patients without diabetes than in those with diabetes.

Bruce Soloway, MD, Associate Professor Emeritus of Family and Social Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

Aroda VR, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet 2023; 402: 693-704.

Knop FK, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023; 402: 705-719.

This summary is taken from the following Journal Watch titles: General Medicine, Ambulatory Medicine.