High-dose semaglutide (up to 16 mg) in people with type 2 diabetes and overweight/obesity: a randomized, placebo-controlled, phase 2 trial

Objective: Studies have demonstrated dose-dependent efficacy of glucagon-like peptide-1 receptor agonists on glycemic control and body weight. This trial aimed to characterize the dose-dependent effects of semaglutide (up to 16 mg/week) in people with type 2 diabetes and overweight/obesity.

Research Design and Methods: In this parallel-group, participant- and investigator-blinded, phase 2 trial (NCT05486065), 245 individuals with type 2 diabetes and BMI≥27 kg/m2 on metformin were randomized to weekly semaglutide s.c. (2, 8 or 16 mg) or placebo for 40 weeks. Doses were escalated every four weeks, followed by a maintenance period. Dose modifications were not allowed. Primary and secondary efficacy endpoints included change from baseline to week 40 in HbA1c and body weight, respectively.

Results: Estimated treatment difference between 16 and 2 mg was -0.3 %-points (95%CI -0.7 to 0.2; p=0.245) for HbA1c change and -3.4 kg (95%CI -6.0 to -0.8; p=0.011) for weight change for the treatment policy estimand and -0.5 %-points (95%CI -1.0 to -0.1; p=0.015) and -4.5 kg (95%CI -7.6 to -1.4; p=0.004), respectively, for the hypothetical estimand. Dose-response modelling confirmed these findings. The treatment-emergent adverse events (AEs) and treatment discontinuations due to AEs, primarily gastrointestinal, were more frequent in the semaglutide 8 and 16 mg groups compared to 2 mg. No severe hypoglycemic episodes were reported.

Conclusions: Higher semaglutide doses for type 2 diabetes and overweight/obesity provide modest additional glucose lowering effect, with additional weight loss, at the expense of more AEs and treatment discontinuations. A study evaluating high-dose semaglutide in obesity is currently underway.