Exposure-response analysis for evaluation of semaglutide dose levels in type 2 diabetes

Abstract

Aims: To evaluate dose levels for semaglutide, a glucagon-like peptide-1 analogue approved for the treatment of type 2 diabetes, by examining the effects of demographic factors on efficacy and safety in an exposure-response analysis. Methods: We analysed data from 1552 adults from four randomized phase III trials of 30 to 56 weeks' duration, investigating once-weekly semaglutide doses 0.5 and 1.0 mg. Exposure-response relationships were investigated using graphical and model-based techniques to assess the two dose levels and subgroups with the highest and lowest exposure and response. Results: The population had the following demographic characteristics: baseline mean age between 53.2 and 58.4 years, glycated haemoglobin (HbA1c) between 64 and 67 mmol/mol (8.0% and 8.3%), body weight between 71.3 and 96.2 kg, and diabetes duration between 4.2 and 8.9 years. Exposure-response analysis showed a clear HbA1c and weight reduction across exposures after 30 weeks, irrespective of baseline values. The exposure-response for HbA1c was influenced by baseline HbA1c, and body weight exposure-response was influenced by sex, with limited impact of other factors. Analyses for relevant subgroups of baseline body weight, baseline HbA1c and sex indicated clinically relevant additional benefits with regard to HbA1c and weight with 1.0 vs 0.5 mg semaglutide. The proportion of participants reporting gastrointestinal (GI) side effects increased with increasing exposure, but was counteracted by tolerance development. Conclusions: The analysis showed that all subgroups obtained a clinically relevant benefit with semaglutide 0.5 mg and an additional benefit with semaglutide 1.0 mg. The increase in GI side effects with higher exposure was mitigated by gradually increasing the dose.