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

Kristin C C Petri, Steen H Ingwersen, Anne Flint, Jeppe Zacho, Rune V Overgaard, Kristin C C Petri, Steen H Ingwersen, Anne Flint, Jeppe Zacho, Rune V Overgaard

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.

Keywords: GLP-1; GLP-1 analogue; type 2 diabetes.

Conflict of interest statement

K.C.C.P., S.H.I., A.F., J.Z. and R.V.O. are employed by and hold stock in Novo Nordisk.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Semaglutide exposure and glycated haemoglobin (HbA1c). HbA1c change from baseline A, stratified by baseline HbA1c B, and treatment outcome in terms of absolute HbA1c after 30 weeks of treatment stratified by baseline HbA1c C, are shown vs semaglutide exposure. Data are mean values with 95% confidence interval (CI) vs exposure expressed as quantiles of Cavg, plus a value of 0 exposure assigned to participants treated with placebo. The sigmoidal curved lines through the data represent covariate‐adjusted model‐derived estimates for each population. Horizontal lines with diamonds along the x‐axis represent median and 95% exposure ranges for each dose level. To convert %‐points to mmol/mol, please use the following equation: IFCC (mmol/mol) = (10.93 * NGSP %‐points) ‐ 23.50. IFCC, International Federation of Clinical Chemistry and Laboratory Medicine; NGSP, National Glycohemoglobin Standardization Program; Cavg, average semaglutide concentrations at steady state
Figure 2
Figure 2
Semaglutide exposure and body weight. Data are mean values of body weight change from baseline with 95% confidence interval (CI) vs exposure expressed as 6 quantiles of Cavg A, or stratified by sex B, with four quantiles, plus a value of 0 exposure assigned to participants treated with placebo. The lines through the data represent covariate‐adjusted model‐derived estimates for each population. Horizontal lines with diamonds along the x‐axis represent median and 95% exposure ranges for each dose level. Cavg, average semaglutide concentrations at steady state
Figure 3
Figure 3
Semaglutide exposure and nausea. Data show the proportion of participants reporting nausea over time A, and vs exposure by week B, and the proportion of participants with nausea at any time vs steady‐state exposure by treatment C, and by sex D. Data in A are mean proportions for participants dosed with semaglutide 0.5 and 1.0 mg, respectively split into two quantiles with high/low exposures. Data in B‐D are mean response values with 95% confidence interval (CI) vs exposure expressed as quantiles of Cavg. The lines through the data represent covariate‐adjusted model‐derived estimates for each population. Horizontal lines with diamonds along the x‐axis represent median and 95% exposure ranges for each dose level. Cavg, average semaglutide concentrations at steady state

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