Similar efficacy and gastrointestinal tolerability versus exposure for oral and subcutaneous semaglutide
RV Overgaard, A Navarria, CL Hertz, SH Ingwersen
Novo Nordisk
Objectives:
Semaglutide is a glucagon-like peptide-1 analogue formulated both as an approved once-weekly subcutaneous (s.c.) injection and a once-daily oral tablet in development for the treatment of type 2 diabetes (T2D). The s.c. and oral formulations have been studied across a series of clinical trials in the SUSTAIN and PIONEER programmes, respectively. The long half-life and daily dosing with oral semaglutide mitigate variability in absorption, leading to stable steady-state exposure levels. Nevertheless, the plasma concentrations are more variable with oral compared with s.c. administration.
The objective of the analysis was to apply population PK and exposure-response data from the SUSTAIN and PIONEER trials, to inform whether the route of administration affected the efficacy and gastrointestinal (GI) tolerability vs exposure for semaglutide.
Methods:
PK and response data were compared from:
- Four trials (SUSTAIN 1, 2, 3 and SUSTAIN-Japan) of once-weekly s.c. semaglutide 0.5 and 1.0 mg evaluated after 30 weeks.
- Six trials (PIONEER 1, 2, 3, 5, 8 and 9 [PIONEER 9 conducted in Japan]) of once-daily oral semaglutide 3, 7 or 14 mg given for 26 weeks.7–12
Population pharmacokinetic model: A population pharmacokinetic (PK) model was developed for each PIONEER and SUSTAIN dataset.13
For HbA1c and body weight change from baseline, the data were adequately described by maximum response (Emax) models with baseline HbA1c, sex and trial population as main influential factors, and additional effects of diabetes duration, race and ethnicity.
For binary safety endpoints (proportions of patients with nausea and vomiting, respectively), linear models on the logit scale were used. The main influential factors were sex and trial population.
Propensity score matching: Overall the PIONEER and SUSTAIN exposure–response populations were similar, with the main difference being the inclusion of a dedicated study of patients with moderate renal impairment and a trial with concomitant insulin treatment in the PIONEER programme. Propensity score matching was used to analyse the effect of balancing the differences between the SUSTAIN and PIONEER populations based on baseline HbA1c,trial population, diabetes duration, race, ethnicity and sex.
Results:
Before matching, data from 1552 patients from SUSTAIN and 3003 patients from PIONEER were included. After matching, both datasets contained 1551 patients with well-matched characteristics, although the SUSTAIN population contained more Asian patients and more patients with mild renal impairment (Table 1).
Population PK analysis indicated dose-proportional PK profiles for both oral and s.c. semaglutide, with body weight the main factor influencing exposure.
The exposure range was wider with oral vs s.c. administration, but with considerable overlap between oral semaglutide 7 and 14 mg, and s.c. semaglutide 0.5 and 1.0 mg, indicating consistent exposure across formulations.
Exposure–response analyses showed greater HbA1c and body weight reductions, and more GI side effects, with increasing semaglutide exposure.
Conclusions: Exposure–response relationships for efficacy and safety were consistent across the SUSTAIN and PIONEER datasets, and even more consistent with overlapping 95% confidence intervals when propensity matching was used.
[1] Presented at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD), Barcelona, Spain, 16–20 September 2019.
[2] Published as: Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes, Overgaard et. al. 2021. Cell Reports Medicine.