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Similar efficacy and gastrointestinal tolerability versus exposure for oral and subcutaneous semaglutide

Rune Overgaard (RUVO@novonordisk.com),1 Andrea Navarria,1 Christin Hertz,1 Steen Ingwersen1

1Novo Nordisk A/S, Søborg, Denmark

 

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Similar efficacy and gastrointestinal tolerability versus exposure for oral and subcutaneous semaglutide

 

Video

Poster Slides

Aim

  • Semaglutide is a glucagon-like peptide-1 analogue formulated both as a once-weekly subcutaneous (s.c.) injection and a once-daily oral tablet for the treatment of type 2 diabetes.1,2
  • An exposure–response analysis investigated the effect of administration route on the efficacy and gastrointestinal (GI) tolerability of semaglutide vs exposure.

Methods

  • Response data were compared from:
    • Four SUSTAIN trials of once-weekly s.c. semaglutide 0.5 and 1.0 mg over 30 weeks.3–6
    • Six PIONEER trials of once-daily oral semaglutide 3, 7 or 14 mg over 26 weeks.7–12
  • A population pharmacokinetic (PK) model was developed for each PIONEER and SUSTAIN dataset.13
  • Glycated haemoglobin (HbA1c) and body weight change from baseline data were adequately described by maximum response (Emax) models.
  • Linear models on the logit scale were used for the proportions of patients with GI side effects (nausea or vomiting).
  • Propensity score-matching was used to analyse the effect of balancing population differences between datasets.

Results

  • The SUSTAIN and PIONEER datasets both contained 1,551 patients with well-matched characteristics (see supplementary materials).
  • Oral and s.c. semaglutide PK profiles were dose-proportional, 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.
  • There were greater HbA1c and body weight reductions, and more GI side effects, with increasing semaglutide exposure.
  • Exposure–response relationships for efficacy and safety were consistent across the SUSTAIN and PIONEER datasets, with overlapping 95% confidence intervals when propensity matching was used (Figure; see supplementary materials for unmatched data).

Conclusions

Oral and s.c. semaglutide have similar efficacy and GI safety profiles vs exposure

Propensity matching helped to confirm that the differences between trial populations did not influence the exposure–response evaluation

Increasing semaglutide exposure is associated with greater efficacy and an increased proportion of patients reporting GI side effects

References
(1) Buckley ST, et al. Sci Transl Med 2018;10:eaar7047;
(2) Aroda VR, et al. Diabetes Metab 2019;45:409–18;
(3) Seino Y, et al. Diabetes Obes Metab 2018;20:378–88;
(4) Sorli C, et al. Lancet Diabetes Endocrinol 2017;5:251–60;
(5) Ahrén B, et al. Lancet Diabetes Endocrinol 2017;5:341–54;
(6) Ahmann AJ, et al. Diabetes Care 2018;41:258–66;
(7) Aroda VR, et al. Diabetes Care 2019;42:1724–32;
(8) Rodbard HW, et al. Diabetes Care 2019;42:2272–81;
(9) Rosenstock J, et al. JAMA 2019;321:1466–80;
(10) Mosenzon O, et al. Lancet Diabetes Endocrinol 2019;7:515–27;
(11) Zinman B, et al. Diabetes Care 2019;42:2262–71;
(12) Yamada Y, et al. J Diabetes Investig 2019;10(suppl 1):All-6-11;
(13) Carlsson Petri KC, et al. Diabetes Ther 2018;9:1533–47.