Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A post hoc subgroup analysis of the PIONEER 1, 3, 4 and 8 trials

Abstract

Aims: To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials.

Materials and methods: Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively.

Results: Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild-to-moderate constipation, nausea and diarrhoea.

Conclusions: Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum.

Keywords: Glucagon-like peptide-1 receptor agonist; Japanese; PIONEER; oral semaglutide; post hoc; subgroup analyses.

Conflict of interest statement

E.A. has received honoraria for lectures from AstraZeneca, Daiichi Sankyo, Kowa Company, Merck Sharp and Dohme (MSD), Novo Nordisk Pharma, Ono Pharmaceutical, Sanofi and Sumitomo Dainippon Pharma, and scholarship grants from Astellas Pharma, Bayer, Daiichi Sankyo, Eli Lilly Japan, Kowa Company, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Sanofi, Sumitomo Dainippon Pharma and Takeda Pharmaceutical. Y.T. reports receiving honoraria for serving on advisory boards for MSD, Boehringer Ingelheim, Tanabe‐Mitsubishi, Daiichi Sankyo, Novo Nordisk, Eli Lilly, Sanofi, Astellas Pharma, AstraZeneca and Teijin, speaker's fees from MSD, Ono, Boehringer Ingelheim, Takeda, Tanabe‐Mitsubishi, Daiichi Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk, Eli Lilly, Sanofi, Dainippon‐Sumitomo, Shionogi, Bayer Yakuhin, Astellas and AstraZeneca, and research support from MSD, Ono, Boehringer Ingelheim, Novartis, Takeda, Daiichi Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk, Eli Lilly, Sanofi, Dainippon‐Sumitomo, Shionogi, Astellas Pharma and AstraZeneca. H.W. reports receiving honoraria (eg, lecture fees) from Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Sanwa Kagaku Kenkyusho, Takeda, Sanofi, Kowa, MSD, Boehringer Ingelheim, Novo Nordisk and Eli Lilly, research support from Takeda, Boehringer Ingelheim, Kissei Pharma, Novo Nordisk, Mitsubishi Tanabe Pharma, Lifescan Japan, Dainippon‐Sumitomo, Kyowa‐Kirin and MSD, and endowed courses supported by Boehringer Ingelheim, Kowa, MSD, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho, Soiken, Takeda and Dainippon Sumitomo Pharma. S.D., E.C., and H.H. are employees of Novo Nordisk. E.C. holds shares in Novo Nordisk. T.K. reports receiving honoraria (eg, lecture fees) from MSD Corporation, Daiichi Sankyo Co., Ltd, Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Kowa Pharmaceutical Co., Ltd, Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd, AstraZeneca K.K., Sumitomo Dainippon Pharma Co., Ltd, Sanofi K.K., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Kyowa Hakko Kirin Co., Ltd, Taisho Pharmaceutical Co., Ltd and Novo Nordisk Pharma Ltd, research funding (endowed departments by commercial entities) from Asahi Mutual Life Insurance Company, Takeda Pharmaceutical Co., Ltd, TERUMO Corporation, MSD Corporation, Novo Nordisk Pharma Ltd and Nippon Boehringer Ingelheim Co., Ltd, and scholarship donation from MSD Corporation, Daiichi Sankyo Co., Ltd, Novo Nordisk Pharma Ltd, Sanofi K.K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, Eli Lilly Japan K.K. and Kyowa Hakko Kirin Co., Ltd.

© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Change from baseline in glycated haemoglobin (HbA1c) for Japanese patients in PIONEER 1, 3, 4 and 8. Data from the in‐trial observation period were included in the statistical analysis. The efficacy endpoints were analysed for the treatment policy estimand using a pattern mixture model with multiple imputation to impute missing data for the landmark visits. Imputation of missing data was done using an analysis of covariance (ANCOVA) model within groups defined by randomized treatment and treatment status (on‐treatment without use of rescue medication; premature discontinuation of trial product or initiation rescue medication). After imputation, each of the 1000 imputed, complete datasets were analysed using an ANCOVA model with treatment, strata (PIONEER 3, 4 and 8) and interaction between strata (PIONEER 8) as categorical fixed effects and the baseline value as a covariate. Rubin's rule was used to combine the 1000 analysis results to draw inference. †Upper limit of 95% confidence interval (CI) for estimated treatment difference (ETD) for oral semaglutide 3, 7 and 14 mg versus placebo <0. ‡Upper limit of 95% CI for ETD for oral semaglutide 14 mg versus sitagliptin <0. §Lower limit of 95% CI for ETD for oral semaglutide 3 mg versus sitagliptin ≥0. ¶Upper limit of 95% CI for ETD for oral semaglutide 14 mg versus liraglutide and placebo <0. N, number of randomized patients contributing to the analyses; Nobs, number of patients with observations; SGLT2i, sodium‐glucose cotransporter‐2 inhibitor; SU, sulphonylurea

FIGURE 2

Change from baseline in body weight (%) for Japanese patients in PIONEER 1, 3, 4 and 8. Data from the in‐trial observation period were included in the statistical analysis. The efficacy endpoints were analysed for the treatment policy estimand using a pattern mixture model with multiple imputation to impute missing data for the landmark visits. Imputation of missing data was done using an analysis of covariance (ANCOVA) model within groups defined by randomized treatment and treatment status (on‐treatment without use of rescue medication; premature discontinuation of trial product or initiation rescue medication). After imputation, each of the 1000 imputed, complete datasets were analysed using an ANCOVA model with treatment, strata (PIONEER 3, 4 and 8) and interaction between strata (PIONEER 8) as categorical fixed effects and the baseline value as a covariate. Rubin's rule was used to combine the 1000 analysis results to draw inference. †Upper limit of 95% confidence interval (CI) for estimated treatment difference (ETD) for oral semaglutide 3, 7 and 14 mg versus placebo <0. ‡Upper limit of 95% CI for ETD for oral semaglutide 7 and 14 mg versus sitagliptin <0. ¶Upper limit of 95% CI for ETD for oral semaglutide 14 mg versus liraglutide and placebo <0. N, number of randomized patients contributing to the analyses; Nobs, number of patients with observations; SGLT2i, sodium‐glucose cotransporter‐2 inhibitor; SU, sulphonylurea