Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial

Abstract

Aim: To evaluate the safety and efficacy of once-weekly subcutaneous semaglutide as monotherapy or combined with an oral antidiabetic drug (OAD) vs an additional OAD added to background therapy in Japanese people with type 2 diabetes (T2D) inadequately controlled on diet/exercise or OAD monotherapy.

Methods: In this phase III, open-label trial, adults with T2D were randomized 2:2:1 to semaglutide 0.5 mg or 1.0 mg, or one additional OAD (a dipeptidyl peptidase-4 inhibitor, biguanide, sulphonylurea, glinide, α-glucosidase inhibitor or thiazolidinedione) with a different mode of action from that of background therapy. The primary endpoint was number of adverse events (AEs) after 56 weeks.

Results: Baseline characteristics were balanced between treatment arms (601 randomized). More AEs were reported in the semaglutide 0.5 mg (86.2%) and 1.0 mg (88.0%) groups than in the additional OAD group (71.7%). These were typically mild/moderate. Gastrointestinal AEs were most frequent with semaglutide, which diminished over time. The mean glycated haemoglobin (HbA1c) concentration (baseline 8.1%) was significantly reduced with semaglutide 0.5 mg and 1.0 mg vs additional OAD (1.7% and 2.0% vs 0.7%, respectively; estimated treatment difference [ETD] vs additional OAD -1.08% and -1.37%, both P < .0001). Body weight (baseline 71.5 kg) was reduced by 1.4 kg and 3.2 kg with semaglutide 0.5 mg and 1.0 mg, vs a 0.4-kg increase with additional OAD (ETD -1.84 kg and -3.59 kg; both P < .0001). For semaglutide-treated participants, >80% achieved an HbA1c concentration <7.0% (Japanese Diabetes Society target).

Conclusions: Semaglutide was well tolerated, with no new safety issues identified. Semaglutide treatment significantly reduced HbA1c and body weight vs additional OAD treatment in Japanese people with T2D.

Trial registration: ClinicalTrials.gov NCT02207374.

Keywords: GLP-1 analogue; glycaemic control; incretin therapy; phase III study; randomized trial; type 2 diabetes.

Conflict of interest statement

K.K. has received honoraria or consulting fees from Astellas Pharma, AstraZeneca KK, MSD KK, Ono Pharmaceutical, Kissei Pharmaceutical, Kowa Pharmaceutical, Sanofi KK, Sanwakagaku Kenkyusyo, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Novartis Pharma KK, Novo Nordisk, Nippon Boehringer Ingelheim, Taisho Toyama Pharmaceutical and Takeda, and research grants from Taisho Pharmaceutical, Mitsubishi Tanabe Pharma and Nippon Boehringer Ingelheim. Y.Y. has received honoraria or consulting fees from Novo Nordisk. H.W. has received honoraria for consulting from Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kowa Pharmaceutical, Merck Sharp & Dohme, Novo Nordisk, Novartis, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho, Takeda, Astellas Pharma, Mitsubishi Tanabe Pharma, AstraZeneca, Kyowa Hakko Kirin and Kissei Pharmaceutical, and grants from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Novartis, Novo Nordisk, Pfizer, Sanofi, Sanwakagaku Kenkyusho, Takeda, Terumo Corp, Novartis, Astellas Pharma, Abbott Japan, Ono Pharmaceutical, Kyowa Hakko Kirin Co. Ltd, Kowa Pharmaceutical, Johnson & Johnson, Taisho Toyama Pharmaceutical, Nitto Boseki Company, Bayer, Bristol‐Myers Squibb and Benefit one Health care. A.A. has received consulting and/or speaker fees from Novo Nordisk, Eli Lilly Japan, Nippon Boehringer Ingelheim, Kowa Pharmaceutical, Novartis International, Astellas Pharma, Mitsubishi Tanabe Pharma, Taisho Toyama Pharmaceutical, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Sanofi, MSD, Takeda, AstraZeneca, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho and Daiichi Sankyo, and research grants from Novo Nordisk. T.N. is an employee of Novo Nordisk and holds shares in the company. J.Z. is an employee of Novo Nordisk and holds shares in the company. A.K. has received honoraria and consultation fees from AstraZeneca.

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

Figures

Figure 1

Flow of participants through the trial. *Reflects primary reason for treatment discontinuation, as judged by the investigator. †55 participants did not have a glycated haemoglobin (HbA1c) value within the specified range and 2 participants were not on stable treatment with diet/exercise therapy only for at least 30 days before screening, or on oral antidiabetic drug (OAD) monotherapy, in addition to diet/exercise therapy for at least 60 days before screening. aSeven participants discontinued because of gastrointestinal (GI) adverse events (AEs) and seven discontinued because of other AEs. bEighteen participants discontinued because of GI AEs and 8 discontinued because of other AEs. cNo participants discontinued because of GI AEs and 4 discontinued because of other AEs. Numbers in brackets within treatment discontinuation denote participants who also withdrew from trial, as those who discontinued treatment had the option to continue follow‐up. Trial completers were participants who were exposed, did not discontinue treatment prematurely, did not withdraw from trial and who attended a follow‐up visit

Figure 2

Semaglutide 0.5 mg and 1.0 mg once weekly, compared with an additional OAD, mean glycated haemoglobin (HbA1c) by week, A; change in mean HbA1c after 56 weeks, B; the proportion of participants achieving HbA1c P < .0001. †P < .02