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

AimTo 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.MethodsIn 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.ResultsBaseline 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).ConclusionsSemaglutide 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.

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

“…No restrictions on body weight or body mass index (BMI) applied. Detailed enrolment criteria have been published previously …”

“…The exposure‐response analyses included data from 1423 adults randomized to semaglutide in four trials from the semaglutide SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) programme (Table S1), and from 129 adults randomized to placebo (SUSTAIN 1). The trials investigated semaglutide doses 0.5 and 1.0 mg (SUSTAIN 3 only investigated semaglutide 1.0 mg) and included either placebo as the comparator (SUSTAIN 1) or an active comparator (SUSTAIN 2 and 3, SUSTAIN−Japan; Table S1).…”

“…Three trials were global and one was conducted in Japan (http://Clinicaltrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208 and NCT02207374) . The trials enrolled men and women diagnosed with T2DM; in the global trials participants were aged ≥18 years and in the trial from Japan they were aged ≥20 years.…”

“…In the exposure‐response analyses, we aimed to evaluate the efficacy and safety/tolerability of semaglutide across a broad range of exposures generated from four trials in the clinical development programme with semaglutide doses 0.5 and 1.0 mg . We wanted to determine if all subgroups of patients would obtain effective exposure levels with a semaglutide 0.5 mg dose, and if meaningful additional benefits could be obtained with the higher 1.0 mg dose.…”

Impact on HbA1c and body weight of switching from other GLP‐1 receptor agonists to semaglutide: A model‐based approach

“…Time‐course models of HbA1c and body weight were developed for semaglutide using data up to week 30, which was the duration of the shortest phase 3 trial, based on the SUSTAIN exposure‐response population from four clinical trials, SUSTAIN 1, 2, 3 and SUSTAIN–Japan . Two of the trials were not included as they either applied daily dosing rather than weekly dosing of semaglutide (phase 2 trial) or did not measure semaglutide concentrations (SUSTAIN 7) (Table S1).…”