Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial

Background Despite a broad range of pharmacological options for the treatment of type 2 diabetes, optimum glycaemic control remains challenging for many patients and new therapies are necessary. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue in phase 3 development for type 2 diabetes. We assessed the efficacy, safety, and tolerability of semaglutide monotherapy, compared with placebo, in treatment-naive patients with type 2 diabetes who had insufficient glycaemic control with diet and exercise alone. Methods We did a double-blind, randomised, parallel-group, international, placebo-controlled phase 3a trial (SUSTAIN 1) at 72 sites in Canada, Italy, Japan, Mexico, Russia, South Africa, UK, and USA (including hospitals, clinical research units, and private offices). Eligible participants were treatment-naive individuals aged 18 years or older with type 2 diabetes treated with only diet and exercise alone for at least 30 days before screening, with a baseline HbA(1c) of 7.0%-10.0% (53-86 mmol/mol). We randomly assigned participants (2:2:1:1) to either once-weekly subcutaneously injected semaglutide (0.5 mg or 1.0 mg), or volume-matched placebo (0.5 mg or 1.0 mg), for 30 weeks via prefilled PDS290 pen-injectors. Participants did their own injections and were encouraged to administer them on the same day of each week in the same area of their body; the time of day and proximity of meal times was not specified. We did the randomisation with an interactive voice or web response system. Investigators, participants, and the funder of the study remained masked throughout the trial. The primary endpoint was the change in mean HbA(1c) from baseline to week 30, and the confirmatory secondary endpoint was the change in mean bodyweight from baseline to week 30. We assessed efficacy and safety in the modified intention-to-treat population (ie, all participants who were exposed to at least one dose of study drug); both placebo groups were pooled for assessment. This trial was registered with ClinicalTrials.gov, number NCT02054897. Findings Between February 3, 2014, and August 21, 2014, we randomly assigned 388 participants to treatment; 387 received at least one dose of study medication (128 0.5 mg semaglutide, 130 1.0 mg semaglutide, 129 placebo). 17 (13%) of those assigned to 0.5 mg semaglutide, 16 (12%) assigned to 1.0 mg semaglutide, and 14 (11%) assigned to placebo discontinued treatment; the main reason for discontinuation was gastrointestinal adverse events such as nausea. Mean baseline HbA(1c) was 8.05% (SD 0.85); at week 30, HbA(1c) significantly decreased by 1.45% (95% CI -1.65 to -1.26) with 0.5 mg semaglutide (estimated treatment difference vs placebo -1.43%, 95% CI -1.71 to -1.15; p < 0.0001), significantly decreased by 1.55% (-1.74 to -1.36) with 1.0 mg semaglutide (estimated treatment difference vs placebo -1.53%, -1.81 to -1.25; p < 0.0001), and non-significantly decreased by 0.02% (-0.23 to 0.18) with placebo. Mean baseline bodyweight was 91.93 kg (SD 23.83); at week 30, bodyweight significantly decreased by 3.73 kg (95% CI -4.54 to -2.91) with 0.5 mg semaglutide (estimated treatment difference vs placebo -2.75 kg, 95% CI -3.92 to -1.58; p < 0.0001), significantly decreased by 4.53 kg (-5.34 to -3.72) with 1.0 mg semaglutide (estimated treatment difference vs placebo -3.56 kg, -4.74 to -2.38; p < 0.0001), and non-significantly decreased by 0.98 kg (-1.82 to -0.13) with placebo. No deaths were reported in any of the study groups and most reported adverse events were of mild or moderate severity. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 26 (20%) who received 0.5 mg semaglutide, 31 (24%) who received 1.0 mg semaglutide, and 10 (8%) who received placebo, and diarrhoea was reported in 16 (13%) who received 0.5 mg semaglutide, 14 (11%) who received 1.0 mg semaglutide, and three (2%) who received placebo. Interpretation Semaglutide significantly improved HbA(1c) and bodyweight in patients with type 2 diabetes compared with placebo, and showed a similar safety profile to currently available GLP-1 receptor agonists, representing a potential treatment option for such patients.