Billings Clinic Research Center, Billings, MT, USA.
Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Lancet Diabetes Endocrinol. 2017 Apr;5(4):251-260. doi: 10.1016/S2213-8587(17)30013-X. Epub 2017 Jan 17.
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.
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 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 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.
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 was 8·05% (SD 0·85); at week 30, HbA 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.
Semaglutide significantly improved HbA 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.
Novo Nordisk A/S, Denmark.
尽管有广泛的治疗 2 型糖尿病的药物选择，但许多患者的血糖控制仍不理想，需要新的治疗方法。司美格鲁肽是一种处于 3 期开发阶段的胰高血糖素样肽-1（GLP-1）类似物，用于治疗单独饮食和运动控制不佳的 2 型糖尿病患者。
我们在加拿大、意大利、日本、墨西哥、俄罗斯、南非、英国和美国的 72 个地点进行了一项双盲、随机、平行组、国际、安慰剂对照的 3a 期试验（SUSTAIN 1）（包括医院、临床研究单位和私人办公室）。合格的参与者是未经治疗的成年人，年龄在 18 岁或以上，在筛选前仅接受饮食和运动治疗至少 30 天，基线糖化血红蛋白（HbA）为 7·0%-10·0%（53-86 mmol/mol）。我们将参与者（2:2:1:1）随机分配至每周皮下注射一次司美格鲁肽（0·5 mg 或 1·0 mg）或等容量安慰剂（0·5 mg 或 1·0 mg），共 30 周，使用预填充 PDS290 笔式注射器。参与者自行注射，并鼓励他们在每周相同的一天、身体相同的部位进行注射；注射时间和接近进餐时间没有具体规定。我们使用交互式语音或网络响应系统进行随机分组。整个试验过程中，研究者、参与者和研究资金提供者均处于盲态。主要终点是从基线到第 30 周时平均 HbA 的变化，次要确认终点是从基线到第 30 周时平均体重的变化。我们在修改后的意向治疗人群中评估了疗效和安全性（即，所有至少接受过一次研究药物治疗的参与者）；同时将两个安慰剂组合并进行评估。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02054897。
2014 年 2 月 3 日至 2014 年 8 月 21 日期间，我们随机分配了 388 名参与者接受治疗；387 名参与者至少接受了一次研究药物治疗（128 名接受 0·5 mg 司美格鲁肽，130 名接受 1·0 mg 司美格鲁肽，129 名接受安慰剂）。17 名（13%）接受 0·5 mg 司美格鲁肽治疗的参与者、16 名（12%）接受 1·0 mg 司美格鲁肽治疗的参与者和 14 名（11%）接受安慰剂治疗的参与者停止了治疗；主要停药原因是胃肠道不良反应，如恶心。基线平均 HbA 为 8·05%（SD 0·85）；在第 30 周时，HbA 显著降低了 1·45%（95%CI-1·65 至-1·26），接受 0·5 mg 司美格鲁肽治疗的患者（与安慰剂相比，估计治疗差异为-1·43%，95%CI-1·71 至-1·15；p<0·0001），接受 1·0 mg 司美格鲁肽治疗的患者显著降低了 1·55%（95%CI-1·74 至-1·36）（与安慰剂相比，估计治疗差异为-1·53%，95%CI-1·81 至-1·25；p<0·0001），接受安慰剂治疗的患者仅非显著降低了 0·02%（95%CI-0·23 至 0·18）。基线平均体重为 91.93 kg（SD 23.83）；在第 30 周时，体重显著降低了 3·73 kg（95%CI-4·54 至-2·91），接受 0·5 mg 司美格鲁肽治疗的患者（与安慰剂相比，估计治疗差异为-2·75 kg，95%CI-3·92 至-1·58；p<0·0001），体重显著降低了 4·53 kg（95%CI-5·34 至-3·72），接受 1·0 mg 司美格鲁肽治疗的患者（与安慰剂相比，估计治疗差异为-3·56 kg，95%CI-4·74 至-2·38；p<0·0001），接受安慰剂治疗的患者体重仅非显著降低了 0·98 kg（95%CI-1·82 至-0·13）。在任何研究组中均未报告死亡事件，大多数报告的不良事件为轻度或中度。在接受司美格鲁肽治疗的两组中，最常见的不良事件均为胃肠道事件：接受 0·5 mg 司美格鲁肽治疗的患者中有 26 人（20%）出现恶心，接受 1·0 mg 司美格鲁肽治疗的患者中有 31 人（24%）出现恶心，接受安慰剂治疗的患者中有 10 人（8%）出现恶心，接受 0·5 mg 司美格鲁肽治疗的患者中有 16 人（13%）出现腹泻，接受 1·0 mg 司美格鲁肽治疗的患者中有 14 人（11%）出现腹泻，接受安慰剂治疗的患者中有 3 人（2%）出现腹泻。
与安慰剂相比，司美格鲁肽显著改善了 2 型糖尿病患者的 HbA 和体重，且与目前可用的 GLP-1 受体激动剂具有相似的安全性，为这类患者提供了一种潜在的治疗选择。
丹麦诺和诺德公司。
