Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial,The Lancet Diabetes & Endocrinology

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Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial
The Lancet Diabetes & Endocrinology ( IF 44.5 ) Pub Date : 2021-07-21 , DOI: 10.1016/s2213-8587(21)00174-1
Juan P Frías ₁ , Pernille Auerbach ₂ , Harpreet S Bajaj ₃ , Yasushi Fukushima ₄ , Ildiko Lingvay ₅ , Stanislava Macura ₂ , Anette L Søndergaard ₂ , Tsvetalina I Tankova ₆ , Nikolaos Tentolouris ₇ , John B Buse ₈

Affiliation

Background

Semaglutide is an effective treatment for type 2 diabetes; however, 20–30% of patients given semaglutide 1·0 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea.

Methods

We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (≥18 years) with inadequately controlled type 2 diabetes (HbA_1c 8·0–10·0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2·0 mg or 1·0 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA_1c (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162.

Findings

Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58·0 years [SD 10·0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2·0 mg (n=480 [50%]) or 1·0 mg (n=481 [50%]); 462 (96%) patients in the semaglutide 2·0 mg group and 471 (98%) in the semaglutide 1·0 mg group completed the trial. Mean baseline HbA_1c was 8·9% (SD 0·6; 73·3 mmol/mol [SD 6·9]) and BMI was 34·6 kg/m² (SD 7·0). Mean change in HbA_1c from baseline at week 40 was −2·2 percentage points with semaglutide 2·0 mg and −1·9 percentage points with semaglutide 1·0 mg (estimated treatment difference [ETD] −0·23 percentage points [95% CI −0·36 to −0·11]; p=0·0003; trial product estimand) and −2·1 percentage points with semaglutide 2·0 mg and −1·9 percentage points with semaglutide 1·0 mg (ETD −0·18 percentage points [–0·31 to −0·04]; p=0·0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was −6·9 kg with semaglutide 2·0 mg and −6·0 kg with semaglutide 1·0 mg (ETD −0·93 kg [95% CI −1·68 to −0·18]; p=0·015; trial product estimand) and −6·4 kg with semaglutide 2·0 mg and −5·6 kg with semaglutide 1·0 mg (ETD −0·77 kg [–1·55 to 0·01]; p=0·054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2·0 mg group and 148 [31%] in the 1·0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2·0 mg and 25 (5%) participants given semaglutide 1·0 mg. Three deaths were reported during the trial (one in the semaglutide 1·0 mg group and two in the semaglutide 2·0 mg group).

Interpretation

Semaglutide 2·0 mg was superior to 1·0 mg in reducing HbA_1c, with additional bodyweight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control.

Funding

Novo Nordisk.

中文翻译：

每周一次 2·0 毫克与 1·0 毫克司美鲁肽在 2 型糖尿病患者中的疗效和安全性 (SUSTAIN FORTE)：一项双盲、随机、3B 期试验

背景

Semaglutide 是一种有效的 2 型糖尿病治疗方法；然而，20-30% 的患者服用 semaglutide 1·0 mg 没有达到血糖治疗目标。我们旨在研究每周一次 semaglutide 2·0 毫克与 1·0 毫克在控制不佳的 2 型糖尿病成人中使用稳定剂量的二甲双胍联合或不联合磺脲类药物的疗效和安全性。

方法

我们在 10 个国家的 125 家门诊进行了一项为期 40 周的随机、活性对照、平行组、双盲、3B 期试验 (SUSTAIN FORTE)。患有二甲双胍和磺脲类药物控制不佳的 2 型糖尿病（HbA _1c 8·0–10·0%）的参与者（≥18 岁）通过交互式网络响应系统随机分配（1:1）到 2·0 mg 或 1·0 mg 每周一次 semaglutide。参与者、现场人员、临床研究组和研究人员对随机治疗不知情。结果包括第 40 周 HbA _{1c 相}对于基线的变化（主要结果）和体重（次要确认结果），通过试验产品估计（不停止治疗或没有救援药物）和治疗政策估计（无论治疗中断或救援药物）策略进行评估。本研究已在 ClinicalTrials.gov 注册，NCT03989232；EudraCT，2018-004529-96；和世界卫生组织，U1111-1224-5162。

发现

2019 年 6 月 19 日至 11 月 28 日期间，在评估合格的 1515 名成年人中，包括 961 名参与者（平均年龄 58·0 岁 [SD 10·0]；398 名 [41%] 女性）。参与者被随机分配到每周一次的 semaglutide 2·0 mg (n=480 [50%]) 或 1·0 mg (n=481 [50%])；司美鲁肽 2·0 毫克组的 462 名 (96%) 患者和司美鲁肽 1·0 毫克组的 471 名 (98%) 患者完成了试验。平均基线 HbA _1c为 8·9% (SD 0·6；73·3 mmol/mol [SD 6·9])，BMI 为 34·6 kg/m ² (SD 7·0)。HbA _{1c 的}平均变化在第 40 周时与基线相比，semaglutide 2·0 mg 为 -2·2 个百分点，semaglutide 1·0 mg 为 -1·9 个百分点（估计治疗差异 [ETD] -0·23 个百分点 [95% CI -0 ·36 至 -0·11]；p=0·0003；试验产品估计值）和 semaglutide 2·0 mg 的 -2·1 个百分点和 semaglutide 1·0 mg 的 -1·9 个百分点（ETD -0· 18 个百分点 [–0·31 到 -0·04]；p=0·0098；治疗政策估计值）。第 40 周时体重从基线的平均变化为 -6·9 kg，使用 semaglutide 2·0 mg 和 -6·0 kg，使用 semaglutide 1·0 mg（ETD -0·93 kg [95% CI -1·68 至 - 0·18]；p=0·015；试验产品估计值）和 -6·4 kg 使用 semaglutide 2·0 mg 和 -5·6 kg 使用 semaglutide 1·0 mg（ETD -0·77 kg [-1· 55 到 0·01]；p=0·054；治疗政策估计）。胃肠道疾病是最常报告的不良事件（2·0 毫克组 163 例 [34%]，1·0 毫克组 148 例 [31%]）。严重不良事件在治疗组之间相似，据报道，21 名 (4%) 参与者服用司美鲁肽 2·0 毫克，25 名 (5%) 参与者服用司美鲁肽 1·0 毫克。试验期间报告了三例死亡（司美鲁肽 1·0 毫克组中的一名，司美鲁肽 2·0 毫克组中的两名）。