Background

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. In this study, we used continuous glucose monitoring (CGM) to compare the 24 h glucose profile for participants given tirzepatide compared with those given insulin degludec.

Methods

This substudy of the open-label, parallel-group, phase 3 SURPASS-3 trial, was done at 45 sites across six countries (Hungary, Poland, Romania, Spain, Ukraine, and the USA). Eligible participants in the main study were adults with type 2 diabetes, a baseline HbA_1c of 7·0–10·5% (53–91 mmol/mol), and a BMI of 25 kg/m² or more, who were insulin-naive, and treated with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. Participants in the main study were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injection of tirzepatide 5 mg, 10 mg, or 15 mg, or once-daily subcutaneous injection of titrated insulin degludec (100 U/mL), using an interactive web-response system. Participants were stratified by country, HbA_1c concentration, and concomitant oral antihyperglycaemic medication. A subset of these patients with a normal wake–sleep cycle were enrolled into this substudy, and interstitial glucose values were collected by CGM for approximately 7 days at baseline, 24 weeks, and 52 weeks. The primary outcome was to compare pooled participants assigned to 10 mg and 15 mg tirzepatide versus insulin degludec for the proportion of time that CGM values were in the tight target range (71–140 mg/dL) at 52 weeks, assessed in all randomly assigned participants who received at least one dose of study drug and had an evaluable CGM session at either baseline or after baseline. The secondary outcomes were to compare tirzepatide (5 mg, 10 mg, and 15 mg) versus insulin degludec for the proportion and duration of time in tight target range at 24 and 52 weeks. This was a substudy of the trial registered with ClinicalTrials.gov, NCT03882970, and is complete.

Findings

From April 1 to Nov 27, 2019, 313 participants were screened for eligibility, 243 of whom were enrolled in CGM substudy (tirzepatide 5 mg, n=64; tirzepatide 10 mg, n=51; tirzepatide 15 mg, n=73; and insulin degludec, n=55). Patients given once-weekly tirzepatide (pooled 10 mg and 15 mg groups) had a greater proportion of time in tight target range compared with patients given insulin degludec (estimated treatment difference 25% [95% CI 16–33]; p<0·0001). Participants assigned to tirzepatide spent significantly more time in tight target range at 52 weeks compared with those assigned to insulin degludec (5 mg 12% [1–22], p=0·031; 10 mg 24% [13–35], p<0·0001; and 15 mg 25% [14–35], p<0·0001). Participants assigned to tirzepatide 10 mg and 15 mg, but not to tirzepatide 5 mg, spent significantly more time in tight target range at 24 weeks compared with insulin degludec (10 mg 19% [8–30], p=0·0008; 15 mg 21% [11–31], p<0·0001).

Interpretation

Once-weekly treatment with tirzepatide showed superior glycaemic control measured using CGM compared with insulin degludec in participants with type 2 diabetes on metformin, with or without a SGLT2 inhibitor. These new data provide additional evidence to the effect of tirzepatide and potential for achieving glycaemic targets without increase of hypoglycaemic risk compared with a basal insulin.

Funding

Eli Lilly and Company.

中文翻译：

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每周一次的替西帕肽与每天一次的德谷胰岛素对 2 型糖尿病成人连续血糖监测 (SURPASS-3 CGM) 的血糖控制效果：随机、开放标签、平行组、3 期 SURPASS 的子研究-3 试用

背景

Tirzepatide 是一种新型双葡萄糖依赖性促胰岛素多肽 (GIP) 和 GLP-1 受体激动剂，正在开发用于治疗 2 型糖尿病。在这项研究中，我们使用连续血糖监测 (CGM) 来比较服用替西帕肽的参与者与服用德谷胰岛素的参与者的 24 小时血糖曲线。

方法

这项开放标签、平行组、3 期 SURPASS-3 试验的子研究在六个国家（匈牙利、波兰、罗马尼亚、西班牙、乌克兰和美国）的 45 个地点进行。主要研究的合格参与者是患有 2 型糖尿病、基线 HbA _1c为 7·0–10·5% (53–91 mmol/mol) 和 BMI ≥ 25 kg/m ²的成年人，他们是胰岛素-未经治疗，在筛选前单独使用二甲双胍或与 SGLT2 抑制剂联合治疗至少 3 个月。主要研究的参与者被随机分配（1:1:1:1）接受每周一次皮下注射替西帕肽 5 mg、10 mg 或 15 mg，或每天一次皮下注射滴定胰岛素德谷胰岛素（100 U/ mL)，使用交互式网络响应系统。参与者按国家分层，HbA _1c浓度和伴随的口服降糖药。这些具有正常唤醒-睡眠周期的患者的一个子集被纳入该子研究，并通过 CGM 在基线、24 周和 52 周时收集了大约 7 天的间质葡萄糖值。主要结果是在 52 周时比较分配到 10 mg 和 15 mg tirzepatide 与胰岛素 degludec 的汇总参与者的 CGM 值处于严格目标范围 (71-140 mg/dL) 的时间比例，在所有随机分配接受至少一剂研究药物并在基线或基线后进行了可评估的 CGM 会议的参与者。次要结局是比较 tirzepatide（5 mg、10 mg 和 15 mg）与德谷胰岛素在 24 周和 52 周时在严格目标范围内的比例和持续时间。

发现

从 2019 年 4 月 1 日至 11 月 27 日，筛选了 313 名参与者的资格，其中 243 人参加了 CGM 子研究（替西帕肽 5 mg，n=64；替西帕肽 10 mg，n=51；替西帕肽 15 mg，n=73；和德谷胰岛素，n = 55)。与给予德谷胰岛素的患者相比，给予每周一次 tirzepatide（合并 10 mg 和 15 mg 组）的患者在严格目标范围内的时间比例更大（估计治疗差异 25% [95% CI 16-33]；p<0· 0001)。与分配给德谷胰岛素的参与者相比，分配给 tirzepatide 的参与者在 52 周时在严格目标范围内花费的时间显着更多（5 mg 12% [1-22]，p=0·031；10 mg 24% [13-35]，p <0·0001；和 15 mg 25% [14-35]，p<0·0001)。参与者分配到 tirzepatide 10 mg 和 15 mg，但未分配到 tirzepatide 5 mg，

解释

与德谷胰岛素相比，使用二甲双胍治疗的 2 型糖尿病患者（无论是否使用 SGLT2 抑制剂）每周一次使用 tirzepatide 治疗显示出更好的血糖控制。这些新数据为 tirzepatide 的作用和实现血糖目标的潜力提供了额外的证据，而与基础胰岛素相比，不会增加低血糖风险。

资金

礼来公司。