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Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial
The Lancet Diabetes & Endocrinology ( IF 44.5 ) Pub Date : 2022-04-22 , DOI: 10.1016/s2213-8587(22)00070-5
Amalia Gastaldelli 1 , Kenneth Cusi 2 , Laura Fernández Landó 3 , Ross Bray 3 , Bram Brouwers 3 , Ángel Rodríguez 4
Affiliation  

Background

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist under development for the treatment of type 2 diabetes. The aim of this substudy was to characterise the changes in liver fat content (LFC), volume of visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) in response to tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study.

Methods

This substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial was done at 45 medical research centres and hospitals across eight countries (Argentina, Austria, Greece, Hungary, Italy, Romania, Spain, and the USA). Eligible participants were adults with type 2 diabetes, a baseline HbA1c 7·0–10·5% (53–91 mmol/mol), a BMI of at least 25 kg/m2, stable weight, were insulin-naive, and on treatment with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. In addition to the main study inclusion criteria, substudy participants had a fatty liver index of at least 60. Participants had an MRI scan and were randomised (1:1:1:1) in the main study to subcutaneous injection once per week of tirzepatide 5 mg, 10 mg, or 15 mg, or subcutaneous injection once per day of titrated insulin degludec, using an interactive web-response system, and were stratified by country, HbA1c, and concomitant oral anti-hyperglycaemic medication. The primary efficacy endpoint was the change from baseline in LFC (as measured by MRI-proton density fat fraction [MRI-PDFF]) at week 52 using pooled data from the tirzepatide 10 mg and 15 mg groups versus insulin degludec. Analyses were assessed in the enrolled MRI population, which consisted of participants in the modified intention-to-treat population of the main study who also had a valid MRI at either baseline or after baseline. This is a substudy of the trial registered with ClinicalTrials.gov, number NCT03882970, and is complete.

Findings

From April 1, 2019, to Nov 15, 2019, 502 participants were assessed for eligibility to participate in this substudy, 296 (59%) of whom were included in the enrolled MRI population and randomly assigned to treatment (tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). Baseline demographics and clinical characteristics were similar across all treatment groups. From an overall mean baseline LFC of 15·71% (SD 8·93), the absolute reduction in LFC at week 52 was significantly greater for the pooled tirzepatide 10 mg and 15 mg groups (–8·09%, SE 0·57) versus the insulin degludec group (–3·38%, 0·83). The estimated treatment difference versus insulin degludec was –4·71% (95% CI –6·72 to –2·70; p<0·0001). The reduction in LFC was significantly correlated (p≤0·0006) with baseline LFC (ρ=–0·71), reductions in VAT (ρ=0·29), reductions in ASAT (ρ=0·33), and reductions in body weight (ρ=0·34) in the tirzepatide groups.

Interpretation

Tirzepatide showed a significant reduction in LFC and VAT and ASAT volumes compared with insulin degludec in this subpopulation of patients with type 2 diabetes in the SURPASS-3 study. These data provide additional evidence on the metabolic effects of this novel dual GIP and GLP-1 receptor agonist.

Funding

Eli Lilly and Company.



中文翻译:

替西帕肽与德谷胰岛素对 2 型糖尿病患者肝脏脂肪含量和腹部脂肪组织的影响 (SURPASS-3 MRI):随机、开放标签、平行组、3 期 SURPASS-3 试验的子研究

背景

Tirzepatide 是一种新型双葡萄糖依赖性促胰岛素多肽 (GIP) 和胰高血糖素样肽-1 受体激动剂,正在开发用于治疗 2 型糖尿病。本子研究的目的是描述 SURPASS-3 亚群中替西帕肽或德谷胰岛素对肝脏脂肪含量 (LFC)、内脏脂肪组织体积 (VAT) 和腹部皮下脂肪组织 (ASAT) 的影响。学习。

方法

这项随机、开放标签、平行组、3 期 SURPASS-3 试验的子研究在 8 个国家(阿根廷、奥地利、希腊、匈牙利、意大利、罗马尼亚、西班牙和美国)的 45 个医学研究中心和医院进行)。符合条件的参与者是患有 2 型糖尿病的成年人,基线 HbA 1c 7·0–10·5% (53–91 mmol/mol),BMI 至少为 25 kg/m 2,体重稳定,未使用过胰岛素,并且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。除主要研究纳入标准外,子研究参与者的脂肪肝指数至少为 60。参与者进行了 MRI 扫描,并在主要研究中随机(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的德谷胰岛素,使用交互式网络响应系统,并按国家分层,HbA 1c,以及伴随的口服抗高血糖药物。主要疗效终点是使用 tirzepatide 10 mg 和 15 mg 组与德谷胰岛素组的汇总数据,在第 52 周时 LFC 相对于基线的变化(通过 MRI-质子密度脂肪分数 [MRI-PDFF] 测量)。在纳入的 MRI 人群中进行了分析评估,该人群包括主要研究的改良意向治疗人群中的参与者,他们在基线或基线后也有有效的 MRI。这是在 ClinicalTrials.gov 注册的试验的子研究,编号为 NCT03882970,并且已完成。

发现

从 2019 年 4 月 1 日到 2019 年 11 月 15 日,评估了 502 名参与者参加该子研究的资格,其中 296 名 (59%) 被纳入登记的 MRI 人群并随机分配接受治疗(替西帕肽 5 mg,n= 71;替西帕肽 10 mg,n=79;替西帕肽 15 mg,n=72;和德谷胰岛素,n=74)。所有治疗组的基线人口统计学和临床​​特征相似。从 15·71% (SD 8·93) 的总体平均基线 LFC 来看,合并 tirzepatide 10 mg 和 15 mg 组在第 52 周 LFC 的绝对降低显着更大(–8·09%,SE 0·57 ) 与德谷胰岛素组相比 (–3·38%, 0·83)。与德谷胰岛素的估计治疗差异为 –4·71%(95% CI –6·72 至 –2·70;p<0·0001)。LFC 的降低与基线 LFC (ρ=–0·71) 显着相关 (p≤0·0006),

解释

在 SURPASS-3 研究中,与德谷胰岛素相比,在该 2 型糖尿病患者亚群中,Tirzepatide 显示 LFC 和 VAT 和 ASAT 体积显着减少。这些数据为这种新型 GIP 和 GLP-1 受体激动剂的代谢作用提供了额外的证据。

资金

礼来公司。

更新日期:2022-04-22
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