Background

Visceral and ectopic fat are key drivers of adverse cardiometabolic outcomes in obesity. We aimed to evaluate the effects of injectable liraglutide 3·0 mg daily on body fat distribution in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk.

Methods

In this randomised, double-blind, placebo-controlled, phase 4, single centre trial, we enrolled community-dwelling adults, recruited from the University of Texas Southwestern Medical Center, with BMI of at least 30 kg/m² or BMI of at least 27 kg/m² with metabolic syndrome but without diabetes and randomly assigned them, in a 1:1 ratio, to 40 weeks of treatment with once-daily subcutaneous liraglutide 3·0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. The primary endpoint was percentage reduction in visceral adipose tissue (VAT) measured with MRI. All randomly assigned participants with a follow-up imaging assessment were included in efficacy analyses and all participants who received at least one dose of study drug were included in the safety analyses. The trial is registered on ClinicalTrials.gov: NCT03038620.

Findings

Between July 20, 2017 and Feb 21, 2020 from 235 participants assessed for eligibility, 185 participants were randomly assigned (n=92 liraglutide, n=93 placebo) and 128 (n=73 liraglutide, n=55 placebo) were included in the final analysis (92% female participants, 37% Black participants, 24% Hispanic participants, mean age 50·2 years (SD 9·4), mean BMI 37·7 kg/m²). Mean change in VAT over median 36·2 weeks was −12·49% (SD 9·3%) with liraglutide compared with −1·63% (SD 12·3%) with placebo, estimated treatment difference −10·86% (95% CI −6·97 to −14·75, p<0·0001). Effects seemed consistent across subgroups of age, sex, race–ethnicity, BMI, and baseline prediabetes. The most frequently reported adverse events were gastrointestinal-related (43 [47%] of 92 with liraglutide and 12 [13%] of 93 with placebo) and upper respiratory tract infections (10 [11%] of 92 with liraglutide and 14 [15%] of 93 with placebo).

Interpretation

In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3·0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes.

Funding

NovoNordisk.

中文翻译：

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利拉鲁肽对心血管风险高的超重和肥胖成人内脏和异位脂肪的影响：一项随机、双盲、安慰剂对照的临床试验

背景

内脏和异位脂肪是肥胖患者不良心脏代谢结果的关键驱动因素。我们旨在评估每天注射利拉鲁肽 3·0 mg 对患有高心血管疾病风险的无 2 型糖尿病的超重或肥胖成人体内脂肪分布的影响。

方法

在这项随机、双盲、安慰剂对照、4 期、单中心试验中，我们招募了来自德克萨斯大学西南医学中心的 BMI 至少为 30 kg/m ²或 BMI 为至少 27 公斤/米²患有代谢综合征但没有糖尿病，并以 1:1 的比例将他们随机分配至 40 周每天一次皮下注射利拉鲁肽 3·0 mg 或安慰剂，以及 500 kcal 缺乏饮食和指南推荐的身体活动辅导。主要终点是用 MRI 测量的内脏脂肪组织 (VAT) 的减少百分比。所有随机分配的具有后续影像学评估的参与者都包括在功效分析中，所有接受至少一剂研究药物的参与者都包括在安全性分析中。该试验已在 ClinicalTrials.gov 注册：NCT03038620。

发现

在 2017 年 7 月 20 日至 2020 年 2 月 21 日期间，235 名参与者进行了资格评估，其中 185 名参与者被随机分配（n=92 利拉鲁肽，n=93 安慰剂）和 128 名（n=73 利拉鲁肽，n=55 安慰剂）被纳入最终分析（92% 女性参与者，37% 黑人参与者，24% 西班牙裔参与者，平均年龄 50·2 岁 (SD 9·4)，平均 BMI 37·7 kg/m ²）。中位 36·2 周的 VAT 平均变化为 -12·49% (SD 9·3%)，利拉鲁肽组与安慰剂组 -1·63% (SD 12·3%) 相比，估计治疗差异 -10·86% （95% CI -6·97 至 -14·75，p<0·0001）。在年龄、性别、种族-民族、BMI 和基线前驱糖尿病的亚组中，效果似乎是一致的。最常报告的不良事件是胃肠道相关（利拉鲁肽组 92 例中的 43 [47%] 和安慰剂组 93 例中的 12 [13%]）和上呼吸道感染（利拉鲁肽组 92 例中的 10 [11%] 和 14 [15 %] 的 93 与安慰剂）。

解释

在心血管疾病高风险的超重或肥胖成人中，每日一次的利拉鲁肽 3·0 毫克加上生活方式干预在 40 周的治疗中显着降低了内脏脂肪组织。减少内脏脂肪可能是一种机制，可以解释先前在 2 型糖尿病患者中使用利拉鲁肽进行的试验对心血管结果的益处。

资金

诺和诺德。