Effects of Liraglutide on Gastric Functions and their Relationship to Weight Loss in Obesity

摘要 肥胖症在全球范围内持续增加; 69%的美国成年人超重或肥胖。尽管 在了解肥胖病理生理学、当前非手术治疗的体重减轻（饮食和 药物治疗）是高度可变的，并且肥胖药物治疗的体重减轻的预测因子是未知的。在 由RO 1-DK 67071资助的509例受试者的研究中，肥胖与空腹胃 容量，加速胃排空（固体和液体），降低餐后血浆PYY峰值， 为达到饱足感（体积到饱足感）和通过随意进食引起饱足感而消耗的热量。我们 显示短效GLP-1激动剂艾塞那肽5µg，SQ，BID持续30天，可延迟胃排空， 导致体重减轻。因此，定量胃肠道（GI）性状与较高的BMI相关，区分 肥胖表型，并可能预测肥胖药物治疗的疗效。在R56-DK 67071资助的试点中， 一项长效GLP-1激动剂利拉鲁肽每日3 mg SQ的随机、安慰剂对照试验，我们发现： (a)在8个月内招募30名患者并将其随机分配到4个月研究中的可行性（仅2名患者脱落， （B）所有30例随机化患者的安全性数据;（c）胃肠道的基线定量特征 固体和液体排空、空腹和餐后胃容量;饱足和饱足数据;餐后 所有随机化患者的血浆肠促胰岛素（GLP-1和PYY）;（d）完全递增剂量下的胃排空数据 （e）在30例患者中重复测量（如c）第16周时的数量性状。 28例患者的治疗;（f）28例患者治疗期间的每月体重数据。 我们的总体假设是，药物减肥可能是个性化的，基于 定量GI性状的特定异常。我们提出了一个随机的，对照的临床和 药效学试验，使用2种治疗分层设计，以评估数量性状 （胃排空率）可以影响超重（BMI > 27 kg/m2+肥胖共 发病率）或肥胖（BMI > 30 kg/m2）患者接受FDA批准的GLP-1受体激动剂治疗， 与安慰剂相比，利拉鲁肽（剂量递增至最大3 mg SQ/天，持续12周）。效应将 与正常胃排空相比，基线胃排空加速的患者进行比较。 我们的目的是：首先，评估利拉鲁肽（3 mg/天）对胃运动功能、饱腹感、饱腹感的影响， 体重减轻和肠促胰岛素;第二，评估基线胃排空加速与 利拉鲁肽治疗后体重减轻。通过在基线和12天后测量GI数量性状， 利拉鲁肽治疗6周后，我们将进一步了解这种GLP-1激动剂的作用机制。 意义：我们的研究解决了肥胖的治疗，引入了个体化药物治疗的时代 肥胖的定量生物标志物。因此，它解决了一个重要的公共卫生挑战。

ABSTRACT Obesity prevalence continues to increase worldwide; 69% of U.S. adults are overweight or obese. Despite advances in understanding obesity pathophysiology, weight loss with current non-surgical treatments (diet and medications) is highly variable, and predictors of weight loss with obesity pharmacotherapy are unknown. In studies funded by RO1-DK67071 in 509 participants, obesity was associated with greater fasting gastric volume, accelerated gastric emptying (solids and liquids), lower postprandial peak plasma PYY, and greater calories consumed to achieve satiation (volume to fullness) and to evoke satiety with an ad-libitum meal. We showed that a short-acting GLP-1 agonist, exenatide, 5µg, SQ, BID for 30 days, delays gastric emptying and induces weight loss. Thus, quantitative gastrointestinal (GI) traits are associated with higher BMI, distinguish obesity phenotypes, and may predict efficacy of obesity drug therapy. In the R56-DK67071-funded pilot randomized, placebo-controlled trial of the longer-acting GLP-1 agonist, liraglutide, 3mg, SQ daily, we showed: (a) feasibility to recruit and randomize, over 8 months, 30 patients into a 4-month study (only 2 dropouts on treatment, to date); (b) safety data in all 30 randomized patients; (c) baseline quantitative traits of gastric emptying of solids and liquids, fasting and postprandial gastric volumes; satiation and satiety data; postprandial plasma incretins (GLP-1 and PYY) in all randomized patients; (d) gastric emptying data at fully escalated dose of liraglutide (weeks 5-6) in 30 patients; (e) repeat measurement (as in c) of quantitative traits at 16 weeks' treatment in 28 patients; (f) monthly weight data for duration on treatment in 28 patients. Our overall hypothesis is that weight loss with pharmacological agents may be individualized, based on specific abnormalities in quantitative GI traits. We propose a randomized, controlled clinical and pharmacodynamics trial, using a 2-treatment stratified design, to assess the hypothesis that a quantitative trait (gastric emptying rate) can impact the weight loss response among overweight (BMI >27kg/m2 plus obesity co- morbidities) or obese (BMI >30kg/m2) patients to treatment with the FDA-approved GLP-1 receptor agonist, liraglutide (dose escalated to maximum of 3mg, SQ, per day for 12 weeks) compared to placebo. Effects will be compared for those with baseline accelerated in comparison with normal gastric emptying. Our aims are: first, to assess the effects of liraglutide, 3mg/day, on gastric motor functions, satiation, satiety, weight loss and incretins; and second, to appraise the association of baseline accelerated gastric emptying on weight loss in response to liraglutide treatment. By measuring quantitative Gl traits at baseline and after 12 weeks of liraglutide treatment, we shall further understand the mechanism of action of this GLP-1 agonist. Significance: Our study addresses the treatment of obesity, introducing an era of individualizing drug therapy for obesity based on quantitative biomarkers. Therefore, it addresses an important public health challenge.