Urolithin A

重要的说在前面：在Ai编程能力的加持下，写综述参考文献的限制终于突破了，现在一口气吃下300篇文章没有问题。由于不是用之前Dify搭建的流程，目前还没有办法上线。如果有感兴趣的，可以留言私聊。 Abstract 司美格鲁肽是一种长效胰高血糖素样肽-1受体激动剂（GLP-1 RA），最初为治疗2型糖尿病而开发。本综述旨在全面分析司美格鲁肽的药理学特性、临床疗效、安全性及其在多个治疗领域的应用。通过整合关键临床试验（如SUSTAIN、PIONEER、STEP、SELECT、FLOW等）的数据，我们系统阐述了司美格鲁肽在血糖控制、体重管理、心血管保护、肾脏获益、心力衰竭（尤其是射血分数保留型心衰）和代谢功能障碍相关脂肪性肝炎（MASH）等方面的确切证据。此外，本文还探讨了其在成瘾、神经退行性疾病等新兴领域的潜在应用，并比较了其与其他代谢药物的疗效，讨论了联合用药策略。最后，我们总结了司美格鲁肽的安全性特征、真实世界数据和成本效益，并展望了其未来的研究方向和临床前景。 1. 引言 2型糖尿病（Type 2 Diabetes, T2D）与肥胖已成为全球性的重大公共卫生挑战，其患病率持续攀升，并带来了沉重的社会经济负担。这两种紧密相关的慢性代谢性疾病是心血管疾病、慢性肾脏病（Chronic Kidney Disease, CKD）、心力衰竭（Heart Failure, HF）及代谢功能障碍相关脂肪性肝炎（Metabolic dysfunction-associated steatohepatitis, MASH）等多种合并症的主要驱动因素，显著增加了患者的致残率和死亡风险，并对医疗系统造成巨大压力 [1, 2]。特别是在东亚人群中，由于其独特的身体成分特征和较低的肥胖诊断阈值，这一挑战更显严峻 [3]。因此，开发能够同时有效管理血糖和体重，并改善多系统并发症的创新疗法，对于减轻全球健康负担至关重要。 肠促胰素系统在维持葡萄糖稳态中扮演着核心角色。其中，胰高血糖素样肽-1（Glucagon-like peptide-1, GLP-1）是一种由肠道L细胞在进食后分泌的多肽激素。GLP-1通过与广泛分布于胰腺、大脑、心脏、肾脏及胃肠道等组织的GLP-1受体（GLP-1R）结合，发挥多效性生理作用：它能以葡萄糖依赖的方式刺激胰岛素分泌、抑制胰高血糖素释放，从而有效降低血糖；同时，它还能延缓胃排空，并通过作用于中枢神经系统来增强饱腹感、抑制食欲，进而调节能量平衡与体重 [4, 5]。然而，天然GLP-1在体内会被二肽基肽酶-4（DPP-4）迅速降解，半衰期仅为几分钟，这限制了其直接作为治疗药物的应用。 为克服天然GLP-1的局限性，长效GLP-1受体激动剂（GLP-1 RA）应运而生，司美格鲁肽（Semaglutide）是其中的杰出代表。司美格鲁肽是在人GLP-1骨架基础上进行分子结构修饰的产物，其与天然人GLP-1有94%的序列同源性。关键的结构优化包括：1）在第8位丙氨酸被α-氨基异丁酸（AIB）取代，以抵抗DPP-4的降解；2）在第26位赖氨酸上通过一个连接子连接了一个C18脂肪二酸侧链。这一脂肪酸侧链的引入，使得司美格鲁肽能够与血清白蛋白紧密结合，从而有效减少肾脏清除并保护其免受酶促降解，最终使其半衰期延长至约7天，实现了每周一次的皮下注射给药 [6, 7]。这一创新的药代动力学特性极大地提高了患者的用药便利性和依从性。更具里程碑意义的是，通过与吸收促进剂N-(8-[2-羟基苯甲酰]氨基)辛酸钠（SNAC）共同配制，司美格鲁肽成功开发出全球首个口服GLP-1 RA剂型，进一步拓宽了其临床应用场景 [8, 9, 10]。 司美格鲁肽最初作为降糖药物获批，随后凭借其卓越的减重效果，其适应症扩展至肥胖症的长期管理，成为代谢性疾病治疗领域的基石药物 [7, 11]。然而，其临床价值远不止于此。近年来，一系列大规模临床试验揭示了司美格鲁肽超越降糖和减重之外的多系统保护作用。例如，在伴有心血管疾病的超重或肥胖患者中，司美格鲁肽显著降低了主要不良心血管事件的风险 [12, 13]。在T2D合并CKD患者中，它有效延缓了肾脏疾病进展并降低了相关死亡率 [14, 15]。此外，在肥胖相关的心力衰竭 [16, 17]、MASH [18] 以及肾脏保护 [19] 等领域，司美格鲁肽也展现出巨大的治疗潜力，其背后的分子机制研究亦在不断深入 [20, 21]。鉴于司美格鲁肽在临床实践中的地位日益重要及其不断拓展的治疗版图，本综述旨在全面梳理司美格鲁肽从其核心适应症（T2D和肥胖）到多系统器官获益的临床研究证据，并对其未来的发展方向和潜在应用进行展望，以期为临床医生和研究人员提供全面而深入的参考。2. 司美格鲁肽的药理学特征 司美格鲁肽是一种长效胰高血糖素样肽-1（Glucagon-like peptide-1, GLP-1）受体激动剂（GLP-1 RA），其氨基酸序列与人内源性GLP-1具有高达94%的同源性。通过结构修饰——在第8位丙氨酸被α-氨基异丁酸取代以抵抗二肽基肽酶-4（DPP-4）的降解，并在第26位赖氨酸上连接一个间隔子和C18脂肪二酸侧链，使其能够与白蛋白牢固结合，从而显著延长了其半衰期，实现了每周一次的皮下给药。其核心药理作用在于模拟内源性GLP-1，激活广泛分布于胰腺、胃肠道、中枢神经系统等组织的GLP-1受体，从而发挥多方面的代谢调节效应。 首先，司美格鲁肽以葡萄糖浓度依赖的方式调节血糖。在高血糖状态下，它能有效刺激胰岛β细胞增殖并促进胰岛素的合成与分泌，增强机体对葡萄糖的摄取和利用。同时，它还能抑制胰岛α细胞分泌胰高血糖素，减少肝糖输出。这种双重调节机制具有低血糖风险低的优点，因为其作用会随着血糖水平的降低而减弱 [22, 23]。其次，司美格鲁肽通过作用于胃肠道，能够延缓胃排空，减慢食物从胃进入小肠的速度。这不仅有助于降低餐后血糖峰值，还能延长饱腹感，是其抑制食欲和控制体重的重要外周机制之一。 除了外周作用，司美格鲁肽在中枢神经系统（CNS）的食欲和能量代谢调控中也扮演着关键角色。GLP-1受体广泛分布于脑干和下丘脑等关键脑区，这些区域是整合饱腹感信号和调节能量平衡的核心。司美格鲁肽能够穿过血脑屏障，直接作用于这些中枢区域，且中枢与外周的GLP-1系统可独立地抑制食欲 [5]。临床前研究揭示了其详细的中枢作用通路。司美格鲁肽能够激活后脑区域（如最后区，Area Postrema, AP）和孤束核（Nucleus of the Solitary Tract, NTS）的GLP-1受体阳性神经元。这些脑区缺乏完整的血脑屏障，能够直接感知循环中的信号分子。近期研究发现，司美格鲁肽在背侧迷走神经复合体（Dorsal Vagal Complex）中激活的许多表达Adcyap1（腺苷酸环化酶激活多肽1）的神经元，其再激活可模拟药物降低食物摄入、减轻体重、促进脂肪利用和引发条件性味觉厌恶等效应，表明这些神经元是介导司美格鲁肽能量平衡效应的关键节点 [24]。此外，司美格鲁肽还作用于下丘脑的弓状核（Arcuate Nucleus），通过调节阿片-黑皮质素原（POMC）神经元和刺鼠相关蛋白（AgRP）神经元的活性，增强饱腹感信号并抑制饥饿信号，从而全面调控能量摄入。这些中枢机制与外周的胃排空延缓效应协同作用，共同实现了强大的食欲抑制和体重控制效果。值得注意的是，GLP-1药物的益处可能超越了单纯的体重减轻，其在调节能量底物利用 [20] 和其他代谢通路方面也显示出独立于体重减轻的作用 [25]。 司美格鲁肽目前有两种临床应用的剂型：每周一次的皮下注射剂和每日一次的口服剂型，两者在药代动力学（PK）和药效学（PD）上表现出不同特征。皮下注射剂型给药后吸收缓慢，约在1-3天内达到最大血药浓度（Cmax）。由于其分子结构中的脂肪酸侧链能与血浆白蛋白强力结合，极大地减少了肾脏清除并保护其免受酶促降解，其终末半衰期长达约168小时（7天），为每周一次给药方案提供了药代动力学基础。这种给药方式能够维持相对平稳的血药浓度，确保持续的GLP-1受体激活。 口服剂型的开发是肽类药物递送领域的重大突破。传统上，肽类药物口服生物利用度极低，因为它们在胃肠道中易被蛋白酶降解且难以穿透肠道上皮屏障。口服司美格鲁肽通过与吸收增强剂——沙卡布仑钠（SNAC, salcaprozate sodium）共同给药，成功克服了这些障碍 [26]。SNAC是一种小分子化合物，其作用机制是多方面的：首先，它能在胃部局部环境中起到缓冲作用，中和胃酸，从而抑制胃蛋白酶的活性，保护司美格鲁肽免于降解；其次，SNAC能够瞬时性地增加胃上皮细胞膜的流动性，可能是通过诱导膜的暂时性缺陷，促进司美格鲁肽分子以跨细胞途径被完整吸收进入血液循环 [26, 27]。这种吸收过程主要发生在胃部，而非小肠。为确保最佳吸收，口服司美格鲁肽需在清晨空腹状态下，用少量水（不超过120毫升）送服，并在服药后至少等待30分钟再进食、饮水或服用其他口服药物。口服剂型每日给药一次，其PK特征表现为给药后血药浓度快速上升，随后下降，呈现出比皮下注射更显著的峰谷波动。尽管PK曲线不同，但临床试验（如PIONEER系列研究）已证实，每日一次的口服司美格鲁肽在达到治疗剂量后，同样能有效降低糖化血红蛋白和体重，其疗效和安全性在不同人群中（包括日本患者）得到了验证 [28]，并且更高剂量的口服剂型（如25mg）在超重或肥胖成人中也显示出良好的减重效果 [29]。3. 核心适应症的临床疗效 司美格鲁肽作为一种长效GLP-1受体激动剂（GLP-1 RA），通过其全面的临床开发项目，已在2型糖尿病（T2D）和肥胖症两大核心适应症中确立了卓越的临床疗效和价值。本节将系统回顾支持其在这两大领域应用的关键临床试验证据。3.1 2型糖尿病 司美格鲁肽在T2D领域的临床开发涵盖了每周一次皮下注射（SUSTAIN项目）和每日一次口服（PIONEER项目）两种剂型，旨在全面评估其在不同治疗背景、不同人群中的降糖、减重及心血管获益。 皮下注射司美格鲁肽 (SUSTAIN系列试验) SUSTAIN系列试验奠定了皮下注射司美格鲁肽作为T2D治疗优选药物的地位。在作为单药治疗的SUSTAIN 1试验中，与安慰剂相比，司美格鲁肽0.5 mg和1.0 mg治疗30周即可显著降低糖化血红蛋白（HbA1c）达1.4%和1.5%，并带来3.7 kg和4.5 kg的体重减轻 [30]。 在与现有主流降糖药物的头对头比较中，司美格鲁肽展示了一致的优效性。SUSTAIN 2试验表明，在二甲双胍或/和噻唑烷二酮类药物基础上，司美格鲁肽0.5 mg和1.0 mg在降低HbA1c（-1.3%和-1.6%）和体重（-4.3 kg和-6.1 kg）方面的效果均显著优于DPP-4抑制剂西格列汀 [31]。同样，在与SGLT-2抑制剂的直接比较中，SUSTAIN 8试验证实，司美格鲁肽1.0 mg相较于卡格列净300 mg，在HbA1c（-1.5% vs -1.0%）和体重（-5.3 kg vs -4.2 kg）的降低上更具优势 [32]。一项基于真实世界数据的靶向试验模拟研究进一步提示，与恩格列净相比，司美格鲁肽可能在降低主要不良心血管事件（MACE）和全因死亡率方面具有更大获益 [33]。 在GLP-1 RA类别内部，SUSTAIN 7试验首次直接比较了两种周制剂，结果显示司美格鲁肽0.5 mg和1.0 mg在降糖和减重方面均优于度拉糖肽0.75 mg和1.5 mg [34]。与基础胰岛素的比较（SUSTAIN 4）也显示，司美格鲁肽在实现更优血糖控制的同时，伴随显著的体重减轻，而甘精胰岛素组则出现体重增加 [35]。此外，对于已接受SGLT-2抑制剂治疗的患者，SUSTAIN 9试验表明联合司美格鲁肽可带来进一步的显著降糖（-1.5%）和减重（-4.7 kg）获益，凸显了其在现代联合治疗方案中的价值 [36]。值得注意的是，在与双重GIP/GLP-1受体激动剂Tirzepatide的头对头比较（SURPASS-2试验）中，Tirzepatide在降糖和减重方面显示出更强的效力，这为临床医生在选择强效肠促胰素类药物时提供了新的参照 [37, 38]。 口服司美格鲁肽 (PIONEER系列试验) PIONEER项目成功开发了首个口服GLP-1 RA，为不愿或不便接受注射治疗的患者提供了创新选择。PIONEER 1试验确立了口服司美格鲁肽（3, 7, 14 mg）作为单药治疗相较于安慰剂的优越降糖和减重疗效 [39]。 在一系列与口服降糖药的头对头比较中，PIONEER 2试验显示，口服司美格鲁肽14 mg在降低HbA1c方面优于SGLT-2抑制剂恩格列净 [10]。PIONEER 3和PIONEER 7试验则证实其相较于DPP-4抑制剂西格列汀在降糖和减重方面均具有显著优势，且PIONEER 7的灵活剂量调整策略也验证了其临床应用的实用性 [40, 41]。更重要的是，PIONEER 4试验表明，口服司美格鲁肽14 mg在降低HbA1c方面不劣于皮下注射的GLP-1 RA利拉鲁肽1.8 mg，且减重效果更优 [42]。 在心血管结局方面，PIONEER 6试验首先确立了口服司美格鲁肽在高心血管风险T2D患者中的心血管安全性（MACE非劣效于安慰剂） [43]。近期公布的SOUL试验（NCT03914326）则进一步证实了其心血管获益，结果显示口服司美格鲁肽可显著降低高风险T2D患者的首次MACE发生率，实现了从心血管安全到心血管获益的跨越 [44]。此外，PIONEER 5试验还证实了口服司美格鲁肽在中度肾功能不全患者中的有效性和安全性，拓展了其适用人群 [45]。3.2 肥胖与体重管理 司美格鲁肽在体重管理领域的成功是其临床应用的另一大里程碑。STEP（Semaglutide Treatment Effect in People with obesity）系列临床试验系统评估了每周一次皮下注射司美格鲁肽2.4 mg在伴或不伴T2D的超重/肥胖成人中的减重疗效。 在成人中的减重疗效 针对不伴有T2D的超重或肥胖成人，STEP 1试验是该领域的标志性研究。经过68周治疗，司美格鲁肽2.4 mg组的平均体重降幅高达14.9%，而安慰剂组仅为2.4%。超过三分之一的受试者实现了20%以上的体重减轻，这一效果堪比某些减重手术 [46]。当与强化行为疗法相结合时（STEP 3），司美格鲁肽组的平均体重降幅可达16.0% [47]。 减重效果的持续性是评估肥胖治疗的关键。STEP 4试验创新性地采用撤药设计，结果显示，在经过20周的司美格鲁肽导入治疗后，继续用药的患者体重进一步下降7.9%，而换用安慰剂的患者体重则反弹了6.9%，这有力地证明了肥胖作为一种慢性疾病需要长期治疗以维持疗效 [48]。长达两年的STEP 5试验证实了其长期疗效，在104周时，司美格鲁肽组维持了15.2%的体重降幅 [49]。 对于伴有T2D的肥胖患者，其体重管理通常更具挑战性。STEP 2试验显示，司美格鲁肽2.4 mg在该人群中仍能实现9.6%的显著体重减轻，远超安慰剂组的3.4% [7]。 在特殊人群中的应用 司美格鲁肽的减重疗效已在更广泛的人群中得到验证。STEP TEENS试验首次在12至18岁以下的青少年肥胖患者中证实了其有效性和安全性，司美格鲁肽组的身体质量指数（BMI）平均下降16.1%，而安慰剂组则增加了0.6%，这一突破性结果使其获批用于青少年肥胖治疗 [50]。一项该试验的二次分析还表明，司美格鲁肽显著改善了青少年的胰岛素敏感性和其他心脏代谢风险因素 [51]。 考虑到种族差异，STEP 6和STEP 7试验分别在日本/韩国和以中国为主的东亚人群中进行，结果均显示出强大的减重效果（平均体重降幅分别为13.2%和12.1%），证实了其在该人群中的应用价值 [3, 52]。此外，OASIS 2试验进一步探索了口服司美格鲁肽50 mg在东亚超重/肥胖人群（伴或不伴T2D）中的疗效，也观察到具有临床意义的体重减轻 [53]。 对肥胖相关合并症的获益 司美格鲁肽的临床价值远不止于减重本身，其对肥胖相关合并症的改善尤为引人注目，特别是在射血分数保留的心力衰竭（HFpEF）领域。STEP-HFpEF项目（包括STEP-HFpEF和STEP-HFpEF DM试验）是首个专门评估减重药物对肥胖相关HFpEF患者影响的大型临床试验。结果显示，无论患者是否合并T2D，司美格鲁肽2.4 mg治疗52周均能显著改善患者的心衰相关症状（以堪萨斯城心肌病问卷临床总结评分[KCCQ-CSS]衡量）、身体活动能力（以6分钟步行距离[6MWD]衡量）和生活质量，同时大幅减轻体重 [54, 55, 56]。 对STEP-HFpEF项目数据的汇总分析提供了更深入的见解，证实了司美格鲁肽的疗效不受患者基线利尿剂使用情况、性别或左心室射血分数水平的影响，并能减少患者对利尿剂的需求 [57, 58, 59]。此外，治疗还与心房颤动事件的减少相关，提示其可能通过改善代谢和炎症状态对心脏结构和电生理产生积极影响 [60]。这些发现共同开创了将肥胖本身作为HFpEF治疗靶点的新范式。4. 多效性与扩展治疗领域 司美格鲁肽的治疗价值已远超其作为降糖和减重药物的初衷，展现出对心血管、肾脏、心脏和肝脏等多系统的广泛保护作用，即多效性（pleiotropy），从而极大地扩展了其临床应用领域。4.1 心血管保护：从糖尿病到更广泛人群 司美格鲁肽在心血管领域的保护作用最初在2型糖尿病（T2D）患者中得到证实。关键的心血管结局试验（CVOTs），如评估皮下注射制剂的SUSTAIN 6试验和评估口服制剂的PIONEER 6试验，均表明司美格鲁肽在伴有高心血管风险的T2D患者中，与安慰剂相比显著降低了主要不良心血管事件（MACE）的复合终点风险（分别为26%和21%），奠定了其心血管获益的基础 [61, 43]。 近期公布的里程碑式研究进一步将这一获益扩展至非糖尿病人群。SELECT试验招募了超过17,000名伴有心血管疾病的超重或肥胖但无糖尿病的患者，结果显示，每周一次皮下注射司美格鲁肽2.4 mg可使MACE风险降低20% [12]。这一发现至关重要，因为它首次证实了GLP-1受体激动剂在非糖尿病人群中的心血管一级预防价值。对SELECT试验的预设分析进一步揭示，司美格鲁肽的心血管获益与患者基线糖化血红蛋白（HbA1c）水平无关，且不受治疗后HbA1c变化幅度的影响，这表明其保护机制超越了传统的血糖控制，可能涉及抗炎、改善内皮功能和直接作用于动脉粥样硬化等通路 [62]。最新的SOUL试验再次确证了口服司美格鲁肽在T2D合并动脉粥样硬化性心血管疾病或慢性肾脏病（CKD）患者中的心血管保护作用，进一步巩固了其作为心血管疾病二级预防关键药物的地位 [63]。其潜在机制复杂多样，包括显著降低血压 [64]，以及可能通过调节骨髓源性祖细胞，使其向抗炎和促再生表型转化，从而促进血管修复并降低动脉粥样硬化血栓形成的风险 [65]。4.2 心力衰竭：开创HFpEF治疗新纪元 肥胖是射血分数保留型心力衰竭（HFpEF）的核心驱动因素之一，但长期以来缺乏针对这一病理生理表型的有效疗法。STEP-HFpEF项目（包括STEP-HFpEF和STEP-HFpEF DM试验）的公布标志着该领域的重大突破。这两项试验分别入组了伴或不伴T2D的肥胖相关HFpEF患者，结果一致表明，司美格鲁肽治疗52周后，患者的堪萨斯城心肌病问卷临床总分（KCCQ-CSS）和体重这两项双重主要终点均得到显著改善 [54, 55]。 司美格鲁肽不仅带来了统计学上的显著差异，更重要的是为患者带来了切实的临床获益。患者报告的心衰相关症状、身体活动受限和生活质量均得到大幅提升 [66]。机制层面，司美格鲁肽的益处可能不仅源于体重减轻带来的机械性卸负，还涉及对心衰病理生理的直接干预。一项对STEP-HFpEF项目数据的分析发现，司美格鲁肽能显著降低N末端B型利钠肽原（NT-proBNP）水平，这是一种反映心肌壁张力和应激的关键生物标志物，提示其可能直接影响心脏的病理生理过程 [67]。近期的汇总分析进一步证实，司美格鲁肽能够改善HFpEF患者的临床事件，为治疗推荐提供了更坚实的证据 [68]。此外，在FLOW试验的T2D合并CKD患者中，司美格鲁肽同样展现出降低心衰相关结局的潜力，进一步拓宽了其在心衰领域的应用前景 [69]。4.3 肾脏保护：延缓CKD进展的关键干预 继心血管获益之后，司美格鲁肽在肾脏保护方面的作用也得到了高级别证据的证实。早期的CVOTs已初步显示其具有降低新发或恶化肾病风险的趋势。然而，专门为评估肾脏结局而设计的FLOW试验证实了其确切的肾脏保护地位。该试验在超过3500名T2D合并CKD（eGFR 25-75 ml/min/1.73m²）的患者中进行，结果显示，与安慰剂相比，司美格鲁肽将主要肾脏复合终点（肾病进展、肾脏或心血管原因导致的死亡）的风险显著降低了24% [15]。这一结果不仅确立了司美格鲁肽作为继SGLT2抑制剂和非甾体类MRA之后，T2D合并CKD患者肾脏保护治疗的“新支柱”，也为其在更广泛肾脏病人群中的应用提供了理论依据 [70]。FLOW试验的亚组分析还表明，无论患者基线是否联用SGLT2抑制剂，司美格鲁肽的肾脏保护作用均保持一致，这为临床联合用药策略提供了重要支持 [71]。4.4 肝脏保护：攻克MASH治疗难题 代谢功能障碍相关脂肪性肝炎（MASH，旧称NASH）是一种与代谢综合征密切相关的慢性进展性肝病，此前一直缺乏有效的药物治疗。司美格鲁肽在这一领域的探索取得了令人鼓舞的成果。一项关键的II期临床试验证明，与安慰剂相比，司美格鲁肽治疗72周能显著提高MASH组织学缓解率（消退且肝纤维化不恶化）[72]。 最新的III期临床试验中期分析结果进一步巩固了这些发现。该研究纳入了经活检证实的F2或F3期肝纤维化的MASH患者，结果显示，与安慰剂组相比，接受司美格鲁肽2.4 mg治疗的患者在MASH消退（58.7% vs 14.2%）和肝纤维化改善至少一个分级（44.0% vs 25.8%）方面均表现出显著优势 [73]。这些数据为司美格鲁肽成为首批有效治疗MASH的药物之一铺平了道路。其作用机制研究表明，司美格鲁肽通过调节肝脏内的代谢、炎症和纤维化通路，改善纤维化和炎症的组织学标志物，并下调与纤维生成相关的基因表达，从而实现对MASH病理过程的根本性改善 [74]。5. 新兴及潜在应用前景 司美格鲁肽在其已获批的降糖和减重适应症之外，正展现出治疗多种其他疾病的巨大潜力。其广泛的生物学效应，尤其是在中枢神经系统、免疫调节和炎症通路中的作用，为其在成瘾行为、神经系统疾病、精神障碍及炎症相关疾病等新兴领域的应用开辟了广阔的前景。5.1 对成瘾行为的干预潜力 GLP-1受体广泛分布于大脑中与奖赏、动机和冲动控制相关的区域，如腹侧被盖区（VTA）和伏隔核（NAc）。司美格鲁肽通过激活这些中枢GLP-1R，可能调节多巴胺能神经通路，从而减弱成瘾物质（如酒精、尼古丁）带来的愉悦感和渴求。 越来越多的证据支持司美格鲁肽在成瘾治疗中的应用。针对酒精使用障碍（AUD），多项大规模真实世界研究发现，使用司美格鲁肽的肥胖或2型糖尿病患者，其AUD的首次发生率和复发风险显著降低，风险降幅可达50%-56% [75]。一项在瑞典全国范围内开展的队列研究同样证实，与未使用GLP-1受体激动剂的时期相比，个体在使用司美格鲁肽或利拉鲁肽期间因AUD住院的风险显著下降 [76]。这些观察性研究的积极结果得到了近期一项2期随机临床试验（RCT）的支持，该试验评估了司美格鲁肽对AUD成年患者酒精消耗和渴求的影响，为司美格鲁肽在该领域的应用提供了更高级别的临床证据 [77]。 同样，在烟草依赖方面，一项基于真实世界数据的靶向试验模拟研究显示，在合并烟草使用障碍（TUD）的2型糖尿病患者中，司美格鲁肽的使用与TUD相关医疗保健指标的改善相关，提示其可能有助于降低吸烟欲望 [78]。这些初步发现为将司美格鲁肽等GLP-1RA开发为新型戒断辅助药物提供了有力依据，但仍需更多前瞻性RCT加以验证。5.2 神经保护作用的探索 司美格鲁肽的神经保护潜力可能源于其抗炎、抗氧化、改善脑血流和葡萄糖代谢以及抑制神经元凋亡等多重机制。在阿尔茨海默病（AD）领域，一项基于美国大型电子健康记录数据库的靶向试验模拟研究发现，在2型糖尿病患者中，使用司美格鲁肽与首次诊断为AD的风险降低相关 [79]。尽管这是观察性证据，但它为正在进行的评估司美格鲁肽治疗早期AD的临床试验提供了支持。 在帕金森病（PD）方面，临床前研究揭示了其潜在的作用机制。一项在PD小鼠模型中进行的研究表明，司美格鲁肽能够抑制与神经炎症和神经元损伤密切相关的反应性星形胶质细胞的活化。更重要的是，这种抑制作用增强了移植的神经干细胞（NSCs）的存活和治疗效果，提示司美格鲁肽不仅可能延缓疾病进程，还可能为细胞替代疗法提供协同增效作用 [80]。5.3 在精神及认知障碍中的应用 精神分裂症患者，尤其是接受第二代抗精神病药物（SGA）治疗的患者，常面临严重的代谢综合征，包括肥胖、高血糖和血脂异常，这极大地增加了心血管疾病风险并缩短了预期寿命。司美格鲁肽为此类患者的管理带来了新的希望。多项RCT证实了其有效性：HISTORI试验显示，在接受SGA治疗、合并肥胖和糖尿病前期的精神分裂症患者中，司美格鲁肽能显著改善血糖控制并实现大幅体重减轻 [81]。同样，COaST试验也证明了其在服用氯氮平的肥胖精神分裂症患者中的疗效 [82]。另一项研究则关注于早期干预，发现在精神分裂症谱系障碍患者出现早期代谢异常时，司美格鲁肽同样能有效控制体重和改善血糖指标，提示其在预防该人群长期心脏代谢风险方面的价值 [83]。 此外，司美格鲁肽在改善认知功能方面的潜力也受到关注。代谢异常与重度抑郁症（MDD）患者的认知功能障碍存在关联。基于GLP-1RA可能具有的促认知作用，一项随机、双盲、安慰剂对照的临床试验专门评估了司美格鲁肽治疗MDD成人患者认知功能障碍的有效性和安全性，这是该领域首个直接的临床研究探索 [84]。5.4 炎症相关疾病的治疗前景 司美格鲁肽的抗炎特性使其在多种以慢性炎症为特征的疾病中展现出治疗潜力。外周动脉疾病（PAD）是一种与动脉粥样硬化和炎症相关的疾病，严重影响患者的行走能力和生活质量。关键性的STRIDE试验结果表明，在合并2型糖尿病的症状性PAD患者中，司美格鲁肽能够显著改善其功能能力，包括最大步行距离、相关症状和健康相关生活质量 [85]。进一步的亚组分析显示，无论性别如何，患者均能从中获益，这拓宽了其在PAD管理中的应用前景 [86]。 在骨关节炎领域，特别是与肥胖密切相关的膝骨关节炎（OA），司美格鲁肽也显示出巨大潜力。在一项为期68周的大型RCT中，与安慰剂相比，司美格鲁肽不仅显著减轻了肥胖合并膝OA患者的体重，还显著改善了患者的膝关节疼痛和身体功能评分。值得注意的是，其症状改善效果部分独立于减重效果，这可能意味着司美格鲁肽通过直接的抗炎作用或其他未知机制对关节健康产生了积极影响 [87]。这一发现为治疗肥胖相关的退行性关节疾病提供了新的治疗策略。6. 比较疗效与联合治疗策略 司美格鲁肽的问世极大地改变了2型糖尿病和肥胖症的治疗格局，但为了更精准地指导临床实践，必须将其与现有及新兴的治疗方案进行比较。本节将深入探讨司美格鲁肽与其他肠促胰素类药物的头对头研究，分析其与不同药物类别的联合治疗潜力，并展望基于司美格鲁肽的下一代复方制剂。6.1 与同类及新一代肠促胰素药物的比较 司美格鲁肽在多项头对头临床试验中展示了其在GLP-1受体激动剂（GLP-1 RA）类别中的领先地位。与日制剂利拉鲁肽（liraglutide）相比，在针对无糖尿病的肥胖或超重成年人的STEP 8试验中，每周一次的司美格鲁肽2.4 mg在68周时实现了-15.8%的体重降幅，显著优于每日一次的利拉鲁肽3.0 mg（-6.4%）[88]。同样，在SUSTAIN 3试验中，与周制剂艾塞那肽缓释剂型（exenatide ER）相比，司美格鲁肽在降低糖化血红蛋白（HbA1c）和体重方面也表现出更优的疗效 [89]。与度拉糖肽（dulaglutide）的直接比较（SUSTAIN 7试验）也证实了司美格鲁肽在降糖和减重方面的优势 [34]。此外，针对日本2型糖尿病患者的PIONEER 9研究验证了口服司美格鲁肽的剂量依赖性疗效，并显示其优于安慰剂和利拉鲁肽 [90]。这些研究共同确立了司美格鲁肽作为高效GLP-1 RA的地位。 然而，新一代多靶点肠促胰素药物的出现，特别是葡萄糖依赖性促胰岛素多肽/GLP-1（GIP/GLP-1）双重受体激动剂替尔泊肽（tirzepatide），对司美格鲁肽的地位提出了挑战。在针对2型糖尿病患者的SURPASS-2头对头试验中，所有剂量的替尔泊肽（5, 10, 15 mg）在降低HbA1c和体重方面均优于司美格鲁肽1.0 mg [37]。近期一项针对无糖尿病的肥胖症患者的开放标签3b期试验进一步显示，在72周的治疗中，替尔泊肽最大耐受剂量组的平均体重降幅（-20.9%）显著高于司美格鲁肽2.4 mg组（-16.4%）[91]。真实世界研究也得出了相似的结论，观察性队列研究显示，使用替尔泊肽的患者比使用司美格鲁肽的患者实现了更大幅度的体重减轻 [92]。尽管缺乏直接比较的心血管结局试验（CVOTs），一项基于真实世界数据的队列研究提示，在心血管风险升高的2型糖尿病患者中，替尔泊肽与司美格鲁肽在降低主要不良心血管事件（MACE）方面的效果相似 [93]。 在安全性方面，胃肠道不良事件是肠促胰素类药物最常见的副作用。一项比较度拉糖肽、司美格鲁肽和替尔泊肽在2型糖尿病患者中胃肠道安全性的真实世界研究发现，与度拉糖肽相比，司美格鲁肽和替尔泊肽与更高的严重胃肠道不良事件（如胆道疾病、胰腺炎、肠梗阻和胃轻瘫）风险相关，但三者之间的绝对风险差异较小 [94]。有趣的是，临床前模型研究表明，替尔泊肽中的GIPR激动作用可能通过抗催吐效应，相比于纯GLP-1R激动剂司美格鲁肽，在达到同等食欲抑制和减重效果的同时，引发的胃肠道不良反应更少 [95]。此外，尽管有监管机构对GLP-1 RA与自杀意念风险的关注，一项大规模真实世界队列研究并未发现司美格鲁肽与自杀意念风险增加相关 [96]。另一个值得关注的方面是减重过程中的身体成分变化，一项在小鼠中的研究提示司美格鲁肽可能对骨骼肌质量和力量产生非预期的影响，这提示需要在人类中进行更仔细的评估 [97]。6.2 与其他药物的联合治疗策略 为了实现疗效最大化并覆盖更广泛的病理生理通路，司美格鲁肽与其他药物的联合应用成为重要的治疗策略。其中，与钠-葡萄糖协同转运蛋白-2抑制剂（SGLT-2i）的联合尤为引人关注。这两类药物通过互补的机制（肠促胰素效应与促进尿糖排泄）协同控制血糖和体重，并有望在心血管和肾脏保护方面产生叠加获益。SUSTAIN 9试验证实，在已接受SGLT-2i治疗但血糖控制不佳的2型糖尿病患者中，加用司美格鲁肽能显著进一步降低HbA1c和体重 [36]。 从器官保护的角度看，GLP-1 RA和SGLT-2i均已证明具有独立的心肾获益。一项对SUSTAIN 6和LEADER试验的汇总分析显示，司美格鲁肽和利拉鲁肽能显著降低蛋白尿并减缓肾功能下降 [98]，而SGLT-2i的肾脏保护作用也已得到广泛证实。因此，理论上联合使用这两类药物能最大化心肾双重保护。最近来自FLOW试验的亚组分析数据支持了这一观点，结果显示无论患者基线是否使用SGLT-2i，司美格鲁肽均能一致地带来肾脏和心血管获益 [71]。在联合用药时，考虑患者的耐受性至关重要。一项试点研究表明，与标准的8周剂量递增方案相比，采用更缓慢、更灵活的16周递增方案可以提高司美格鲁肽的治疗依从性并减少胃肠道不良事件的发生 [99]，这一策略对于管理联合用药的潜在副作用具有重要的临床指导意义。6.3 下一代复方制剂的潜力 在单药疗效的基础上，开发基于司美格鲁肽的复方制剂是实现更强效减重和代谢改善的未来方向。其中，司美格鲁肽与长效胰淀素（amylin）类似物Cagrilintide的固定剂量组合（CagriSema）已展现出巨大的潜力。胰淀素与GLP-1在食欲调节中枢具有协同作用，能增强饱腹感并延缓胃排空。 早期的1b期和2期临床试验证明了CagriSema在减重和降糖方面的协同效应，且耐受性良好 [100, 101]。近期公布的3a期临床试验结果进一步巩固了其作为“超级减重药”的潜力。在一项针对无糖尿病的肥胖或超重成人的试验中，经过68周治疗，CagriSema组的平均体重降幅达到了惊人的-25.3%，显著优于司美格鲁肽2.4 mg单药组（-17.5%）和安慰剂组 [102]。在合并2型糖尿病的肥胖或超重患者中，CagriSema同样显示出卓越的疗效，不仅实现了-22.6%的体重降幅，还在血糖控制方面优于安慰剂 [103]。这些数据表明，CagriSema的减重效果已接近甚至超越了某些减重手术。临床前研究揭示了其背后的潜在机制：CagriSema在显著减少能量摄入的同时，能够维持能量消耗，从而有效减弱了减重过程中常见的代谢适应性下降，这可能是其强效减重的原因之一 [104]。CagriSema的成功预示着一个多靶点联合疗法的新时代，为未来肥胖症和相关代谢性疾病的治疗提供了更强有力的武器。7. 安全性、耐受性与真实世界证据 司美格鲁肽的安全性在广泛的临床试验项目（包括SUSTAIN、PIONEER和STEP系列）以及日益增多的真实世界数据中得到了充分的验证。总体而言，其耐受性良好，但特定的不良事件谱系，尤其是胃肠道反应，需要临床密切关注和管理。7.1 常见不良事件与耐受性管理 司美格鲁肽最常见的不良事件（Adverse Events, AEs）主要集中在胃肠道系统，呈剂量依赖性，通常为一过性且严重程度为轻至中度。这些事件包括恶心、腹泻、呕吐和便秘 [46, 7]。在针对肥胖症的STEP系列试验中，接受司美格鲁肽2.4 mg治疗的参与者中，恶心（约44%）、腹泻（约30%）、呕吐（约24%）和便秘（约24%）的发生率显著高于安慰剂组 [46]。更高剂量的研究，如口服50 mg的OASIS 1试验和皮下注射7.2 mg的STEP UP试验，也报告了相似但发生率更高的胃肠道AE谱系，这进一步证实了其剂量相关性 [105, 106, 107]。一项高达16 mg的皮下注射司美格鲁肽的2期试验同样观察到剂量依赖性的胃肠道AEs，但总体上仍可控 [108]。 这些胃肠道AEs的发生与药物作用机制（如延缓胃排空）直接相关，通常在治疗初期或剂量增加时出现，并随时间推移而减轻。为了最大限度地提高患者的耐受性和治疗依从性，缓慢的剂量滴定策略至关重要。一项随机对照试验明确指出，与标准的8周滴定方案相比，采用更缓慢、更灵活的16周滴定方案，能够显著降低胃肠道AEs的发生率并提高治疗的持续性 [99]。临床实践中，根据患者的个体反应调整滴定速度是减少因不良反应导致治疗中断的关键。此外，一项对LEADER、STEP 2、SUSTAIN-6和PIONEER 6试验的汇总分析显示，在GLP-1受体激动剂（GLP-1RA）起始治疗期间，联用二甲双胍并未显著增加胃肠道AE的发生 [109]，这为合并用药提供了安全性参考。7.2 重要安全性信号评估 尽管司美格鲁肽的总体安全性良好，但一些罕见但重要的安全性信号受到了监管机构和临床研究的密切关注。 自杀意念与行为： 近期，关于GLP-1RA与自杀意念和行为风险的关联引发了广泛讨论。然而，多项大规模研究未能证实这一因果关系。一项基于大型电子健康记录网络的回顾性队列研究发现，与非GLP-1RA抗肥胖药物相比，司美格鲁肽与自杀意念的风险并无增加 [96]。对STEP 1、2、3和5试验的汇总事后分析也显示，在无已知重度精神病史的肥胖或超重个体中，司美格鲁肽并未增加精神类不良事件的风险 [110]。此外，一项基于世界卫生组织全球个例安全性报告数据库（VigiBase）的比例失调分析，尽管发现了信号，但研究者强调该方法固有的局限性，无法确定因果关系，且可能受到媒体报道和适应症偏倚的影响 [111]。基于现有证据，欧洲药品管理局（EMA）和美国食品药品监督管理局（FDA）等主要监管机构的初步审查结论均认为，目前的数据不支持GLP-1RA（包括司美格鲁肽）与自杀意念或行为之间存在因果关联，但持续监测仍在进行中。 胰腺炎与胰腺癌： 作为GLP-1RA的类效应，急性胰腺炎是司美格鲁肽临床试验中报告的罕见严重不良事件。尽管发生率低，但在处方时仍需告知患者相关风险和症状。关于胰腺癌的风险，大型心血管结局试验（CVOTs）和荟萃分析并未显示司美格鲁肽会增加胰腺癌的风险，但由于其潜伏期长，长期安全性仍需进一步观察。 甲状腺髓样癌（MTC）： 临床前啮齿类动物研究显示GLP-1RA可导致甲状腺C细胞肿瘤的发生，因此司美格鲁肽在美国的药品说明书中带有关于MTC风险的黑框警告。然而，这一发现在非人灵长类动物中未被重现，且在人类中的相关性尚不明确。大规模的观察性研究和临床试验数据尚未证实司美格鲁肽与人类MTC风险增加之间存在关联。尽管如此，该药物禁用于有MTC个人史或家族史，或患有2型多发性内分泌肿瘤综合征（MEN 2）的患者。 其他安全性信号： 随着药物的广泛应用，新的安全性信号也在持续监测中。例如，一项大型跨国回顾性队列研究探讨了司美格鲁肽与非动脉炎性前部缺血性视神经病变（NAION）的潜在关联，提示需要进一步的前瞻性研究来明确风险 [112]。7.3 真实世界证据与社会经济因素 真实世界研究（Real-World Studies, RWS）为司美格鲁肽在常规临床实践中的应用模式、治疗持久性以及社会经济因素的影响提供了宝贵见解。 处方模式与患者特征： 丹麦的一项全国性队列研究分析了超过11万名Wegovy®（用于体重管理的司美格鲁肽品牌）使用者，发现真实世界中的使用者中位年龄为49岁，70%为女性，且剂量滴定模式多样，反映了临床实践中的个体化调整 [113]。 治疗中断率： 真实世界中的治疗中断率是一个关键问题。一项针对美国商业保险数据库的回顾性研究显示，在开始使用GLP-1RA（包括司美格鲁肽）治疗肥胖或超重的患者中，一年内的停药率较高 [114]。中断的原因复杂，可能包括胃肠道不耐受、费用高昂、药物短缺以及对治疗期望的管理等。 社会经济因素与可及性： 司美格鲁肽的高昂价格和不均衡的医保覆盖范围导致了显著的可及性问题和公平性挑战。一项针对美国Medicare受益人的研究发现，种族/民族、是否拥有低收入补贴以及是否同时享有Medicaid等社会经济因素，显著影响司美格鲁肽或替尔泊肽的启用，其中非西班牙裔黑人患者的启用率较低 [115]。另一项研究则揭示了在人类免疫缺陷病毒（HIV）感染者这一特殊人群中，尽管符合用药指征，但在司美格鲁肽的处方上存在显著的种族不平等现象 [116]。 成本效益分析： 司美格鲁肽的成本效益是各国卫生系统决策的关键考量。一项全面的系统综述和荟萃分析评估了司美格鲁肽用于治疗2型糖尿病的成本效益，结果显示其结论因国家、支付方视角和支付意愿阈值的不同而存在很大差异 [117]。针对不同适应症的分析也正在进行，例如，有研究评估了其在肥胖症 [1] 和伴有肥胖的膝骨关节炎 [118] 患者中的成本效益。这些分析普遍认为，尽管司美格鲁肽能带来显著的临床获益和生活质量改善，但其当前的高昂定价是实现广泛成本效益的主要障碍，未来价格的调整或长期获益数据的进一步证实将是关键。8. 结论与展望 司美格鲁肽作为一种革命性的GLP-1受体激动剂，已深刻重塑了2型糖尿病、肥胖及其相关合并症的治疗格局。大量临床试验证据，包括SELECT、FLOW和STEP-HFpEF项目，确凿无疑地证明了其在降低心血管事件风险、延缓肾病进展以及改善心力衰竭患者症状和功能状态方面的显著临床获益 [12, 15, 119, 120]。通过模拟内源性肠促胰岛素的作用，司美格鲁肽不仅能有效控制血糖和体重，还在炎症通路、心脏重构和血管功能等多个层面展现出多效性保护作用，使其成为代谢性疾病管理领域的一个里程碑 [121]。近期对SELECT、FLOW及STEP-HFpEF系列试验的汇总分析进一步证实，司美格鲁肽能够显著降低射血分数轻度降低或保留的心力衰竭（HFpEF）患者的心衰恶化和临床事件风险，无论其是否患有2型糖尿病 [122, 123]。 尽管司美格鲁肽的成就斐然，但当前研究仍存在一些亟待填补的空白，这也为未来的探索指明了方向。首先，关于其对身体成分的长期影响，特别是对肌肉质量和功能的影响，尚需深入研究。一项在小鼠模型中的研究提示，司美格鲁肽可能对骨骼肌质量和力量产生非预期的影响，这凸显了在人类中进行长期、精确评估的必要性，以确保减重带来的整体健康效益 [97]。其次，现有关于司美格鲁肽在HFpEF中获益的证据主要集中于肥胖相关表型 [119]，其在非肥胖HFpEF患者中的疗效和安全性仍是未知领域，需要专门的临床试验来验证。此外，司美格鲁肽的治疗潜力正向更多新兴领域扩展。初步研究显示，其在改善HIV相关脂肪增生症 [124]、改善有症状的外周动脉疾病患者的功能结局 [125]、作为1型糖尿病的辅助治疗 [126] 以及在代谢功能障碍相关脂肪性肝炎（MASH）的治疗中均显示出巨大潜力，但这些领域的疗效仍需通过更大规模的临床试验证实 [127]。 展望未来，代谢性疾病的治疗正朝着更高效、更个体化的方向发展。首先，更高剂量的司美格鲁肽正在被积极探索，以期获得更优的降糖和减重效果。例如，PIONEER PLUS试验证明了每日口服25mg和50mg司美格鲁肽相比于已获批的14mg剂量，在2型糖尿病患者中能带来更显著的HbA1c和体重下降 [128]。同样，更高剂量的皮下注射制剂（如每周7.2mg甚至16mg）也已在临床试验中显示出强大的疗效潜力 [107, 108]。其次，超越单靶点激动剂的新一代药物正在涌现。以GLP-1为基础，协同激动GIP、胰高血糖素、胰淀素或PYY等多重受体的多靶点激动剂，有望通过协同增效机制，实现前所未有的代谢改善，同时可能优化药物的耐受性 [129]。最后，药物递送系统的创新将是推动治疗进步的另一关键驱动力。研究人员正致力于开发新型口服递送技术，如利用靶向肠道新生儿Fc受体（FcRn）的生物工程纳米药物来提高口服生物利用度 [130]，这将极大提升治疗的便捷性和患者依从性。这些前沿探索预示着，通过剂量优化、靶点创新和递送系统革新，我们将能够为广大代谢性疾病患者提供更加精准化和个体化的治疗方案，开启一个全新的治疗时代。Supplementary Studies / Further Reading (Part 1)补充研究 / 进一步阅读 (第一部分) 近年来，胰高血糖素样肽-1受体激动剂（GLP-1RA）领域的研究取得了爆炸性增长，特别是在司美格鲁肽（Semaglutide）及其相关药物的临床应用和基础机制探索方面。本节旨在补充讨论一系列关键研究，这些研究进一步拓展了我们对这类药物在体重管理、器官保护、心力衰竭治疗以及其他新兴领域的理解。GLP-1RA在肥胖症和体重管理中的应用扩展 司美格鲁肽的出现被认为是肥胖治疗学“新纪元的开端” [131]，其卓越的减重效果在多项临床试验中得到证实。早期的II期剂量探索研究已显示，相比于利拉鲁肽（Liraglutide）和安慰剂，司美格鲁肽在肥胖患者中能带来更显著的体重下降 [132]。后续研究进一步确认，在无糖尿病的超重或肥胖成人中，每周一次的司美格鲁肽相比每日一次的利拉鲁肽，在68周时能实现更大幅度的体重减轻 [133]。STEP系列试验提供了强有力的证据，表明司美格鲁肽能有效增加体重减轻，尽管伴随胃肠道不良事件的增加 [134]，并且在经过20周的导入期后继续使用司美格鲁肽能够有效维持并改善减重效果 [135]。 这些发现推动了司美格鲁肽在特定人群中的应用探索。STEP 10试验专门针对肥胖合并糖尿病前期的个体，证实了司美格鲁肽2.4 mg在体重管理和血糖控制方面的有效性和安全性 [136]。考虑到亚洲人群在肥胖定义（BMI ≥25 kg/m²）和身体构成上的特点，STEP 11试验在韩国和泰国进行，结果表明司美格鲁肽2.4 mg在该人群中同样有效 [137]。此外，肥胖治疗的范围已扩展至青少年。一项为美国预防服务工作组（USPSTF）提供的系统回顾，评估了在医疗机构中对高BMI儿童和青少年进行体重管理的干预措施的利弊，为该领域的临床决策提供了证据支持 [138]。 多项系统回顾和网络荟萃分析对现有减肥药物的疗效和安全性进行了全面评估，进一步巩固了司美格鲁肽等新一代药物在成人肥胖症药物治疗中的地位 [139, 140, 141]。美国胃肠病学会（AGA）也发布了针对成人肥胖症药物干预的临床实践指南，为临床医生提供了决策支持 [142]。然而，一项对过去三十年肥胖药物临床试验的人口统计学特征（包括性别、种族和BMI）的系统回顾指出，试验人群与全球受肥胖影响的人群之间仍存在代表性差异，提示未来研究需更加关注多样性和包容性 [143]。肾脏保护作用的深入研究 GLP-1RA的肾脏保护作用是近年来备受关注的焦点。早期的事后分析已经揭示了积极信号。一项对SUSTAIN 1-7期试验的汇总分析表明，每周一次的皮下注射司美格鲁肽对2型糖尿病（T2D）患者的肾功能具有积极影响 [144]。同样，对SUSTAIN 6和PIONEER 6试验（均为心血管结局试验）的事后分析也提示，在高心血管风险的T2D患者中，与安慰剂相比，司美格鲁肽治疗与更稳定的估算肾小球滤过率（eGFR）相关 [145]。 这些线索最终在FLOW试验中得到了确证。该试验首次将主要肾脏疾病事件作为主要终点，结果表明在T2D合并慢性肾病（CKD）的患者中，司美格鲁肽显著降低了主要肾脏疾病事件的风险 [146]。FLOW试验的预设分析进一步探讨了司美格鲁肽对不同CKD严重程度患者心血管结局的影响，深化了对其肾脏和心血管双重获益的理解 [147]。更重要的是，司美格鲁肽的肾脏获益似乎超越了降糖范畴。在无糖尿病但伴有超重/肥胖和心血管疾病的SELECT试验人群中，司美格鲁肽同样显示出长期的肾脏保护作用 [148]。一项专门针对无糖尿病的超重/肥胖合并CKD患者的随机对照试验，进一步探索了司美格鲁肽在这一群体的肾脏保护潜力 [149]。为深入理解其肾脏保护机制，有学者提出应采用多模态、以组织为中心的方法来重塑肾脏疾病的机理研究试验，以全面揭示司美格鲁肽的作用机制 [150]。心力衰竭治疗的新范式 针对射血分数保留的心力衰竭（HFpEF）的肥胖表型，STEP-HFpEF系列试验的成功被誉为“治疗上的一大步”，开创了将肥胖作为HFpEF治疗靶点的新范式 [151]。预设分析显示，无论患者的肥胖等级如何，司美格鲁肽均能改善其症状、身体限制和运动功能 [152]。在合并T2D的肥胖相关HFpEF患者中，STEP-HFpEF DM试验的结果表明，司美格鲁肽的疗效与基线糖化血红蛋白（HbA1c）水平无关，具有广泛适用性 [153]。总体而言，司美格鲁肽治疗52周后，无论患者初始健康状况如何，均能显著改善健康状态并实现体重减轻 [154]。 在更广泛的心血管领域，SELECT试验是一项里程碑式的研究，它证实了在无糖尿病的超重/肥胖合并心血管疾病（CVD）患者中，司美格鲁肽能显著降低主要不良心血管事件（MACE）的发生率 [155]。该试验的一项预设分析进一步揭示，基线肥胖指标以及治疗引起的肥胖指标变化与后续MACE风险之间存在关联，强调了减重本身在心血管保护中的重要作用 [156]。肝脏疾病及其他代谢领域的探索 代谢功能障碍相关脂肪性肝病（MASLD）是另一个充满潜力的研究领域。一项IIa期研究比较了GLP-1/胰高血糖素受体双重激动剂efinopegdutide与司美格鲁肽对非酒精性脂肪性肝病（NAFLD）患者肝脏脂肪含量的影响，探索了多靶点激动剂的潜力 [157]。网络荟萃分析对多种用于代谢功能障碍相关脂肪性肝炎（MASH）的药物进行了比较，旨在评估它们在纤维化消退和MASH缓解方面的相对疗效，为临床用药选择提供了参考 [158]。对MASLD的综述性文章也系统总结了该疾病的流行、诊断与治疗现状 [159]。此外，研究人员还发现了一种羧基富勒烯衍生物作为新型脂滴调节剂，在抑制MASLD方面显示出潜力 [160]。 GLP-1RA的应用领域正在不断拓宽。STRIDE试验的结果提示，GLP-1RA可能对外周动脉疾病（PAD）患者有益，被认为是“朝着正确方向迈出的重要一步” [161]。同时，越来越多的证据表明GLP-1RA可能影响中枢奖赏通路，临床前和观察性研究提示其在治疗酒精使用障碍（AUD）方面具有潜力 [162, 163]。药物比较、联合用药及基础机制研究 在药物比较方面，一项早期研究比较了每日一次的司美格鲁肽与利拉鲁肽和安慰剂在T2D患者中的疗效 [164]。与双重GIP/GLP-1受体激动剂Tirzepatide的比较研究则揭示了后者在改善胰岛功能和胰岛素敏感性方面的独特机制 [165]，其结构基础研究也阐明了其在不同受体上的多重药理作用机制 [166]。 新一代药物和联合疗法也在积极开发中。例如，一种活性平衡的GLP-1/GDF15双重激动剂在小鼠和非人灵长类动物中显示出强大的减重和改善代谢紊乱的效果 [167]。固定剂量复方制剂IcoSema（基础胰岛素icodec和司美格鲁肽的周制剂组合）在COMBINE 3试验中与基础-餐时胰岛素方案进行了头对头比较，为T2D患者提供了新的治疗选择 [168]。 基础研究方面，科学家们正致力于阐明GLP-1RA的作用机制。研究发现，肠促胰岛素受体激动可快速抑制刺鼠相关蛋白（AgRP）神经元，从而抑制食物摄入 [169]。对β细胞特异性β-arrestin 2敲除小鼠的研究则揭示了GLP-1R在急性与长期药理反应中的差异 [170]。利用含有人诱导多能干细胞（iPSC）来源细胞的微生理系统，研究人员发现脂肪细胞炎症是肝脏胰岛素抵抗的主要驱动因素 [171]。在药物开发和递送技术方面，通过工程化手段构建GLP-1治疗药物的超分子纳米纤维储库，有望实现药物的缓释 [172]。同时，计算化学和自动化合成平台的发展，如分层反应逻辑和化学处理单元（Chemputer）的应用，正在加速复杂肽类药物（如司美格鲁肽）的合成与发现 [173, 174]。 在真实世界中，随着Tirzepatide等新药的获批，药物使用趋势发生了显著变化 [175]。安全性方面，一项队列研究评估了新使用GLP-1RA患者发生过敏反应的风险 [176]。最后，荟萃分析的证据也在不断演进，从早期的系统回顾 [177, 178, 179] 到纳入了FLOW和SOUL等最新试验的全面荟萃分析，不断更新和巩固了GLP-1RA在T2D患者中对心血管和肾脏结局的获益证据 [180]。这些研究共同构成了我们对这一重要药物类别不断深化的认识。Supplementary Studies / Further Reading (Part 2)补充研究 / 深入阅读 (Part 2) 近年来，随着对GLP-1受体激动剂（GLP-1RAs）及其相关多靶点激动剂研究的不断深入，其临床应用范围、作用机制和药物递送系统等方面均取得了显著进展。本节将探讨一些尚未在前文中详述的补充性研究，以期为读者提供更广阔的视角。临床应用的拓展与深化 GLP-1RAs的治疗潜力已远远超出了传统的降糖和减重领域，其在多种代谢相关并发症中的应用正被广泛探索。在肝脏疾病方面，针对代谢功能障碍相关脂肪性肝炎（MASH）的研究显示，每周一次的司美格鲁肽（semaglutide）治疗72周后，能够显著改善中度或晚期肝纤维化患者的肝脏组织学[181]。一项对多种MASH药物疗法的网络荟萃分析也证实，包括GLP-1RAs在内的药物能有效降低肝脏质子密度脂肪分数（PDFF），从而减少肝脏脂肪含量[182]。这些发现为欧洲肝病学会（EASL）、欧洲糖尿病研究协会（EASD）和欧洲肥胖研究协会（EASO）联合发布的代谢功能障碍相关脂肪性肝病（MASLD）临床实践指南提供了新的循证依据[183]。 在心血管和外周循环系统疾病中，司美格鲁肽同样展现出多重获益。对于伴有2型糖尿病（T2D）的症状性外周动脉疾病（PAD）患者，司美格鲁肽治疗一年后能增加其最大步行距离[184]。在合并肥胖的膝骨关节炎（OA）患者中，司美格鲁肽在饮食和运动咨询的基础上，有效减轻了体重并缓解了膝关节疼痛[185]。此外，对于肥胖相关的射血分数保留型心力衰竭（HFpEF）患者，司美格鲁肽不仅改善了运动功能[186]，其疗效在不同年龄段和衰弱状态的患者中均保持一致[187, 188]，而全身性炎症可能是HFpEF病理生理学中的一个关键因素[189]。除了这些领域，初步研究还提示司美格鲁肽可能改善慢性足底筋膜炎的预后[190]，并通过恢复中性粒细胞功能来对抗糖尿病和肥胖小鼠模型中的植入物相关感染[191]。然而，其对腰椎后路融合术后融合率的影响仍需进一步研究明确[192]。新一代激动剂与联合疗法 随着药物研发的推进，新一代多靶点激动剂和创新的联合疗法不断涌现。双重GIP/GLP-1受体激动剂替西帕肽（tirzepatide）在无T2D的肥胖成人中，其减重效果优于司美格鲁肽[193]，这建立在其已证实的对T2D患者（包括早发性T2D）的强大降糖和减重效果之上[194, 195]。另一项备受关注的联合疗法是cagrilintide与司美格鲁肽的组合，该组合在超重或肥胖成人中显示出更强的减重效果[196]。为了简化T2D患者的治疗方案，每周一次的固定剂量复方制剂IcoSema（基础胰岛素icodec与司美格鲁肽）在与单独使用icodec的对比中，显示出更优的疗效和安全性[197]。 除了已上市的药物，针对GLP-1和胰高血糖素受体（GCGR）的双重激动剂（如cotadutide）正在被积极评估其在肝脏和肾脏疾病中的治疗潜力[198, 199]。同时，靶向黑皮质素4受体（MC4R）等多个通路的多重激动剂也在开发中，旨在为糖尿病和肥胖症提供更高效且耐受性更好的治疗选择[200]。在一项对美国退伍军人T2D患者的比较效果研究中，司美格鲁肽、利拉鲁肽（liraglutide）和度拉糖肽（dulaglutide）在肾脏、心血管和死亡终点方面的风险差异得到了评估，为临床个体化用药提供了参考[201]。心血管、神经系统及其他系统性效应 自21世纪初以来，降糖药物的心血管安全性一直是监管和临床关注的焦点[202]。多项大型临床试验和荟萃分析已证实GLP-1RAs的心血管获益[203]。一项覆盖近10万名患者的系统回顾和荟萃分析进一步巩固了GLP-1RAs在不同人群中的心血管保护作用[204]。近期研究显示，口服司美格鲁肽能降低高风险T2D患者的主要不良心血管事件（MACE）风险[205]。其潜在机制可能包括对心肌细胞的直接保护作用，例如调节钙（Ca²⁺）和钠（Na⁺）的稳态[206]。真实世界研究观察到，司美格鲁肽的使用与心血管风险因素的改善和医疗支出的变化相关[207]。为了优化治疗策略，有研究提出可根据冠状动脉钙化（CAC）评分和BMI对患者进行分层，以识别获益最大的群体[208]。 在神经系统方面，GLP-1RAs的潜在影响正成为新的研究热点。探索性研究正在评估司美格鲁肽和替西帕肽与痴呆、帕金森病、卒中等神经退行性疾病和脑血管疾病风险的关联[209]，以及它们与视神经及视觉通路疾病（如非动脉炎性前部缺血性视神经病变，NAION）的潜在关系[210]。此外，对摄食行为的神经生物学研究发现，由多巴胺神经元介导的享乐性进食通路与GLP-1R介导的饱腹感信号存在拮抗作用，这为理解肥胖的复杂性提供了新视角[211]。一项针对退伍军人健康记录的大型队列研究发现，GLP-1RAs（而非DPP-4抑制剂）能显著减少酒精摄入量，提示其在治疗酒精使用障碍（AUD）方面具有潜力[212]。作用机制与前沿药物递送技术 对GLP-1受体激活机制的深入理解是开发新一代高效激动剂的基础。研究揭示了GLP-1R激活的“G蛋白优先”机制及其构象变化过程[213]，以及“激动-变构调节剂”（ago-allosteric modulators）在增强正构配体效能中的作用[214]。在细胞层面，研究发现GLP-1RAs可通过抑制铁死亡来减轻糖尿病肾损伤，其中β-Klotho蛋白可能扮演了关键角色[215]。更有趣的是，司美格鲁肽与尿石素A（Urolithin A）联用可通过代谢重编程增强CAR-T细胞的持久性和抗肿瘤活性[216]。 克服肽类药物的口服递送障碍是该领域面临的核心挑战。研究人员正积极开发多种创新递送系统。例如，通过优化纳米颗粒表面的胆甘酸（GCA）密度来平衡药物在肠道的吸收屏障[217]；利用具有自适应表面特性的牛奶外泌体-脂质体杂化囊泡来提高口服递送效率[218]；开发可在体内原位形成的合成上皮衬里，以增强大分子的生物利用度[219]。一项在猪模型中的研究通过内镜给药，成功实现了对回肠的靶向递送，并评估了其对司美格鲁肽吸收的影响[220]。此外，肽类药物的化学结构、脂质化修饰及制剂配方均对其在肠腔内的稳定性和吸收效率有重要影响[221]。除了口服途径，非注射给药方式也在探索中，如利用生物启发的颊部拉伸贴片[222]或可生物降解的颊部吸引贴片[223]实现经颊粘膜递送，以及通过调控吸入性纳米颗粒的表面亲水性实现精准的肺部给药[224]。人工智能（AI）驱动的从头设计方法也为开发超长效GLP-1RAs带来了新的机遇[225]。真实世界证据、安全性与社会经济学考量 随着GLP-1RAs的广泛应用，其在真实世界中的使用模式、安全性和社会经济学影响日益受到关注。一项回顾性队列研究探讨了影响肥胖患者开始使用司美格鲁肽的因素[226]，而另一项纵向分析则揭示了肥胖药物的处方趋势与公众认知度之间的相互作用[227]。在治疗选择上，与代谢减容手术相比，GLP-1RAs的长期减重效果和成本效益是临床决策中的重要考量因素[228]。在安全性方面，一项包含68项随机对照试验的网络荟萃分析评估了GLP-1RAs和SGLT2抑制剂与结直肠肿瘤风险的关联[229]。此外，GLP-1RAs对身体成分（特别是瘦体重）的影响也是一个持续关注的研究方向，相关系统回顾为此提供了全面的证据总结[230]。Supplementary Studies / Further Reading (Part 3) 除了核心治疗领域，近年来涌现出大量补充性研究，进一步拓展了我们对GLP-1受体激动剂（GLP-1 RAs）及其相关多肽疗法的理解。这些研究涵盖了从创新的药物递送系统到扩展的临床应用，再到真实世界证据和卫生经济学考量，为该领域的未来发展提供了重要参考。创新的肽类药物非侵入性递送系统 肽类药物的临床应用长期受限于其需要注射给药的缺点。为了克服生物屏障，实现口服或其他非侵入性递送，研究人员正在探索多种前沿策略。一项开创性研究表明，可以利用酶作为吸收促进剂，通过瞬时降低生物屏障的完整性来提高肽类药物的吸收 [231]。另一种策略是构建基于天然载体的混合囊泡系统。例如，通过调节牛奶外泌体与脂质体融合形成的杂化囊泡的弹性，可以优化其跨上皮细胞的运输，从而显著增强口服肽类药物的递送效率 [232]。此外，利用靶向策略的纳米技术也显示出巨大潜力。研究人员开发了靶向肠道新生儿Fc受体（FcRn）的PLGA-PEG纳米粒，成功增强了司美格鲁肽（semaglutide）的肠道细胞运输 [233]。另一项研究发现，天然二萜化合物毛喉鞘蕊花醇（forskolin）能够上调肠道或肺部黏膜上皮细胞中转运蛋白的表达和活性，从而放大配体修饰纳米载体的靶向转运效率，为生物大分子的口服和肺部递送提供了新思路 [234]。除了口服途径，舌下给药也是一种极具吸引力的非侵入性选择。通过合成新型肽（如脂质偶联鱼精蛋白），研究人员实现了与治疗性蛋白的简单物理混合，即可促进其通过舌下途径的全身性递送 [235]。GLP-1 RAs治疗领域的扩展与新机制探索 GLP-1 RAs的治疗潜力已远远超出降糖和减重的范畴，其在心血管、肝脏及神经系统等多个领域的应用正成为研究热点。 心血管与心力衰竭： 口服司美格鲁肽的心血管保护作用在SOUL试验中得到证实，进一步巩固了GLP-1 RAs在心血管疾病二级预防中的地位 [236]。美国心脏病学会（ACC）发布的2025年科学声明，强调了在合并肥胖的射血分数保留型心力衰竭（HFpEF）患者中，司美格鲁肽和替尔泊肽（tirzepatide）等减重药物结合健康行为干预的重要性 [237]。STEP-HFpEF系列研究的成功，标志着靶向肥胖成为治疗HFpEF的新范式，为这一患者群体带来了希望 [238, 239, 240]。系统评价也证实，在超重和肥胖的心衰患者中，通过药物治疗等方式实现的主动减重，对改善症状和生活质量具有积极意义 [241]。机制研究方面，司美格鲁肽被发现可通过改善BNIP3介导的线粒体功能障碍，有效减轻多柔比星（doxorubicin）引起的心脏毒性，揭示了其直接的心肌保护作用 [242]。这些进展共同推动了GLP-1 RAs在心脏病学领域的应用，正如2023年的心脏病学年度回顾所强调的，司美格鲁肽在肥胖患者中的应用是年度重要进展之一 [243, 244]。 代谢性肝病（MASH/NAFLD）： 全球非酒精性脂肪性肝病（NAFLD，现称为MASLD）的临床试验格局分析显示，GLP-1 RAs是研发管线中的关键药物类别 [245]。在临床实践中，GLP-1 RAs与其他机制药物的联合治疗显示出协同增效的潜力。一项II期研究评估了Fc-FGF21类似物efruxifermin与GLP-1 RA联合治疗在合并2型糖尿病的NASH/MASH患者中的安全性和有效性，探索了新的联合治疗方案 [246]。另一项临床前研究表明，ATP柠檬酸裂解酶（ACLY）抑制剂与GLP-1 RA联用，在改善小鼠NASH和肝纤维化方面表现出叠加获益 [247]。针对病情更严重的NASH相关肝硬化患者，一项II期试验证实司美格鲁肽2.4 mg能够改善肝脏健康指标，且安全性良好 [248]。考虑到MASH在2型糖尿病患者中的高负担，一项针对12个国家的广义成本效益分析，为预防、筛查和治疗该人群的MASH及肝纤维化提供了经济学依据 [249]。这些研究的进展也反映出，现有的NAFLD/FLD指南可能已无法完全涵盖最新的治疗进展，需要不断补充和更新 [250]。 神经保护、免疫调节及其他领域： GLP-1 RAs的潜在神经保护作用备受关注。一项基于大规模真实世界数据库的药物流行病学研究发现，GLP-1 RAs和SGLT-2抑制剂的使用与阿尔茨海默病风险降低相关，为这些药物在神经退行性疾病中的应用提供了初步线索 [251]。在免疫学层面，司美格鲁肽等肽类激素与胆汁酸被认为在塑造肝脏的免疫耐受中扮演重要角色，通过调节餐后代谢和免疫功能，可能对多种炎症相关疾病产生有益影响 [252]。此外，一项大规模队列研究发现，在银屑病患者中，使用GLP-1 RAs与全因死亡率、心血管及精神疾病风险的降低相关，提示其具有广泛的抗炎和多效性益处 [253]。超越代谢领域，肽类药物的设计思路也为其他疾病提供了借鉴。例如，一项研究设计了一种模拟Insig1/2蛋白loop 1区氨基酸序列的肽，成功抑制了固醇调节元件结合蛋白（SREBP）的活化，从而抑制了肿瘤的脂肪生成和生长，展示了肽类药物在肿瘤治疗中的潜力 [254]。新型肥胖药物疗法与临床实践考量 随着新型高效减重药物的问世，肥胖症的药物治疗进入了新纪元，同时也带来了临床实践、卫生经济学和社会层面的新挑战。 新兴疗法与系统评价： 多项系统回顾和网络荟萃分析对新兴的肥胖药物疗法进行了全面评估，比较了包括司美格鲁肽、替尔泊肽、retatrutide在内的七种GLP-1 RAs及多靶点激动剂的减重效果和安全性，为临床选择提供了循证依据 [255, 256, 257]。这些新疗法的开发深受代谢手术机制研究的启发，模拟了术后肠道激素分泌的改变，实现了前所未有的减重效果 [258, 259]。 真实世界证据与临床管理： 真实世界研究证实了司美格鲁肽和利拉鲁肽在临床实践中的长期减重效果，并探讨了达到显著减重（≥10%）的相关因素 [260, 261]。临床经验表明，药物的滴定方案对患者的治疗依从性和不良事件发生率至关重要。一项随机对照试点研究发现，与标签推荐的8周方案相比，采用更缓慢的16周灵活滴定方案能够提高司美格鲁肽的治疗依从性并减少胃肠道不良事件 [262]。此外，研究证实无论是口服还是注射给药，血浆中司美格鲁肽的循环水平是决定其降糖和减重效果的关键 [263]。在临床决策中，根据患者不同的病理生理学特征选择药物也至关重要，一项随机开放标签试验比较了司美格鲁肽和达格列净在不同病理生理特征的2型糖尿病患者中的疗效差异 [264]。同时，随着GLP-1 RAs应用的普及，临床医生也需关注其对特定医疗操作的影响，例如美国胃肠病学会（AGA）就发布了关于内镜检查前如何管理使用GLP-1 RAs患者的快速临床实践更新 [265]。FLOW试验的成功，也进一步确立了GLP-1 RAs作为2型糖尿病合并慢性肾病患者治疗的“第四大支柱”的地位 [266]。 卫生经济学与药物可及性： 新型减重药物的高昂费用引发了对其成本效益的广泛讨论。研究比较了司美格鲁肽与内镜下袖状胃成形术（ESG）的成本效益，为不同减重干预措施的选择提供了经济学视角 [267]。在青少年肥胖治疗领域，多项研究评估了不同减重药物（包括司美格鲁肽、利拉鲁肽、芬特明/托吡酯）的成本效益，为儿科临床决策和卫生政策制定提供了重要数据 [268, 269]。然而，药物的可及性仍是巨大挑战，尤其是在老年人群中。一项调查研究揭示了老年人对减重药物的看法以及对医疗保险覆盖范围的担忧，指出Medicare等保险不覆盖减重药物是推广应用的主要障碍 [270]。尽管如此，数据显示，针对12-17岁青少年的肥胖药物处方量在近年来呈上升趋势，反映了临床实践对药物治疗态度的转变 [271]。前沿研究工具与未来方向 基础科学的进步为药物研发提供了新的工具和方向。例如，研究人员开发了一种基于历史上首个化学发光化合物——洛粉碱（Lophine）的新型分子余辉发光探针，并成功应用于小鼠体内成像，为药物作用机制的可视化研究提供了新工具 [272]。在药物化学领域，通过引入氮杂肽（azapeptide）化学，成功设计出对蛋白酶具有抗性且效力强大的GLP-1和GIP受体双重激动剂，为开发更稳定、长效的新一代多靶点激动剂铺平了道路 [273]。这些基础研究的突破，将持续推动肥胖与代谢性疾病治疗领域的创新与发展。参考文献 Monica Saumoy, Devika Gandhi, Seth Buller, Shae Patel, Yecheskel Schneider, Gregory Cote, et al. 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