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目的 系统评价胰高血糖素样肽1受体激动剂（GLP-1RA）治疗合并超重或肥胖2型糖尿病（T2DM）患者的有效性与安全性。
方法 计算机检索PubMed、Embase、Cochrane Library、Ovid、ClinicalTrial.gov、SinoMed、CNKI、WanFang Data和VIP数据库，搜集有关GLP-1RA治疗T2DM合并超重或肥胖患者的随机对照试验（RCT），检索时限均从2005年1月1日至2023年11月1日。由2位研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后，采用R软件进行Meta分析，并采用GRADE系统进行证据质量评价。
结果 共纳入71个RCT，包括29 476例患者。Meta分析结果显示，相比于其他降糖药，GLP-1RA在改善糖化血红蛋白[WMD=-0.55，95%CI（-0.65，-0.45），P＜0.001]、减重[WMD=-2.61，95%CI（-3.25，-1.97），P＜0.001]方面均具有优势；GLP-1RA对空腹血糖的改善效果呈时间依赖性[16周以内：WMD=0.25，95%CI（-0.17，0.66），P=0.250 ；16~52周：WMD=-0.06，95%CI（-0.32，0.20），P=0.650；＞52~104周：WMD=-1.67，95%CI（-1.91，-1.43），P＜0.001]；安全性方面，GLP-1RA的总体不良反应发生率较高[RR=1.11，95%CI（1.07，1.15），P＜0.001]；但低血糖发生率低于胰岛素[RR=0.58，95%CI（0.48，0.71），P＜0.001]，而与口服降糖药的差异无统计学意义[RR=0.83，95%CI（0.58，1.19），P=0.310]。GRADE系统评价显示，仅低血糖发生率的证据等级为中等，其余结局指标的证据水平均为低级。
结论 当前证据显示，对于T2DM合并肥胖或超重患者，GLP-1RA尤其是司美格鲁肽相比于安慰剂、胰岛素或口服降糖药，能更有效兼顾降糖和减重，虽总体不良反应较多，但可减少低血糖发生。
糖尿病（diabetes mellitus，DM）和肥胖都是威胁全球公众健康的重大公共卫生问题。超重和肥胖已成为对2型糖尿病（type 2 diabetes mellitus，T2DM）影响最强的危险因素，占其总风险因素的80%~85%[1]，且肥胖对T2DM患者的预后也有重大影响。据统计DM患者的心血管疾病发病率是非DM人群的2~3倍[2]，而在合并超重或肥胖的T2DM患者中，心血管事件以及其他慢性并发症风险进一步增加[3]。因此，对于合并超重或肥胖的T2DM患者，降糖药的减重效果尤其受到重视。
胰高血糖素样肽1受体激动剂（glucagon-like peptide 1 receptor agonist，GLP-1RA）是一类新型降糖药，为内源性胰高血糖素样肽1（glucagon-like peptide 1，GLP-1）的类似物，其通过与GLP-1受体结合，以血糖依赖性方式促进胰岛素分泌，从而发挥降糖作用。GLP-1RA自上市以来，其减重作用尤其受到重视，美国食品药品管理局已批准2种GLP-1RA类药物利拉鲁肽和司美格鲁肽用于肥胖或超重个体[4]。此外，研究[5-6]报道GLP-1RA在减重同时，并不减少肌肉含量，且低血糖发生风险较低，因此被认为适用于老年患者。然而GLP-1RA可能导致一些不良反应，其中以胃肠道反应较常见。目前国内外已有关于GLP-1RA在T2DM合并超重或肥胖的患者中应用的Meta分析[7-15]，其中仅2项研究对于GLP-1RA进行了全方位评估，然而其纳入的文献数量较少，且缺乏综合性评估指标；其余研究涉及的GLP-1RA类药物、对照药物或结局指标较为单一，尚缺乏全面评估GLP-1RA对比其他降糖药疗效和安全性的研究。基于此，本研究对合并超重或肥胖的T2DM患者使用GLP-1RA的疗效和不良反应进行Meta分析，以期为临床治疗此类人群选用该类药物进行充分评估。
1 资料与方法
1.1 纳入与排除标准
1.1.1 研究类型
随机对照试验（randomized controlled trial，RCT）。
1.1.2 研究对象
T2DM患者，且病程＞1年，糖化血红蛋白（HbA1c）＞7%，身体质量指数（body mass index，BMI）≥24 kg·m-2。未伴严重或急性并发症。
1.1.3 干预措施
观察组：GLP-1RA类药物，包括利拉鲁肽、艾塞那肽、艾塞那肽微球、度拉糖肽、司美格鲁肽或聚乙二醇洛塞那肽；对照组：安慰剂、胰岛素或口服降糖药[包括钠-葡萄糖协同转运蛋白2抑制剂（sodium-dependent glucose transporters 2 inhibitors，SGLT-2i）、二肽基肽酶Ⅳ抑制剂（dipeptidyl peptidase Ⅳ inhibitors，DPP-4i）、噻唑烷二酮类药（thiazolidinediones，TZD）、磺脲类降糖药（sulfonylurea，SU）、α-葡萄糖苷酶抑制剂（α-glucosidase inhibitors，AGI）]。治疗持续时间至少为12周。
1.1.4 结局指标
主要结局指标为HbA1c；次要结局指标包括空腹血糖（fasting plasma glucose，FPG）、体重、优质达标率、总体不良反应和低血糖发生率。其中优质达标定义为在患者血糖达标（HbA1c≤7%）的同时，不额外增加体重以及低血糖发生风险[16]。
1.1.5 排除标准
①重复发表；②RCT设计、研究方法不合理或描述不完整的研究，主要包括：直接采用患者就诊顺序进行分组等不合理的随机化分配的研究；未描述随机化如何实施的研究；③缺乏主要结局指标的研究；④非英文、中文文献。
1.2 文献检索策略
计算机检索PubMed、Embase、Cochrane Library、SinoMed、Ovid、ClinicalTrial.gov、CNKI、WanFang Data和VIP数据库，搜集有关GLP-1RA治疗合并超重或肥胖的T2DM患者的RCT，由于第1个GLP-1RA类药物在我国于2005年上市[17]，因此检索时限设置为2005 年1 月1日—2023 年 11 月1日；中文检索词包括：2型糖尿病、胰高血糖素样肽1受体激动剂、随机对照试验等； 英文检索词包括：type 2 diabetes mellitus、GLP-1RAs、randomized controlled trial等。以PubMed为例，具体检索策略见框1。
1.3 文献筛选、数据提取与纳入研究的偏倚风险评价
由2名研究者独立筛选文献、提取资料、评价纳入研究的偏倚风险并交叉核对。如遇分歧，通过讨论和咨询第3名研究者解决。资料提取内容包括结局指标和研究其他相关信息，如样本量、平均年龄、性别、人种或国家、GLP-1RA制剂类型等基本特征。使用针对RCT的偏倚风险评价工具（risk of bias 2.0，RoB 2.0）[18]对纳入研究的偏倚风险进行评价。
1.4 统计学分析
采用R软件4.2.1版本进行统计分析。计量资料采用加权平均差（WMD）为效应指标，计数资料采用相对危险度（RR）为效应指标，各效应量均给出其点估计值和95%置信区间（CI）。纳入研究结果间的异质性采用Q检验进行分析，同时结合I2定量判断异质性的大小。若P＞0.1且I2＜50%认为研究结果间无统计学异质性，则采用固定效应模型进行Meta分析；反之，采用随机效应模型进行Meta分析。明显的临床异质性采用亚组分析或敏感性分析等方法进行处理，或只行描述性分析。使用漏斗图对于发表偏倚进行定性评价。
1.5 GRADE证据质量评价
使用推荐分级的评价、制订与评估（grading of recommendations assemssment，development and evaluation，GRADE）系统的GRADEpro在线评估工具（https: //gdt.gradepro.org/）评价各结局指标的证据质量。RCT被定为高质量证据，可能降低其证据质量的5个因素包括研究局限性、研究不一致性、研究结果间接性、研究不精确性和发表偏倚。
2 结果
2.1 文献筛选流程及纳入研究的基本特征
初检获得文献5 088篇，通过逐层筛选后，最终纳入71个RCT[19-89]，所有文献均为英文文献。文献筛选流程见图 1。
研究包括29 476例患者，男性占比55%，研究周期范围为12~104周，HbA1c基线水平为7%~12%，纳入文献的基线特征见表 1。
2.2 纳入研究偏倚风险评价结果
所有研究均对于各自随机化过程中分配序列的产生方式、患者随机入组情况进行了客观描述，以确保患者入组严格遵循随机化原则，同时各项研究均对于组间的基线信息进行了描述和比较，组间基线信息差异无统计学意义、具有可比性，故发生选择偏倚的风险较低；33项研究[24,26-27,29-31,34,36,40-41,44,47,49-50,54-56,62,65,67,69-71,73-74,76-80,84,86-87]未采用盲法，可能原因是GLP-1RA采用皮下注射给药、尤其是周制剂的给药周期较长，为每周1次，与其他口服降糖药在给药方式和周期上有较大差异，因此难以实施盲法，造成实施偏倚增加。虽然组间的干预措施不同，且部分研究未采用盲法，但是所有受试者的各结局的定义、评价方式、测量方法均标准化，因此不额外增加测量偏倚风险。所有研究的失访率均小于15%且均完整汇报了预先制定的所有结局指标，报告偏倚和失访偏倚发生风险较低。所有纳入研究产生偏倚风险的项目所占百分比情况见图 2。
2.3 Meta分析结果
2.3.1 HbA1c
共纳入71项研究[19-89]。随机效应模型Meta分析结果显示，在T2DM合并超重或肥胖患者中，GLP-1RA对HbA1c的改善效果优于安慰剂[WMD=-0.85，95%CI（-1.01，-0.69），P＜0.001]、胰岛素[WMD=-0.20，95%CI（-0.32，-0.08），P=0.001]、口服降糖药[WMD=-0.48，95%CI（-0.63，-0.32），P＜0.001]，见表2。在各种GLP-1RA类药物中，司美格鲁肽对HbA1c的改善效果最佳，可使HbA1c绝对值降低约1.61%，见表3。
2.3.2 FPG
共纳入55项研究[19-22,24-35,40-41,43-48,50-52,55,57- 58,60-73,76-77,79-83,85-89]。随机效应模型Meta分析结果显示，GLP-1RA与口服降糖药[WMD=-0.34，95%CI（-0.68，0.01），P=0.050]、胰岛素[WMD=0.14，95%CI（-0.21，0.48），P=0.430]对FPG的改善效果差异无统计学意义，见表2。此外，按治疗时长进行亚组分析，发现在治疗初期GLP-1RA对FPG改善效果虽不如胰岛素和口服降糖药[WMD=0.25，95%CI（-0.17，0.66），P=0.250]，但随着治疗时间增加，当治疗时长＞ 16周[WMD=-0.06，95%CI（-0.32，-0.20），P=0.650]，甚至＞52~104周时[WMD=-1.67，95%CI（-1.91，-1.43），P＜0.001]，GLP-1RA改善FPG的效果逐渐优于胰岛素和口服降糖药，见表2。在各种GLP-1RA类药物中，司美格鲁肽对FPG的绝对改善效果最佳，可使FPG降低约2.26 mmol·L-1，见表3。
2.3.3 体重
共纳入63项研究[19-38,40-50,52,54-66,68-73,76-78,80-83,85-89]。Meta分析结果显示，GLP-1RA的减重效果分别优于安慰剂[WMD=-2.25，95%CI（-3.14，-1.36），P＜0.001]、胰岛素[WMD=-3.20，95%CI（-3.49，-2.90），P＜0.001]、口服降糖药[WMD=-2.60，95%CI（-3.80，- 1.40），P＜0.001]，见表2。在各种GLP-1RA类药物中，司美格鲁肽减重效果更好，在整个研究周期中减重可达4.33 kg [95%CI（-5.10，-3.56），P＜0.001]，见表3。
2.3.4 优质达标率
共纳入11项研究[24,39,46,56,59-60,62,64,67,76-77]。Meta分析结果显示，GLP-1RA的优质达标率分别高于安慰剂[RR=3.76，95%CI （2.29，6.17），P＜0.001]、胰岛素[RR=2.74，95%CI （1.74，4.32），P＜0.001]和口服降糖药[RR=2.52，95%CI（1.84，3.44），P＜0.001]，见表2。
2.3.5 安全性
共38项研究[23-24,26,29,33-40,42,44,46-47,49-50,53,55,58-59,61-64,66,71-72,74-75,77,80-84,89]报告了总体不良反应发生率、55项研究[19,22-26,28-31,33-39,41-50,54,56,58-66,69-78,80-82,84-85,88-89]报告了低血糖发生率。。Meta分析结果显示，GLP-1RA组患者的总体不良反应发生率高于胰岛素组[RR=1.12，95%CI（1.03，1.21），P=0.006]和口服降糖药组[RR=1.10，95%CI（1.05，1.15），P＜0.001]，大多为胃肠道反应，主要包括恶心、呕吐、腹泻、消化不良；GLP-1RA组患者的低血糖发生率低于胰岛素组[RR=0.58，95%CI（0.48，0.71），P＜0.001]，而与口服降糖药组[RR=0.83，95%CI（0.58，1.19），P=0.310]差异无统计学意义，见表4。按口服降糖药种类进行亚组分析，结果显示，GLP-1RA与SU相比低血糖发生风险显著降低[RR=0.30，95%CI（0.19，0.45），P＜0.001]，与SGLT-2i [RR=1.00，95%CI（0.45，2.22），P=0.991]、DPP-4i [RR=0.90，95%CI（0.68，1.18），P=0.790]、TZD [RR=1.45，95%CI（0.82，2.55），P=0.203]相比低血糖发生率差异无统计学意义，见表4。
2.4 敏感性分析和发表偏倚的评价
各研究间存在异质性，分别按GLP-1RA类药物种类、GLP-1RA制剂类型、对照组药物类别、超重或肥胖、年龄、性别、纳入人群人种或国家以及口服降糖药种类进行亚组分析，发现各研究结果间的统计学异质性可通过亚组分析改善，但无法完全消除。敏感性分析发现，在对GLP-1RA有效性和安全性指标的Meta分析中，去除任一研究后合并效应量未发生明显变化，故认为该Meta分析虽然存在较大异质性，但结果较稳健。所有统计分析中，漏斗图均未见明显不对称，提示存在发表偏倚的可能性较低。
2.5 GRADE证据质量
6个结局指标的GRADE系统证据级别及升、降级原因见表5，经判定除低血糖发生率的证据级别为中等质量外，其余5项结局指标的证据级别均为低质量。
3 讨论
本研究采用Meta分析方法，全面评估了GLP-1RA（包括度拉糖肽、利拉鲁肽、艾塞那肽、艾塞那肽微球、聚乙二醇洛塞那肽和司美格鲁肽）在T2DM合并超重或肥胖患者中，其降糖、减重的效果及其安全性与其他降糖药综合比较的结果，完善了先前研究对于GLP-1RA与其他降糖药综合比较方面的结果。
在有效性方面，相比于胰岛素、口服降糖药，GLP-1RA在降低HbA1c、减重以及优质达标率等3项指标中优势显著。本研究结果显示，GLP-1RA对FPG的改善效果较口服降糖药、胰岛素并不具优势，与此前的一项研究结果一致[95]；但按干预时间进行亚组分析的结果显示，虽然在治疗早期GLP-1RA对FPG的改善效果确无优势，然而随着治疗时间延长，其对FPG的改善效果最终优于胰岛素和口服降糖药。可能原因是GLP-1RA的降糖作用呈血糖依赖性，导致FPG的改善效果在短期优势不明显；然而随着药物的持续使用，GLP-1RA的减重、控制食欲、促进β细胞增殖、改善胰岛素抵抗等其他效应逐渐开始呈现[96-98]，这些因素的改善同样有助于控制血糖，因此，认为在用药初期，GLP-1RA对血糖的改善作用依赖于其直接降糖效果，即血糖依赖性地刺激胰岛素释放从而发挥降糖作用；而后期对于血糖改善则是直接和间接降糖效应共同作用的结果，当GLP-1RA使用时间足够长，其降糖效果将优于胰岛素和口服降糖药。同样，Caruso等[99]研究也指出，GLP-1RA 的心血管获益与其治疗时间相关，即随着治疗时间延长，主要心血管不良事件发生率呈下降趋势，而心脑血管合并症是T2DM致死致残的主要原因[100]；此外，除对心脑血管的保护作用，GLP-1RA亦可通过多项机制改善心肌能量代谢，利于防治或延缓糖尿病心肌病发生发展[101]。因此以上证据提示，GLP-1RA的使用宜长期坚持。
肥胖使机体处于一种慢性炎症状态，增加了心血管疾病、高脂血症、T2DM和多囊卵巢综合征等疾病的风险，研究[102]表明减重对于超重或肥胖的T2DM患者的血糖、血脂、血压、动脉硬化均有不同程度的改善。GLP-1RA以葡萄糖依赖的方式刺激胰岛β细胞分泌胰岛素，减少胰岛α细胞产生胰高血糖素，从而降低空腹和餐后血浆葡萄糖。此外，GLP-1RA可通过激活下丘脑内的饱食中枢以抑制食欲，同时可减缓胃排空，以上机制共同诱导减重[103]。本研究结果显示，与安慰剂、胰岛素或口服降糖药相比，GLP-1RA表现出更显著的减重效果。按GLP-1RA种类进行亚组分析的结果显示，在6种GLP-1RA类药物中，司美格鲁肽表现出更明显的减重效果。因此，在治疗合并超重或肥胖的T2DM患者时，司美格鲁肽可能是更有效的药物。
安全性方面，虽GLP-1RA总体不良反应发生率更高，但绝大部分均为胃肠道反应。研究[104]显示GLP-1RA的不良反应多为剂量依赖性，大多数患者可耐受，且随治疗时间延长逐渐缓解。本研究在对GLP-1RA的剂量进行亚组分析时也发现同样的规律，即使用相对大剂量GLP-1RA时不良反应发生率更高。然而由于所纳入的研究中仅报道了在整个随访过程中不良反应的总体发生情况，未按照随访时间对不良反应进行分段记录，因此本研究在分析时无法按照治疗时间对不良反应进行亚组分析。尤为重要的是，相比于胰岛素，GLP-1RA在减少低血糖发生率方面具有明显优势，可减少约42%的低血糖发生率；与口服降糖药相比，GLP-1RA也不额外增加低血糖的发生风险，按口服降糖药种类进行亚组分析的结果显示，GLP-1RA与SGLT-2i、DPP-4i、TZD的低血糖发生风险相当，而较SU可显著降低低血糖风险；因此对于使用胰岛素、传统磺脲类药物治疗下反复发作低血糖的超重或肥胖患者，可优先考虑GLP-1RA。
本研究仍存在以下局限性：①本研究在确定检索年限时，主要基于GLP-1RA类药物在中国市场的可用性，然而，这一决策可能限制了对更广泛时期内全球研究成果的纳入。②纳入的研究中近一半（33项）的研究没有使用盲法，使文献整体质量下降，可导致潜在的偏倚。③总体上，研究结果间的统计学异质性较高，且部分异质性无法通过使用常规亚组分析消除。可能的原因包括纳入的各项研究间背景用药、基线情况无法保证严格一致；部分研究未配合饮食和运动的标准化控制，上述都为异质性来源，但难以避免。然而，由于各项研究的主要干预方式一致，药物剂量均为说明书推荐的标准剂量，纳入研究结局指标一致性较好，且敏感性分析结果显示其Meta分析结果稳定，故本研究结论仍有尚有较好的临床意义。
综上所述，GLP-1RA相对于安慰剂、胰岛素或口服降糖药具有多方位的临床应用价值，尤其在长期使用后，其效用优势更为突出；基于本研究的结果，对于合并超重或肥胖T2DM患者，针对其血糖控制不佳、并有高心血管风险等特点，建议应早期起始、长期坚持使用GLP-1RA制剂，其中司美格鲁肽为较优选择，具有较好的临床获益。
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