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中华移植杂志(电子版) ›› 2023, Vol. 17 ›› Issue (04): 205 -220. doi: 10.3877/cma.j.issn.1674-3903.2023.04.002

专家共识

成人实体器官移植后糖尿病管理专家共识
中国康复医学会器官移植康复专业委员会   
  • 收稿日期:2023-04-06 出版日期:2023-08-25

Expert consensus on diabetes mellitus after solid organ transplantation in adults

Organ Transplantation and Rehabilitation Committee of Chinese Medical Association of Rehabilitation   

  • Received:2023-04-06 Published:2023-08-25

移植后糖尿病(PTDM)是成人实体器官移植(SOT)后常见的内分泌代谢紊乱疾病,累及10%~40%的受者,严重威胁受者生存质量与长期存活。为进一步规范PTDM的诊治,相关专家依据国内外成人PTDM的研究进展并结合我国实际情况,对PTDM的流行病学、危险因素与发病机制、筛查与诊断、治疗、预防、心血管危险因素管理以及微血管并发症筛查等方面达成一致意见,提出指导建议。旨在规范化综合管理PTDM,以提高SOT受者的生存质量与长期存活。

Post-transplant diabetes mellitus (PTDM) is a common endocrine and metabolic disorder after adult solid organ transplant (SOT), affecting 10% to 40% of recipients. PTDM has been associated with increased mortality, heightened risk of infections, graft-related complications and cardiovascular diseases, all of which seriously threaten the quality of life and long-term survival of recipients. According to recent studies and the domestic healthcare system, this consensus provides a comprehensive overview of the epidemiology, risk factors, pathogenesis, screening and diagnosis, treatments, prevention strategies, cardiovascular risk factor management and microvascular complications associated with PTDM, in order to further standardize the diagnosis and treatment of PTDM. The objective is to standardize the comprehensive management of PTDM with the aim of enhancing the long-term quality of life and clinical outcomes for SOT recipients.

表1 不同免疫抑制剂的主要机制及与PTDM发生风险的关系
免疫抑制剂 主要机制 与PTDM发生风险的关系
糖皮质激素 刺激胰高糖素分泌,增加肝糖输出,这一效应呈剂量相关性[39],增加胰岛素抵抗并抑制胰岛素分泌,诱导胰岛细胞凋亡[40] 泼尼松龙逐渐减量至5 mg/d有助于改善肾移植后胰岛素敏感性[41],糖皮质激素减撤方案可以作为降低PTDM风险的一种优选方案[42]
CNI(他克莫司、环孢素) 抑制钙调神经磷酸酶活性,抑制细胞质钙调神经磷酸酶-活化T细胞的核因子亚单位的去磷酸化。CNI下调胰岛素受体底物2表达[43],影响胰岛β细胞中胰岛素和细胞增殖基因的转录,引起血糖升高。环孢素和他克莫司还可以通过增加脂肪细胞表面的葡萄糖转运蛋白4内吞速率,降低葡萄糖转运蛋白4表达来抑制葡萄糖摄取,而不依赖于胰岛素信号传导[44]。他克莫司减少胰岛素分泌效应更强,与环孢素相比更易导致PTDM。肾移植后使用他克莫司治疗1年的PTDM发病风险是环孢素的2.7倍[45,46,47,48] CNI减量可以作为降低PTDM风险的措施,肾移植后PTDM患者可将他克莫司调整为环孢素以减少PTDM发生[46]
mTORi(西罗莫司、依维莫司和贝拉西普) mTORi干扰胰岛素信号传导,加重胰岛素抵抗;同时具有抗增殖作用,抑制胰岛β细胞增殖,促进β细胞凋亡。西罗莫司促进胰岛素受体底物2的磷酸化,抑制β细胞分泌胰岛素[47] mTORi会增加PTDM发生风险,但较CNI略低[48]
ATG和阿仑单抗 ATG诱导促进Treg细胞增多[49]。阿仑单抗是靶向CD52特异性单克隆抗体,CD52富集于B和T淋巴细胞表面,阿仑单抗可诱导T和B淋巴细胞凋亡[50],对糖代谢无直接影响 阿仑单抗或ATG诱导不增加PTDM风险[51]
巴利昔单抗 IL-2受体的单抗(抗CD25),可显著抑制IL-2介导的T淋巴细胞增殖。动物实验中表明,巴利昔单抗使用后诱导Treg细胞减少,出现胰岛炎、胰岛β细胞破坏及糖尿病发生[52] 巴利昔单抗诱导发生PTDM的风险增加[53]
其他免疫抑制剂(麦考酚酸、硫唑嘌呤和咪唑立宾) 抑制嘌呤核苷酸的生物合成发挥抗增殖、抗代谢作用,对糖代谢无直接影响 麦考酚酸或硫唑嘌呤单独应用对PTDM无影响,联合用药目前证据尚不足[54];吗替麦考酚酯是常用麦考酚酸类药物,与其他免疫抑制剂联用时,减少CNI、类固醇药物等药物的剂量,间接降低实体器官移植受者PTDM的风险[55];咪唑立宾与PTDM的关系尚无研究报道
表2 PTDM的诊断标准
表3 糖代谢状态分类
表4 PTDM非胰岛素类降糖药物的安全性、有效性、与免疫抑制剂的相互作用以及注意事项
药物种类 常用代表药物 有效性a 安全性 药物相互作用 心肾获益 主要不良反应 注意事项
双胍类 二甲双胍 强效 循证证据较多,主要来源于肾移植受者,安全、优选用药。(1)肾移植:肾功能稳定情况下安全,降低全因死亡率、感染相关死亡率、恶性肿瘤相关死亡率[76,77,78];(2)肝、心、肺移植:证据缺乏 降低超重T2DM患者心血管风险,SOT受者获益情况不明 胃肠道反应常见,乳酸酸中毒罕见 注意监测肾功能,禁用于eGFR<45 mL·min-1·(1.73 m2)-1;肝功能不全、严重感染、缺氧或接受大手术的患者禁用
DPP-4i 西格列汀、沙格列汀、利格列汀、维格列汀、阿格列汀 中效 循证证据相对较少,安全。(1)肾移植:安全,耐受性良好[79,80,81,82,83,84,85];(2)心移植:安全,对体重无影响[86];(3)肝、肺移植:证据缺乏 西格列汀和CsA,维格列汀和TAC可能存在DDI T2DM人群中性,沙格列汀可能增加心力衰竭住院风险;SOT受者暂无依据 肾功能不全者需根据eGFR调整用量(利格列汀除外)
α-糖苷酶抑制剂 阿卡波糖、伏格列波糖、米格列醇 中效 循证证据缺乏,但国内专家有限的使用经验提示安全有效 循证证据缺乏 T2DM人群中性,SOT受者暂无依据 胃肠道反应常见 严重肝功能或肾功能不全、肠粘连、肠梗阻病史患者禁用
磺脲类 格列本脲、格列齐特、格列美脲、格列喹酮、格列吡嗪 强效 循证证据相对少,但临床使用经验较多。(1)肾移植:耐受性良好,存在一定程度低血糖风险[85,87];(2)肝、心、肺移植:证据缺乏 格列本脲、格列喹酮与CsA可能存在DDI T2DM人群中性,SOT受者暂无依据 低血糖、体重增加 eGFR下降者使用时低血糖风险增加;严重肝或肾功能不全、糖尿病急性并发症时禁用
噻唑烷二酮类 吡格列酮、罗格列酮 中效 循证证据较少。(1)肾移植:安全,耐受性良好[88,89];(2)肝移植:样本量少,短期应用安全[89];(3)心、肺移植:证据缺乏 吡格列酮与CNI无DDI T2DM人群心血管不良事件潜在获益(吡格列酮);心力衰竭风险增加;SOT受者暂无依据 体重增加、水肿、贫血、骨折等 心力衰竭、活动性肝病、严重骨质疏松和有病理性骨折病史的患者禁用
格列奈类 瑞格列奈、那格列奈、米格列奈钙 强效 循证证据较少。(1)肾移植:安全,耐受性良好[85,90,91];(2)肝、心、肺移植:证据缺乏 和CsA可能存在DDI T2DM人群中性;SOT受者暂无依据 低血糖、体重增加 可在肾功能不全患者中使用;与CsA联用时注意低血糖风险
SGLT2i 达格列净、恩格列净、卡格列净、恒格列净、艾托格列净 中-强效 循证证据较少。(1)肾移植:安全,耐受性良好,减少胰岛素使用剂量,小样本研究中未发现泌尿系统感染风险增加[92,93,94];(2)心移植:小样本研究发现降低体重、血压,减少利尿剂剂量,耐受性良好,偶发尿路感染[95,96],部分RCT研究进行中[97];(3)肝、肺移植:证据缺乏 与CNI、mTORi可能存在DDI T2DM人群获益,SOT受者使用大样本循证证据缺乏,小样本研究提示可能降低尿蛋白排泄;心脏移植PTDM者可能存在潜在获益 泌尿系统和生殖系统感染、血容量不足;糖尿病酮症酸中毒罕见 不建议用于eGFR<45 mL·min-1·(1.73 m2)-1患者
GLP-1RA 日制剂:利拉鲁肽、艾塞那肽、贝那鲁肽、利司那肽;周制剂:度拉糖肽、洛塞那肽、艾塞那肽周制剂、司美格鲁肽 强效 循证证据较少。(1)肾、肝、心移植:降低体重、体重指数、胰岛素剂量,未增加心血管疾病、移植物失功或全因死亡等风险[98,99];(2)肺移植:证据缺乏 T2DM人群获益,SOT受者大样本循证证据缺乏,获益情况不明 胃肠道反应 禁用于有甲状腺髓样癌病史或家族史的患者以及2型多发性内分泌肿瘤综合征患者;急性胰腺炎病史者慎用;严重高甘油三酯血症者建议降脂治疗后使用;使用司美格鲁肽时需注意监测糖尿病视网膜病变;需注意GLP-1RA致胃排空延迟可能影响免疫抑制剂的吸收
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