中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Effect of dapagliflozin on metabolic markers and autonomic function in patients with type 2 diabetes mellitus and metabolic associated fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2021.12.023
Research funding:

Science and Technique Foundation of He'nan (182102310596)

  • Received Date: 2021-05-07
  • Accepted Date: 2021-06-25
  • Published Date: 2021-12-20
  •   Objective  To investigate the effect of dapagliflozin on metabolic markers, hepatic fat content, and autonomic nervous function in patients with type 2 diabetes mellitus (T2DM) and metabolic associated fatty liver disease (MAFLD).  Methods  A total of 90 patients with T2DM and MAFLD who were admitted to The Second Affiliated Hospital of Zhengzhou University from October 2019 to October 2020 were enrolled and randomly divided into control group and dapagliflozin group, with 45 patients in each group. All patients were given conventional treatment before enrollment; the patients in the control group were treated with the original hypoglycemic regimen, and those in the dapagliflozin group were given dapagliflozin in addition to the treatment in the control group. The treatment cycle was 24 weeks. General information was collected before and after treatment, and the two groups were compared in terms of the changes in body mass index (BMI), glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), blood lipids, serum uric acid (SUA), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), liver function, liver fat content, and heart rate variability after treatment. The paired t-test was used for comparison of normally distributed continuous data within each group, and the independent samples t-test was used for comparison between groups; the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data within each group, and the Mann-Whitney U test was used for comparison between groups. The Chi-square test was used for comparison of categorical data between two groups.  Results  A total of 43 patients in the dapagliflozin group and 40 patients in the control group completed the study. After 24 weeks of treatment, the dapagliflozin group had significant reductions in BMI, HbA1c, FBG, triglyceride (TG), SUA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), HOMA-IR, and liver fat content (t=8.781, 8.765, 8.813, 3.485, 6.199, 5.694, 3.428, 6.492, and 4.925, all P < 0.05) and significant increases in high-density lipoprotein cholesterol, standard deviation of all normal R-R intervals (SDNN), standard deviation of average NN intervals (SDANN), root mean square of successive differences, percent of the number whose difference between adjacent NN interval are more than 50 ms (pNN50), high frequency (HF), and low frequency (LF) (t=-2.055, -6.307, -7.696, -3.388, and -7.928, Z=-3.339 and -3.309, all P < 0.05), while the control group had significant reductions in HbA1c, FBG, and HOMA-IR (t=9.220, 7.214, and 3.340, all P < 0.05). Compared with the control group after treatment, the dapagliflozin group had significantly lower levels of BMI, HbA1c, TG, SUA, HOMA-IR, ALT, AST, and liver fat content (t=-4.055, -2.670, -2.056, -2.496, -3.976, -3.703, -2.123, and -5.184, all P < 0.05) and significantly higher levels of SDNN, SDANN, pNN50, LF, and HF (t=4.136, 5.433, and 5.971, Z=-2.333 and -2.010, all P < 0.05).  Conclusion  For patients with T2DM and MAFLD, dapagliflozin can reduce BMI, HbA1c, TG, SUA, and liver fat content, improve insulin resistance and liver function, reduce the activity of sympathetic nerve, and regulate autonomic nerve function.

     

  • 肝硬化是各种慢性肝病导致肝脏弥漫性纤维化、再生结节形成的病理阶段[1],我国由HBV所致的肝硬化约为77%[2],患者处于代偿期时可无特异性症状和体征,起病常隐匿[1],而一旦进入有明显症状如腹水、肝性脑病等失代偿期,5年生存率仅为14%~35%[3]。相关指南、共识意见[1-2, 4-5]及研究[6-9]显示了肝硬化无创诊断方法如肝纤维化4因子指数(fibrosis 4 score,FIB-4)、AST和PLT比值指数(APRI)、GGT-PLT比值(GPR)、红细胞体积分布宽度(RDW)-PLT比值(red cell distribution width to platelet ratio,RPR)、肝脏瞬时弹性成像技术(TE)对肝硬化有着良好的诊断效应,但关于中医辨证分型与无创诊断方法的相关性分析较少,特别是在患者处于代偿期时临床症状轻,甚至“无症可辨”,这就给中医辨病、辨证论治造成一定的困难。近数十年的临床研究[4, 10]已经表明中医药在肝硬化防治领域具有疗效优势,且尚未有不良反应的报道。因此,寻找一种客观化指标辅助中医的诊治有着重要的意义。不但为中医辨证分型提供量化指标,使分型不仅结合病机更注重疾病所处阶段;而且中西医相结合,进一步准确客观的评估中医辨证论治的临床疗效。本研究通过回顾性分析代偿期乙型肝炎肝硬化患者相关临床资料,探讨以上5种肝硬化无创诊断方法在代偿期乙型肝炎肝硬化中与中医证型的关系,以期提高临床诊断辨证的准确性。

    回顾性纳入河南中医药大学第一附属医院2017年1月—2020年1月期间门诊和住院的代偿期乙型肝炎肝硬化患者共327例。

    (1) 西医诊断标准:参照《慢性乙型肝炎防治指南(2019年版)》[2]、《肝硬化诊治指南(2019年版)》[1]。(2)中医辨病辨证标准: ①诊断标准,参照《肝纤维化中西医结合诊疗指南(2019年版)》[4]与《肝硬化中西医结合诊疗共识(2011年版)》[5]分为肝郁脾虚证、肝胆湿热证、肝肾阴虚证、脾肾阳虚证、瘀血阻络证5型;②中医辨证分型,由1名主任医师和2名具有执业医师资格证的医师进行辨证并意见一致。

    (1) 符合代偿期乙型肝炎肝硬化西医诊断标准;(2)相关检验检查资料完整无缺失;(3)年龄18~75岁。

    (1) 其他类型的肝硬化(丙型肝炎肝硬化、自身免疫性肝炎肝硬化、酒精性肝硬化等)及合并此类疾病;(2)肝硬化失代偿期;(3)合并肝癌、其他恶性肿瘤。

    采用本研究小组制定的《肝硬化患者信息采集表》采集信息,使用EpiData3.1软件进行采集,并采用双人进行数据同步录入、核对、管理与质量控制。采集信息包括:(1)患者一般资料:姓名、性别、年龄等;(2)检验检查结果:PLT、RDW、ALT、AST、Alb、血清球蛋白(Glb)、GGT、FibroScan肝脏硬度值(LSM值)、彩超(具体报告及门静脉主干宽度等)。以上实验室指标均来自河南中医药大学第一附属医院检验科,LSM值来自河南中医药大学第一附属医院肝病实验室,彩超结果来自河南中医药大学第一附属医院超声科。肝纤维化无创诊断计算公式:(1)APRI=AST/AST正常值上限/PLT×100;(2)FIB-4=年龄×AST/(PLT×ALT的平根);(3)GPR=GGT/GGT正常值上限/PLT×100;(4)RPR=RDW/PLT。

    本研究通过河南中医药大学第一附属医院临床伦理委员会批准,批号: 2021HL-113-01。

    采用SPSS 21.0统计软件进行数据分析。所有的统计检验均采用双侧检验,符合正态分布的计量资料以x±s表示,多组间均数比较用单因素方差分析,进一步两两比较采用LSD-t检验;不符合正态分布的计量资料采用M(P25~P75)表示,多组间比较用多个独立样本Kruskal-Wallis H秩和检验,采用Kruskal-Wallis单因素ANOVE(k样本)进行多重比较;采用二元logistic回归分析进行中医证型与肝硬化无创诊断的关系;应用ROC曲线评价各无创诊断在中医证型中的价值。采用MedCalc 15.2.2软件计算各证型无创诊断的AUC、临界值、敏感度、特异度、阳性预测值、阴性预测值、似然比。P<0.05为差异有统计学意义。

    本研究共收集病历327例,其中男238例,女89例,年龄最小20岁,最大75岁,平均(44.14±11.26)岁, 各证型间性别与年龄分布差异无统计学意义(P值均>0.05)(表 1)。在代偿期乙型肝炎肝硬化患者中,主要的中医证型为肝郁脾虚证、肝胆湿热证、瘀血阻络证。

    表  1  中医证型分布情况
    证型 例数 性别 年龄(岁)
    男(例) 女(例)
    肝郁脾虚证 160 120 40 42.96±10.74
    肝胆湿热证 84 60 24 43.17±11.12
    肝肾阴虚证 13 8 5 45.46±10.41
    脾肾阳虚证 5 4 1 46.60±9.74
    瘀血阻络证 65 46 19 47.80±10.92
    统计值 χ2=1.569 F=2.451
    P 0.814 0.056
    下载: 导出CSV 
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    主要中医证型的检验检查资料除Glb以外,差异均具有统计学意义(P<0.05),进一步两两比较,发现瘀血阻络证PLT、Alb降低最为明显,门静脉宽度升高均最为明显;肝胆湿热证ALT、AST升高最为明显;在5种无创诊断方法中,除APRI外,瘀血阻络证升高均最为明显(P值均<0.05)(表 2)。

    表  2  代偿期乙型肝炎肝硬化患者主要中医证型基线资料比较
    相关指标 肝郁脾虚证(n=160) 肝胆湿热证(n=84) 瘀血阻络证(n=65) 统计量 P
    PLT(×109/L) 138.00(85.25~177.25) 110.50(92.25~142.75) 44.00(34.00~55.50)1)2) χ2=155.337 <0.05
    ALT(U/L) 34.00(21.95~43.63) 68.85(48.75~109.43)1) 29.50(17.95~39.75)2) χ2=123.210 <0.05
    AST(U/L) 28.95(23.60~39.63) 61.40(40.15~94.03)1) 27.60(21.55~38.05)2) χ2=86.659 <0.05
    Alb(g/L) 44.97±3.13 46.25±3.331) 31.41±2.461)2) F=542.512 <0.05
    GLB(g/L) 29.04±4.46 28.76±4.71 29.09±4.62 F=0.128 0.88
    GGT(U/L) 31.20(20.83~53.13) 39.10(27.33~65.15)1) 27.70(21.70~44.05)2) χ2=13.079 <0.05
    门静脉主干宽度(mm) 12.79±0.76 12.18±0.991) 13.40±0.581)2) F=43.373 <0.05
    LSM值(kPa) 16.00(13.40~18.08) 18.65(16.63~25.00)1) 24.40(22.30~26.50)1)2) χ2=131.312 <0.05
    APRI 1.10(0.62~1.35) 1.30(0.88~2.00)1) 1.55(1.26~2.31)1) χ2=54.280 <0.05
    FIB-4 1.90(1.38~2.74) 2.66(1.99~3.54)1) 6.19(4.66~8.37)1)2) χ2=129.893 <0.05
    GPR 0.67(0.27~1.18) 0.81(0.49~1.27)1) 1.52(0.94~2.46)1)2) χ2=57.485 <0.05
    RPR 0.37±0.16 0.39±0.10 1.10±0.341)2) F=351.219 <0.05
    注:与肝郁脾虚证相比,1)P<0.05;与肝胆湿热证相比, 2)P<0.05。
    下载: 导出CSV 
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    在肝胆湿热证中,AST(OR=1.981,95%CI:1.8225~2.139,P<0.05)、LSM(OR=2.002,95%CI:1.840~2.160,P<0.05)是代偿期乙型肝炎肝硬化的影响因素;在肝郁脾虚证中,门静脉宽度(OR=4.402,95%CI:4.050~4.754,P<0.05)、LSM值(OR=3.901,95%CI:3.589~4.213,P<0.05)、APRI(OR=1.891,95%CI:1.740~2.042,P<0.05)、FIB-4(OR=1.845,95%CI:1.697~1.993,P<0.05)是代偿期乙型肝炎肝硬化的影响因素;在瘀血阻络证中,LSM值(OR=2.465,95%CI:2.268~2.662, P<0.05)、APRI(OR=1.298,95%CI:1.194~1.402, P<0.05)、FIB-4(OR=1.849,95%CI:1.701~1.997, P<0.05)是代偿期乙型肝炎肝硬化的影响因素。

    2.4.1   肝郁脾虚证

    5种无创诊断方法在诊断肝郁脾虚证中的ROC曲线见图 1,临界值(cut-off值)、敏感度、特异度、阳性预测值、阴性预测值、阳性似然比、阴性似然比见表 3,由图表可知,在代偿期乙型肝炎肝硬化患者中,LSM值与FIB-4模型评估肝郁脾虚证的诊断价值明显优于其他诊断方法。

    图  1  肝郁脾虚证各无创诊断的ROC曲线
    表  3  各无创诊断评估肝郁脾虚证比较
    无创诊断方法 AUC(95%CI) cut-off值 敏感度(%) 特异度(%) 阳性预测值 阴性预测值 阳性似然比 阴性似然比
    LSM值 0.982(0.955~0.995) 0.875 98.12 89.33 95.2 95.7 9.20 0.02
    APRI 0.899(0.853~0.934) 0.629 86.87 76.00 88.5 73.1 3.62 0.17
    FIB-4 0.950(0.913~0.974) 0.776 85.62 92.00 95.8 75.0 10.70 0.16
    GPR 0.618(0.553~0.680) 0.303 55.63 74.67 82.4 44.1 2.20 0.59
    RPR 0.752(0.692~0.806) 0.533 61.25 92.00 94.2 52.7 7.66 0.42
    下载: 导出CSV 
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    2.4.2   肝胆湿热证

    5种无创诊断方法在诊断肝胆湿热证中的ROC曲线见图 2,cut-off值、敏感度、特异度、阳性预测值、阴性预测值、阳性似然比、阴性似然比见表 4,由图表可知,在代偿期乙型肝炎肝硬化患者中,LSM值与RPR模型评估肝胆湿热证的诊断价值明显优于其他诊断方法。

    图  2  肝胆湿热证各无创诊断的ROC曲线
    表  4  各无创诊断评估肝胆湿热证比较
    无创诊断方法 AUC(95%CI) cut-off值 敏感度(%) 特异度(%) 阳性预测值 阴性预测值 阳性似然比 阴性似然比
    LSM值 0.922(0.868~0.958) 0.806 95.24 85.33 87.9 94.1 6.49 0.06
    APRI 0.834(0.767~0.888) 0.570 80.95 76.00 79.1 78.1 3.37 0.25
    FIB-4 0.848(0.783~0.900) 0.536 86.90 66.67 74.5 82.0 2.61 2.61
    GPR 0.844(0.778~0.896) 0.553 72.62 82.67 82.4 72.9 4.19 0.33
    RPR 0.958(0.914~0.983) 0.777 85.71 92.00 92.3 85.2 10.71 0.16
    下载: 导出CSV 
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    2.4.3   瘀血阻络证

    5种无创诊断方法在诊断瘀血阻络证中的ROC曲线见图 3,cut-off值、敏感度、特异度、阳性预测值、阴性预测值、阳性似然比、阴性似然比见表 5,由图表可知,在代偿期乙型肝炎肝硬化患者中,5种无创诊断方法均能较好地评估瘀血阻络证。

    图  3  瘀血阻络证各无创诊断的ROC曲线
    表  5  各无创诊断评估瘀血阻络证比较
    无创诊断方法 AUC(95%CI) cut-off值 敏感度(%) 特异度(%) 阳性预测值 阴性预测值 阳性似然比 阴性似然比
    LSM值 0.969(0.925~0.991) 0.893 100.00 89.33 89.0 100.0 9.37 0.00
    APRI 0.895(0.831~0.940) 0.731 98.46 74.67 77.1 98.2 3.89 0.02
    FIB-4 0.949(0.899~0.979) 0.845 93.85 90.67 89.7 94.4 10.05 0.07
    GPR 0.941(0.888~0.973) 0.765 93.85 82.67 82.4 93.9 5.41 0.07
    RPR 0.935(0.880~0.969) 0.893 100.00 89.33 89.0 100.0 9.37 0.00
    下载: 导出CSV 
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    本研究对327例代偿期乙型肝炎肝硬化患者进行中医证候分析,发现以肝郁脾虚证、肝胆湿热证、瘀血阻络证最为常见,且肝郁脾虚证患者明显高于其他证型,同时发现5种肝硬化无创诊断方法在证型之间的差异均具有统计学意义(P<0.05),且数值均在瘀血阻络证中最高,而后依次为肝胆湿热证、肝郁脾虚证,这与既往的研究结果具有一致性[11]。结果说明在代偿期乙型肝炎肝硬化中不同证型其肝硬化程度不同,这与本病的中医病机演变规律相同。本病的形成多是由于HBV湿热疫毒之邪外侵袭人体,阻滞肝经,肝失疏泄,又湿邪最易伤脾,脾气虚弱,木郁犯土,发为本病;脾失健运,水湿内停,脾虚湿盛,邪正相争,湿郁化热,病情加重;湿滞血行不畅,瘀血阻滞经络,气病及血,瘀血阻滞经络,疾病进一步发展。故代偿期乙型肝炎肝硬化病位以肝、脾为主,病性以气滞、脾虚、湿热、血瘀为主,本病初始病理状态为肝郁、脾虚,湿热为病情发展的病理过程,瘀血为代偿期即将向失代偿期发展的关键病理因素。同时发现肝胆湿热证ALT、AST升高最为明显,肝胆湿热证尚属于本病的早中期,此期邪盛而正未虚,为疾病的进展期,大量的ALT、AST由肝细胞释放入血,导致ALT、AST明显高于其他证型,同时logistic回归分析显示,AST为肝胆湿热证的影响因素。而在瘀血阻络证中门静脉宽度明显高于其他证型,Alb、PLT较其他证型降低。在病变尚处于初期的肝郁脾虚证时,患者的肝脏尚可合成人体所需的蛋白,营养状态尚可;随着病情逐渐发展,气病及血,此时患者血中Alb水平则降低,患者营养状态较差;另一方面,长期的瘀血导致脾充血性肿大,门静脉宽度随之增宽,大量的正常细胞在脾脏被破坏,造成PLT的下降[12]

    乙型肝炎肝硬化发病率高,然而作为“金标准”的肝脏病理学检查因样本取材偏差、肝脏穿刺组织易碎、患者不宜接受有创操作等原因,在临床中往往受到一定程度的制约[13],而肝硬化无创诊断可以在一定程度上弥补病理学检查的不足之处[2, 14]。《慢性乙型肝炎防治指南(2019年版)》[2]指出,在评估HBV相关肝纤维化方面,FIB-4对于慢性乙型肝炎及乙型肝炎肝硬化的鉴别参考价值优于APRI,在代偿期与失代偿肝硬化鉴别过程中APRI及FIB-4指数具有参考价值[15-16]。有研究[17]发现,GPR模型在诊断明显肝纤维化和肝硬化方面的价值要高于APRI、FIB-4模型。RPR模型是基于乙型肝炎建立的诊断肝硬化的无创模型,可作为临床诊断及检测乙型肝炎肝硬化的有力补充,丁予昀等[18]认为,RDW及PLT是影响肝硬化程度的独立危险因素。《无创伤检查评估肝脏疾病严重程度及预后临床指南(2015年版)》[19]中指出:TE可作为低风险患者判定是否出现严重肝纤维化或肝硬化的首选方法。本研究发现,APRI与FIB-4在评估肝胆湿热证时的诊断价值明显低于其他方法,而LSM值与RPR模型高于其他方法,这可能与APRI、FIB-4模型里均有转氨酶有关,在肝胆湿热证时ALT、AST明显高于其他证型,而患者在此时常常会应用保肝降酶药物,从而导致转氨酶发生变化,以致APRI、FIB-4模型评估存在误差;而当患者处于肝硬化初期肝郁脾虚证时,患者肝功能一般无明显异常,故APRI、FIB-4模型在评估肝郁脾虚证的诊断价值较好,这与既往研究[12, 20-21]的结果类似;而5种无创诊断方法均能较好地评估瘀血阻络证,这可能和瘀血阻络证处于代偿期乙型肝炎肝硬化后期,患者持续保持肝硬化状态,肝硬化程度进一步严重,影响评分的血常规、肝功能等情况较为稳定。最后,本研究还发现LSM值对三个主要中医证型均有很好的诊断价值(P值均<0.05),对于其他无创诊断方法明显占据优势,这可能与TE结果受转氨酶、肝功能的影响较小有关[20],这与既往的研究[22-23]结果类似。

    综上所述,5种肝硬化无创诊断方法在评估代偿期乙型肝炎肝硬化不同中医证型有一定的诊断参考价值:TE技术在乙型肝炎肝硬化代偿期时有很好的诊断价值,肝郁脾虚证时,LSM值与FIB-4模型明显优于其他诊断方法,LSM值与RPR模型评估肝胆湿热证时占优势,5种无创诊断方法均能较好地评估瘀血阻络证。虽然在当前条件下无创诊断方法不能完全替代肝活检,不过在今后,非侵入性肝纤维化检测技术将成为诊断肝纤维化的主要研究方向[24],在接下来的研究中可进行大样本、多重资料的验证,同时结合长期的临床试验,利用肝硬化无创诊断方法联合与中医证型间差异性明显的指标,以期提高中医临床诊断辨证的准确性。

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