ACRVM Asian Case Reports in Vascular Medicine 2326-3490 Scientific Research Publishing 10.12677/ACRVM.2022.101001 ACRVM-48683 ACRVM20220100000_19120439.pdf 医药卫生 达格列净对2型糖尿病伴慢性心力衰竭患者的疗效及心外膜脂肪厚度影响 Efficacy of Dapagliflozin on Type 2 Diabetic Patients with Chronic Heart Failure and Its Effect on Thickness of Epicardial Adipose Tissue 叶 炳华 2 1 杨 淑芳 3 1 唐 宝康 4 1 戚 文群 4 1 史 爱梅 2 1 李 伯堂 5 1 江苏省泰州市第三人民医院内分泌科，江苏 泰州 江苏省泰州市人民医院内分泌科，江苏 泰州 江苏省泰州市第三人民医院超声科，江苏 泰州 江苏省泰州市第三人民医院心内科，江苏 泰州 null 17 01 2022 10 01 1 7 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

目的：观察达格列净对2型糖尿病(T2DM)伴慢性心力衰竭(CHF)患者的临床疗效以及对心外膜脂肪(EAT)厚度的影响。方法：选择2018年8月~2021年01月住院的T2DM伴心功能II~IV级CHF患者72例，随机分为治疗组和对照组各36例，两组基础治疗相同，治疗组加用达格列净，6个月后分别比较两组患者治疗前后及两组之间EAT厚度、左房前后径(LAD)、左室舒张末内径(LVDd)、左室射血分数(LVEF)、糖化血红蛋白(HbA1c)、N端脑钠肽前体(NT-proBNP)水平、6分钟步行试验(6MWT)及生活质量变化，并观察治疗效果、再住院人次及药物不良反应。结果：与治疗前相比，治疗组EAT厚度明显降低(P < 0.01)，对照组无明显变化，两组治疗后LAD、LVDd、HbA1c、NT-proBNP、生活质量评分均明显下降，6MWT、LVEF明显提高(P < 0.01)；治疗后组间比较，两组除LAD外，其他指标均有显著差异，以治疗组为优(P < 0.05或0.01)；治疗组显效率优于对照组(P < 0.01)，但总有效率与对照组无统计学差异(P > 0.05)；治疗组再入院人次较对照组减低(P < 0.05)，两组不良反应发生率相似(P > 0.05)。结论：T2DM伴CHF患者加用达格列净能进一步改善患者心功能，提高生活质量，降低再住院次数，使用安全性高，降低EAT厚度可能是其中一个机制。 Objective: To observe the clinical effect of Dapagliflozin on type 2 diabetes mellitus (T2DM) patients with chronic heart failure (CHF) and the influence on the thickness of epicardial adipose tissue (EAT). Methods: 72 T2DM patients with CHF of cardiac function grade II~IV who were hospitalized from August 2018 to January 2021 were randomly divided into treatment group (N = 36) and control group (N = 36). The basic treatment was the same in both groups, and Dagligliflozin was added to the treatment group. After 6 months, thickness of EAT, left atrial anter-oposterior diameter (LAD), left ventricular end-diastolic diameter (LVDd), left ventricular ejection fraction (LVEF), hemoglobin A1c (HbA1c), N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walking test (6MWT) and quality of life were compared before and after treatment and between the two groups. At the same time, the therapeutic effect, the number of readmission and drug reactions were observed. Results: Compared with pre-treatment, the thickness of EAT in the treatment group was significantly decreased (P < 0.01), and there was no significant change in the control group. After treatment, the scores of LAD, LVDd, HbA1c, NT-proBNP and quality of life in the two groups were significantly decreased, and 6 MWT and LVEF were significantly increased (P < 0.01). Except LAD, there were significant differences in other indexes between the two groups, the treatment group was better than the control group (P < 0.05 or 0.01). The effective rate of the treatment group was better than that of the control group (P < 0.01), but there was no significant difference in the total effective rate between the two groups (P > 0.05). The number of readmission in the treatment group was significantly lower than that in the control group (P < 0.05), and the incidence of adverse reactions was similar in the two groups (P > 0.05). Conclusion: Adding Dapagliflozin to T2DM patients with CHF can improve heart function, improve the quality of life, reduce the number of readmission, and can use safely. One of the mechanisms may be related to reducing the thickness of EAT.

 达格列净，慢性心力衰竭，N-端脑钠肽前体，6分钟步行试验，心外膜脂肪, Dapagliflozin Chronic Heart Failure N-Terminal Pro-Brain Natriuretic Peptide 6-Minute Walking Test Epicardial Adipose Tissue 摘要

目的：观察达格列净对2型糖尿病(T2DM)伴慢性心力衰竭(CHF)患者的临床疗效以及对心外膜脂肪(EAT)厚度的影响。方法：选择2018年8月~2021年01月住院的T2DM伴心功能II~IV级CHF患者72例，随机分为治疗组和对照组各36例，两组基础治疗相同，治疗组加用达格列净，6个月后分别比较两组患者治疗前后及两组之间EAT厚度、左房前后径(LAD)、左室舒张末内径(LVDd)、左室射血分数(LVEF)、糖化血红蛋白(HbA1c)、N端脑钠肽前体(NT-proBNP)水平、6分钟步行试验(6MWT)及生活质量变化，并观察治疗效果、再住院人次及药物不良反应。结果：与治疗前相比，治疗组EAT厚度明显降低(P < 0.01)，对照组无明显变化，两组治疗后LAD、LVDd、HbA1c、NT-proBNP、生活质量评分均明显下降，6MWT、LVEF明显提高(P < 0.01)；治疗后组间比较，两组除LAD外，其他指标均有显著差异，以治疗组为优(P < 0.05或0.01)；治疗组显效率优于对照组(P < 0.01)，但总有效率与对照组无统计学差异(P > 0.05)；治疗组再入院人次较对照组减低(P < 0.05)，两组不良反应发生率相似(P > 0.05)。结论：T2DM伴CHF患者加用达格列净能进一步改善患者心功能，提高生活质量，降低再住院次数，使用安全性高，降低EAT厚度可能是其中一个机制。

 关键词

达格列净，慢性心力衰竭，N-端脑钠肽前体，6分钟步行试验，心外膜脂肪

 Efficacy of Dapagliflozin on Type 2 Diabetic Patients with Chronic Heart Failure and Its Effect on Thickness of Epicardial Adipose Tissue<sup> </sup>

Binghua Ye1*#, Shufang Yang2, Baokang Tang3, Wenqun Qi3, Aimei Shi1, Botang Li4

1Department of Cardiology, Taizhou Third People’s Hospital of Jiangsu Province, Taizhou Jiangsu

2Department of Endocrinology, Taizhou People’s Hospital of Jiangsu Province, Taizhou Jiangsu

3Department of Endocrinology, Taizhou Third People’s Hospital of Jiangsu Province, Taizhou Jiangsu

4Department of Ultrasound, Taizhou Third People’s Hospital of Jiangsu Province, Taizhou Jiangsu

Received: Nov. 22nd, 2021; accepted: Feb. 9th, 2022; published: Feb. 16th, 2022

 ABSTRACT

Objective: To observe the clinical effect of Dapagliflozin on type 2 diabetes mellitus (T2DM) patients with chronic heart failure (CHF) and the influence on the thickness of epicardial adipose tissue (EAT). Methods: 72 T2DM patients with CHF of cardiac function grade II~IV who were hospitalized from August 2018 to January 2021 were randomly divided into treatment group (N = 36) and control group (N = 36). The basic treatment was the same in both groups, and Dagligliflozin was added to the treatment group. After 6 months, thickness of EAT, left atrial anter-oposterior diameter (LAD), left ventricular end-diastolic diameter (LVDd), left ventricular ejection fraction (LVEF), hemoglobin A1c (HbA1c), N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walking test (6MWT) and quality of life were compared before and after treatment and between the two groups. At the same time, the therapeutic effect, the number of readmission and drug reactions were observed. Results: Compared with pre-treatment, the thickness of EAT in the treatment group was significantly decreased (P < 0.01), and there was no significant change in the control group. After treatment, the scores of LAD, LVDd, HbA1c, NT-proBNP and quality of life in the two groups were significantly decreased, and 6 MWT and LVEF were significantly increased (P < 0.01). Except LAD, there were significant differences in other indexes between the two groups, the treatment group was better than the control group (P < 0.05 or 0.01). The effective rate of the treatment group was better than that of the control group (P < 0.01), but there was no significant difference in the total effective rate between the two groups (P > 0.05). The number of readmission in the treatment group was significantly lower than that in the control group (P < 0.05), and the incidence of adverse reactions was similar in the two groups (P > 0.05). Conclusion: Adding Dapagliflozin to T2DM patients with CHF can improve heart function, improve the quality of life, reduce the number of readmission, and can use safely. One of the mechanisms may be related to reducing the thickness of EAT.

Keywords:Dapagliflozin, Chronic Heart Failure, N-Terminal Pro-Brain Natriuretic Peptide, 6-Minute Walking Test, Epicardial Adipose Tissue

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 1. 引言

慢性心力衰竭(chronic heart failure, CHF)是各种心脏病的严重阶段，其发病率高，预后差，因此有必要探索新的治疗手段包括药物以改善患者的生活质量及预后。目前国外多项研究证实钠–葡萄糖共转运蛋白2 (SGLT-2)抑制剂可以降低2型糖尿病(type 2 diabetes mellitus, T2DM)患者发生心力衰竭住院治疗的风险，并改善CHF预后 [ 1 ] [ 2 ] [ 3 ] [ 4 ]，但对T2DM伴CHF患者心外膜脂肪组织(epicardial adipose tissue, EAT)的影响目前少见报道。达格列净是一种SGLT-2抑制剂，我们在常规药物基础上加用达格列净辅助治疗T2DM伴CHF患者，取得了满意疗效，现将结果报告如下。

 2. 资料与方法 2.1. 一般资料

选取2018年8月~2021年01月在我院心内科、内分泌科住院的T2DM伴心功能II~IV级(NYHA分级) CHF患者72例，纳入标准：CHF诊断符合《中国心力衰竭诊断和治疗指南2018》 [ 5 ]，心功能分级按纽约心脏病学会(NYHA)标准；T2DM诊断符合《中国2型糖尿病防治指南》2017版标准 [ 6 ]；排除标准：伴发冠心病、脑梗死、严重肾功能不全CKD3期及以上、恶性肿瘤、既往服用可能会影响EAT药物如他汀类及利拉鲁肽、肢体活动受限以及不合作患者。所有患者按分层随机结合随机数字表法分为治疗组和对照组各36例，两组一般情况(治疗组/对照组)：性别(例)分别为：男21/19，女15/17；平均年龄(岁)分别为：61.4 ± 6.2/60.8 ± 5.9；不同心功能分级例数：II级分别为11/10，III级分别为15/17，IV级分别为10/9；病因分别包括：老年退行性心瓣膜病16/15例，风湿性心脏瓣膜病6/8例，高血压性心脏病5/4例，扩张型心肌病5/6例，先天性心脏病4/3例，2组年龄、性别、心功能分级、基础疾病的构成比差异无统计学意义(P > 0.05)，两组治疗前EAT厚度、左房前后径(LAD)、左室舒张末内径(LVDd)、左室射血分数(LVEF)、糖化血红蛋白(HbA1c)、血清N端脑钠肽前体(NT-proBNP)、6分钟步行距离(6MWT)、明尼苏达州心力衰竭生活质量量表(MLWHFQ)评分也均具有可比性(P > 0.05) (见表1)。本研究经医院伦理委员会批准，所有患者及家属入组前均签署知情同意书。

 2.2. 研究方法 2.2.1. 治疗方法

两组患者均按照CHF诊治指南，常规治疗原发病，并选择二甲双胍、格列美脲片、利尿剂(包含醛固酮受体拮抗剂)、血管紧张素转换酶抑制剂或血管紧张素受体拮抗剂、选择性加用β受体阻滞剂、洋地黄类强心剂、胰岛素等作为基础治疗；治疗组在常规治疗的基础上加用达格列净(安达唐)治疗，每次10 mg，每天1次口服，6个月后评价疗效。

 2.2.2. 观察指标

① 用药过程中观察症状改善情况、药物的副作用；② 治疗前及治疗6个月后检查肝、肾功能、空腹血糖、HbA1c、血脂、电解质、血清NT-proBNP；③ 心脏超声检查：受检者取左侧卧位，平稳呼吸，由同一具有丰富操作经验的医师通过超声心动图(ACUSONSC-2000彩超，探头频率为3.0 MHz)，选取胸骨旁左室长轴切面，以主动脉瓣环为定位基准，超声束中线与右室游离壁相垂直，于心室收缩末期即心电图T波终点冻结图像，测量心肌外层与脏层心包之间的无、低或中等回声区的宽度，确立EAT厚度，同时按照《中国成年人超声心动图检查测量指南》推荐测量方法 [ 7 ]，测取LAD、LVDd、LVEF，上述检查均连续测量3个心动周期并取其均值；④ 研究前后由专人测定患者6MWT，并使用MLWHFQ评定生活质量；⑤ 观察再住院人次及药物不良反应。

 2.2.3. 血浆标本采集与检测

患者空腹过夜10小时以上，采静脉血10 ml加入抗凝试管中，离心后(3000 r/min, 10 min)血清保存于−20℃冰箱，2个月内备检。血清NT-proBNP测定采用电化学发光免疫法，肝肾功能、电解质、血脂、空腹血糖、HbA1c采用全自动生化分析仪检测。

 2.2.4. 疗效评价

根据卫生部1993年颁布的《新药治疗研究指导原则》标准制定，心功能评价采用NYHA分级。显效：心功能改善二级或以上；有效：心功能改善一级；无效：心功能无明显变化或加重；死亡。显效 + 有效为总有效。

 2.3. 统计学分析

利用stata12.0软件包对数据进行处理，计量资料用平均值 ± 标准差( x ¯ ± s)表示，组间两样本均数比较采用t检验，组内用药前、后比较采用自身配对t检验，计数资料采用χ2检验或精确概率法，P < 0.05为差异有统计学意义。

 3. 结果 3.1. 治疗前后两组各项指标的比较

对照组两例于观察期内病情恶化死亡，其检测指标不纳入统计。结果发现：与治疗前相比，对照组EAT厚度治疗后变化不明显(P > 0.05)，而治疗组治疗后EAT厚度明显降低(P < 0.01)；两组治疗后HbA1c、LAD、LVDd、NT-proBNP、MLWHFQ评分均明显下降，6MWT、LVEF明显提高(P均 < 0.01)；两组治疗后组间指标比较，除LAD外，其他指标均有显著差异，以治疗组为优(P < 0.05或0.01)，见表1。两组治疗后肝肾功能、血脂、电解质比较无统计学差异(P均 > 0.05)。

Comparison of indexes between the two groups before and after intervention ( x ¯ ± s
临床 参数 治疗组(n = 36) 对照组(n = 34) 两组间治疗后比较
治疗前 治疗后 t值 P值 治疗前 治疗后 t值 P值 t值 P值
EAT (mm) 5.41 ± 1.72 3.74 ± 1.32 4.6215 0.0000 5.45 ± 1.79 4.86 ± 1.63 1.4622 0.1482 −3.2039 0.0020
LAD (mm) 44.2 ± 4.5 41.2 ± 4.1 2.9568 0.0042 44.9 ± 4.4 42.3 ± 4.3 2.4642 0.0163 −1.0956 0.2771
LVDd (mm) 61.1 ± 6.7 55.2 ± 5.1 4.2042 0.0001 60.9 ± 6.5 57.8 ± 5.4 2.0817 0.0413 −2.1116 0.0384
LVEF (%) 36.7 ± 5.2 49.3 ± 6.3 −9.2547 0.0000 37.4 ± 5.5 45.2 ± 6.1 −5.6246 0.0000 2.7636 0.0073
HbA1c (%) 9.48 ± 2.23 7.13 ± 1.52 5.2246 0.0000 9.53 ± 2.19 7.96 ± 1.67 3.3240 0.0015 −2.1766 0.0330
NT-proBNP (pg/mL) 3873 ± 1132 1586 ± 560 10.8651 0.0000 3925 ± 1104 2394 ± 749 6.6916 0.0000 −5.1307 0.0000
6MWT (m) 264 ± 83 472 ± 127 −8.1558 0.0000 271 ± 87 403 ± 108 −5.5500 0.0000 2.4418 0.0086
MLWHFQ (分) 2.96 ± 0.48 1.22 ± 0.24 19.0069 0.0000 2.93 ± 0.46 1.87 ± 0.32 11.1298 0.0000 −9.6495 0.0000

表1. 两组各项指标干预前后比较( x ¯ ± s)

 3.2. 两组治疗后临床疗效比较

治疗组治疗后显效率优于对照组(P < 0.01)，但总有效率与对照组无统计学差异(P > 0.05)；再住院人次治疗组明显少于对照组(P < 0.05)，见表2。

Comparison of clinical efficacy between the two groups after treatment (case
组别 n 疗效 总有效 再住院人次
显效 有效 无效 死亡
治疗组 36 20 14 2 0 34 4
对照组 36 9 19 6 2 28 13
χ2值 6.9864 1.3986 -- -- -- --
P值 0.008 0.237 0.260 0.493 0.085 0.013

表2. 两组治疗后临床疗效比较(例)

 3.3. 药物不良反应

治疗组发生低血糖3例次，低血压1例，低钾血症1例，泌尿系统感染2例，对照组发生低血糖2例次，低血压2例，低钾血症1例、低钠血症1例，两组不良反应发生率无统计学差异，P > 0.05。

 4. 讨论

CHF是一种复杂的临床症状群，为各种心脏病的严重阶段，尽管近20多年来心衰的药物及非药物治疗有了划时代的进展，但其预后仍然较差，因此心衰的治疗除了现有方法外，必须探索其他新的治疗手段包括药物以改善生活质量及预后，减少住院及死亡率。

达格列净作为SGLT-2抑制剂，可以抑制肾脏对葡萄糖的重吸收，直接降低血糖。目前多项研究证实了SGLT-2抑制剂对于T2DM患者具有心血管保护作用 [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ]。EMPA-REG的一项前瞻性临床试验 [ 1 ] 显示，SGLT-2抑制剂恩格列净治疗组较安慰剂组可明显降低心血管病高危的T2DM患者的心血管病风险；最近公布的DAPA-HF研究 [ 2 ] 证实，达格列净10 mg/d，可显著降低EF降低的CHF患者心衰恶化、心血管死亡及全因死亡风险，无论是否合并糖尿病。

本研究结果进一步证实了上述结论，我们观察了在常规药物基础上加用达格列净治疗T2DM伴CHF的临床疗效，结果显示：常规治疗加达格列净组(治疗组)显效率优于常规治疗组(对照组)，两组均可明显降低血糖、改善心房、心室扩大、提高LVEF，降低血清NT-proBNP，增加6MWT，提高生活质量，除LAD大小外，治疗组优势更加明显，并能进一步降低再住院次数(P < 0.05或0.01)，两组治疗前后肝肾功能、电解质变化、不良反应发生率差异不显著(P > 0.05)，提示达格列净对T2DM伴CHF心功能有进一步改善作用，并且安全性较高。

EAT是位于脏层心包与心肌之间的一种特殊的内脏脂肪，被认为是一种活跃的分泌组织，具有较高的促炎细胞因子(TNFα，IL-6，IL-1β等)表达能力 [ 13 ]，一些研究表明EAT的分泌作用破坏了心肌细胞的新陈代谢 [ 14 ]，抑制了心肌的收缩功能；在大鼠心肌梗死模型中进行的干预研究 [ 15 ] 显示，心肌梗死通过手术切除EAT可以改善心肌功能；对于患有T2DM和CHF患者来说，EAT与左心室结构和收缩舒张功能的异常以及患者的运动能力具有相关性 [ 16 ] [ 17 ] [ 18 ] [ 19 ]；EAT与左心室收缩末期体积、舒张末期体积、心肌质量、E峰、E/A比和体重指数呈正相关 [ 20 ]；蒋凌云等 [ 21 ] 研究认为，初诊T2DM内脏脂肪与心功能相关，降低内脏脂肪具有改善心功能的作用；而刘福成等 [ 22 ] 研究发现，稳定性冠心病患者EAT与N端脑利钠肽前体水平、心脏功能正相关；因此，降低T2DM患者EAT对于改善CHF具有重要意义。虽然SGLT-2抑制剂改善CHF作用已经获得多个循证医学证据支持，但其作用机制还不是很明确，有学者认为：SGLT-2抑制剂可通过降低体脂含量，减少脂肪因子、细胞因子和EAT的合成，改变脂肪因子的产生和/或作用，恢复促炎性和抗炎性脂肪因子之间的平衡、抑制心肌细胞凋亡及心肌纤维化，从而增加心肌收缩力，改善心脏舒张功能 [ 23 ] [ 24 ]。本研究也进一步证实了上述观点，加用达格列净治疗组EAT厚度较对照组有明显降低(P < 0.01)，相对应的是治疗组心功能及各项指标较对照组明显改善，提示达格列净改善CHF疗效的机制可能与其减少EAT有关。

综上，T2DM伴CHF患者加用达格列净治疗后，可明显减少患者EAT厚度，进一步改善心脏功能，提高生活质量、减少再住院率，使用安全，值得临床进一步推广应用。

 文章引用

叶炳华,杨淑芳,唐宝康,戚文群,史爱梅,李伯堂. 达格列净对2型糖尿病伴慢性心力衰竭患者的疗效及心外膜脂肪厚度影响Efficacy of Dapagliflozin on Type 2 Diabetic Patients with Chronic Heart Failure and Its Effect on Thickness of Epicardial Adipose Tissue[J]. 亚洲心脑血管病例研究, 2022, 10(01): 1-7. https://doi.org/10.12677/ACRVM.2022.101001

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