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GLP-1受体激动剂对2型糖尿病患者短期与长期代谢控制的影响

2014-08-07郭桂喜李娟娟刘传梅徐建祥闫晓芸李慧张磊董砚虎

中国医药科学 2014年9期
关键词:激动剂组间胰岛素

郭桂喜+李娟娟+刘传梅+徐建祥+闫晓芸+李慧+张磊+董砚虎

[摘要] 目的 探讨GLP-1受体激动剂对2型糖尿病(T2DM)患者短期与长期代谢控制的影响。方法 选取2010~2013年于青岛市内分泌糖尿病医院应用艾塞那肽治疗的120例T2DM患者,根据使用时间分两组:使用时间≤24周(A组,n=58),使用时间>24周(B组,n=62)。分别记录治疗前后体重、WC、HC、FBG、P2hBG、HbA1C、TG、TC、LDL、HDL、SBP、DBP,并计算BMI、WSR、WHR,均行骨密度检查,测定全身脂肪含量。结果 A、B两组体重、BMI、全身脂肪含量均较治疗前下降,但组间差异无统计学意义(P>0.05);A、B两组WC、WSR、FBG、P2hBG、HbA1C、SBP、DBP均较治疗前下降,组间比较差异有统计学意义(P<0.05)。两组TG、TC、LDL、HDL较治疗前后及组间差异无统计学意义(P>0.05)。两组胃肠道不良反应及低血糖发生率组间差异无统计学意义(P>0.05)。 结论 长期应用GLP-1受体激动剂治疗2型糖尿病临床疗效较好,不增加胃肠道及低血糖反应发生风险,使体脂重新分布,改善腹型肥胖及胰岛素抵抗。

[关键词] 2型糖尿病;艾塞那肽;体脂分布

[中图分类号] R587.1   [文献标识码] A   [文章编号] 2095-0616(2014)09-25-03

Investigate the effect of the GLP-1 receptor agonist on patients with type 2 diabetes mellitus (T2DM) between the short-term and long-term metabolic control

GUO Guixi1  LI Juanjuan1  LIU Chuanmei1  XU Jianxiang1  YAN Xiaoyun1  LI Hui1ZHANG Lei2  DONG Yanhu2

1.Clinical Medicine of Weifang Medical College, Weifang 261042, China; 2.Qingdao Endocrinology Diabetes Hospital, Qingdao 266071, China

[Abstract] Objective To Investigate the effect of the GLP-1 receptor agonist on patients with type 2 diabetes mellitus (T2DM) between the short-term and long-term metabolic control. Methods 120 patients with T2DM treated with Exenatide in Qingdao Endocrinology Diabetes Hospital from 2010 to 2013 were divided into two groups due to the term of drug use. Patients in group A (n=58) applied Exenatide not less than 24 weeks, while those in goup B (n=62) more than 24 weeks. Indicates included body weight (before and after the treatment), WC, HC, FBG, P2Hbg, HbA1C, TG, TC, LDL, HDL, SBP, DBP, BMI, WSR, WHR, BMD, and body fat content. Results The body weight, BMI and the body fat content in two groups were both decreased than that before treatment, which had no significant difference in the comparison between groups (P>0.05); WC, WSR, FBG, P2hBG, HbA1C, SBP, DBP in two groups were both decreased than that before treatment, which had statistically significant difference in the comparison between the two groups (P<0.05).TG, TC, LDL, HDL in two groups had no statistically different neither before nor after treatment (P>0.05). Neither the gastrointestinal adverse reaction nor the rate of hypoglycemia in the two groups had no statistically different in the comparison between groups (P>0.05). Conclusion The better clinical effect of GLP-1 receptor agonists for T2DM lies in long-term application, which can also decrease the risk of the gastrointestinal reactions and hypoglycemia, redistribute the body fat and improve abdominal obesity and insulin resistance.

[Key words] Type 2 diabetes mellitus; Exenatide; Body fat distribution

艾塞那肽是一种胰高糖素样肽-1(GLP-1)类似物,通过激动GLP-1受体,刺激葡萄糖依赖的胰岛素分泌[1-2],在临床中已大量应用,主要作用是控制血糖、减轻体重、改善胰岛素抵抗。然而,艾塞那肽使用时间尚无定论,目前尚未有研究探讨短期与长期应用是否对重要代谢指标产生不同的影响,本研究通过对120例T2DM病例的分析,探讨GLP-1受体激动剂短期与长期应用对重要代谢指标控制的影响,指导GLP-1受体激动剂临床应用时间,以期达最佳治疗效果。

表1  两组一般情况及治疗前后各项代谢指标的比较

组别 n W(kg) WC(cm) WSR(cm) BMI (kg/m2)

A组 治疗前 58 72.92±7.79 85.8±7.16 0.51±0.27 25.55±1.36

治疗后 58 69.60±7.44 82.2±6.86 0.49±0.28 24.41±1.46

B组 治疗前 62 72.78±7.51 85.4±7.40 0.50±0.03 25.27±1.22

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治疗后 62 68.90±6.54 78.30±5.65 0.41±0.22 23.94±1.10

t 0.223 2.525 2.380 0.825

P 0.826 0.022 0.029 0.420

组别 FBG(mmol/L) 2hPG(mmol/L) HbA1C(%) SBP(mm Hg) DBP(mm Hg)

A组 治疗前 7.29±0.79 10.82±1.21 8.24±0.74 128.50±9.44 84.00±7.75

治疗后 6.47±0.59 9.89±1.25 7.57±0.64 123.60±8.73 79.00±6.58

B组 治疗前 7.40±0.74 10.91±1.14 8.25±0.72 130.00±9.13 85.00±6.24

治疗后 5.87±0.51 8.21±1.45 6.49±0.75 121.50±7.44 75.50±6.25

t 2.874 2.603 2.577 2.610 2.348

P 0.010 0.018 0.019 0.018 0.031

组别 TG(mmol/L) TC(mmol/L) HDL(mmol/L) LDL(mmol/L) 全身脂肪含量(%)

A组 治疗前 1.88±0.40 4.74±0.95 1.22±0.20 2.66±0.59 28.42±2.66

治疗后 1.83±0.35 4.71±0.94 1.20±0.21 2.62±0.56 26.82±2.58

B组 治疗前 1.89±0.37 4.79±0.92 1.22±0.21 2.65±0.61 28.42±2.67

治疗后 1.85±0.33 4.76±0.91 1.19±0.22 2.63±0.62 26.54±2.36

t 0.144 0.354 0.062 0.417 0.251

P 0.887 0.728 0.952 0.681 0.804

注:t值与P值为A、B两组治疗后结果比较

1 资料与方法

1.1 一般资料

选取2010~2013年于青岛内分泌糖尿病医院应用艾塞那肽(Baxter Pharmaceutical Solutions LLC,H20090381/H20090382)治疗的T2DM患者120例(男65例,女55例),平均年龄(48.75±6.79)岁。根据艾塞那肽使用时间分为两组:短期治疗组A组 (使用时间≤24周,n=58),长期治疗组B组 (使用时间>24周,n=62)。两组性别、血糖、血压、病程等差异无统计学意义(P>0.05)。

1.2 治疗方法

两组均予以艾塞那肽治疗,起始剂量5μg,每日2次,在早餐和晚餐前30min内皮下注射,根据临床应答,在治疗1个月后剂量为10μg,每日2次。

1.3 观察指标

观察两组治疗后体重、WC、HC、FBG、P2hBG、HbA1C、TG、TC、LDL、HDL、SBP、DBP、全身脂肪含量的变化,同时比较两组胃肠道不良反应及低血糖发生率。

1.4 统计学处理

采用SPSS18.0统计软件进行统计分析,计量资料采用()表示,组间比较采用t检验,率比较采用x2检验,显著性水准α设置为0.05。

2 结果

2.1 临床疗效

两组体重、BMI、全身脂肪含量均较治疗前下降,但组间差异无统计学意义(P>0.05);两组WC、WSR、FBG、P2hBG、HbA1C、SBP、DBP均较治疗前下降,组间比较差异有统计学意义(P<0.05)。两组TG、TC、LDL、HDL较治疗前后及组间差异无统计学意义(P>0.05)。结果见表1。

2.2 不良反应

两组胃肠道不良反应及低血糖发生率组间差异无统计学意义(P>0.05)。结果见表2。

表2  两组不良反应发生率比较[n(%)]

组别 n 胃肠道不良反应 低血糖发生率

A组 58 15(25.86) 2(3.45)

B组 62 18(29.03) 3(4.83)

x2 0.151 0.145

P 0.698 0.703

3 讨论

有相关报道显示,中国已经成为世界肥胖人数最多的国家之一,而肥胖是导致T2DM的危险因素[3-4]。亦有研究[5]表明,肥胖患者存在高胰岛素血症及胰岛素敏感性的下降, 认为腹内脂肪增加是胰岛素抵抗的主要原因。因此,减轻体重、改善胰岛素抵抗为治疗2型糖尿病的重要作用靶点。艾塞那肽是一种39个氨基酸组成的胰高糖素样肽类似物,通过葡萄糖依赖性的促胰岛素释放和抑制胰高糖素释放而调节血糖,并具有延缓胃排空、抑制食欲、减轻体重、改善胰岛素抵抗以及保护胰岛细胞功能等作用[6-7]。

本研究显示,长期应用艾塞那肽可以更有效的控制血糖及糖化血红蛋白达标,且不增加胃肠道反应及低血糖发生风险,无严重不良事件发生。艾塞那肽亦具有减轻体重的作用,但随着用药时间的延长,体重、BMI及全身脂肪含量未得到进一步改善,本研究有一定的局限性,其是否可以持续性的减轻体重的作用有待观察[8]。但本研究可见腰围明显下降,结果示长期应用艾塞那肽虽不能进一步减轻体重,但可以明显的减轻腰围,使体脂得到重新分布,改善腹型肥胖及胰岛素抵抗[9-10]。

艾塞那肽具有改善T2DM患者血压的作用,与其通过抑制肾脏对Na+的重吸收或抑制肾脏血管紧张素诱导的细胞外信号调节激酶的磷酸化,从而促进肾钠排泄与利尿,同时通过对血管内皮的直接作用,增强NO依赖的血管扩张有关[11-12]。本研究表明,两组治疗后SBP及DBP均有一定程度下降[13],且与药物使用时间成正比。但本研究中未见血脂改善,与其他临床试验结果不一致[14],可能与研究样本量较少,且用药前血脂水平大致在正常水平有关。

本研究观察例数较少,有一定的局限性,长期应用艾塞那肽的疗效有待进一步研究。

[参考文献]

[1] Salehi M,Aulinger BA,DAlessio DA.Targeting beta-cell mass in type 2 diabetes:promise and limitations of new drugs based on incretins[J].Endocr Rev,2008,29:367-379.

[2] Giugliano D,Standl E,Vilsboll T,et al.Is the current therapeutic armanmentarium in diabetes enough to control the epidemic and its consequences? What are the current shortcomings?[J].Acta Diabetol,2009,46(3):173-181.

[3] 贾伟平, 项坤三, 陆俊茜,等.中国人糖耐量异常与胰岛素抵抗和胰岛素分泌[J].中国糖尿病杂志,2000,18:67-71.

[4] 毕婉蓉,季静.2型糖尿病老年女性与肥胖、糖脂代谢关系[J].实用糖尿病杂志,2007(1):25-27.

[5] 项坤三,贾伟平,陆俊茜,等.中国上海地区40岁以上成人中肥胖与代谢综合征的关系[J].中华内科杂志, 2000,39(4):224-228.

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[6] Yoder SM,Yang Q,Kindel TL,et al.Differential responses of the incretin hormones GIP and GLP-1 to increasing doses of dietary carbohydrate but not dietary protein in lean rats[J].Am J Physiol Gastrointest Lixer Physiol,2010,299(13):476-485.

[7] Gautier JF,Fetita S,Sobngwi E,et al.Biological actions of the incretins GIP and GLP-1and therapeutic perspectives in patients with type 2diabetes[J].Diabetes Matab,2005,31(3pt1):233.

[8] Gao Y,Yoon KH,Chuang LM,et al.Efficacy and safety of exenatide inpatients of Asian descent with type 2 diabetes inadequately controlled with metformin ormetformin and a sulphonylurea[J].Diabetes Res Clin Pract,2009,83(5):69-76.

[9] 施广德,张晓兰,黄文龙.艾塞那肽对2型糖尿病患者的疗效观察[J].中国糖尿病杂志,2011(10):770-772.

[10] 付鸿玉,刘冰梅,刘立波.艾塞那肽治疗2型糖尿病20例临床观察[J].中国医疗前沿,2011(18):32,45.

[11] Buse JB,Rosenstock J,Sesti G,et al.Liralutide once a day versus exenatide twice a day for type 2 diabetes:a 26-week randomized,parallel-group,multinational,open-label trial(LEAD-6)[J].Lancet,2009,374(9683):39-47.

[12] Erdogdu O,Nathanson D,Sjoholm A,et al.Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-,PKA-and P13K/Akt-dependent pathways and requires GLP-1 receptor[J].Mol Cell Endocrionl.2010,325(1/2):26-35.

[13] Drucker DJ,Buse JB,Taylor K,et al.Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomized,open-label,non-inferiority study[J].Lancet,2008 372(9645):1240-250.

[14] 蔡玉立,文重远,黄兵.艾塞那肽治疗2型糖尿病对患者血脂影响的系统评价[J].医学研究杂志,2012,41(10):116-120.

(收稿日期:2014-03-03)

endprint

[6] Yoder SM,Yang Q,Kindel TL,et al.Differential responses of the incretin hormones GIP and GLP-1 to increasing doses of dietary carbohydrate but not dietary protein in lean rats[J].Am J Physiol Gastrointest Lixer Physiol,2010,299(13):476-485.

[7] Gautier JF,Fetita S,Sobngwi E,et al.Biological actions of the incretins GIP and GLP-1and therapeutic perspectives in patients with type 2diabetes[J].Diabetes Matab,2005,31(3pt1):233.

[8] Gao Y,Yoon KH,Chuang LM,et al.Efficacy and safety of exenatide inpatients of Asian descent with type 2 diabetes inadequately controlled with metformin ormetformin and a sulphonylurea[J].Diabetes Res Clin Pract,2009,83(5):69-76.

[9] 施广德,张晓兰,黄文龙.艾塞那肽对2型糖尿病患者的疗效观察[J].中国糖尿病杂志,2011(10):770-772.

[10] 付鸿玉,刘冰梅,刘立波.艾塞那肽治疗2型糖尿病20例临床观察[J].中国医疗前沿,2011(18):32,45.

[11] Buse JB,Rosenstock J,Sesti G,et al.Liralutide once a day versus exenatide twice a day for type 2 diabetes:a 26-week randomized,parallel-group,multinational,open-label trial(LEAD-6)[J].Lancet,2009,374(9683):39-47.

[12] Erdogdu O,Nathanson D,Sjoholm A,et al.Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-,PKA-and P13K/Akt-dependent pathways and requires GLP-1 receptor[J].Mol Cell Endocrionl.2010,325(1/2):26-35.

[13] Drucker DJ,Buse JB,Taylor K,et al.Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomized,open-label,non-inferiority study[J].Lancet,2008 372(9645):1240-250.

[14] 蔡玉立,文重远,黄兵.艾塞那肽治疗2型糖尿病对患者血脂影响的系统评价[J].医学研究杂志,2012,41(10):116-120.

(收稿日期:2014-03-03)

endprint

[6] Yoder SM,Yang Q,Kindel TL,et al.Differential responses of the incretin hormones GIP and GLP-1 to increasing doses of dietary carbohydrate but not dietary protein in lean rats[J].Am J Physiol Gastrointest Lixer Physiol,2010,299(13):476-485.

[7] Gautier JF,Fetita S,Sobngwi E,et al.Biological actions of the incretins GIP and GLP-1and therapeutic perspectives in patients with type 2diabetes[J].Diabetes Matab,2005,31(3pt1):233.

[8] Gao Y,Yoon KH,Chuang LM,et al.Efficacy and safety of exenatide inpatients of Asian descent with type 2 diabetes inadequately controlled with metformin ormetformin and a sulphonylurea[J].Diabetes Res Clin Pract,2009,83(5):69-76.

[9] 施广德,张晓兰,黄文龙.艾塞那肽对2型糖尿病患者的疗效观察[J].中国糖尿病杂志,2011(10):770-772.

[10] 付鸿玉,刘冰梅,刘立波.艾塞那肽治疗2型糖尿病20例临床观察[J].中国医疗前沿,2011(18):32,45.

[11] Buse JB,Rosenstock J,Sesti G,et al.Liralutide once a day versus exenatide twice a day for type 2 diabetes:a 26-week randomized,parallel-group,multinational,open-label trial(LEAD-6)[J].Lancet,2009,374(9683):39-47.

[12] Erdogdu O,Nathanson D,Sjoholm A,et al.Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-,PKA-and P13K/Akt-dependent pathways and requires GLP-1 receptor[J].Mol Cell Endocrionl.2010,325(1/2):26-35.

[13] Drucker DJ,Buse JB,Taylor K,et al.Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomized,open-label,non-inferiority study[J].Lancet,2008 372(9645):1240-250.

[14] 蔡玉立,文重远,黄兵.艾塞那肽治疗2型糖尿病对患者血脂影响的系统评价[J].医学研究杂志,2012,41(10):116-120.

(收稿日期:2014-03-03)

endprint

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