二肽基肽酶4抑制剂对2型糖尿病患者胰岛素抵抗的作用的系统评价
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摘要
背景：2型糖尿病是一种以胰岛素抵抗和胰岛功能受损为特征的慢性进展性疾病,发病率在近年来增高明显。同时也涌现出不同种类的作用机制各异的新型降糖药物,DPP-4抑制剂(二肽基肽酶4抑制剂)就是其中一种。DPP-4抑制剂通过抑制体内肠促胰素GLP-1的降解酶DPP-4的活性而延长其作用时间,达到促进胰岛素分泌的作用,因其具有显著降低血糖,胃肠道不良反应少,不增加体重以及能够改善胰岛β细胞功能等特点备受关注。但其对胰岛素抵抗的作用并不确定,不同的临床研究显示出不同的结论。
目的：我们进行这项系统评价,旨在通过综合DPP-4抑制剂与安慰剂或其他口服降糖药物比较的临床研究,以胰岛素抵抗作为研究指标进行荟萃分析,就临床应用DPP-4抑制剂对胰岛素抵抗的改善作用做出比较合理的分析。
方法：我们通过检索PUBMED和EMBASE数据库(检索时间截止至2013年3月12日)的英文文献,以“DPP-4抑制剂”和“临床试验”为关键词检索相关临床研究,只有研究人群为成年非孕2型糖尿病患者并且有胰岛素抵抗相关指标评价DPP-4抑制剂和安慰剂或其他口服降糖药物的的临床研究被纳入荟萃分析,按照事先制定的策略进行文献筛查,数据提取和质量评价,数据合并、异质性和偏倚分析,并对分析过程中出现的问题进行进一步探索。
结果：DPP-4抑制剂与安慰剂相比能够显著改善以HOMA-IR指数评价的胰岛素抵抗水平,但作用效果较弱,HOMA-IR较基线变化的加权均数差为-0.109(95%可信区间；-0.191,-0.027),I2=3.9%。采用其他胰岛素抵抗评价指标进行评价时结论基本一致(Composit ISI除外),但应用OGIS和高胰岛素正常葡萄糖钳夹试验评价胰岛素抵抗时显示的效果差异更明显,采用钳夹试验时,以M值评价胰岛素抵抗的加权均数差是0.789(95%可信区间；0.503,1.075),I2=0；并且在单药治疗未用药的2型糖尿病患者时,DPP-4抑制剂改善胰岛素(HOMA-IR指数较基线的变化)更为明显,WMD=-0.193(95%可信区间；-0.356,-0.030),而联合用药组则不显著WMD=-0.078(95%可信区间；-0.188,0.031)。此外DPP-4抑制剂与二甲双胍比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为0.398(95%可信区间；0.194,0.602),I2=0；与噻唑脘二酮类药物比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为1.063(95%可信区间；0.613,1.514),I2=28.1%；与磺脲类胰岛素促泌剂相比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为-0.550(95%可信区间；-0.782,-0.319),I2=0；与α-糖苷酶抑制剂比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为-0.061(95%可信区间；-0.242,0.120),I2=3.5%。
结论：DPP-4抑制剂较安慰剂具有轻度的改善胰岛素抵抗的作用,但作用效果弱于传统的改善胰岛素抵抗的药物噻唑烷二酮类药物和二甲双胍,而与璜尿类胰岛素促泌剂相比,其对胰岛素抵抗的作用具有明显的改善,作用效果与α-糖苷酶抑制剂相比没有发现明显的差异性。
Background:Type2diabetes mellitus is a chronic and progressive disease characterised by insulin resistance and decreased islet function, and rates of this disease have increased markedly in recent years. Meanwhile some new antidiabetic drugs were presented to us with novel and different mechanisms, including DPP-4inhibitors (Dipeptidyl Peptidase4inhibitors). The DPP-4inhibitor is a kind of incretin enhancer which promotes insulin secretion by inhibiting the activity of DPP-4which is a degrading enzyme of GLP-1and extending the action of this incretin. As a result of its good capacity in lowering blood glucose and improving islet beta cell function with a low incidence of gastrointestinal adverse reaction and no addition of body weight, DPP-4inhibitors have been accept gradually. However, their roles in insulin resistance are still uncertain, and different clinical studies have provided different results.
Objective:We conducted this systematic review to compare DPP-4inhibitors with placebo and other oral antidiabetic drugs in aspects of insulin resistance and give a more reasonable answer for clinical use of this kind of drug in patients of insulin resistance.
Methods:We searched MEDLINE and EMBASE using the following terms:"controlled clinical trial" and "dipeptidyl peptidase IV inhibitors". Only randomized controlled trials comparing DPP-IV inhibitors with placebo or other oral antidiabetic drugs in non-pregnant drug-naive adults with type2diabetes were included. According to the predefined strategy, we progressed paper screening, data extraction, quality assessment and results combination with tests of heterogeneity and bias.
Results:DPP-4inhibitors can significantly improve the level of insulin resistance (HOMA-IR index evaluation) compared with placebo, but the efficacy is weak and the weighted mean difference of change from baseline in HOMA-IR index is-0.109(95%CI;-0.191,-0.027), I2=3.9%. Other indicators of insulin resistance are similar to this result (except Composite ISI), but the application of the OGIS index and the glucose clamp test for evaluating insulin resistance shows more obvious differences. In the clamp test, weighted mean difference (WMD) in M value which stands for insulin resistance was0.789(95%CI;0.503,1.075), I2=0; and in patients with type2diabetes using monotherapy, DPP-4inhibitors improve insulin resistance (change in HOMA-IR index from baseline) more significantly with WMD=-0.193(95%CI,-0.356,-0.030), while the combination treatment the results are not significant:WMD=-0.078(95%CI;-0.188,0.031). In addition, the weighted mean difference of the DPP-4inhibitor compared with metformin in improving insulin resistance (HOMA-IR index change from baseline) is0.398(95%CI;0.194,0.602), I2=0; while1.063(95%CI;0.613,1.514),I2=28.1%with thiazolidinediones;-0.550(95%CI;-0.782,-0.319),I2=0with sulfonylureas; and-0.061(95%CI;-0.242,0.120), I2=3.5%) compared with alpha-glucosidase inhibitors.
Conclusions:DPP-4inhibitors can lead to a mild improvement in insulin resistance compared with placebo, but the effect is weaker than that of the traditional insulin sensitizer such as thiazolidinedione and metformin. However, DPP-4inhibitors show obvious advantages over sulfonylureas in this aspect and the advantage over a-glycosidase inhibitors is not significant.
目的：我们进行这项系统评价,旨在通过综合DPP-4抑制剂与安慰剂或其他口服降糖药物比较的临床研究,以胰岛素抵抗作为研究指标进行荟萃分析,就临床应用DPP-4抑制剂对胰岛素抵抗的改善作用做出比较合理的分析。
方法：我们通过检索PUBMED和EMBASE数据库(检索时间截止至2013年3月12日)的英文文献,以“DPP-4抑制剂”和“临床试验”为关键词检索相关临床研究,只有研究人群为成年非孕2型糖尿病患者并且有胰岛素抵抗相关指标评价DPP-4抑制剂和安慰剂或其他口服降糖药物的的临床研究被纳入荟萃分析,按照事先制定的策略进行文献筛查,数据提取和质量评价,数据合并、异质性和偏倚分析,并对分析过程中出现的问题进行进一步探索。
结果：DPP-4抑制剂与安慰剂相比能够显著改善以HOMA-IR指数评价的胰岛素抵抗水平,但作用效果较弱,HOMA-IR较基线变化的加权均数差为-0.109(95%可信区间；-0.191,-0.027),I2=3.9%。采用其他胰岛素抵抗评价指标进行评价时结论基本一致(Composit ISI除外),但应用OGIS和高胰岛素正常葡萄糖钳夹试验评价胰岛素抵抗时显示的效果差异更明显,采用钳夹试验时,以M值评价胰岛素抵抗的加权均数差是0.789(95%可信区间；0.503,1.075),I2=0；并且在单药治疗未用药的2型糖尿病患者时,DPP-4抑制剂改善胰岛素(HOMA-IR指数较基线的变化)更为明显,WMD=-0.193(95%可信区间；-0.356,-0.030),而联合用药组则不显著WMD=-0.078(95%可信区间；-0.188,0.031)。此外DPP-4抑制剂与二甲双胍比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为0.398(95%可信区间；0.194,0.602),I2=0；与噻唑脘二酮类药物比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为1.063(95%可信区间；0.613,1.514),I2=28.1%；与磺脲类胰岛素促泌剂相比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为-0.550(95%可信区间；-0.782,-0.319),I2=0；与α-糖苷酶抑制剂比较改善胰岛素抵抗(HOMA-IR指数较基线的变化)的加权均数差为-0.061(95%可信区间；-0.242,0.120),I2=3.5%。
结论：DPP-4抑制剂较安慰剂具有轻度的改善胰岛素抵抗的作用,但作用效果弱于传统的改善胰岛素抵抗的药物噻唑烷二酮类药物和二甲双胍,而与璜尿类胰岛素促泌剂相比,其对胰岛素抵抗的作用具有明显的改善,作用效果与α-糖苷酶抑制剂相比没有发现明显的差异性。
Background:Type2diabetes mellitus is a chronic and progressive disease characterised by insulin resistance and decreased islet function, and rates of this disease have increased markedly in recent years. Meanwhile some new antidiabetic drugs were presented to us with novel and different mechanisms, including DPP-4inhibitors (Dipeptidyl Peptidase4inhibitors). The DPP-4inhibitor is a kind of incretin enhancer which promotes insulin secretion by inhibiting the activity of DPP-4which is a degrading enzyme of GLP-1and extending the action of this incretin. As a result of its good capacity in lowering blood glucose and improving islet beta cell function with a low incidence of gastrointestinal adverse reaction and no addition of body weight, DPP-4inhibitors have been accept gradually. However, their roles in insulin resistance are still uncertain, and different clinical studies have provided different results.
Objective:We conducted this systematic review to compare DPP-4inhibitors with placebo and other oral antidiabetic drugs in aspects of insulin resistance and give a more reasonable answer for clinical use of this kind of drug in patients of insulin resistance.
Methods:We searched MEDLINE and EMBASE using the following terms:"controlled clinical trial" and "dipeptidyl peptidase IV inhibitors". Only randomized controlled trials comparing DPP-IV inhibitors with placebo or other oral antidiabetic drugs in non-pregnant drug-naive adults with type2diabetes were included. According to the predefined strategy, we progressed paper screening, data extraction, quality assessment and results combination with tests of heterogeneity and bias.
Results:DPP-4inhibitors can significantly improve the level of insulin resistance (HOMA-IR index evaluation) compared with placebo, but the efficacy is weak and the weighted mean difference of change from baseline in HOMA-IR index is-0.109(95%CI;-0.191,-0.027), I2=3.9%. Other indicators of insulin resistance are similar to this result (except Composite ISI), but the application of the OGIS index and the glucose clamp test for evaluating insulin resistance shows more obvious differences. In the clamp test, weighted mean difference (WMD) in M value which stands for insulin resistance was0.789(95%CI;0.503,1.075), I2=0; and in patients with type2diabetes using monotherapy, DPP-4inhibitors improve insulin resistance (change in HOMA-IR index from baseline) more significantly with WMD=-0.193(95%CI,-0.356,-0.030), while the combination treatment the results are not significant:WMD=-0.078(95%CI;-0.188,0.031). In addition, the weighted mean difference of the DPP-4inhibitor compared with metformin in improving insulin resistance (HOMA-IR index change from baseline) is0.398(95%CI;0.194,0.602), I2=0; while1.063(95%CI;0.613,1.514),I2=28.1%with thiazolidinediones;-0.550(95%CI;-0.782,-0.319),I2=0with sulfonylureas; and-0.061(95%CI;-0.242,0.120), I2=3.5%) compared with alpha-glucosidase inhibitors.
Conclusions:DPP-4inhibitors can lead to a mild improvement in insulin resistance compared with placebo, but the effect is weaker than that of the traditional insulin sensitizer such as thiazolidinedione and metformin. However, DPP-4inhibitors show obvious advantages over sulfonylureas in this aspect and the advantage over a-glycosidase inhibitors is not significant.
引文
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