DPP-4抑制剂治疗合并中重度肾功能不全2型糖尿病的有效性及安全性Meta分析

Efficiency and safety of DDP-4 inhibitor in treatment of type 2 diabetes with moderate and severe renal insufficiency： a systemic review and Meta-analysis

目的 二肽基肽酶-4抑制剂[Dipeptidyl peptidase-4（DPP-4）inhibitors]是近几年逐渐被接受并运用于2型糖尿病合并肾功能不全患者的一种新型降糖药,然而其安全性及耐受性仍需要进一步验证.因此我们通过Meta分析评价DPP-4抑制剂对于伴有肾损害的2型糖尿病患者的临床疗效及安全性,为临床治疗选择提供参考数据.方法 计算机检索PubMed、EMBASE、Elsevier Science、Cochrane图书馆等数据库文献,检索时间从建库至2015年7月,关键词为“2型糖尿病”和“DPP-4抑制剂”（分别包括西格列汀sitagliptin,沙格列汀saxagliptin,维格列汀vildagliptin,里格列汀linagliptin和特力利汀Teneligliptin）和“糖尿病肾病”或“糖尿病肾脏疾病”或“慢性肾功能不全”.通过摘要或全文阅读筛选观察DPP-4抑制剂与安慰剂或其他降糖药进行疗效及安全性对照观察的RCT研究以及队列研究相关文献纳入Meta分析.结果 纳入12项研究（13篇文献）,共2838例患者;Meta分析结果显示,总体比较DPP-4抑制剂组能够有效地降低糖化血红蛋白（HbAlC）水平（权重均数差weighted mean difference,WMD-0.57,95％ CI[-0.54,-0.38],P＜0.00001）,但异质性较大（I^2=93％）;亚组分析提示对比安慰剂组,DPP-4抑制剂对HbA1C的效应更加明显,且异质性较低（WMD-0.62,95％ CI[-0.71,-0.53],P＜0.00001,I^2=4％）;肾功能损害分层的亚组分析显示在中度与重度肾功能损害亚组中,DPP-4抑制剂均能显著降低HbA1C水平（中度组WMD-0.19,95％ CI [-0.38,-0.01],P=0.04,I^2=90％,重度组WMD-0.56,95％CI[-0.66,-0.46],P＜0.00001,I^2=86％）.而DPP-4抑制剂对于快速血糖（Fasting Plasma Glucose,FPG）水平则无明显影响（总体效应）,对比安慰剂也未显示有统计学差异（WMD 0.03,95％ CI[-0.33,0.39],P=0.86,I^2=90％）.而在安全性评价中,与安慰剂组比DPP-4抑制剂组低血糖的风险稍高（OR[95％CI]：1.38[1.07,1.78],P=0.01,I^2=0％）,而与其他降糖药组相比DPP-4抑制剂组低血糖风险则显著下降（OR[95％CI]：0.46 [0.33,0.65],P＜0.0001,I^2=31％）.肾功能分层分析提示,无论是中度肾损害组还是重度肾功能不全组中DPP-4抑制剂组低血糖风险与对照组均无统计学差异（中度OR[95％CI]：1.34 [0.89,2.04],P=0.16,I^2=37％,重度OR[95％ CI]：1.04,[0.74,1.48],P=0.81,I^2=0％）.不良事件总体分析未显示DPP-4与对照组间有统计学差异（OR[95％CI]：0.93 （0.79,1.13）,P=0.81,I^2=0％）,且肾功能亚组分析亦无明显差异：中度肾功能不全（OR[95％ CI]：0.80 [0.52,1.21],P=0.29,I^2=0％）,重度肾功能不全（OR[95％CI]：0.99 [0.65,1.50],P=0.95,I^2=0％）;药物相关不良事件与死亡风险DPP-4抑制剂组与对照组间无统计学差异,药物相关不良事件（OR[95％ CI]：0.93[0.71,1.22],P=0.6,I^2=7％;死亡OR[95％CI]：0.77 [0.47,1.26],P=0.3,I^2=0％）.结论 对于中度至重度肾功能不全（包括终末期肾衰竭及透析）的2型糖尿病患者,DPP-4抑制剂仍是一个安全有效的降糖药,但由于受文献资料数量及质量限制,仍需要大样本、多中心、设计良好的RCT进一步验证.

Objectives Dipeptidyl peptidase-4 （DDP-4） inhibitors were considered as an effective treatment choice in patients with type 2 diabetes and renal insufficiency,while its safety and tolerability still needed more confirmation.We performed A systematic review of the safety and efficiency of DDP-4 inhibitors in treatment of patients with type 2 diabetic with chronic kidney disease （CKD） were performed by Meta-analysis.Methods A systemic review of randomized controlled triALs （RCTs） on DPP-4 inhibitors （including sitagliptin,saxagliptin,vildagliptin,linagliptin and teneligliptin） in type 2 diabetes with renal insufficiency was conducted.MEDLINE and EMBASE were searched until June 2015.RCTs or quasi-RCTs comparing the efficacy and/or safety outcome between DPP-4 inhibitors and placebo or an antihyperglycemic agent in diabetes patients with chronic renal disease were selected.Results In 13 evaluated articles,DPP-4 inhibitors lowered hemoglobin A1c （HbA1C） significantly.Subgroup of DPP-4 inhibitor VS Placebo resulted in a more obvious effect on HbA1 c,while subgroup analysis among both patients with moderate and severe renal impairment including ESRD and dialysis still showed significant effect to decrease HbA1 c （%）;DPP-4 inhibitors showed little effect on FPG,even compared with placebo（P =O.86,I^2 =90%）;For safety evaluation,DPP-4 inhibitors slightly increased risk of hypoglycemia （OR [95% CI]：1.38 [1.07,1.78],P =0.01,I^2 =0%） compared with placebo,while the risk decreased when compared with other hypoglycemic agents （OR[95%CI]：0.46 [0.33,0.65],P 〈0.0001,I^2 =31%）.No significant difference in hypoglycemia was observed in both subgroups of moderate renal impairment and severe renal impairment including ESRD.Total AEs in DPP-4 inhibitor group also showed no difference compared with control,further analysis based on renal function also resulted in a similar effect without significant difference for moderate renal impairment subgroup and in severe renal impairment including ESRD and dialysis group;Similar odds risk were observed in drug related adverse events （OR[95% CI]：0.93 [0.71,1.22],P =0.6,I^2 =7%）and death（OR[95%CI]：0.77 [0.47,1.26],P =0.3,I^2 =0%） between DPP-4 inhibitors and control.Conclusions DPP-4 inhibitors are effective to reduce A1C with comparable safety profiles in diabetes patients with moderate to severe renal deficiency including ESRD and dialysis compared to placebo,while evidences from more controlled trials concentrating on particular population of patients with renal deficiency including dialysis are needed.