DPP-4抑制剂与α糖苷酶抑制剂治疗2型糖尿病比较的Meta分析
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摘要
目的系统评价二肽基肽酶-4抑制剂(DPPIs)与α糖苷酶抑制剂(AGIs)治疗2型糖尿病疗效及安全性的差异。方法检索PubMed、EMbase、The Cochrane Library、CNKI、Wan Fang Data和VIP数据库,检索时限从建库至2017年7月,搜集DPPIs与AGIs治疗2型糖尿病的相关随机对照试验(RCT)。由2位研究人员独立筛选文献、提取资料和评价纳入研究的偏倚风险后,用STATA 11.0软件进行Meta分析。结果共纳入10个RCT,共3 314例患者。Meta分析结果显示:DPPIs在降低糖化血红蛋白(HbA1C)水平方面优于AGIs(WMD=-0.33,95%CI:-0.5～-0.16,P=0.000);DPPIs在提高胰岛素分泌指数(HOMA-β)水平方面优于AGIs(WMD=7.5,95%CI:0.59～5.42,P=0.000);DPPIs在降低胰岛素抵抗指数(HOMA-IR)水平方面优于AGIs(WMD=-0.1,95%CI:-0.12～-0.08,P=0.000);DPPIs在减轻体重方面劣于AGIs(WMD=0.67,95%CI:0.23～1.11,P=0.003);DPPIs和AGIs低血糖发生率差异无统计学意义(RD=0,95%CI:-0.01～0.00,P=0.458);DPPIs的总体不良反应发生率(RD=-0.13,95%CI:-0.18～-0.08,P=0.000)及胃肠道不良反应发生率(RD=-0.15,95%CI:-0.18～-0.12,P=0.000)均明显低于AGIs,但两组严重的不良反应发生率无统计学差异(RD=0,95%CI:-0.01～0.01,P=0.881)。结论 DPPIs降低HbA1C水平、提高HOMA-β水平及降低HOMA-IR水平方面优于AGIs,且总体不良反应及胃肠道不良反应发生率更低;然而,在减轻体重方面,AGIs优于DPPIs。
Objective To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors(DPPIs) withα-glucosidase inhibitors(AGIs) in treatment of type-2 diabetes mellitus(T2DM) by meta-analysis. Methods The PubMed,Embase, Cochrane Central Register of Controlled Trials, CNKI, Wan Fang Data and VIP databases for articles published before July 2017. Two reviewers independently screened literature, extracted date, and assessed the risk of bias. Then, meta-analysis was performed by using STATA 11.0 software. Results Ten randomized controlled trials involving 3 314 patients were included in the analysis. The results of meta-analysis showed that DPPIs led to a significantly marked reduction of glycated hemoglobin level from the baseline than DPPIs(WMD=-0.33, 95%CI:-0.5～-0.16, P=0.000); DPPIs more markedly improved the homeostatic model assessment for β-cell function(WMD=7.5, 95%CI: 0.59～5.42, P=0.000) and the homeostatic model assessment for insulin resistance(WMD=-0.1, 95%CI:-0.12～-0.08, P=0.000) compared with AGIs. Compared with AGIs, DPPIs were associated with weight gain(WMD=0.67, 95% CI:0.23～1.11, P=0.003). There was no significant difference between the two groups in the prevalence of hypoglycemia(RD=0, 95% CI:-0.01～0.00, P=0.458) or serious drug-related adverse events(RD=0, 95% CI:-0.01～0.01, P=0.881), but DPPIs were associated with a significantly lower incidence of overall adverse events(RD=-0.13, 95% CI:-0.18～-0.08, P=0.000) and gastrointestinal adverse events(RD=-0.15, 95% CI:-0.18～-0.12, P=0.000). Compared with AGIs,DPPIs were associated with weight gain(WMD=0.67, 95%CI:0.23～1.11, P=0.003). Conclusion DPPIs are more effective in glycemic control and improvement in β-cell function and insulin resistance, and have a lower incidence of drug-related adverse events and gastrointestinal adverse events compared with AGIs in treatment of T2 DM. However, DPPIs is associated with body weight gain.
Objective To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors(DPPIs) withα-glucosidase inhibitors(AGIs) in treatment of type-2 diabetes mellitus(T2DM) by meta-analysis. Methods The PubMed,Embase, Cochrane Central Register of Controlled Trials, CNKI, Wan Fang Data and VIP databases for articles published before July 2017. Two reviewers independently screened literature, extracted date, and assessed the risk of bias. Then, meta-analysis was performed by using STATA 11.0 software. Results Ten randomized controlled trials involving 3 314 patients were included in the analysis. The results of meta-analysis showed that DPPIs led to a significantly marked reduction of glycated hemoglobin level from the baseline than DPPIs(WMD=-0.33, 95%CI:-0.5～-0.16, P=0.000); DPPIs more markedly improved the homeostatic model assessment for β-cell function(WMD=7.5, 95%CI: 0.59～5.42, P=0.000) and the homeostatic model assessment for insulin resistance(WMD=-0.1, 95%CI:-0.12～-0.08, P=0.000) compared with AGIs. Compared with AGIs, DPPIs were associated with weight gain(WMD=0.67, 95% CI:0.23～1.11, P=0.003). There was no significant difference between the two groups in the prevalence of hypoglycemia(RD=0, 95% CI:-0.01～0.00, P=0.458) or serious drug-related adverse events(RD=0, 95% CI:-0.01～0.01, P=0.881), but DPPIs were associated with a significantly lower incidence of overall adverse events(RD=-0.13, 95% CI:-0.18～-0.08, P=0.000) and gastrointestinal adverse events(RD=-0.15, 95% CI:-0.18～-0.12, P=0.000). Compared with AGIs,DPPIs were associated with weight gain(WMD=0.67, 95%CI:0.23～1.11, P=0.003). Conclusion DPPIs are more effective in glycemic control and improvement in β-cell function and insulin resistance, and have a lower incidence of drug-related adverse events and gastrointestinal adverse events compared with AGIs in treatment of T2 DM. However, DPPIs is associated with body weight gain.
引文
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[13]Du J,Liang L,Fang H,et al.Efficacy and Safety of Saxagliptin Compared with Acarbose in Chinese Patients with Type 2 Diabetes Mellitus Uncontrolled on Metformin Monotherapy:Results of a Phase IV Open-Label Randomized Controlled Study(The SMARTStudy)[J].Diabetes,obesity&metabolism,2017.DOI:10.1111/dom.12942.
[14]Kawamori R,Inagaki N,Araki E,et al.Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2diabetes:a randomized,placebo and active comparator-controlled,double-blind study[J].Diabetes,obesity&metabolism,2012,14(4):348-357.DOI:10.1111/j.1463-1326.2011.01545.x.
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[16]Mikada A,Narita T,Yokoyama H,et al.Effects of miglitol,sitagliptin,and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes."the MAS-TER randomized,controlled trial"[J].Diabetes research and clinical practice,2014,106(3):538-547.DOI:10.1016/j.diabres.2014.09.040.
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[18]Seino Y,Fujita T,Hiroi S,et al.Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus:a randomized,double-blind,dose-ranging comparison with placebo,followed by a long-term extension study[J].Current medical research and opinion,2011,27(9):1781-1792.DOI:10.1185/03007995.2011.599371.
[19]Yokoh H,Kobayashi K,Sato Y,et al.Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone(Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1):A multicenter,randomized,open-label,non-inferiority trial[J].Journal of diabetes investigation,2015,6(2):182-191.DOI:10.1111/jdi.12282.
[20]Iwamoto Y,Tajima N,Kadowaki T,et al.Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes:a randomized,double-blind trial[J].Diabetes,obesity&metabolism,2010,12(7):613-622.DOI:10.1111/j.1463-1326.2010.01197.x.
[21]Iwamoto Y,Kashiwagi A,Yamada N,et al.Efficacy and safety of vildagliptin and voglibose in Japanese patients with type 2 diabetes:a 12-week,randomized,double-blind,active-controlled study[J].Diabetes,obesity&metabolism,2010,12(8):700-708.DOI:10.1111/j.1463-1326.2010.01222.x.
[22]潘长玉,姬秋和,杨文英,等.2型糖尿病患者维格列汀与阿卡波糖单药治疗的比较研究--24周多中心、随机、双盲、双模拟、阳性对照试验[J].中华内分泌代谢杂志,2009,25(4):386-390.DOI:10.3760/cma.j.issn.1000-6699.2009.04.008.
[23]Lyu X,Zhu X,Zhao B,et al.Effects of dipeptidyl peptidase-4 inhibitors on beta-cell function and insulin resistance in type 2 diabetes:meta-analysis of randomized controlled trials[J].Scientific reports,2017,7:44865.DOI:10.1038/srep44865.
[24]Rudovich NN,Weickert MO,Pivovarova O,et al.Effects of acarbose treatment on markers of insulin sensitivity and systemic inflammation[J].Diabetes technology&therapeutics,2011,13(6):615-623.DOI:10.1089/dia.2010.0235.
[25]Sato H,Kubota N,Kubota T,et al.Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice[J].Diabetologia,2016,59(11):2426-2434.DOI:10.1007/s00125-016-4071-8.
[26]Cai X,Han X,Luo Y,et al.Efficacy of dipeptidyl-peptidase-4 inhibitors and impact on beta-cell function in Asian and Caucasian type 2 diabetes mellitus patients:A meta-analysis[J].Journalofdiabetes,2015,7(3):347-359.DOI:10.1111/1753-0407.12196.
[27]He K,Shi JC,Mao XM.Safety and efficacy of acarbose in the treatment of diabetes in Chinese patients[J].Therapeutics and clinical risk management,2014,10:505-511.DOI:10.2147/tcrm.s50362.
[28]Mertes G.Safety and efficacy of acarbose in the treatment of Type 2 diabetes:data from a 5-year surveillance study[J].Diabetes research and clinical practice,2001,52(3):193-204.DOI.10.1016/S0168-8227(01)00221-2.
[29]Gilbert RE,Krum H.Heart failure in diabetes:effects of anti-hyperglycaemic drug therapy[J].Lancet(London,England),2015,385(9982):2107-2117.DOI:10.1016/s0140-6736(14)61402-1.
[30]Zannad F,Cannon CP,Cushman WC,et al.Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE:a multicentre,randomised,double-blind trial[J].Lancet(London,England),2015,385(9982):2067-2076.DOI:10.1016/s0140-6736(14)62225-x.
[31]Green JB,Bethel MA,Armstrong PW,et al.Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes[J].The New England journal of medicine,2015,373(3):232-242.DOI:10.1056/NEJMoa1501352.
[32]Scirica BM,Braunwald E,Raz I,et al.Heart Failure,Saxagliptin,and Diabetes Mellitus:Observations from the SAVOR-TIMI 53Randomized Trial[J].Circulation,2015,132(15):e198.DOI:10.1161/cir.0000000000000330.
[2]Inzucchi SE,Bergenstal RM,Buse JB,et al.Management of hyperglycemia in type 2 diabetes,2015:a patient-centered approach:update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes[J].Diabetes care,2015,38(1):140-149.DOI:10.2337/dc14-2441.
[3]Nathan DM,Buse JB,Davidson MB,et al.Medical management of hyperglycemia in type 2 diabetes:a consensus algorithm for the initiation and adjustment of therapy:a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[J].Diabetes care,2009,32(1):193-203.DOI:10.2337/dc08-9025.
[4]Barnett A.DPP-4 inhibitors and their potential role in the management of type 2 diabetes[J].International journal of clinical practice,2006,60(11):1454-1470.DOI:10.1111/j.1742-1241.2006.01178.x.
[5]Aaboe K,Krarup T,Madsbad S,et al.GLP-1:physiological effects and potential therapeutic applications[J].Diabetes,obesity&metabolism,2008,10(11):994-1003.DOI:10.1111/j.1463-1326.2008.00853.x.
[6]Rehfeld JF.Incretin physiology beyond glucagon-like peptide 1and glucose-dependent insulinotropic polypeptide:cholecystokinin and gastrin peptides[J].Acta physiologica,2011,201(4):405-411.DOI:10.1111/j.1748-1716.2010.02235.x.
[7]中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中国糖尿病杂志,2014,8(22):2-42.DOI:10.3760/cma.j.issn.1674-5809.2014.07.004.
[8]Van de Laar FA,Lucassen PL,Akkermans RP,et al.Alpha-glucosidase inhibitors for type 2 diabetes mellitus[J].The Cochrane database of systematic reviews,2005(2):Cd003639.DOI:10.1002/14651858.CD003639.pub2.
[9]Lebovitz HE.alpha-Glucosidase inhibitors[J].Endocrinology and metabolism clinics of North America,1997,26(3):539-551.DOI.10.1016/S0889-8529(05)70266-8.
[10]Jadad AR,Moore RA,Carroll D,et al.Assessing the quality of reports of randomized clinical trials:is blinding necessary?[J].Controlled clinical trials,1996,17(1):1-12.DOI.10.1016/0197-2456(95)00134-4.
[11]Higgins JP,Thompson SG,Deeks JJ,et al.Measuring inconsistency in meta-analyses[J].BMJ(Clinical research ed),2003,327(7414):557-560.DOI:10.1136/bmj.327.7414.557.
[12]Macaskill P,Walter SD,Irwig L.A comparison of methods to detect publication bias in meta-analysis[J].Statistics in medicine,2001,20(4):641-654.DOI:10.1002/sim.698.
[13]Du J,Liang L,Fang H,et al.Efficacy and Safety of Saxagliptin Compared with Acarbose in Chinese Patients with Type 2 Diabetes Mellitus Uncontrolled on Metformin Monotherapy:Results of a Phase IV Open-Label Randomized Controlled Study(The SMARTStudy)[J].Diabetes,obesity&metabolism,2017.DOI:10.1111/dom.12942.
[14]Kawamori R,Inagaki N,Araki E,et al.Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2diabetes:a randomized,placebo and active comparator-controlled,double-blind study[J].Diabetes,obesity&metabolism,2012,14(4):348-357.DOI:10.1111/j.1463-1326.2011.01545.x.
[15]Matsushima Y,Takeshita Y,Kita Y,et al.Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent:a multicenter,randomized trial[J].BMJ open diabetes research&care,2016,4(1):e000190.DOI:10.1136/bmjdrc-2015-000190.
[16]Mikada A,Narita T,Yokoyama H,et al.Effects of miglitol,sitagliptin,and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes."the MAS-TER randomized,controlled trial"[J].Diabetes research and clinical practice,2014,106(3):538-547.DOI:10.1016/j.diabres.2014.09.040.
[17]Pan C,Yang W,Barona JP,et al.Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes:a24-week,double-blind,randomized trial[J].Diabetic medicine:a journal of the British Diabetic Association,2008,25(4):435-441.DOI:10.1111/j.1464-5491.2008.02391.x.
[18]Seino Y,Fujita T,Hiroi S,et al.Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus:a randomized,double-blind,dose-ranging comparison with placebo,followed by a long-term extension study[J].Current medical research and opinion,2011,27(9):1781-1792.DOI:10.1185/03007995.2011.599371.
[19]Yokoh H,Kobayashi K,Sato Y,et al.Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone(Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1):A multicenter,randomized,open-label,non-inferiority trial[J].Journal of diabetes investigation,2015,6(2):182-191.DOI:10.1111/jdi.12282.
[20]Iwamoto Y,Tajima N,Kadowaki T,et al.Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes:a randomized,double-blind trial[J].Diabetes,obesity&metabolism,2010,12(7):613-622.DOI:10.1111/j.1463-1326.2010.01197.x.
[21]Iwamoto Y,Kashiwagi A,Yamada N,et al.Efficacy and safety of vildagliptin and voglibose in Japanese patients with type 2 diabetes:a 12-week,randomized,double-blind,active-controlled study[J].Diabetes,obesity&metabolism,2010,12(8):700-708.DOI:10.1111/j.1463-1326.2010.01222.x.
[22]潘长玉,姬秋和,杨文英,等.2型糖尿病患者维格列汀与阿卡波糖单药治疗的比较研究--24周多中心、随机、双盲、双模拟、阳性对照试验[J].中华内分泌代谢杂志,2009,25(4):386-390.DOI:10.3760/cma.j.issn.1000-6699.2009.04.008.
[23]Lyu X,Zhu X,Zhao B,et al.Effects of dipeptidyl peptidase-4 inhibitors on beta-cell function and insulin resistance in type 2 diabetes:meta-analysis of randomized controlled trials[J].Scientific reports,2017,7:44865.DOI:10.1038/srep44865.
[24]Rudovich NN,Weickert MO,Pivovarova O,et al.Effects of acarbose treatment on markers of insulin sensitivity and systemic inflammation[J].Diabetes technology&therapeutics,2011,13(6):615-623.DOI:10.1089/dia.2010.0235.
[25]Sato H,Kubota N,Kubota T,et al.Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice[J].Diabetologia,2016,59(11):2426-2434.DOI:10.1007/s00125-016-4071-8.
[26]Cai X,Han X,Luo Y,et al.Efficacy of dipeptidyl-peptidase-4 inhibitors and impact on beta-cell function in Asian and Caucasian type 2 diabetes mellitus patients:A meta-analysis[J].Journalofdiabetes,2015,7(3):347-359.DOI:10.1111/1753-0407.12196.
[27]He K,Shi JC,Mao XM.Safety and efficacy of acarbose in the treatment of diabetes in Chinese patients[J].Therapeutics and clinical risk management,2014,10:505-511.DOI:10.2147/tcrm.s50362.
[28]Mertes G.Safety and efficacy of acarbose in the treatment of Type 2 diabetes:data from a 5-year surveillance study[J].Diabetes research and clinical practice,2001,52(3):193-204.DOI.10.1016/S0168-8227(01)00221-2.
[29]Gilbert RE,Krum H.Heart failure in diabetes:effects of anti-hyperglycaemic drug therapy[J].Lancet(London,England),2015,385(9982):2107-2117.DOI:10.1016/s0140-6736(14)61402-1.
[30]Zannad F,Cannon CP,Cushman WC,et al.Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE:a multicentre,randomised,double-blind trial[J].Lancet(London,England),2015,385(9982):2067-2076.DOI:10.1016/s0140-6736(14)62225-x.
[31]Green JB,Bethel MA,Armstrong PW,et al.Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes[J].The New England journal of medicine,2015,373(3):232-242.DOI:10.1056/NEJMoa1501352.
[32]Scirica BM,Braunwald E,Raz I,et al.Heart Failure,Saxagliptin,and Diabetes Mellitus:Observations from the SAVOR-TIMI 53Randomized Trial[J].Circulation,2015,132(15):e198.DOI:10.1161/cir.0000000000000330.