吡格列酮研究进展.ppt

盐酸吡格列酮研究进展,内 容,吡格列酮防治心血管,脑血管病变PROactive 2007 吡格列酮2008研究,吡格列酮对2445例有心梗的2型糖尿病患者再次梗塞的影响 PROactive 研究结果,proactive-,1,到复合心脏终点的时间(心源性死亡,非致命 MI,冠脉重建或 ACS),12,proactive-,0.100.080.060.040.020.0,吡格列酮(180/1230)Placebo(217/1215),N at Risk:,2445,2350,2260,2186,2116,2036,357（127）,0,6,12,18,24,30,36,Kapan-Meier event rate,从随机开始的时间(months),到 ACS时间,13,proactive-,0.060.050.040.030.020.010.00,吡格列酮(180/1230)Placebo(217/1215),N at Risk:,2445,2397,2351,2308,2265,2222,406(139),0,6,12,18,24,30,36,Kapan-Meier event rate,从随机开始的时间(months),吡格列酮对于伴有中风病史或不伴有中风病史患者的作用 PROactive研究亚组分析结果,入组标准：大血管疾病病史,Previous MI(6 months prior),n(%)177(18)2268(53)Previous PCI/CABG(6 months prior),n(%)102(10)1509(36)Previous ACS(3 months prior),n(%)50(5)655(16)Symptomatic PAOD,n(%)97(10)946(22),PreviousStrokeN=984,No PreviousStrokeN=4254,到致死性中风或非致死性中风的时间,结论,针对伴发中风病史的2型糖尿病患者：吡格列酮可以显著减低致死性或非致死性中风的风险，达47%吡格列酮不降低无中风病史的患者发生中风的风险,IRIS研究目的,针对有中风病史的非糖尿病患者服用吡格列酮是否可以预防中风和心脏病的再发；,IRIS研究设计,随机、安慰剂对照、双盲的多中心研究。计划入组3136名患者，随访期为5年 入组标准45岁的非糖尿病患者最近6个月内发生过非栓塞性的缺血性中风的患者经过血液检测有胰岛素抵抗 排除标准由于外伤或颈动脉手术引起的中风严重的心脏病、肝病、贫血或其它导致生命期小于5年的疾病正在服用口服避孕药和激素的患者HbA1c7%的患者患者被随机分到吡格列酮组和对照组，每四个月随访一次；,CHICAGO,A Study Evaluating Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone在使用吡格列酮的动脉粥样硬化患者中评价颈动脉内中膜厚度的研究,研究目的和设计,目的 在2型糖尿病患者中，比较吡格列酮和格列美脲对CIMT治疗前后变化的影响。研究设计72周，多中心，随机，双盲研究15-45 mg PIO vs.1-4 mg GLM(调整剂量到HbA1c目标值)462 例在 0,24,48,and 72周或者最后一次随访(LOCF)时测量CIMT。,研究设计,筛查,Week 7 W0 W4 W8 W16 W24 W32 W40 W48 W60 W72 CIMT CIMT CIMT CIMT EBT EBT,吡格列酮15-45mg QD,格列美脲1-4mg QD,研究终点,主要终点颈动脉后壁IMT平均值从基线到最后一次随访时的变化次要终点颈动脉后壁IMT最大值从基线到最后一次随访的变化心血管联合终点（独立评价）,CIMT的测量,在左、右颈总动脉的后壁平均进行89次测量，没有造影剂同一影像学中心（同一设备）、超声技术员以及影像阅读者采用计算机化的边缘探测技术进行CIMT的自动测量 CIMT测量的低变异性,随机化N=462,测量了CIMT N=186(81%),测量了CIMT N=175(75%),对象分组,格列美脲N=230,吡格列酮N=232,p=0.01,0.012,-0.001,-0.010,-0.005,0.000,0.005,0.010,0.015,0.020,后壁CIMT与基线相比的平均变化(mm),格列美脲,吡格列酮,治疗组间的差异,最后一次随访-0.013(95%CI:-0.024,-0.002),基线CIMTLS Mean(SE),GLM(N=186)0.779(0.0085)mm,PIO(N=175)0.771(0.0085)mm,CIMT 的平均变化,-0.010,-0.005,0.000,0.005,0.010,0.015,Baseline,Week 24,Week 48,Week 72,后壁CIMT与基线相比的平均变化(mm),*,*P=0.01,格列美脲,吡格列酮,T治疗组间差异,最后一次随访t-0.013(95%CI:-0.024,-0.002),平均CIMT的平均变化,72周(LOCF)时远壁CIMT最大值与基线相比的变化,与基线相比的变化(mm),和格列美脲的差别-0.024(-0.042,-0.006),*P-Value=0.008 和格列美脲的比较,*,0.026,0.002*,-0.02,-0.01,0.00,0.01,0.02,0.03,0.04,后壁最大CIMT与基线相比的平均变化(mm),Baseline,Week 24,Week 48,Week 72,*,*,Glimepiride,Pioglitazone HCl,最后一次随访时治疗组间的差别-0.024(95%CI:-0.042,-0.006),*P0.01,最大CIMT的平均变化,Baseline,Week 24,Week 48,Week 60,Week 40,Week 32,Week 16,Week 72,与基线相比的平均改变,HbA1c(%),-1.0,-0.8,-0.6,-0.4,-0.2,0.0,0.2,0.4,Glimepiride,Pioglitazone HCl,治疗组间差别,最后一次随访-0.32(95%CI:-0.522,-0.124),基线 HbA1c(%)LS mean(SE),GLM(N=206)7.36(0.075),PIO(N=203)7.42(0.074),*,*,*,*P 0.05,血糖的影响,HDL-C与基线相比的变化(mg/dL),Baseline,Week 24,Week 48,Week 72,*,*,*,治疗组间差别,最后一次随访6.45(95%CI:4.97,7.93),基线 HDL-C(mg/dL)LS mean(SE),GLM(N=206)47.6(0.91),PIO(N=201)47.1(0.90),*P0.0001,格列美脲,吡格列酮,-2,0,2,4,6,8,10,HDL胆固醇的变化,-1.1%,12.8%,其他血脂和血压的影响,血脂资料以均值(SE)表示,SBP 以均值(SD)表示.变化值是指基线到最后一次随访之间的变化.,小结,在72周的治疗期比较了吡格列酮和格列美脲对CIMT均值(主要)和最大值(次要)变化的影响.研究对象来自多种族的芝加哥市区,总体代表2型糖尿病人群.总的说来,病人的心血管危险因素控制较好.,和格列美脲相比,PIO 延缓CIMT平均值(p=0.017)和最大值(p0.01)的进展.在预先确定的亚组包括他汀类药物使用亚组可以见到一致的结果.,来自19个临床研究的16,390患者分析,JAMA,september 12,2007.vol 298,No.10,结论：吡格列酮显著降低心血管事件,Conclusions:Pioglitazone is associated with a significantly lower risk of death,myocardial infarction,or stroke among a diverse population of patients with diabetes.Serious heart failure is increased by pioglitazone,although without an associated increase in mortality.,结论:吡格列酮显著降低糖尿病患者死亡，心梗和中风的风险。尽管严重的心衰事件在吡格列酮使用过程中有所增加，但是与心衰相关的死亡率并没有因此增加。,JAMA,september 12,2007.vol 298,No.10,单用吡格列酮显著改善胰岛素指标,空腹胰岛素(IU/ml),C-肽(ng/mL),32,33裂解胰岛素原(pmol/l),p=NS,p=NS,p 0.001,Schernthaner G et al.(J.Clin.Endocrin.Metab.2004,89:6068),(-5.3%),(2.7%),(-16.6%),(-2.1%),(-34.2%),(-30.2%),空腹血糖,Schernthaner G et al.(J.Clin.Endocrin.Metab.2004,89:6068,单用吡格列酮显著降低HbA1c/FPG,p=0.09,HbA1c,二甲双胍,吡格列酮,p=0.016,二甲双胍,吡格列酮,(N=597),(N=597),(N=597),(N=597),(mmol/L),(%),联合应用吡格列酮显著降低HbA1c/FPG,Charbonnel B,et al.Diabetologia 2005;48:1093-1104,吡格列酮二甲双胍,格列奇特二甲双胍,研究终点时HbA1c降低比例,研究终点时FPG降低比例,百分比,血糖浓度,(mmol/L),(%),p=0.003,p0.001,(N=317),(N=313),4.92,5.34,52周,基线,4.92,5.34,mmol/L,mmol/L,Ratio,0.62,0.66,0.54,0.66,1.21,1.13,1.29,1.13,mmol/L,2.31,2.61,2.03,2.64,-19,14,8,-8,-18,-10,7,-3,-8,-6,-25,-20,-15,-10,-5,0,5,10,15,20,与基线比较的变化比例(%),TG,HDL-C,LDL-C,TC/HDL,FFAs,吡格列酮,mmol/L,3.44,3.56,3.83,3.56,二甲双胍,25,单用吡格列酮显著改善血脂谱Schernthaner G et al.J.Clin.Endocrin.Metab.2004,89:6068-6076,(N=597),(N=597),P0.001,P0.001,P0.001,P0.001,P=NS,4.87,5.38,52周,基线,4.86,5.45,mmol/L,Ratio,1.19,1.11,1.25,1.09,mmol/L,2.15,2.38,2.01,2.47,-16,14,2,-11,-9,8,-5,-10,-25,-20,-15,-10,-5,0,5,10,15,20,与基线比较的变化比例(%),TG,HDL-C,LDL-C,TC/HDL,mmol/L,3.41,3.58,3.66,3.57,25,联合应用吡格列酮显著改善血脂谱 MARKOLF HANEFELD,et al.Diabetes Care 2004(27):141147,p=0.008,p0.0001,p0.0002,p=NS,(N=319),(N=320),磺脲吡格列酮磺脲二甲双胍,吡格列酮改善2型糖尿病患者高血压,基线150-159/90-95mmHg,基线160/100mmHg,血压降低值,N=3140,吡格列酮治疗16周，表现出有益的降压作用,Konrad T,et al.Clin Drug Invest.2005(25):337-340,(mmHg),单用吡格列酮显著降低尿白蛋白/肌酐比值,二甲双胍,尿白蛋白/肌酐比值变化百分比(%),P0.001,(N=588),(N=588),吡格列酮,(N=616),吡格列酮,(N=616),格列奇特,P=NS,Erdmann E.Int J Cardiol.2006(107)2:147-153,吡格列酮显著降低C反应蛋白,P0.05,C反应蛋白浓度,Park SJ,et al.J Am College of Cardiology.2006(47)4:Supplement A,(mg/L),抑制平滑肌增殖、降低CIMT,吡格列酮(N=175),格列美脲(N=186),后壁CIMT平均变化,p=0.017,Mazzone T,et al.(Reprinted)JAMA,Published online November 13,2006 E1-E10,(mm),吡格列酮逆转动脉硬化、消退斑块,硬化斑块体积,p=0.0003,吡格列酮治疗可显著减少动脉硬化斑块体积,Nakayama T,et al.J Am College of Cardiology.2006(47)4:Supplement A,(mm3),内 容,吡格列酮防治心血管,脑血管病变PROactive 2007 吡格列酮2008研究,PROactive-CKD分析,111,2型糖尿病胰岛素强化治疗期间加吡格列酮或雷米普利可改善血管功能不全,内 容,吡格列酮防治心血管,脑血管病变PROactive 2007 吡格列酮2008研究,吡格列酮与格列美脲对2型糖尿病冠脉硬 化进展的作用比较(PERISCOPE),Stephen J.Nicholls MBBS PhD,et al.for the PERISCOPE Investigators*,Steven E.Nissen MD,Comparison of Pioglitazone vs.Glimepiride on Progression of Coronary Atherosclerosis in Patients with Type 2 Diabetes,背景与目的,心血管疾病是糖尿病患者死亡的主要原因糖尿病药物治疗中除了比较降糖作用外极少研究不良结局我们比较了二种药物对血管内超声检查所显示的冠脉病变进展：Glimepiride(an insulin secretagogue)Pioglitazone(an insulin sensitizer),方 法,临床有冠脉造影指证的2型糖尿病基线测定血管内超声（IVUS）动脉斑块大小543例病人,随机分为格列美脲组(1-4mg)或吡格列酮组(15-45mg),只要能耐受调至最大量，时间16周18个月后,360例完成IVUS复查。,基线资料(n=543),*P=0.002,P=0.01,基线治疗(n=543),基线实验检查与血压*,P=0.05,*N=360(patients with both baseline and final IVUS),HbAlc 变化,HbA1c(%),Weeks after Randomization,血压变化(n=360),P=0.03,P=0.003,Systolic,Diastolic,血生化改变的百分比,P 0.001,P=0.69,HDL-cholesterol,LDL-cholesterol,4.1%,16.0%,-15.3%,0.6%,Triglycerides,6.9%,6.6%,hs C-reactive Protein,-18.0%,-44.9%,P 0.001,P 0.001,动脉斑块体积变化(PAV)(%),P 0.001,P=0.44,P=0.002,Glimepiride,Pioglitazone,主要的有效性指标,血管内超声:次极终点,P=0.006,P=0.06,Atheroma Thickness(mm),Atheroma Volume(mm3),-5.5,-1.5,0.011,-0.011,P=0.93,-2.1,-2.0,Most Diseased 10mm(mm3),Glimepiride,Pioglitazone,Favors Pioglitazone,Favors Glimepiride,HbA1c,median median,Diabetesduration,Statinuse,Yes(306)no(54),SystolicBP,BMI,Gender,Age,median median,130 mmHg 130 mmHg,median median,MaleFemale,60 years 60 years,事先设定的亚组PAV变化,P=0.07,Favors Pioglitazone,Favors Glimepiride,0,1,2,1,median median,PAV,CRP,MetabolicSyndrome,Trigs,LDL-C,HDL-C,median median,事后分析亚组PAV变化,median median,median median,Yes(295)no(65),median median,调整后的CVD事件,Other Adverse Effects,PERISCOPE:与其他试验比较,REVERSALpravastatin,ASTEROIDrosuvastatin,ILLUSTRATEatorvastatin,REVERSALatorvastatin,CAMELOTplacebo,ACTIVATEplacebo,PERISCOPEglimepiride,PERISCOPEpioglitazone,结论,吡格列酮与格列美脲相比能预防冠脉粥样硬化(P=0.002).与格列美脲相比,吡格列酮降糖作用类似,但更持久.与格列美脲相比,吡格列酮降低血压,升高 HDL-C(16.0%vs.4.1%),降低甘油三酯(-15.3%vs.+0.6%)和降低hsCRP(-44.9%vs.-18.0%).格列美脲组的低血糖和心绞痛更常见 吡格列酮组的水肿，骨折和体重增加更常见,实验室数值与BP的变化,Other Biomarkers:Insulin Levels and BNP,P0.001,P0.001,Change in Fasting Insulin Levels,Final Brain Natiuretic Peptide,32.4,22.6,8.5%,-28.3%,Actos Now for Prevention of Diabetes(ACT NOW),Dr.Ralph DeFronzo,professor of medicine at the Health Science Center and deputy director of the Texas Diabetes Institute,said the trial should demonstrate pioglitazones ability to improve the bodys sensitivity to insulin and prevent insulin-producing beta cells from dying.Dr.DeFronzo is principal investigator for the ACT NOW Trial(Actos Now for the Prevention of Type 2 Diabetes),which will compare outcomes of pre-diabetic individuals receiving pioglitazone with those receiving a placebo.,Actos Now for Prevention of Diabetes(ACT NOW)ADA 2008,The purpose of this study is to examine whether pioglitazone versus placebo can reduce the conversion rate of impaired glucose tolerance(IGT)to type 2 diabetes mellitus,Pioglitazone Prevents Conversion to Diabetes Among Insulin-Resistant Patients:Presented at ADA,SAN FRANCISCO-June 11,2008 Patients with impaired glucose tolerance treated with pioglitazone were able to stave off conversion to type 2 diabetes by 81%when compared with individuals who received placebo,according to long-term results of a phase 3 trial presented here at the American Diabetes Association(ADA)68th Scientific Sessions.,IGT n=602-407 IGT+IFG-195 I-IGT,The mean age 52 years;BMI 34.,DM significant relative risk reduction of 81%(P.00001)P.001,主要结果,Thank You,