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1、中国新诊断2型糖尿病初始治疗方案的探讨Metformin and AcaRbose in Chinese as the initialHypoglycaemic treatment,研究注册号：ChiCTR-TRC-00000231,世界糖尿病联盟（IDF）的最新数据,糖尿病患者数超过3.82亿,IDF Diabetes Atlas 6th Edition,糖尿病患者数排名前10个国家(20-79岁)，2013,2012年ADA/EASD立场声明,Diabetes Care.2012 Jun;35(6):1364-79,2013 AACE糖尿病管理路径:二甲双胍不是唯一的一线治疗药物,2013
2、AACE Comprehensive Diabetes Management Algorithm,Endocr Pract.2013;19(No.2),除二甲双胍外，AGI等其他药物也被列为单药和联合治疗的一线药物,2007-2008年中国流行病学调查成人新诊断糖尿病：IPH占46.6,男性：IPH患病率 2.9%,N=46,239,IPH(Isolated Postchallenge Hyperglycemia)单纯OGTT后2小时血糖符合糖尿病诊断标准,IPH 44,PH/FH 36,IFH 20,女性：IPH患病率 2.6%,IPH 50,PH/FH 35,IFH 15,Yang WY.
3、et al.N Engl J Med.2010 Mar 25;362(12):1090-101,Rosak C,Mertes G.Curr Diabetes Rev.2009;5(3):157-64.,阿卡波糖着眼餐后，改善多种代谢因素,阿卡波糖是否可以作为中国新诊断患者的初始单药治疗？,MARCH研究,第一项在新诊断糖尿病患者中头对头比较阿卡波糖和二甲双胍的多中心、RCT研究主要假设：阿卡波糖在中国新诊断患者中的疗效是否非劣于二甲双胍？评价-糖苷酶抑制剂阿卡波糖和二甲双胍对中国新诊断2型糖尿病患者的降糖疗效(HbA1c)非劣效假设：两组糖化血红蛋白降幅差异的非劣效界值为0.3%(FDA gu
4、ideline),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,内容概要,MARCH研究设计MARCH研究结果,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,研究设计,前瞻性、随机、多中心、开放、平行对照、非劣效研究随访时间1年,Yang WY,et al.The Lancet Diabetes&Endocrinology,Ear
5、ly Online Publication,18 October 2013.,导入期四周,0周,1周,2周,4周,24周,48周,0周,1周,2周,4周,24周,48周,100mg tid,1500mg qd,阿卡波糖组(第一阶段),阿卡波糖组(第二阶段),二甲双胍组(第一阶段),二甲双胍组(第二阶段),不达标(HbA1c7%)患者可联合胰岛素促泌剂继续治疗，达标患者维持原治疗至研究结束,主要入选标准,新诊断的2型糖尿病患者(WHO标准，1999年)病程12月以内，未用过降糖药物或用药史1月，但是入组前3个月未用药物者HbA1c7%且 10%；FBG11.1 mmol/L年龄30-70岁体重指
6、数19BMI30kg/m2入选前3个月内未参加任何药物临床试验者无严重心、肝、肾疾病,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,主要排除标准,肾脏疾病病史，肌酐1.5mg/dl(133mol/L)严重胃肠道疾病心脏疾病(过去6个月罹患不稳定性心绞痛或心肌梗死，或心力衰竭NYHA分级III或IV级)肝脏疾病，或AST/ALT高于正常上限2倍或以上慢性缺氧性疾病(肺气肿或肺心病)血液系统疾病内分泌疾病(甲状腺功能低下，甲状腺功能亢进，库欣综合征)未控制的高血压（
7、收缩压160mmHg或舒张压95 mmHg）急性疾病；肠道手术史准备怀孕的妇女，或妊娠或哺乳期妇女受试前3个月参与其他任何药物的临床试验精神障碍；滥用药物需胰岛素治疗糖尿病酮症酸中毒或高渗性非酮症昏迷,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,中心化标本检测,HbA1c(Biorad Variant-II,Biorad,CA,USA)胰岛素(Beckman insulin kit,Prague,Czech Republic)胰高糖素(Linco GL-32K
8、 kit,CA,USA)GLP-1(Linco GLP1A-35HK kit,CA,USA)尿微量白蛋白,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,研究中心,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,研究终点,首要终点第24和第48周时的HbA1c变化次要终点药物对空腹及餐后血糖的影响药物对体重的影响 药物对胰岛素抵抗、胰
9、岛细胞功能的影响药物对肠促胰岛激素的影响药物对尿微量白蛋白的影响了解中国新诊断2型糖尿病患者的饮食特点，药物干预是否与饮食成份具有内在联系,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,内容概要,MARCH研究设计MARCH研究结果,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,研究流程图,Patients screened n=
10、1099,Acarbosen=391,Metforminn=393,Complete studyn=314,Complete studyn=326,Patients discontinued,n=65 AEs,n=10 Lack of efficacy，n=6 Lost to follow,n=20 Out of window,n=7 Protocol deviation,n=5 Others,n=17,Patients randomizedn=788,Patients discontinued,n=79 AEs,n=17 Lack of efficacy，n=2 Lost to follow
11、,n=24 Out of window,n=4 Protocol deviation,n=8 Others,n=24,Patients excluded n=315,*Drop out rate 18.8%,Patients discontinued before drug intervention n=4,5 in acarbose and 3 in metformin received sulfonylurea as add-on therapy during the second 24-week phase,Yang WY,et al.The Lancet Diabetes&Endocr
12、inology,Early Online Publication,18 October 2013.,患者基线特征,ITT；图中数据=均数标准差（SD）；两组间比较没有统计学差异标准餐后,主要终点指标-HbA1c,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,HbA1c 相对于基线变化值,=0.03,95%CI(-0.08,0.14)P=0.6320,7.49 7.59,7.49 7.59,Baseline,ITT人群和PP人群结果一致；表中数据为LS mean(
13、最小均方差),主要终点：达到非劣效,=0.01,95%CI(-0.12,0.14)P=0.8999,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,根据基线HbA1c分层-HbA1c相对于基线变化,ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,-0.32-0.23
14、-0.46-0.32,-0.99-1.00-1.02-0.97,-2.38-2.25-2.28-2.23,根据基线碳水化合物(CHO)%分层-HbA1c相对于基线变化,所有两组间P值均0.05；表中数据为LS mean(最小均方差)ITT人群；ITT人群和PP人群结果一致,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,-1.11-1.02-1.24-1.17,-1.24-1.17-1.21-1.09,患者数量(24周)148 134 212 216 患者数量(4
15、8周)139 123 196 194,次要终点指标,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,两组达标率比较,达标率%(HbA1c 7%),P=0.51,P=0.45,*ITT人群；ITT和PP人群的结果一致,达标率%(HbA1c 6.5%),%of Patients,%of Patients,P=0.62,P=0.54,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publicat
16、ion,18 October 2013.,FPG(静脉)相对于基线变化值,P=0.0421,P0.0001,Baseline,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),8.27 8.44,8.27 8.44,降低空腹血糖：以二甲双胍为优,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,2h-PPG(静脉)相对于基线变化值,P=0.0003,P=0.0385,Baseline,12.63 12.55,12.63 12.55,降低餐后2h
17、血糖：阿卡波糖优于二甲双胍,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,体重相对于基线变化值,P=0.0194,P=0.0054,Baseline,70.10 70.7,70.10 70.7,治疗24周和48周后，两组体重减轻有显著差异阿卡波糖优于二甲双胍,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabet
18、es&Endocrinology,Early Online Publication,18 October 2013.,甘油三酯相对于基线变化值,P.0001,2.34 2.41,2.34 2.41,P.0001,Baseline,治疗24周和48周后，两组甘油三酯降低有显著差异阿卡波糖优于二甲双胍,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,总胆固醇相对于基线变化值,P=0.9581,P=
19、0.5077,5.25 5.24,5.25 5.24,Baseline,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,LDL-C 相对于基线变化值,P=0.0535,P=0.0421,3.10 3.04,3.10 3.04,Baseline,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabetes&Endocr
20、inology,Early Online Publication,18 October 2013.,HDL-C 相对于基线变化值,P=0.0243,P=0.0747,1.23 1.24,1.23 1.24,Baseline,*ITT人群和PP人群结果一致；表中数据为LS mean(最小均方差),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,胰岛素相对于基线变化值 ITT人群,0min 30min 120min 180min,*,*,*,mean insulin(
21、uIU/mL),治疗24周和48周后，两组餐后胰岛素水平都降低，且阿卡波糖明显优于二甲双胍,*p0.01 between two groups p0.05,p0.01,compared with baseline Baseline(week 0)data are means.Post treatment(week 24 and 48)data are LS means.,Acarbose,Metformin,0min 30min 120min 180min,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publicat
22、ion,18 October 2013.,细胞功能(HOMA-B)-ITT人群,HOMA-B=20*FINS/(FPG-3.5)；表中数据为LS mean;*p值为两组相对于基线差值比较结果,*P=0.9113,Acarbose(week0),Acarbose(week24),Acarbose(week48),Metformin(week0),Metformin(week24),Metformin(week48),*P=0.9685,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 Octob
23、er 2013.,P=0.5268,P=0.2167,HOMA-IR=FINS*FPG/22.5；表中数据为LS mean；*p值为两组相对于基线差值比较结果,胰岛素抵抗(HOMA-IR)ITT人群,Acarbose(week0),Acarbose(week24),Acarbose(week48),Metformin(week0),Metformin(week24),Metformin(week48),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,*p0.05
24、between two groups p0.05,p0.01,compared with baseline Baseline(week 0)data are means.Post treatment(week 24 and 48)data are LS means.,*,胰高糖素相对于基线变化值 ITT人群,0min 30min 120min 180min,mean glucogan(pg/mL),Acarbose,Metformin,0min 30min 120min 180min,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early O
25、nline Publication,18 October 2013.,p0.01,compared with baseline Baseline(week 0)data are means.Post treatment(week 24 and 48)data are LS means.,Mean plasma GLP-1(pM),活性GLP-1相对于基线变化值 ITT人群,0min 30min 120min 180min,Acarbose,Metformin,0min 30min 120min 180min,Yang WY,et al.The Lancet Diabetes&Endocrino
26、logy,Early Online Publication,18 October 2013.,阿卡波糖的作用机制,Ronald CW Ma,Cooment to MARCH study.The Lancet Diabetes&Endocrinology,Online Publication,18 October 2013.,摘自MARCH研究述评,膳食能量摄入比例,ITT 人群；两组间比较没有差异,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,安全性数据分析结果
27、,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,两组胃肠道不良反应发生率比较,两组比较，P=NS,安全集人群,Gastrointestinal disorders，%of patient,Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,小结(1),新诊断2型糖尿病患者经24周和48周治疗后，阿卡波糖组和二甲双胍组降低HbA1c水平相
28、当本研究中基线平均HbA1c为7.49%，阿卡波糖降低HbA1c均为1.17%和1.11%(24周和48周)当基线HbA1c8%，阿卡波糖降低HbA1c分别达2.38%(24周)和2.25%(48周),Yang WY,et al.The Lancet Diabetes&Endocrinology,Early Online Publication,18 October 2013.,小结(2),经48周治疗后，两组达标率(HbA1c 6.5%)均超过62%降低空腹血糖：二甲双胍优于阿卡波糖降低餐后2h血糖：阿卡波糖优于二甲双胍阿卡波糖降低空腹血糖达1.46 mmol/L，降低餐后血糖达3.08 mmol/L阿卡波糖降低餐后胰岛素水平优于二甲双胍阿卡波糖减轻体重及降低甘油三酯优于二甲双胍,致谢,感谢各中心研究者和工作人员对本研究的大力支持和辛勤工作！,
