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1、心血管病人降糖药物的应用,中山大学附属第一医院内分泌科肖 海 鹏,心血管疾病在糖尿病者中的比率,新诊断的2型糖尿病患者25%总糖尿病人群50%占糖尿病死亡原因 65-75%,Am Heart J 1999;138:5330,欧洲心脏调查结果-分组,n=2107,n=2854,The Euro Heart Survey on diabetes and the heart，European Heart Journal(2004)25,18801890,43,509 例高危人群中9,125例合并心血管疾病 OGTT 检测结果,任一心血管事件,n=9,125,NGT I-IFG IGT DM,相对比例
2、(%),Presentation of Novartis Satellite symposium during ESC 2004,Munich,Germany,NAVIGATOR,GAMI:急性心梗患者中的糖代谢异常,心肌梗死患者,Bartnik M,et al.J Intern Med.2004 Oct;256(4):288-97.,GAMI:新诊断高血糖是心肌梗死后“无心血管事件存活”的预测因素,Bartnik M,et al.Eur Heart J.2004;25(22):1990-7.,中位数随访时间:34月,中国心脏调查 患者入选标准,冠心病慢性稳定型心绞痛陈旧性心肌梗死急性冠脉综合
3、征不包括心律失常、心衰,中华内分泌代谢杂志 2006,22:7,中国心脏调查结果-汇总（n=3513）,中华内分泌代谢杂志 2006,22:7,结 论,在本研究入组人群(n=3513)中，高血糖人群 的比例约为80%糖尿病检出率为52.92%(1859例)，其中20.1%（706例）为新诊断病例糖调节受损检出率为26.38%（927例），除1例外均为新诊断,中华内分泌代谢杂志 2006,22:7,TZDs,Glucose,Insulin,I,I,I,I,I,I,I,I,G,G,G,G,G,G,G,G,I,G,G,G,Adipose tissue,Liver,Pancreas,Muscle,Gu
4、t,I,G,Carbohydrate,Stomach,Adapted from Kobayashi M.Diabetes Obes Metab 1999;1(Suppl 1):S3240.,TZDs,Primary sites of action of oral antidiabetic agents,美国大学组糖尿病计划(UGDP),UGDP主要结果,甲磺丁脲组因猝死率较高，估计可能为心血管原因,停止继续用药苯乙双胍组18个月后开始，因不良反应多而提前中止仅安慰剂、固定胰岛素、按需胰岛素3组相比,历时13年（1962-1975)，按需胰岛素组较前两组血糖低1.7-2.2 mmol/L最终的结
5、果未能证实较好的血糖控制可预防或延缓并发症的发生,SUR1/Kir 6.2胰岛细胞,SUR2A/Kir 6.2心脏,SUR2B/Kir 6.2血管平滑肌,磺脲类药物受体存在的部位,From Lebovitz HE.Diabetes Rev.1999;7:139-153.Ashcroft FM,Gribble FM.Diabetologia.1999;42:903-919.,KATP 通道的生理作用,存在部位,胰岛细胞,心肌细胞,血管平滑肌细胞,刺激状态,血糖浓度增加时关闭,缺血和缺氧状态下开放,作用,胰岛素分泌,1.减少心肌耗能2.潜在心律失常缺血预适应,血管扩张,From Gross GJ,
6、Fryer RM.Circ Res.1999;84:973-979.Murry CE,Jennings RB,Reimer KA.Circulation.1986;74:1124-1136.ORourke B.Circ Res.2000;87:845-855.,KATP通道的基础状态,开放,关闭,关闭,缺血和缺氧状态下开放,缺血预适应现象,心外膜上一根动脉的长时间堵塞造成心肌梗塞,同一血管反复短暂的堵塞使得心肌在之后的长时间堵塞中形成较小的梗塞灶（缺血预适应现象）,IP 是一种强力的内源性机制，心脏保 护自身免于致死性的缺血。当发生轻度心肌缺血，心脏KATP 通道 自动开放时，出现IP 抑制心
7、脏 KATP 通道开放的药物对缺血的 心肌可能有害，因为 KATP 通道开放是产 生IP反应的基础,Brady et al.J Am Coll Cardiol 1998;31(5):950.,缺血预适应现象(IP),磺脲类药物与心肌缺血的关系临床实验,格列本脲一次口服7,5毫克-降低正常人小腿血流格列本脲静脉0.33微克降低二氮嗪增加的前臂血流格列本脲口服4周2型糖尿病,血压正常者循环阻力增加格列本脲口服10毫克2型糖尿病急性缺血后心律失常的发生下降CHD冠状A成型术后,格列本脲对IP(二次扩张)阻断.提示:磺脲类药物对心脏可能有影响,循证医学研究 UKPDS,新诊断2型糖尿病，疗程(中位数)
8、10年饮食控制组为主对照组优降糖、氯磺丙脲(1234例)或胰岛素强化治疗组强化治疗组较对照组心梗减少16%(p0.052)UKPDS观察性研究(3642例)按病例10年疗程内HbA1c平均值分层，HbA1c下降1%，心肌梗死下降14%(p 0.0001)糖尿病血管死亡下降 21%(p0.0001),DIAMICRON MR preserves the ability of ischemic preconditioning to reduce infarct size,Yellon DM.Cardiovas Drugs Ther.2004.In press.,格列吡嗪对缺血预适应(IP)没有影响
9、：梗死区(IA)/缺血区(AAR)比例,NS,NS,胰岛素促分泌剂,格列苯脲,瑞格列奈,D-860,格列美脲,O,O,HN,HN,O,S,O,O,O,OH,O,O,HN,HN,HN,O,CI,N,O,S,O,O,HN,HN,O,S,O,O,O,HN,HN,Ashcroft FM.Diabetologia.1999;42:903-919.,DIAMICRON MR structure-function relationships?,Sulfonylurea and benzamido groups(eg,GLIBENCLAMIDE),磺脲类药物对不同亚型受体的亲和力(on SUR)IC50,格列
10、齐特甲苯磺丁脲氯茴苯酸格列苯脲格列美脲瑞易宁（格列吡嗪控释片）,SUR2A,480 nM27 nM3nM无效,无效无效,From Stephen J Tucker.5th IDF-WPR Congress,May 6th,2002,Beijing International Convention CenterDorschner H,Brekardin E,Uhde I,et al.Molec Pharmacol.1999;55:1060-1066.Hu S,Wang S,Fanelli B,et al.J Pharmacol 293:444-452.,有关SUR亚型与心肌缺血预适应的研究结果,
11、总的说来，磺脲类对新诊断的2型糖尿病患者并不增加心血管事件，血糖得到良好控制可降低心血管事件发生率,对慢性冠心病的2型糖尿病患者最好选用高选择性的磺脲药物,对急性心肌梗塞、血管成型术后急性缺血期的糖尿病患者暂停使用磺脲药物，换用胰岛素治疗，以避免潜在的心血管不良事件发生,Exogenous Insulin Administration and Increased CVD,Early Epidemilogical StudiesThe Paris Prospective Study,ten years later.Horm Metab Res Suppl 1985,15:41CHD and ca
12、rdiovascular mortality in Busselton with reference to gucose and insulin concentrations.Diabetes Care 1979,2:154The 5-year follow-up analysis of the Helsinki Policeman Study.Acta Med Scand Suppl 1985,701:38,循证医学研究 UKPDS,新诊断2型糖尿病，疗程(中位数)10年饮食控制组为主对照组优降糖、氯磺丙脲(1234例)或胰岛素强化治疗组强化治疗组较对照组心梗减少16%(p0.052)UKP
13、DS观察性研究(3642例)按病例10年疗程内HbA1c平均值分层，HbA1c下降1%，心肌梗死下降14%(p 0.0001)糖尿病血管死亡下降 21%(p0.0001),DIGAMI 1研究,602例血糖11mmol/l的急性心梗患者在溶栓和使用阻滞剂的基础上随机分为两组：1.常规降糖治疗组；2.胰岛素治疗组（静脉输注至少24小时-皮下胰岛素治疗至少3个月）,胰岛素治疗组血糖显著低于常规治疗组,DIGAMI Study:Results,Malmberg K,BMJ 1997;314:1512.,Acturarial mortality curves during long term foll
14、ow-up in patients receiving insulin glucose infusion and in control group among DIGAMI cohort.Absolute reduction in risk was 11%;relative risk 0.72(0.55 to 0.92);p=0.011,No.of patients at riskControl3142321871165814Infusion3062482021285013,Death rate(No.of Deaths/No.Originally in group)(n=620),Contr
15、ol,Infusion,Years in Study,DIGAMI-I的意义,积极意义：尽早降低高血糖可显著降低心梗2型糖尿病患者的死亡率（此后众多研究显示急性心梗期间用胰岛素-葡萄糖溶液可降低死亡率）尚未解决的问题：最有效的治疗是早期的胰岛素静脉滴注还是长期的胰岛素皮下治疗？据此结果设计了DIGAMI 2研究,DIGAMI 2 研究,Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction2型糖尿病合并心梗的患者不同血糖控制方法对死亡率的影响,DIGAMI-2:设计,Insulin+Glucose i.
16、v.st.Conventional473例,平均 随访1.941.03年,1,2,3,研究方案与目的,心梗治疗依据最新指南进行降糖治疗目标静脉输注期间尽快降低血糖，维持血糖7-10mmol/l皮下注射胰岛素保持空腹血糖5-7mmol/l，非空腹血糖10mmol/l首要目的比较第1组和第2组死亡率次要目的比较第2组和第3组死亡率三级目的比较3组间中风、非致死性再梗塞等心血管疾病的发病率,三组的实际血糖控制没有差异,月,4,3,5,7,6,%,24 h,3,18,36,12,24,6,8,10,9,1,0,2,30,Baseline,Grpoup 2,Grpoup 3,HbA1c,实际上第3组有1
17、4.4%的患者静脉滴注了胰岛素，2、3组各有32.6%和40.5%的患者随后采用了皮下胰岛素注射,结论：与DIGAMI 1 研究结论不同,DIGAMI 2 研究不支持以下3个假说心梗后立即进行并维持胰岛素强化治疗可改善2型糖尿病患者的生存率胰岛素-葡萄糖输注治疗优于常规降糖治疗胰岛素治疗可降低非致死性的再次梗塞和中风的发生率,原因分析,强化胰岛素治疗组血糖没有达到控制目标第2、3组实际上都有相当比例的患者采用了胰岛素治疗三个组虽然治疗策略不同，但是达到的血糖控制没有差异总体死亡率尤其是常规治疗组的死亡率远远低于预期值，实际样本量不足没有观察其他危险因子的情况,DIGAMI 2 引起的思考,DI
18、GAMI 2 研究再次证实了高血糖是2型糖尿病患者心梗后远期死亡的一个独立危险因素进行大型的临床试验会遇到许多未想到的问题应对DIGAMI 2 还会有进一步的分析，并设计更完善、操作更严格的临床研究，方能明确胰岛素治疗是否优于常规治疗单纯控制血糖对防治大血管并发症的作用有限,高血糖,胰岛素分泌缺陷,增加肝糖产生,DeFronzo.Diabetes 1988;37:667-687,抑制肝糖产生,减少糖摄取,延缓 肠道对葡萄糖的吸收,Metformin降糖机制,分解游离脂肪酸,增加葡萄糖利用,降糖以外的益处,心血管危险因素 改善值（）血糖 2030 LDL胆固醇 010 甘油三酯 2030 胰岛素
19、 510 PAI1活性 2025 纤维蛋白原 血小板释放活性,Grant Diabetes Care 1996;19:64-66DeFronzo et al N Engl J Med 1995;333:541-549Nagi and Yudkin Diabetes Care 1993;16:621-629,任何糖尿病相关终点 糖尿病相关死亡 任何原因的死亡 心肌梗塞*与常规治疗相比较 UKPDS Group.Lancet 1998;352:854-865,危险性改变*32%42%36%39%,P 值0.00230.0170.0110.01,危险性改变*7%20%8%21%,P 值NSNSNSN
20、S,二甲双胍（格华止）强化治疗,磺脲类/胰岛素强化治疗,UKPDS:在超重病人中不同药物的研究结果比较,UKPDS:结 论,二甲双胍（格华止）、磺脲类和胰岛素的强化血糖控制可以预防微血管并发症的发生（眼、足、神经）唯一证实：二甲双胍（格华止）的强化血糖控制还可以预防大血管并发症的发生（死亡、心肌梗塞、中风）,Potential side-effects of Metformin,Diarrhea leading to Malabsortion of Vitamin B and Folic Acid,which in turn results in hyperhomocysteinemiaPot
21、ential risk of developing lactoacidosisInteraction with other drugsIncreased metformin-associated mortality over a 5-year follow-up.Cardiology.1999,91:195Increased mortality in combination with glibenclamide,餐后高血糖,氧化应激,血栓形成,粘附分子表达,内皮功能失调,动脉粥样硬化,早餐,中餐,晚餐,餐后高血糖加重内皮功能失调 促进动脉粥样硬化病变的发生和进展,Ceriello A.Diab
22、etologia.2003 Mar;46 Suppl 1:M9-16,甘油三酯升高,LDL氧化,a 因子活化,拜唐苹与心血管危险因素,心血管危险因素 拜唐苹作用特点高血糖/餐后血糖峰值 下降胰岛素抵抗 改善(NGT/IGT/DM)甘油三酯 下降LDL-胆固醇 下降HDL-胆固醇 升高血压 预防高血压 降低血压(收缩/舒张)体重 下降或不增加纤溶/凝血机制异常 改善血管炎症 有益交感神经兴奋性 下降增龄 中老年患者尤其适用,拜唐苹降低IGT人群心血管事件发病危险,91%p=0.0226,心肌梗死,34%p=0.0059,高血压,49%p=0.0326,任一心血管事件,46,Chiasson JL
23、 et al.JAMA.2003 Jul 23;290(4):486-94.,STOPNIDDM,拜唐苹显著降低IGT人群平均IMT厚度,平均IMT厚度增加值(mm),P=0.027,M.Hanefeld et al.Stroke.2004;35:1073-1078,平均干预时间为3.9年日治疗剂量为300 mg/天,STOPNIDDM,拜唐苹显著降低2型糖尿病患者心血管事件发病危险,70,60,50,40,30,20,10,0,发病危险(%),心肌梗死,任一心血管事件,Hanefeld M et al.Eur Heart J.2004;25(1):10-16.,P=0.012,P=0.006
24、1,HDL,BP,Thiazolidinediones,monocyte subendothelial transmigration,Effects of TZD on cardiovascular risk factors and atherosclerotic mechanisms,Experimental Evidence-effect in Acute MI,Avandia,Vehicle,Nonischemicarea,Ischemicarea,Infarction,Effect of Rosiglitazone on Ang II-accelerated Atherosclerot
25、ic Lesion Formation in Male LDLR-/-Mice,Preventive Effects of Rosiglitazone on Restenosis After Stent Implantation in Patients with type 2 DiabetesDiabetes Care 2004,27(11),Restenosis Avndia vs Placebo 17.6%vs 38.2%,Potential Disadvantages of TZD,Fluid retention(2%5%)Peripheral edema(2%5%)Increased
26、body weightTransient decrease in hemoglobinIncreased in circulating plasma volumeNot indicated in patients with NYHA class 34 congestive heart failure,Rosiglitazone:effect on cardiac function,Glyburide,RSG 4 mg bd,Baseline,Week 28,Week 52,Baseline and week 28:glyburide n=68;RSG n=72Week 52:GLY n=60;
27、RSG n=58*Represents patients with a baseline and week 28 value.Mean ejection fraction determined by M-mode echocardiography.,0,0.10,0.20,0.30,0.40,0.50,0.60,0.70,0.80,Mean ejection fraction,*,*,St John Sutton M et al.Diabetes Care 2002;25:205864.,Error bars=SE,TZD and Cardiac Function(Circulation,20
28、03;107:1350-4),Decreased Vascular Insulin ResistanceDecreased AfterloadImproved Neurohormoral Function(Decreased AT-II,ET-1,TNF-a)Improved Endothelial FunctionImproved Myocardial Function by increasing glucose uptake and decreasing FFA RelianceLVH regression,TZD in Patients with Heart Failure,Only 7
29、4(0.3%)0f the 24973 subjects without prior history of heart failure experienced new-onset HF.Only 69(3.5%)of the 1964 patients with a history of heart failure experienced a subsequent decompensationTZD hazard ratio was similar to that of insulin combined with other oral hypoglycemic agents,Presented
30、 to ADAChicago,BARI-2D:Design,Objectives&Timings,PatientsT2DM and angio-documented CAD for which urgent revascularization not requiredAny background Rx at baseline and switched to randomization schemeTreatment goal-HbA1c 7.0%,Revasc Strategy,Gly Control Strategy,Revasc,Medical,650,650,650,650,Hypoth
31、esesInitial revasc+medical Rx results in lower 5yr mortality vs med Rx aloneTargeting HbA1c 7%,an IS regimen(Avandia)will result in lower 5yr mort vs IPRates of MI,ischemic events,and anginaPharmacoeconomics of Tx stratMechanism of vasculopathy,IS=Insulin sensitiserIP=Insulin providers,PPAR-gamma ag
32、onists for the Prevention of Adverse Eventsfollowing Percutaneous Coronary Revascularization,PPAR,PPAR:Design&Objectives,Hypothesis Via actions on vascular response to injury and anti-inflammatory effects,PPAR gamma agonists may prevent late ischaemic events following PCTAPrimary Objective Determine
33、 whether treatment w/RSG(8mg/day)prevents mortality,MI and Restenosis at 12 months(composite endpoint)Secondary Objectives Effect of RSG on 30 day and 6 month composite endpoint;Change in angina or heart failure class,Secondary Objectives Markers of inflammation,Lipids,Insulin levels,Insulin resista
34、nce,Proteinuria and Microalbuminuria Patient population Obese hypertensive or diabetic patients presenting for elective or urgent PCTAStudy design 200 patientsDouble-blind,randomized,RSG 8 mg/day vs placebo,Avandia in Acute Myocardial Infarction,AMI Study:,Acute MI Study:Objectives,ObjectiveExamine
35、the role of Avandia as a cardio-protection agentPrimaryPilot study to examine if Avandia can reduce mortality and CV morbidity over 30 days in diabetic and non-diabetic patients experiencing an AMI,SecondaryTo study if Avandia improves some of the key complications of AMICardiac damage Cardiac ischa
36、emic burdenArrhythmia occurrenceHyperglycaemia Ventricular dysfunction,Acute MI Study:Design,AMI,Standard acute care,Diabetics-Avandia,Non-Diabetics-Avandia,Diabetics-Placebo,Non-Diabetics-Placebo,30 days,Standard care-insulin optional,Standard care-insulin optional,60,60,60,60,RECORD:Objective and
37、Timings,Hypothesis:Is combination of Avandia plus either metformin or a SU superior to combination of SU and metformin for CV outcomes.Primary Outcomes:Combined CV mortality and morbidity,Secondary Outcomes:All cause mortalityTypes of CV morbidityKey CV Surrogates in all patientsBP,CRP,PAI-1,pro-insulin and split products,ApoB Timings:Study results available Q2008,谢谢！,
