餐后高血糖与心血管危险最新研究进展English (NXPowerLite).ppt

Lessons from recent research the role of postprandial hyperglycaemia in cardiovascular risk,Haller H.Diabetes Res Clin Pract 1998,Consequences of postprandially increased blood glucose levels,Steady state,Metabolic effects,Atherosclerosis and late complications,Endothelial dysfunction,Vascular effects,Prediabetes,Type 2 diabetes,Meal,Normal counter-regulation,Hyper-glycaemia,Stress to vascular walls,The postprandial blood glucose hypothesis,Two open questions,Is ppBG a driving forcein the pathogenesis oftype 2 diabetes?,Is ppBG a driving force in thedevelopment of cardiovascular events?,ppBG:postprandial blood glucose,Knowledge from DECODE and UKPDS,Hyperglycaemia,Total load(HbA1c),Postprandial peaks,Chronicglucose toxicity,Acuteglucose toxicity,Tissue damage,Diabetescomplications,Macroangiopathy,Microangiopathy,UKPDS,DECODE,DECODE:Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe,UKPDS:UK Prospective Diabetes Study,0,1,2,3,4,5,Relative risk,Diabetes-free throughout study,15 yearsbefore diagnosis,1014.9 yearsbefore diagnosis,10 yearsbefore diagnosis,Relative risk of myocardial infarction or stroke and time before clinical diagnosis of diabetes,Hu F et al.Diabetes Care 2002,1.00,2.82,3.71,5.02,Cardiovascular mortality with and without previous myocardial infarction,Haffner S et al.N Engl J Med 1998,MI:myocardial infarction,Cardiovascular mortality7-years incidence(%),30,20,10,0,50,n=1,373,n=1,059,Without,With,Without,With,No diabetesDiabetes,previous MI,previous MI,40,Relation between postprandial blood glucose levels and cardiovascular mortality,DECODE 19991,Pacific and Indian Ocean 19992,Funagata Diabetes Study 19993,Whitehall,Paris and Helsinki Study 19984,Diabetes Intervention Study 19965,The RanchoBernardo Study 19986,ppBG,Honolulu Heart Programme 19877,CVD death,Impact of postprandial blood glucose on cardiovascular mortality risk(DECODE),DECODE Study Group,Lancet 1999,Norhammar A et al.Lancet 2002,Glycometabolic state of patients with an acute myocardial infarction,IGT:impaired glucose tolerance,Vascular damage with generation of atherosclerotic plaques,Vasculotoxic consequences of postprandial blood glucose increase,Generation of free radicals,Endothelial function More agressive lipids,Glycosylation of functional proteins,HDL activity NO release Vasodilation Collagen,Xanthoma cell generationGrowth factors Proliferation of smoothvascular muscle cells,Expression of adhesion molecules,Cholesterin adhesion,Endothelin release,Endothelial function Vasoconstriction,Ceriello A.Diabetes Metab Res Rev 2000Temelkova-Kurktschiev T et al.Diabetologica 1998Esposito K et al.Circulation 2002,ppBG,CRP:C-reactive protein,IL:interleukin,HDL:high-density lipoprotein,NO:nitric oxide,TNF-:tumour necrosis factor-,Inflammatorycytokines,CRP IL-6 IL-18 TNF-,Plaque and risk profile impact,Endothel activation,Hyperlipidaemia,Media,Activation of smooth muscle cells,Monocyte(macrophage)activation Xanthoma cell generation,oxLDL,Glycosylation of matrix proteins,Smoking,Hypertonia,NO,NO,NO,Endothelin,LDL,Matrix,Endothelium,Haller H.Diabetes Praxis 1992,ppBG,IntimaBasal membrane,LDL:low-density lipoprotein,Is there a relationship between hyperinsulinaemia and the development of cardiovascular disease?,Predictors of ischaemic heart disease(Quebec Cardiovascular Study),InsulinLDLcholesterolTriglyceridesHDLcholesterolApolipoprotein BTotal cholesterol HDLcholesterol ratio,1.9*1.9*1.4*0.881.9*1.6*,1.32.4 1.32.7 1.01.90.651.2 1.42.8 1.22.2,Odds ratio*,95%CI,n=2,103 males.Odds ratios are expressed as the increase in the risk of ischaemic heart disease for every increase of 1 SD in the variables in question.Covariates:systolic blood pressure,familyhistory of ischaemic heart disease,use of-blockers or diuretics,and plasma insulin.*p0.001,*p0.05,*p0.004,Desprs J et al.N Engl J Med 1996,Apolipoprotein B,ischaemic heart disease risk,and hyperinsulinaemia,Desprs J et al.N Engl J Med 1996,*p=0.04,*p0.001,15Insulin(U/mL),1.0,1.8,3.0*,9.7*,3.0*,11.0*,0,2,4,6,8,10,12,Odds ratio for ischaemic heart disease,Low apolipoprotein levelHigh apolipoprotein level,Chiasson JL et al.Diabetes Care 1996,0,1,2,4,6,8,10,0,2,4,6,8,10,12,14,16,0,1,2,Pre-treatmentPost treatment,*p0.01 vs pre-treatment,Plasma glucose(mmol/L),Plasma insulin(pmol/L x 10-2),Hours,Hours,Acarbose,Placebo,Effects of acarbose on plasma glucose and insulin in response to a test meal in IGT patients,*,*,*,*,*,*,STOP-NIDDM acarbose reduces the risk of cardiovascular disease by lowering postprandial plasma glucose,Primary objective,Chiasson JL et al.Diabetes Care 1998,To evaluate the effect of acarbose treatment on the delay or prevention of the onset of type 2 diabetes mellitus in a population with IGT,Secondary objectives,To evaluate,in IGT patients,the effects of acarbose treatment onglucose toleranceinsulin sensitivityhyperinsulinaemialipid profileanthropometric profileblood pressurecardiovascular events,Chiasson JL et al.Diabetes Care 1998,Study design,Placebo t.i.d.(n=715),Acarbose 100mg t.i.d.(n=714),1,0,36,6,12,18,24,30,Months,1,2,3,4,5,6,7,8,9,10,11,12,13,14,Visits,Placebon=1,429,Placebo,60,Close out visit,3 monthsplacebo,Baseline characteristics(I),Male/female(%)48.2/51.8 50.1/49.9Age*(years)54.3 7.954.6 7.9Caucasian(%)97.497.7Current smokers(%)11.614.4,*Mean SD,Acarbose(n=682),Placebo(n=686),Characteristic,Baseline characteristics(II),Height(cm)168.4 9.2 168.5 9.2Weight(kg)87.6 15.3 87.1 14.1BMI(kg/m2)31.0 4.3 30.8 4.2Waist circumference(cm)102.1 11.7 102.2 11.2Hip circumference(cm)110.5 11.0 110.2 10.0Waisthip ratio 0.93 0.10 0.93 0.08,Acarbose(n=682),Placebo(n=686),Characteristic,Mean SD,Reduction in incidence of type 2 diabetes in IGT patients receiving acarbose vs placebo,Primary endpoint time to develop diabetes,Average treatment duration 3.3 years,Chiasson JL et al.Lancet 2002,Based on onepositive OGTT,Based on two consecutive positive OGTTs,24.8%,(p=0.0015),35.8%,(p=0.0017),Effect of acarbose on glucose tolerance in IGT patients,*p0.001,Acarbose35.3*28.4 32.4*(n=682)Placebo30.9 24.941.5(n=686),Glucose toleranceat end of treatment(%),Chiasson JL et al.Lancet 2002,Effect of acarbose on the progression of impaired glucose tolerance to diabetes,Acarbose treatment resulted in,an absolute risk reduction of 9%a number needed-to-treat of 11 patients for 3 yearsa relative risk reduction of 24.8%(p=0.0015)a relative risk reduction of 35.8%using two consecutive OGTTs(p=0.0017)a 29.5%increase in incidence of normal glucose tolerance(p0.0001),Chiasson JL et al.Lancet 2002,Secondary endpoints,Glucose toleranceInsulin sensitivityHyperinsulinaemiaLipid profileAnthropometric profileBlood pressure/hypertensionCardiovascular events,Chiasson JL et al.Diabetes Care 1998,Differencein LSmean*,Lipid results*,Lipid profile,Total cholesterol(mmol/L)0.08(0.120.28)0.0184*HDLcholesterol(mmol/L)0.09(0.080.27)0.0293*LDLcholesterol(mmol/L)0.08(0.170.01)0.0075*Triglycerides(mmol/L)0.12(0.250)0.2258.,95%confidenceinterval fordifference,Treatmenteffect(p value),*Statistically significant*Endpoint values analysed in an ANCOVA model using baseline value as a covariate and including a centre effect*LS mean(placebo)minus LS mean(acarbose)from ANCOVA model,Acarbose treatment resulted in statistically significant decrease in LDLcholesterol and increase in HDLcholesterol levels,Weight(kg)0.77(0.011.54)0.0184*Waist circumference(cm)0.68(0.501.86)0.1787 Hip circumference(cm)0.21(0.861.28)0.6461 Waisthip ratio0.00(0.010.01)0.4336 BMI(kg/m2)0.18(0.070.43)0.0862,Anthropometricmeasures*,Anthropometric profile,Differencein LSmean*,95%confidenceinterval fordifference,Treatmenteffect(p value),*Statistically significant*Endpoint values analysed in an ANCOVA model using baseline value as a covariate and including a centre effect*LS mean(placebo)minus LS mean(acarbose)from ANCOVA model,Secondary endpoints,Glucose toleranceInsulin sensitivityHyperinsulinaemiaLipid profileAnthropometric profileBlood pressure/hypertensionCardiovascular events,Chiasson JL et al.Diabetes Care 1998,Study protocol outcome measures,Composite of major cardiovascular eventsincludingmyocardial infarctionnew anginarevascularisation procedurescardiovascular deathcongestive heart failurecerebrovascular accidentsperipheral vascular disease,Post-hoc cardiovascular eventadjudication process,Dr David Fitchett St Michaels Hospital,Toronto,CanadaDr Seppo LehtoKuopion Yliopistollinen Sairaala,Kuopio,FinlandDr Uwe ZeymerKlinikum Ludwigshafen,Germany,Adjudication Committee,Development of first cardiovascular events,Risk red.(%),p,Ac(n=682),Pl(n=686),No.of patients,Favoursacarbose,Favoursplacebo,Coronary heart diseasemyocardial infarction 11291angina 51255revascularisation 112039cardiovascular death 1 245Congestive heart failure 0 2 Cerebrovascular accident/2 444stroke Peripheral vascular 1 1 diseaseAny prespecified153249 cardiovascular event,0.02260.13440.18060.6298 0.50610.92550.0326,Cardiovascular event,Incidence of cardiovascular events(first event only),Cumulative incidence(%),Years after randomisation,Acarbose,Placebo,5,4,3,2,1,0,Effect of acarbose on myocardial infarction,*According to Cox proportional hazards model*According to 2 analysis,No.of clinical 1120.0226*myocardial infarctionsNo.of silent 1 70.0390*myocardial infarctionsTotal 2190.0390*,Acarbose(n=682),Placebo(n=686),p,Acarbose treatment significantly reduced the incidence of myocardial infarction,Effect of acarbose on systolic blood pressure,p=0.0006,according to repeated measures analysis of variance(ANOVA)model up to 3 years after randomisation,2.5,2.0,1.5,1.0,0.5,0,0.5,1.0,1.5,2.0,0,3,6,9,12,15,18,21,24,27,30,33,36,Mean change in systolicblood pressure(mmHg),Months after randomisation,Acarbose,Placebo,Effect of acarbose on diastolic blood pressure,3,2,1,0,1,2,Mean change in diastolic blood pressure(mmHg),Acarbose,Placebo,0,3,6,9,12,15,18,21,24,27,30,33,36,Months after randomisation,p=0.008,according to repeated measures analysis of variance(ANOVA)model up to 3 years after randomisation,Incidence of new cases of hypertension,Cumulative incidence(%),0,4,3,2,1,5,Years after randomisation,8,6,4,2,0,12,10,18,16,14,Acarbose,Placebo,Hypertension defined as blood pressure 140/90mmHg,Risk reduction with acarbose,91%p=0.0226,Myocardial infarction,34%p=0.0059,New hypertension,49%p=0.0326,Any CV event,Incidence of treatment-emergent adverse events,0,2,4,6,8,10,12,14,16,18,20,22,Week,Month,Year,Incidence(%),Abdominal pain,Diarrhoea,Flatulence,Serious treatment-emergent adverse events,*Includes events starting on the first day and up to 7 days after last day of treatment,Adverse events experienced155(21.7)277 160(22.4)260Body as a whole56(7.8)77 58(8.1)72Cardiovascular33(4.6)48 39(5.5)61Endocrine 4(0.6)5 5(0.7)5Haemic and lymphatic 2(0.3)2 4(0.6)4Metabolic and nutritional 2(0.3)2 1(0.1)1 Digestive26(3.6)42 25(3.5)32Musculoskeletal13(1.8)17 12(1.7)12Nervous13(1.8)18 12(1.7)13Respiratory11(1.5)13 16(2.2)17Skin 6(0.8)6 5(0.7)5 Special Senses 7(1.0)10 5(0.7)5 Urogenital29(4.1)37 28(3.9)33,Events*,Acarbose(n=714)Patients Eventsn(%)n,Placebo(n=715)Patients Eventsn(%)n,Retrospective meta-analysis of placebo controlled studies of acarboseGlobal Integrated Analysis Database,Cardiovascular events in type 2 diabetes patients,Analysis based onseven double-blind,randomised,placebo-controlled acarbose studiesin at least 50 type 2 diabetes patientswith a minimum treatment duration of 336 days,Meta-analysis,Cardiovascular events,Acarbose(n=1,248)n(%),Placebo(n=932)n(%),Effect of acarbose on cardiovascular event risk,Cox proportional hazards model,Cost of primary prevention of a non-fatal myocardial infarction,1 Chiasson JL et al.Lancet 2002 2 Shepherd P et al.N Engl J Med 1995,0,50,100,150,200,250,Acarbose(STOP-NIDDM1),87.1,Pravastatin(WOSCOP2),236.9,Total treatment costs(1,000),Calculation based on 1x40mg pravastatin or 3x100mg acarbose,Cardiovascular risk reduction in acarbose studies summary,Acarbose reduces postprandial hyperglycaemia,Dimitriadis G et al.Metabolism 1982,Normal absorptionof carbohydrateswithout acarbose,Acarbose blocksproximal absorption,Duodenum,Jejunum,Ileum,*p0.05,Insulin resistance,Hyperinsulinaemia,Endothelialdysfunction,High-fat diet,overweight,immobility,Hereditary factors,age,sex,Trophic factors ArteriosclerosisLeft ventricular hypertrophy,Dyslipidaemia:high triglycerides low HDL small,dense LDL,Increased sympathetic activity,Arterialhypertension,Consequence:Atherothrombosis,Myocardial infarction,Acarbose,Acarbose reduces cardiovascular risk,IGT,characterised by postprandial hyperglycaemia and insulin resistance,is associated with an increased risk of type 2 diabetes and cardiovascular disease,STOP-NIDDM,The STOP-NIDDM demonstrates that acarbose treatment decreases the risk of type 2 diabetes and cardiovacular disease in individuals with IGT,STOP-NIDDM,Retrospective interrogation of the Global Integrated Analysis Database suggests that the cardiovascular benefits shown in the STOP-NIDDM may translate into cardiovascular benefits in patients withestablished type 2 diabetes,Acarbose reduces cardiovascular risk across the diabetes continuum,The results from epidemiological and pathophysiological studies support the principle that preventing postprandial hyperglycaemia reduces the risk of cardiovascular disease,Epidemiological studies support the results of the STOP-NIDDM,