1、2型糖尿病的现代治疗型糖尿病的现代治疗(2005年年)Main Topics for Discussion The Diabetes Epidemic The Role of Genes vs.Environment:Obesity,Metabolic Syndrome and Lifestyle Changes The Pathogenesis/Pathophysiology of DM2 and its Complications Strategies for Prevention Drugs for Treatment:Old and New The Global Approach to
2、 Treatment of DM2 and CVD Risk Factors The Need to“Treat to Target”2005.American College of Physicians.All Rights Reserved.23.0 M36.2 M57.0%14.2 M26.2 M85%48.4 M58.6 M21%43.0 M 75.8 M 79%7.1M15.0 M111%39.3 M81.6 M108%M=million,AFR=Africa,NA=North America,EUR=Europe,SACA=South and Central America,EMM
3、E=Eastern Mediterranean and Middle East,SEA=South-East Asia,WP=Western PacificDiabetes Atlas Committee.Diabetes Atlas 2nd Edition:IDF 2003.Global Projections for the Diabetes Epidemic:2003-2025World2003=194 M2025=333 M 72%AFRNASACAEURSEAWP19.2 M39.4 M 105%EMME2003 20252005.American College of Physic
4、ians.All Rights Reserved.The Dual Epidemic:Obesity and Diabetes 65%of adult Americans are overweight(BMI 25)and 21%are obese(BMI 30).24%have the Metabolic Syndrome.There are now an estimated 18 million people with DM in the USA and even more with IGT.The lifetime risk of developing DM for people bor
5、n in 2000 is 33%for men and 39%for women.For Hispanic women it is 50%.In this population CVD is the major cause of mortality.2005.American College of Physicians.All Rights Reserved.45.0%56.4%30.0%40.0%50.0%60.0%19912000Mokdad et al.Diabetes Care.2000;23(9):1278-83.Mokdad et al.JAMA.2000;286(10):1195
6、-200.4.9%7.3%1.0%2.0%3.0%4.0%5.0%6.0%7.0%8.0%19902000Overweight BMI 25 Kg/m2Diabetes&Gestational Diabetes49%increase2005.American College of Physicians.All Rights Reserved.CHANGES IN OUR LIFESTYLE!2005.American College of Physicians.All Rights Reserved.To diabetesMetabolic Syndrome?DiabetesR.Heine M
7、D2005.American College of Physicians.All Rights Reserved.2005.American College of Physicians.All Rights Reserved.2005.American College of Physicians.All Rights Reserved.2005.American College of Physicians.All Rights Reserved.The Role ofGenes vs.the Environment2005.American College of Physicians.All
8、Rights Reserved.Obesity(esp.AbdominalObesity)Genetic VariationIn CVD Risk FactorRegulationElevatedBlood PressureAtherogenicDyslipidemiaInsulin ResistancePro-thromboticStatePro-inflammatoryStatePhysicalInactivityAging2005.American College of Physicians.All Rights Reserved.Obesity(esp.AbdominalObesity
9、)Genetic VariationIn CVD Risk FactorRegulationElevated BPBP 130/85 mmHgAtherogenicDyslipidemiaInsulinResistancePro-thromboticStatePro-inflammatoryStateWaist CircumferenceMen:102 cm(40 in)Women:88 cm(35 in)TG 150 mg/dL HDL-C 40 mg/dL(M)110 mg/dL*Metabolic Syndrome ATP III(3 of 5)2005.American College
10、 of Physicians.All Rights Reserved.National Health and Nutrition Examination Survey III,1988-1994Age-Adjusted Prevalence is 23.7%n=8814 Ford et al.JAMA 2002;278:356-3590510152025303540455020-2930-3940-4950-5960-6970MenWomen2005.American College of Physicians.All Rights Reserved.The Metabolic Syndrom
11、e in People with IGT or Diabetes 33%of people 50 yrs.and older with IGT have MS compared to 35-40%in the general population(NHANES III)(Alexander CM et al Diabetes 2003;52:1210-1214)Only limited data on prevalence of MS in DM2(approximately 60-65%in Type 2 DM)The increased risk of CVD in IGT and DM2
12、 is well established,but the role of hyperglycemia vs.other CVD risk factors is not well understood.How much does MS contribute?No prospective studies of the development of MS in people with IGT or DM22005.American College of Physicians.All Rights Reserved.DIABETES AND CARDIOVASCULAR DISEASE2005.Ame
13、rican College of Physicians.All Rights Reserved.CHD Mortality(incidence/1,000)Eschwege E et al.Horm Metab Res.1995;17(suppl):41-46.G 140 mg/dL543210IGTG 200 mg/dL(newly diagnosed diabetes)KnownDiabetesP 0.001(6055)(690)(158)(135)IGT Progressively Increases Risk of CHD Mortality:Paris Prospective Stu
14、dy(10-year follow-up)2005.American College of Physicians.All Rights Reserved.DECODE:Mortality Rate Increases With Increasing 2-Hour Glucose20151050Mortality(%)Fasting glucose:6.17.0(Not DM)7.0(Not DM)7.0(DM)2-h glucose:7.87.811.0(IGT)11.1(DM)11.1(DM)(mmol/L)612DECODE=Diabetes Epidemiology:Collaborat
15、ive Analysis of Diagnostic Criteria in Europe.Adapted from DECODE Study Group.Lancet.1999;354:617-621.(1172/18,252)(325/2766)15(63/432)16(146/909)2005.American College of Physicians.All Rights Reserved.051015202530354045507-Year Incidence of MI(%)No previous MI*Previous MINo previous MI*Previous MIN
16、o DiabetesDiabetes(n=1373)(n=1059)P 0.001P 0.0014%19%20%45%Seven-Year Incidence of Fatal/Nonfatal MI in Finland*At baseline.Haffner SM et al.N Engl J Med.1998;339:229-234.2005.American College of Physicians.All Rights Reserved.Glycemia in Relation to Microvascular Disease and MIUKPDS 35.BMJ 2000;321
17、:40512MIMicrovascular diseaseUpdated mean HbA1C(%)Incidence per1,000 patient-years8060402000 5678910112005.American College of Physicians.All Rights Reserved.Endothelial Dysfunction is an Early Abnormality in Obesity and Pre-diabetes2005.American College of Physicians.All Rights Reserved.05010015020
18、02503002.557.51012.5BMI 28Type 2 diabetesMethacholine chloride infusion rate(g/min)Modified from Steinberg H J Clin Invest 1996;97:2601-2610%change in leg blood flowabove baselineLeg Blood Flow Changes During Methacholine Infusion2005.American College of Physicians.All Rights Reserved.8.49.810.513.7
19、*0481216ControlsRelativesIGTDiabetes%Increase Over BaselineFlow Mediated Dilation Brachial Artery*P 0.001 Controls vs.relatives,IGT and diabetesCaballero AE et al.Diabetes 1999;48:1856-622005.American College of Physicians.All Rights Reserved.Endothelial ActivationControlsRelativesIGTDiabetesvWF(%)1
20、10 49 103 41 121 45 135 51*ET-1(pg/mL)4.8 2.99.4 8.7*10.7 10.5*10.9 10.8*ICAM(ng/mL)222 57 251 89 264 56*301 106*VCAM(ng/mL)661 176747 171*759 254 831 257*vWF=von Willebrand factor;Mean SD*P0.05Caballero AE et al.Diabetes 1999;48:1856-622005.American College of Physicians.All Rights Reserved.THUSA m
21、ajor goal of treatment of pre-diabetes and diabetes is to prevent both the micro-and macrovascular complications!2005.American College of Physicians.All Rights Reserved.Pathogenesis/Pathophysiology Type 2 Diabetes Mellitus is a Progressive Disease2005.American College of Physicians.All Rights Reserv
22、ed.Progression to Type 2 DiabetesFFA=free fatty acid.Kruszynska Y,Olefsky JM.J Invest Med.1996;44:413-428.GeneticsInsulin resistanceHyperinsulinemiaCompensated insulin resistance Normal glucose toleranceImpaired glucose tolerance Type 2 diabetes Insulin resistance Hepatic glucose output Insulin secr
23、etion-cell failureGeneticsAcquired Glucotoxicity FFA levelsOtherAcquired ObesitySedentary lifestyleAging2005.American College of Physicians.All Rights Reserved.ProgressorsNon-ProgressorsEarly Insulin Secretion IncreasesWith Decreasing Insulin Action2005.American College of Physicians.All Rights Rese
24、rved.Natural History of Type 2Diabetes in Pima Indians*P 0.05;*P 0.012005.American College of Physicians.All Rights Reserved.UKPDS:Progressive Deterioration in Glycemic Control Over TimeCUKPDSGroup.Lancet.1998;352:837-853.All patients assigned to regimenIntensiveConventionalPatients followed for 10
25、yearsIntensiveConventionalTime from randomization(y)60391215Time from randomization(y)603912150100MedianFPG(mg/dL)7896Median HbA1c(%)2001801601401201998PPSFPGHbA1c2005.American College of Physicians.All Rights Reserved.-cell Function in the UKPDSYears From Diagnosis-cell Function(%)10090807060504030
26、20100121086420246UKPDS=United Kingdom Prospective Diabetes Study.Holman RR et al.Diabetes Res Clin Pract.1998;40(suppl):S21-S25.2005.American College of Physicians.All Rights Reserved.Strategies for Prevention2005.American College of Physicians.All Rights Reserved.Trials to Prevent/Delay Progression
27、 From IGT to Type 2 DiabetesLifestyle Changes Malmo Study Da Qing Study Finnish Diabetes Prevention Study Diabetes Prevention ProgramMedicationsDiabetes Prevention Program:metformin,(troglitazone)TRIPOD:troglitazoneSTOP-NIDDM:acarboseNAVIGATOR:nateglinide and valsartanDREAM:rosiglitazone and ramipri
28、lXENDOS:orlistatORIGIN:glargine insulinACT NOW:pioglitazoneTRIPOD=Troglitazone in Prevention of Diabetes Study;STOP-NIDDM=Study to Prevent NonInsulin-Dependent Diabetes Mellitus;NAVIGATOR=Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research;DREAM=Diabetes Reduction Approaches wi
29、th Ramipril and Rosiglitazone;XENDOS=Xenical in the Prevention of Diabetes in Obese Subjects;ORIGIN=Outcomes Reduction with Initial Glargine Introduction.2005.American College of Physicians.All Rights Reserved.577 subjects(average BMI 25.8 Kg/m2)With impaired glucose tolerance(according to WHO crite
30、ria)Clinic assigned either to a control group or to one of three active treatment groups:diet only,exercise only,or diet plus exerciseOGTT every 2 years Follow-up period 6 years2005.American College of Physicians.All Rights Reserved.67.7%43.8%41.1%46.0%0%10%20%30%40%50%60%70%80%ControlDietExerciseDi
31、et&ExerciseP 0.052005.American College of Physicians.All Rights Reserved.522 Middle-aged,overweight subjects(172 men and 350 women;mean age,55 years;mean BMI 31 kg/m2)With impaired glucose tolerance Randomly assigned to either the intervention group or the control groupEach subject in the interventi
32、on group received individualized counseling aimed at reducing weight,total intake of fat,and intake of saturated fat and increasing intake of fiber and physical activity An OGTT was performed annually;the diagnosis of diabetes was confirmed by a second test The mean duration of follow-up was 3.2 yea
33、rs 2005.American College of Physicians.All Rights Reserved.-4.20.8-3.50.8-10-8-6-4-202LifestyleControl1 year2 yearsP 0.0012005.American College of Physicians.All Rights Reserved.11%23%0%5%10%15%20%25%30%35%40%45%50%LifestyleControlP 60 20%Age Distribution2005.American College of Physicians.All Right
34、s Reserved.Study Interventions2005.American College of Physicians.All Rights Reserved.Lifestyle&Metformin InterventionsIntensive Lifestyle Goals 2005.American College of Physicians.All Rights Reserved.-8-6-4-2001234Years from RandomizationWeight Change(kg)PlaceboMetforminLifestyleMean Weight Change2
35、005.American College of Physicians.All Rights Reserved.Mean Change in Leisure Physical ActivityPlaceboMetforminLifestyle2005.American College of Physicians.All Rights Reserved.0 1 2 3 4010203040Placebo(n=1082)Metformin(n=1073,p0.001 vs.Plac)Lifestyle(n=1079,p0.001 vs.Met,p0.001 vs.Plac)Percent devel
36、oping diabetes All participants All participantsYears from randomizationCumulative incidence(%)Placebo(n=1082)Metformin(n=1073,p0.001 vs.Placebo)Lifestyle(n=1079,p0.001 vs.Metformin,p0.001 vs.Placebo)2005.American College of Physicians.All Rights Reserved.About the prevalence of the Metabolic Syndro
37、me in people with IGT?About the effect of the DPP interventions on the incidence and/or reversal of Met Synd?2005.American College of Physicians.All Rights Reserved.The Effect of Metformin and Intensive Lifestyle Intervention on the Prevention of the Metabolic Syndrome:Results from the Diabetes Prev
38、ention Program The Diabetes Prevention Program Research GroupAnnals Internal Medicine 2005(in press)2005.American College of Physicians.All Rights Reserved.Objectives To determine the prevalence of the MS in the multiethnic DPP population of subjects with Impaired Glucose Tolerance(IGT)To evaluate t
39、he effect of the two interventions on the incidence of the MS in those subjects without the syndrome at randomization To evaluate the effect of the two interventions on the reversal of the MS in those subjects with the syndrome at randomization2005.American College of Physicians.All Rights Reserved.
40、Cumulative Incidence of Metabolic Syndrome by Treatment Group01234Year from randomization0.000.150.300.450.600.75Cumulative incidence of metabolic syndrome(%)LifestylePlaceboMetforminRisk reduction:17%*by Metformin41%#by Lifestyle Lifestyle vs.Metformin 29%#*p 0.05;#p 0.0012005.American College of P
41、hysicians.All Rights Reserved.3 year incidence(%)of components by treatment group Placebo Metformin Lifestyle Waist Circ.33 15*8*Low HDLc 70 67 68High Trig.27 30 18*High FPG 40 29*28*High BP 41 44 35*p0.001,comparisonvplacebo2005.American College of Physicians.All Rights Reserved.QUESTIONCan TZDs or
42、 Other Medications Prevent or Delay the Onset of Type 2 Diabetes?2005.American College of Physicians.All Rights Reserved.TroglitazoneInthePreventionOfDiabetesTRIPOD:A Test of Chronic B-cell“Rest”SubjectsNon-pregnant,non-diabeticHispanicwomenRecentgestationaldiabetes(medianforwomenwithGDMProceduresPl
43、acebovs400mgtroglitazonedailyFastingglucoseeverythreemonthsoGTTeveryyearivGTTat0and3monthsMainOutcomeVariablesDiabetesincidenceratesB-cellfunctionBuchanan et al:Diabetes 51:2796-2803,20022005.American College of Physicians.All Rights Reserved.TRIPOD:Diabetes RatesMonthsonStudyPeoplewithDiabetes55%Re
44、ductionPlacebo12.1%/yrTroglitazone5.4%/yr60%40%20%0%010203040506050%19%Buchanan et al:Diabetes,20022005.American College of Physicians.All Rights Reserved.Troglitazone in the DPP Investigational use in DPP 1996-98 Discontinued in DPP on June 4,1998 following fatal liver failure in a DPP participant
45、Troglitazone participants offered group lifestyle classes(less intensive than ILS group)and same follow-up as othersApproved in USA from January 1997 to March 20002005.American College of Physicians.All Rights Reserved.0510150.00.51.01.5Cumulative Incidence(%)PLACMETTROGILSDiabetes Cumulative Incide
46、nce(2,343)(1,568)(739)(237)Years from Randomization(total no.of participants)31%58%75%2005.American College of Physicians.All Rights Reserved.03691215July 1996-May 1998June 1998-May 1999June 1999-May 2000June 2000-July 2001Incidence(cases/100 p-yr)PLACTROGTROG discontinued June 4,1998Diabetes Incide
47、nce During TROG Treatment Period&Beyond2005.American College of Physicians.All Rights Reserved.Conclusions1.PPAR gamma Agonists do have the potential to prevent or delay the development of Type 2 Diabetes in high risk individuals.2.Their effectiveness appears to be as good or better than lifestyle c
48、hanges -BUT-3.More complete studies are needed to determine long-term effectiveness.2005.American College of Physicians.All Rights Reserved.STOP-NIDDM:Acarbose Reduces Diabetes RiskAdapted from Chiasson J-L et al.Lancet.2002;359:2072-2077.0.400.500.600.700.800.901.0001002003004005006007008009001000
49、1100 1200 1300Days After RandomizationCumulative Probability of No Diabetes AcarbosePlaceboP=.0022 25%reduction in RR2005.American College of Physicians.All Rights Reserved.STOP-NIDDM:Effect of Acarbose on the Probability of Remaining Free of CV DiseaseProbabilityof AnyCardiovascularEvent14001300120
50、011001000900800700600500400300200100000.010.020.030.040.050.06Days After RandomizationPlaceboAcarboseP=0.04(Log-Rank Test)P=0.03(Cox Proportional Model)No.at riskPlacebo686675667658643638633627615611604519424332232Acarbose682659635622608601596590577567558473376286203Chiasson J-L et al.JAMA.2003;290:
