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1、,Present Therapies of Type 2 Diabetes Mellitus,Edward S.Horton,MDProfessor of MedicineHarvard Medical SchoolDirector of Clinical ResearchJoslin Diabetes Center,ACP Annual SessionMTP 057&058San Francisco,CAApril 15-16,2005,2005.American College of Physicians.All Rights Reserved.,MTP 057,Disclosure of
2、 Relationships with CommercialCompaniesEdward S.Horton,MD,FACPResearch Grants/Contracts:Takeda,Lilly,MannKind,SankyoHonoraria:Merck,Pfizer,Novartis,Takeda,Novo NordiskConsultantship:Novartis,2005.American College of Physicians.All Rights Reserved.,Main Topics for Discussion,The Diabetes EpidemicThe
3、Role of Genes vs.Environment:Obesity,Metabolic Syndrome and Lifestyle ChangesThe Pathogenesis/Pathophysiology of DM2 and its ComplicationsStrategies for PreventionDrugs for Treatment:Old and NewThe Global Approach to Treatment of DM2 and CVD Risk FactorsThe Need to“Treat to Target”,2005.American Col
4、lege 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,EMME=Eastern Mediterranean and Middle East,SEA=South-East Asia,WP=Western Pacifi
5、cDiabetes Atlas Committee.Diabetes Atlas 2nd Edition:IDF 2003.,Global Projections for the Diabetes Epidemic:2003-2025,World2003=194 M2025=333 M 72%,AFR,NA,SACA,EUR,SEA,WP,19.2 M39.4 M105%,EMME,2003 2025,2005.American College of Physicians.All Rights Reserved.,The Dual Epidemic:Obesity and Diabetes,6
6、5%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 born in 2000 is 33%for men and 39%for women.For Hispanic women it is
7、 50%.In this population CVD is the major cause of mortality.,2005.American College of Physicians.All Rights Reserved.,The Prevalence of Overweight and Diabetes over 10 Years,Mokdad et al.Diabetes Care.2000;23(9):1278-83.Mokdad et al.JAMA.2000;286(10):1195-200.,Overweight BMI 25 Kg/m2,Diabetes&Gestat
8、ional Diabetes,49%increase,25%increase,2005.American College of Physicians.All Rights Reserved.,CHANGES IN OUR LIFESTYLE!,WHAT IS DRIVING THE DUAL EPIDEMIC?,2005.American College of Physicians.All Rights Reserved.,To diabetes,Metabolic Syndrome?,Diabetes,R.Heine MD,2005.American College of Physician
9、s.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 Environment,2005.American College of Physicians.All Rights Reserved.,Obesity(esp.A
10、bdominalObesity),Genetic VariationIn CVD Risk FactorRegulation,ElevatedBlood Pressure,AtherogenicDyslipidemia,Insulin Resistance,Pro-thromboticState,Pro-inflammatoryState,PhysicalInactivity,Aging,Hyperglycemia,The Insulin Resistance Syndrome,Modified from S.Grundy MD,2005.American College of Physici
11、ans.All Rights Reserved.,Obesity(esp.AbdominalObesity),Genetic VariationIn CVD Risk FactorRegulation,Elevated BPBP 130/85 mmHg,AtherogenicDyslipidemia,InsulinResistance,Pro-thromboticState,Pro-inflammatoryState,Waist CircumferenceMen:102 cm(40 in)Women:88 cm(35 in),TG 150 mg/dL HDL-C 40 mg/dL(M)50 m
12、g/dL(F),Fasting Glucose 110 mg/dL*,Metabolic Syndrome ATP III(3 of 5),2005.American College of Physicians.All Rights Reserved.,National Health and Nutrition Examination Survey III,1988-1994,Prevalence of the Metabolic Syndrome Among US Adults Using the ATP III Criteria,Age-Adjusted Prevalence is 23.
13、7%n=8814,Ford et al.JAMA 2002;278:356-359,2005.American College of Physicians.All Rights Reserved.,The Metabolic Syndrome 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;52:1210-121
14、4)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 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 p
15、eople with IGT or DM2,2005.American College of Physicians.All Rights Reserved.,DIABETES AND CARDIOVASCULAR DISEASE,2005.American 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/dL,5,4,3,2,1,0,IGT,G 200 mg/dL(new
16、ly diagnosed diabetes),KnownDiabetes,P 0.001,(6055),(690),(158),(135),IGT Progressively Increases Risk of CHD Mortality:Paris Prospective Study(10-year follow-up),2005.American College of Physicians.All Rights Reserved.,DECODE:Mortality Rate Increases With Increasing 2-Hour Glucose,20151050,Mortalit
17、y(%),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),6,12,DECODE=Diabetes Epidemiology:Collaborative Analysis of Diagnostic Criteria in Europe.Adapted from DECODE Study Group.Lancet.1999;354:617-621.,(1172/18,252),(325/2766),2005.American College o
18、f Physicians.All Rights Reserved.,0,5,10,15,20,25,30,35,40,45,50,7-Year Incidence of MI(%),No previous MI*Previous MINo previous MI*Previous MI,No DiabetesDiabetes(n=1373)(n=1059),P 0.001,P 0.001,4%,19%,20%,45%,Seven-Year Incidence of Fatal/Nonfatal MI in Finland,*At baseline.Haffner SM et al.N Engl
19、 J Med.1998;339:229-234.,2005.American College of Physicians.All Rights Reserved.,Glycemia in Relation to Microvascular Disease and MI,UKPDS 35.BMJ 2000;321:40512,MIMicrovascular disease,Updated mean HbA1C(%),Incidence per1,000 patient-years,806040200,0567891011,2005.American College of Physicians.A
20、ll Rights Reserved.,Endothelial Dysfunction is an Early Abnormality in Obesity and Pre-diabetes,2005.American College of Physicians.All Rights Reserved.,Methacholine chloride infusion rate(g/min),Modified from Steinberg H J Clin Invest 1996;97:2601-2610,%change in leg blood flowabove baseline,Leg Bl
21、ood Flow Changes During Methacholine Infusion,2005.American College of Physicians.All Rights Reserved.,8.4,9.8,10.5,13.7*,0,4,8,12,16,Controls,Relatives,IGT,Diabetes,%Increase Over Baseline,Flow Mediated Dilation Brachial Artery,*P 0.001 Controls vs.relatives,IGT and diabetesCaballero AE et al.Diabe
22、tes 1999;48:1856-62,2005.American College of Physicians.All Rights Reserved.,Endothelial Activation,ControlsRelativesIGTDiabetesvWF(%)110 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 W
23、illebrand factor;Mean SD*P0.05Caballero AE et al.Diabetes 1999;48:1856-62,2005.American College of Physicians.All Rights Reserved.,THUSA major goal of treatment of pre-diabetes and diabetes is to prevent both the micro-and macrovascular complications!,2005.American College of Physicians.All Rights R
24、eserved.,Pathogenesis/Pathophysiology Type 2 Diabetes Mellitus is a Progressive Disease,2005.American College of Physicians.All Rights Reserved.,Progression to Type 2 Diabetes,FFA=free fatty acid.Kruszynska Y,Olefsky JM.J Invest Med.1996;44:413-428.,Genetics,Insulin resistance,Hyperinsulinemia,Compe
25、nsated insulin resistance Normal glucose tolerance,Impaired glucose tolerance,Type 2 diabetes Insulin resistance Hepatic glucose output Insulin secretion,-cell failure,Genetics,Acquired Glucotoxicity FFA levelsOther,Acquired ObesitySedentary lifestyleAging,2005.American College of Physicians.All Rig
26、hts Reserved.,Insulin SecretionAIR(U/mL),IGT,NGT,NGT,NGT,NGT,DIA,500,400,300,200,100,0,Insulin SensitivityM-low(mg/kg EMBS per minute),Progressors,Non-Progressors,Early Insulin Secretion IncreasesWith Decreasing Insulin Action,Weyer C,et al.J Clin Invest.1999;104:787794.,1,2,3,4,5,2005.American Coll
27、ege of Physicians.All Rights Reserved.,Natural History of Type 2Diabetes in Pima Indians,Weyer C,et al.J Clin Invest.1999;104:787794.,Acute Insulin Response(U/mL),NGT,Progressors(n=17),Non-Progressors(n=31),NGT,NGT,Time,NGT,IGT,Diabetes,0,50,150,200,300,Time,*P 0.05;*P 0.01,100,250,0,50,150,200,300,
28、100,250,2005.American College of Physicians.All Rights Reserved.,UKPDS:Progressive Deterioration in Glycemic Control Over Time,C,UKPDS Group.Lancet.1998;352:837-853.,Time from randomization(y),6,0,3,9,12,15,Time from randomization(y),6,0,3,9,12,15,0,100,MedianFPG(mg/dL),7,8,9,6,Median HbA1c(%),200,1
29、80,160,140,120,1998 PPS,FPG,HbA1c,2005.American College of Physicians.All Rights Reserved.,-cell Function in the UKPDS,Years From Diagnosis,-cell Function(%),1009080706050403020100,121086420246,UKPDS=United Kingdom Prospective Diabetes Study.Holman RR et al.Diabetes Res Clin Pract.1998;40(suppl):S21
30、-S25.,2005.American College of Physicians.All Rights Reserved.,Strategies for Prevention,2005.American College of Physicians.All Rights Reserved.,Trials to Prevent/Delay Progression From IGT to Type 2 Diabetes,Lifestyle ChangesMalmo Study Da Qing StudyFinnish Diabetes Prevention StudyDiabetes Preven
31、tion Program,MedicationsDiabetes Prevention Program:metformin,(troglitazone)TRIPOD:troglitazoneSTOP-NIDDM:acarboseNAVIGATOR:nateglinide and valsartanDREAM:rosiglitazone and ramiprilXENDOS:orlistatORIGIN:glargine insulinACT NOW:pioglitazone,TRIPOD=Troglitazone in Prevention of Diabetes Study;STOP-NID
32、DM=Study to Prevent NonInsulin-Dependent Diabetes Mellitus;NAVIGATOR=Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research;DREAM=Diabetes Reduction Approaches with Ramipril and Rosiglitazone;XENDOS=Xenical in the Prevention of Diabetes in Obese Subjects;ORIGIN=Outcomes Reduction
33、with Initial Glargine Introduction.,2005.American College of Physicians.All Rights Reserved.,The Da Qing IGT and Diabetes Study Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance,577 subjects(average BMI 25.8 Kg/m2)With impaired glucose tolerance(according to
34、WHO criteria)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 years,Pan et al.Diabetes Care 1997,20(4):537-44,2005.American College of Physicians.All Rights Reserved.,The Da Qing IG
35、T and Diabetes Study,P 0.05,The Cumulative Incidence of Diabetes,Pan et al.Diabetes Care 1997,20(4):537-44,(after 6 years of intervention),2005.American College of Physicians.All Rights Reserved.,Diabetes Prevention Study(Finnish Study)Prevention of Type 2 DM by Changes in Lifestyle Among Subjects w
36、ith IGT,Tuomilehto et al.N Eng J Med 2001,344(18):1390-2,522 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 intervention group receive
37、d 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 years,2005.American
38、 College of Physicians.All Rights Reserved.,Changes in Body Weight in the Finnish Study,P 0.001,Change in Body Weight in Kg,Tuomilehto et al.N Eng J Med 2001,344(18):1390-2,2005.American College of Physicians.All Rights Reserved.,Cumulative Incidence of Diabetes in the Finnish Study,P 0.001,The Cumu
39、lative Incidence of Diabetes,Tuomilehto et al.N Eng J Med 2001,344(18):1390-2,(after 4 years of intervention),58%Risk Reduction,2005.American College of Physicians.All Rights Reserved.,The Finnish Study,Tuomilehto et al.N Eng J Med 2001,344(18):1390-2,The risk of diabetes is reduced by 58%in the int
40、ervention groupThe risk reduction in the intervention group is directly linked to lifestyle changes.Patients who lost 5%or more of their body weight had a 74%risk reductionPatients who exceeded the recommended 4 hours exercise/week had an 80%risk reduction,2005.American College of Physicians.All Rig
41、hts Reserved.,The Diabetes Prevention Program A Randomized Clinical Trial to Prevent Type 2 Diabetes in Persons at High Risk,Sponsored by the NIH,NIDDK,NIA,NICHD,IHS,CDC,ADA and other agencies and corporations,2005.American College of Physicians.All Rights Reserved.,Study Population,Caucasian 1768Af
42、rican-American 645Hispanic-American 508Asian-American&Pacific Islander142American Indian 171,2005.American College of Physicians.All Rights Reserved.,Study Population,45-5949%,25-4431%,60 20%,Age Distribution,2005.American College of Physicians.All Rights Reserved.,Study Interventions,Eligible parti
43、cipantsRandomizedStandard lifestyle recommendations,Intensive Lifestyle(n=1079),Metformin(n=1073),Placebo(n=1082),2005.American College of Physicians.All Rights Reserved.,Lifestyle&Metformin Interventions,Intensive Lifestyle Goals,Reduction of fat and calorie intake Physical activity at least 150 mi
44、nutes/week Achieve and maintain at least 7%weight loss,Metformin Goals Metformin 850 mg twice daily,2005.American College of Physicians.All Rights Reserved.,Placebo,Metformin,Lifestyle,Mean Weight Change,2005.American College of Physicians.All Rights Reserved.,Mean Change in Leisure Physical Activit
45、y,Placebo,Metformin,Lifestyle,2005.American College of Physicians.All Rights Reserved.,Placebo(n=1082),Metformin(n=1073,p0.001 vs.Placebo),Lifestyle(n=1079,p0.001 vs.Metformin,p0.001 vs.Placebo),Incidence of Diabetes,Risk reduction31%by metformin58%by lifestyle,2005.American College of Physicians.Al
46、l Rights Reserved.,About the prevalence of the Metabolic Syndrome in people with IGT?About the effect of the DPP interventions on the incidence and/or reversal of Met Synd?,What can we learn from the Diabetes Prevention Program?,2005.American College of Physicians.All Rights Reserved.,The Effect of
47、Metformin and Intensive Lifestyle Intervention on the Prevention of the Metabolic Syndrome:Results from the Diabetes Prevention Program,The Diabetes Prevention Program Research GroupAnnals Internal Medicine 2005(in press),2005.American College of Physicians.All Rights Reserved.,Objectives,To determi
48、ne the prevalence of the MS in the multiethnic DPP population of subjects with Impaired Glucose Tolerance(IGT)To evaluate the effect of the two interventions on the incidence of the MS in those subjects without the syndrome at randomizationTo evaluate the effect of the two interventions on the rever
49、sal of the MS in those subjects with the syndrome at randomization,2005.American College of Physicians.All Rights Reserved.,Cumulative Incidence of Metabolic Syndrome by Treatment Group,0,1,2,3,4,Year from randomization,0.00,0.15,0.30,0.45,0.60,0.75,Cumulative incidence of,metabolic syndrome(%),Life
50、style,Placebo,Metformin,Risk reduction:17%*by Metformin41%#by Lifestyle Lifestyle vs.Metformin 29%#,*p 0.05;#p 0.001,2005.American College of Physicians.All Rights Reserved.,3 year incidence(%)of components by treatment group,*p 0.001,comparison v placebo,2005.American College of Physicians.All Righ
