1、 Present Therapies of Type 2 Diabetes Mellitus Edward S.Horton,MDProfessor of MedicineHarvard Medical SchoolDirector of Clinical ResearchJoslin Diabetes CenterACP Annual SessionMTP 057&058San Francisco,CAApril 15-16,20192019.American College of Physicians.All Rights Reserved.MTP 057Disclosure of Rel
2、ationships with CommercialCompaniesEdward S.Horton,MD,FACPResearch Grants/Contracts:Takeda,Lilly,MannKind,SankyoHonoraria:Merck,Pfizer,Novartis,Takeda,Novo NordiskConsultantship:Novartis2019.American College of Physicians.All Rights Reserved.Main Topics for Discussion The Diabetes Epidemic The Role
3、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 Treatment of DM2 and CVD Risk Factors The Need to“Treat to Target”2019.American Coll
4、ege 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 PacificDiabete
5、s Atlas Committee.Diabetes Atlas 2nd Edition:IDF 2019.Global Projections for the Diabetes Epidemic:2019-2025World2019=194 M2025=333 M 72%AFRNASACAEURSEAWP19.2 M39.4 M 105%EMME2019 20252019.American College of Physicians.All Rights Reserved.The Dual Epidemic:Obesity and Diabetes 65%of adult Americans
6、 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 50%.In this populat
7、ion CVD is the major cause of mortality.2019.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):1195-200.4.9%7.3%1.0%2.0%3.0%4.0%5.0%6.0%7.0%8.0%19902000Overweight BMI 25 Kg/m2Diabetes&
8、Gestational Diabetes49%increase2019.American College of Physicians.All Rights Reserved.CHANGES IN OUR LIFESTYLE!2019.American College of Physicians.All Rights Reserved.To diabetesMetabolic Syndrome?DiabetesR.Heine MD2019.American College of Physicians.All Rights Reserved.2019.American College of Phy
9、sicians.All Rights Reserved.2019.American College of Physicians.All Rights Reserved.2019.American College of Physicians.All Rights Reserved.The Role ofGenes vs.the Environment2019.American College of Physicians.All Rights Reserved.Obesity(esp.AbdominalObesity)Genetic VariationIn CVD Risk FactorRegul
10、ationElevatedBlood PressureAtherogenicDyslipidemiaInsulin ResistancePro-thromboticStatePro-inflammatoryStatePhysicalInactivityAging2019.American College of Physicians.All Rights Reserved.Obesity(esp.AbdominalObesity)Genetic VariationIn CVD Risk FactorRegulationElevated BPBP 130/85 mmHgAtherogenicDys
11、lipidemiaInsulinResistancePro-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)2019.American College of Physicians.All Rights Reserved.National Health and Nutrition Examination Survey I
12、II,1988-1994Age-Adjusted Prevalence is 23.7%n=8814 Ford et al.JAMA 2019;278:356-3590510152025303540455020-2930-3940-4950-5960-6970MenWomen2019.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 compa
13、red to 35-40%in the general population(NHANES III)(Alexander CM et al Diabetes 2019;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 is well established,but the role of hyperglycemia vs.other CVD risk factors is not w
14、ell understood.How much does MS contribute?No prospective studies of the development of MS in people with IGT or DM22019.American College of Physicians.All Rights Reserved.DIABETES AND CARDIOVASCULAR DISEASE2019.American College of Physicians.All Rights Reserved.CHD Mortality(incidence/1,000)Eschweg
15、e E et al.Horm Metab Res.2019;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 Study(10-year follow-up)2019.American College of Physicians.All Rights Reserved.DECODE:M
16、ortality 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:Collaborative Analysis of Diagnostic Criteria in Europe.Adapted from DECODE Study Group.Lancet.
17、2019;354:617-621.(1172/18,252)(325/2766)15(63/432)16(146/909)2019.American College of Physicians.All Rights Reserved.051015202530354045507-Year Incidence of MI(%)No previous MI*Previous MINo previous MI*Previous MINo DiabetesDiabetes(n=1373)(n=1059)P 0.001P 0.0014%19%20%45%Seven-Year Incidence of Fa
18、tal/Nonfatal MI in Finland*At baseline.Haffner SM et al.N Engl J Med.2019;339:229-234.2019.American College of Physicians.All Rights Reserved.Glycemia in Relation to Microvascular Disease and MIUKPDS 35.BMJ 2000;321:40512MIMicrovascular diseaseUpdated mean HbA1C(%)Incidence per1,000 patient-years806
19、0402000 5678910112019.American College of Physicians.All Rights Reserved.Endothelial Dysfunction is an Early Abnormality in Obesity and Pre-diabetes2019.American College of Physicians.All Rights Reserved.0501001502002503002.557.51012.5BMI 28Type 2 diabetesMethacholine chloride infusion rate(g/min)Mo
20、dified from Steinberg H J Clin Invest 2019;97:2601-2610%change in leg blood flowabove baselineLeg Blood Flow Changes During Methacholine Infusion2019.American College of Physicians.All Rights Reserved.8.49.810.513.7*0481216ControlsRelativesIGTDiabetes%Increase Over BaselineFlow Mediated Dilation Bra
21、chial Artery*P 0.001 Controls vs.relatives,IGT and diabetesCaballero AE et al.Diabetes 2019;48:1856-622019.American College of Physicians.All Rights Reserved.Endothelial ActivationControlsRelativesIGTDiabetesvWF(%)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)2
22、22 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 2019;48:1856-622019.American College of Physicians.All Rights Reserved.THUSA major goal of treatment of pre-diabetes and diabetes is to prevent both the micro-and
23、macrovascular complications!2019.American College of Physicians.All Rights Reserved.Pathogenesis/Pathophysiology Type 2 Diabetes Mellitus is a Progressive Disease2019.American College of Physicians.All Rights Reserved.Progression to Type 2 DiabetesFFA=free fatty acid.Kruszynska Y,Olefsky JM.J Invest
24、 Med.2019;44:413-428.GeneticsInsulin resistanceHyperinsulinemiaCompensated insulin resistance Normal glucose toleranceImpaired glucose tolerance Type 2 diabetes Insulin resistance Hepatic glucose output Insulin secretion-cell failureGeneticsAcquired Glucotoxicity FFA levelsOtherAcquired ObesitySeden
25、tary lifestyleAging2019.American College of Physicians.All Rights Reserved.ProgressorsNon-ProgressorsEarly Insulin Secretion IncreasesWith Decreasing Insulin Action2019.American College of Physicians.All Rights Reserved.Natural History of Type 2Diabetes in Pima Indians*P 0.05;*P 0.012019.American Co
26、llege of Physicians.All Rights Reserved.UKPDS:Progressive Deterioration in Glycemic Control Over TimeCUKPDSGroup.Lancet.2019;352:837-853.All patients assigned to regimenIntensiveConventionalPatients followed for 10 yearsIntensiveConventionalTime from randomization(y)60391215Time from randomization(y
27、)603912150100MedianFPG(mg/dL)7896Median HbA1c(%)2001801601401202019PPSFPGHbA1c2019.American College of Physicians.All Rights Reserved.-cell Function in the UKPDSYears From Diagnosis-cell Function(%)1009080706050403020100121086420246UKPDS=United Kingdom Prospective Diabetes Study.Holman RR et al.Diab
28、etes Res Clin Pract.2019;40(suppl):S21-S25.2019.American College of Physicians.All Rights Reserved.Strategies for Prevention2019.American College of Physicians.All Rights Reserved.Trials to Prevent/Delay Progression From IGT to Type 2 DiabetesLifestyle Changes Malmo Study Da Qing Study Finnish Diabe
29、tes Prevention Study Diabetes Prevention ProgramMedicationsDiabetes Prevention Program:metformin,(troglitazone)TRIPOD:troglitazoneSTOP-NIDDM:acarboseNAVIGATOR:nateglinide and valsartanDREAM:rosiglitazone and ramiprilXENDOS:orlistatORIGIN:glargine insulinACT NOW:pioglitazoneTRIPOD=Troglitazone in Pre
30、vention 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 with Ramipril and Rosiglitazone;XENDOS=Xenical in the Prevention of Diabetes in Obese S
31、ubjects;ORIGIN=Outcomes Reduction with Initial Glargine Introduction.2019.American College of Physicians.All Rights Reserved.577 subjects(average BMI 25.8 Kg/m2)With impaired glucose tolerance(according to WHO criteria)Clinic assigned either to a control group or to one of three active treatment gro
32、ups:diet only,exercise only,or diet plus exerciseOGTT every 2 years Follow-up period 6 years2019.American College of Physicians.All Rights Reserved.67.7%43.8%41.1%46.0%0%10%20%30%40%50%60%70%80%ControlDietExerciseDiet&ExerciseP 0.052019.American College of Physicians.All Rights Reserved.522 Middle-a
33、ged,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 received individualized counseling aimed at reducing weight,total intake of
34、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 2019.American College of Physicians.All Rights Reserved.-4.20.8-3.50.8-10-8-6-4-20
35、2LifestyleControl1 year2 yearsP 0.0012019.American College of Physicians.All Rights Reserved.11%23%0%5%10%15%20%25%30%35%40%45%50%LifestyleControlP 60 20%Age Distribution2019.American College of Physicians.All Rights Reserved.Study Interventions2019.American College of Physicians.All Rights Reserved
36、.Lifestyle&Metformin InterventionsIntensive Lifestyle Goals 2019.American College of Physicians.All Rights Reserved.-8-6-4-2001234Years from RandomizationWeight Change(kg)PlaceboMetforminLifestyleMean Weight Change2019.American College of Physicians.All Rights Reserved.Mean Change in Leisure Physica
37、l ActivityPlaceboMetforminLifestyle2019.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 developing diabetes All participants All participantsYears from randomizationCumulative in
38、cidence(%)Placebo(n=1082)Metformin(n=1073,p0.001 vs.Placebo)Lifestyle(n=1079,p0.001 vs.Metformin,p0.001 vs.Placebo)2019.American College of Physicians.All Rights Reserved.About the prevalence of the Metabolic Syndrome in people with IGT?About the effect of the DPP interventions on the incidence and/
39、or reversal of Met Synd?2019.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 Prevention Program The Diabetes Prevention Program Research GroupAnnals Internal Medicine
40、 2019(in press)2019.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 the effect of the two interventions on the incidence of the MS in those subjects witho
41、ut 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 randomization2019.American College of Physicians.All Rights Reserved.Cumulative Incidence of Metabolic Syndrome by Treatment Group01234Year from randomiza
42、tion0.000.150.300.450.600.75Cumulative incidence of metabolic syndrome(%)LifestylePlaceboMetforminRisk reduction:17%*by Metformin41%#by Lifestyle Lifestyle vs.Metformin 29%#*p 0.05;#p 0.0012019.American College of Physicians.All Rights Reserved.3 year incidence(%)of components by treatment group Pla
43、cebo 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,comparisonvplacebo2019.American College of Physicians.All Rights Reserved.QUESTIONCan TZDs or Other Medications Prevent or Delay the Onset of Type 2 Diabetes?2019.American Colleg
44、e of Physicians.All Rights Reserved.TroglitazoneInthePreventionOfDiabetesTRIPOD:A Test of Chronic B-cell“Rest”SubjectsNon-pregnant,non-diabeticHispanicwomenRecentgestationaldiabetes(medianforwomenwithGDMProceduresPlacebovs400mgtroglitazonedailyFastingglucoseeverythreemonthsoGTTeveryyearivGTTat0and3m
45、onthsMainOutcomeVariablesDiabetesincidenceratesB-cellfunctionBuchanan et al:Diabetes 51:2796-2803,20192019.American College of Physicians.All Rights Reserved.TRIPOD:Diabetes RatesMonthsonStudyPeoplewithDiabetes55%ReductionPlacebo12.1%/yrTroglitazone5.4%/yr60%40%20%0%010203040506050%19%Buchanan et al
46、:Diabetes,20192019.American College of Physicians.All Rights Reserved.Troglitazone in the DPP Investigational use in DPP 2019-98 Discontinued in DPP on June 4,2019 following fatal liver failure in a DPP participant Troglitazone participants offered group lifestyle classes(less intensive than ILS gro
47、up)and same follow-up as othersApproved in USA from January 2019 to March 20002019.American College of Physicians.All Rights Reserved.0510150.00.51.01.5Cumulative Incidence(%)PLACMETTROGILSDiabetes Cumulative Incidence(2,343)(1,568)(739)(237)Years from Randomization(total no.of participants)31%58%75
48、%2019.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 4,2019Diabetes Incidence During TROG Treatment Period&Beyond2019.American College of Physicians.All Rights
49、 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 changes -BUT-3.More complete studies are needed to determine long-term effectiveness.2
50、019.American College of Physicians.All Rights Reserved.STOP-NIDDM:Acarbose Reduces Diabetes RiskAdapted from Chiasson J-L et al.Lancet.2019;359:2072-2077.0.400.500.600.700.800.901.0001002003004005006007008009001000 1100 1200 1300Days After RandomizationCumulative Probability of No Diabetes AcarboseP
