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1、,Present Therapies of Type 2 Diabetes Mellitus,Edward S. Horton, MD Professor of Medicine Harvard Medical School Director of Clinical Research Joslin Diabetes Center,ACP Annual Session MTP 057&058 San Francisco, CA April 15-16, 2005,2005. American College of Physicians. All Rights Reserved.,MTP 057,
2、Disclosure of Relationships with Commercial Companies Edward S. Horton, MD, FACP Research Grants/Contracts:Takeda, Lilly, MannKind, Sankyo Honoraria: Merck, Pfizer, Novartis, Takeda, Novo Nordisk Consultantship: Novartis,2005. American College of Physicians. All Rights Reserved.,Main Topics for Disc
3、ussion,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 Treatment of DM2 and CVD Risk Factors The
4、Need to “Treat to Target”,2005. American College of Physicians. All Rights Reserved.,23.0 M 36.2 M 57.0%,14.2 M 26.2 M 85%,48.4 M 58.6 M 21%,43.0 M 75.8 M 79%,7.1M 15.0 M 111%,39.3 M 81.6 M 108%,M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eas
5、tern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.,Global Projections for the Diabetes Epidemic: 2003-2025,World 2003 = 194 M 2025 = 333 M 72%,AFR,NA,SACA,EUR,SEA,WP,19.2 M 39.4 M 105%,EMME,2003 2025,2005. A
6、merican College of Physicians. 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
7、 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 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. Diab
8、etes Care. 2000; 23(9):1278-83. Mokdad et al. JAMA. 2000;286(10):1195-200.,Overweight BMI 25 Kg/m2,Diabetes & Gestational 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
9、of Physicians. All Rights Reserved.,To diabetes,Metabolic Syndrome ?,Diabetes,R. Heine MD,2005. 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 Physici
10、ans. All Rights Reserved.,The Role of Genes vs. the Environment,2005. American College of Physicians. All Rights Reserved.,Obesity (esp. Abdominal Obesity),Genetic Variation In CVD Risk Factor Regulation,Elevated Blood Pressure,Atherogenic Dyslipidemia,Insulin Resistance,Pro- thrombotic State,Pro- i
11、nflammatory State,Physical Inactivity,Aging,Hyperglycemia,The Insulin Resistance Syndrome,Modified from S. Grundy MD,2005. American College of Physicians. All Rights Reserved.,Obesity (esp. Abdominal Obesity),Genetic Variation In CVD Risk Factor Regulation,Elevated BP BP 130/85 mmHg,Atherogenic Dysl
12、ipidemia,Insulin Resistance,Pro- thrombotic State,Pro- inflammatory State,Waist Circumference Men: 102 cm (40 in) Women: 88 cm (35 in),TG 150 mg/dL HDL-C 40 mg/dL (M) 50 mg/dL (F),Fasting Glucose 110 mg/dL *,Metabolic Syndrome ATP III (3 of 5),2005. American College of Physicians. All Rights Reserve
13、d.,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 23.7% n= 8814,Ford et al. JAMA 2002;278:356-359,2005. American College of Physicians. All Rights Reserved.,The Metabolic Syndr
14、ome 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
15、 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 people with IGT or DM2,2005. American College of Physicians. All Rights Reserved.,DIABETES AND CARDIOVASC
16、ULAR 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 (newly diagnosed diabetes),Known Diabetes,P 0.001,(6055),(690),(158),(135),IGT Progressively Increas
17、es 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,20 15 10 5 0,Mortality (%),Fasting glucose: 6.1 7.0 (Not DM) 7.0 (Not DM) 7.0 (DM) 2-h glucose: 7.8 7.811.0
18、 (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 of Physicians. All Rights Reserved.,0,5,10,15,20,25,30,35,40,45
19、,50,7-Year Incidence of MI (%),No previous MI* Previous MI No previous MI* Previous MI,No Diabetes Diabetes (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 J Med. 1998;339:229-234.,2005. American Colle
20、ge of Physicians. All Rights Reserved.,Glycemia in Relation to Microvascular Disease and MI,UKPDS 35. BMJ 2000;321:40512,MI Microvascular disease,Updated mean HbA1C (%),Incidence per 1,000 patient-years,80 60 40 20 0,0 5 6 7 8 9 10 11,2005. American College of Physicians. All Rights Reserved.,Endoth
21、elial 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 flow above baseline,Leg Blood Flow Changes Duri
22、ng 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 diabetes Caballero AE et al. Diabetes 1999;48:18
23、56-62,2005. American College of Physicians. All Rights Reserved.,Endothelial Activation,Controls Relatives IGT Diabetes vWF (%) 110 49 103 41 121 45 135 51* ET-1 (pg/mL) 4.8 2.9 9.4 8.7* 10.7 10.5* 10.9 10.8* ICAM (ng/mL) 222 57 251 89 264 56* 301 106* VCAM (ng/mL) 661 176 747 171* 759 254 831 257*,
24、vWF = von Willebrand factor; Mean SD *P0.05 Caballero AE et al. Diabetes 1999; 48: 1856-62,2005. American College of Physicians. All Rights Reserved.,THUS A major goal of treatment of pre-diabetes and diabetes is to prevent both the micro- and macrovascular complications!,2005. American College of P
25、hysicians. All Rights Reserved.,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 re
26、sistance,Hyperinsulinemia,Compensated insulin resistance Normal glucose tolerance,Impaired glucose tolerance,Type 2 diabetes Insulin resistance Hepatic glucose output Insulin secretion,-cell “failure“,Genetics,Acquired Glucotoxicity FFA levels Other,Acquired Obesity Sedentary lifestyle Aging,2005. A
27、merican College of Physicians. All Rights Reserved.,Insulin Secretion AIR (U/mL),IGT,NGT,NGT,NGT,NGT,DIA,500,400,300,200,100,0,Insulin Sensitivity M-low (mg/kg EMBS per minute),Progressors,Non-Progressors,Early Insulin Secretion Increases With Decreasing Insulin Action,Weyer C, et al. J Clin Invest.
28、 1999;104:787794.,1,2,3,4,5,2005. American College of Physicians. All Rights Reserved.,Natural History of Type 2 Diabetes 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
29、,150,200,300,Time,*P 0.05; *P 0.01,100,250,0,50,150,200,300,100,250,2005. 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)
30、,6,0,3,9,12,15,0,100,Median FPG (mg/dL),7,8,9,6,Median HbA1c (%),200,180,160,140,120,1998 PPS,FPG,HbA1c,2005. American College of Physicians. All Rights Reserved.,-cell Function in the UKPDS,Years From Diagnosis,-cell Function (%),100 90 80 70 60 50 40 30 20 10 0,12 10 8 6 4 2 0 2 4 6,UKPDS = United
31、 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 Prevention,2005. American College of Physicians. All Rights Reserved.,Trials to Prevent / Delay Progression From IGT to Typ
32、e 2 Diabetes,Lifestyle Changes Malmo Study Da Qing Study Finnish Diabetes Prevention Study Diabetes Prevention Program,Medications Diabetes Prevention Program: metformin, (troglitazone) TRIPOD: troglitazone STOP-NIDDM: acarbose NAVIGATOR: nateglinide and valsartan DREAM: rosiglitazone and ramipril X
33、ENDOS: orlistat ORIGIN: glargine insulin ACT NOW: pioglitazone,TRIPOD = 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 Reductio
34、n Approaches with 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.,The Da Qing IGT and Diabetes Study Effects of diet and exercise i
35、n preventing NIDDM in people with impaired glucose tolerance,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 groups: diet only, exercise only, or diet plus exercise OGTT ev
36、ery 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 IGT 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.
37、 American College of Physicians. All Rights Reserved.,Diabetes Prevention Study (Finnish Study) Prevention of Type 2 DM by Changes in Lifestyle Among Subjects with 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;
38、mean BMI 31 kg/m2) With impaired glucose tolerance Randomly assigned to either the intervention group or the control group Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fib
39、er 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 College of Physicians. All Rights Reserved.,Changes in Body Weight in the Finnish Study,P 0.001,Change in Body Weight in Kg,Tu
40、omilehto 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 Cumulative Incidence of Diabetes,Tuomilehto et al. N Eng J Med 2001, 344(18):1390-2,(after 4 years of intervention),58% Risk R
41、eduction,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 intervention group The risk reduction in the intervention group is directly linked to lifestyle changes. Patients who
42、 lost 5% or more of their body weight had a 74% risk reduction Patients who exceeded the recommended 4 hours exercise/week had an 80% risk reduction,2005. American College of Physicians. All Rights Reserved.,The Diabetes Prevention Program A Randomized Clinical Trial to Prevent Type 2 Diabetes in Pe
43、rsons 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 1768 African-American 645 Hispanic-American 508 Asian-American & Pacific Islander 142 American Indian 17
44、1,2005. American College of Physicians. All Rights Reserved.,Study Population,45 - 59 49%,25-44 31%, 60 20%,Age Distribution,2005. American College of Physicians. All Rights Reserved.,Study Interventions,Eligible participants Randomized Standard lifestyle recommendations,Intensive Lifestyle (n = 107
45、9),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 minutes/week Achieve and maintain at least 7% weight loss,Metformin G
46、oals 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 Activity,Placebo,Metformin,Lifestyle,2005. American College of Physic
47、ians. 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 reduction 31% by metformin 58% by lifestyle,2005. American College of Physicians. All Rights Reserved.,About the prevalence of t
48、he 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 Metformin and Intensive Lifestyle Intervention on the Prevention of the Metabolic Syndrome: Results from the Diabetes Prevention Program,The Diabetes Prevention Program Research Group Annals Internal Medicine 2005 (in press),2005. American College of Physicians. All Rights Reserved.,Objectives,To determ