2 Diabetes Mellitus PPT | Causes Of Diabetes | Causes Of Type 2 Diabetes | Diabetes Mellitus | Diabetes Mellitus Type 2 Pathophysiology | Signs Of Diabetes | Symptom Of Diabetes | Symptom Of Type 2 Diabetes | Type 2 Diabetes Research | Type 2 Diabetes Symptoms | Type 2 Diabetes Treatment : Slideworld Medical PPT Search Engine

Incretin Based Therapy of Type 2 Diabetes Mellitus

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Mohamed on Nov 13, 2009 Says :

Congratulation of being collecting such big subject which is a landmark between who dont beleive in metabolic syndrome and those who agree but refuse the nomenclature.BADR

rosemi on Aug 14, 2009 Says :

useful

ram on Jul 18, 2009 Says :

current strategies in diabetic treatment

Edwin on Jul 15, 2009 Says :

perfect

Edwin on Jul 15, 2009 Says :

perfect

Dr. ganesh on Jun 19, 2009 Says :

Very good and educative

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Show Notes

Slide 1 :

Present Therapies of Type 2 Diabetes Mellitus Edward S. Horton, MDProfessor of MedicineHarvard Medical SchoolDirector of Clinical ResearchJoslin Diabetes Center ACP Annual Session MTP 057&058 San Francisco, CA April 15-16, 2005 ©2005. American College of Physicians. All Rights Reserved.

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MTP 057 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.

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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 Treatment of DM2 and CVD Risk Factors The Need to “Treat to Target” ©2005. American College of Physicians. All Rights Reserved.

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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 = Eastern 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. American College of Physicians. All Rights Reserved.

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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 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.

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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 & Gestational Diabetes 49% increase 25% increase ©2005. American College of Physicians. All Rights Reserved.

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Obesity (esp. Abdominal Obesity) Genetic Variation In CVD Risk Factor Regulation Elevated Blood Pressure Atherogenic Dyslipidemia Insulin Resistance Pro- thrombotic State Pro- inflammatory State Physical Inactivity Aging Hyperglycemia The Insulin Resistance Syndrome Modified from S. Grundy MD ©2005. American College of Physicians. All Rights Reserved.

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Obesity (esp. Abdominal Obesity) Genetic Variation In CVD Risk Factor Regulation Elevated BP BP > 130/85 mmHg Atherogenic Dyslipidemia 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 Reserved.

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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.

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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; 52:1210-1214) 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 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.

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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 ³200 mg/dL (newly diagnosed diabetes) Known Diabetes 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.

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0 5 10 15 20 25 30 35 40 45 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 College of Physicians. All Rights Reserved.

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Glycemia in Relation to Microvascular Disease and MI UKPDS 35. BMJ 2000;321:405–12 MI Microvascular disease Updated mean HbA1C (%) Incidence per1,000 patient-years 80 60 40 20 0 0 5 6 7 8 9 10 11 ©2005. American College of Physicians. All Rights Reserved.

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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 During Methacholine Infusion ©2005. American College of Physicians. All Rights Reserved.

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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;48:1856-62 ©2005. American College of Physicians. All Rights Reserved.

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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* vWF = von Willebrand factor; Mean ±SD *P<0.05 Caballero AE et al. Diabetes 1999; 48: 1856-62 ©2005. American College of Physicians. All Rights Reserved.

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Progression to Type 2 Diabetes FFA = free fatty acid. Kruszynska Y, Olefsky JM. J Invest Med. 1996;44:413-428. Genetics Insulin resistance 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. American College of Physicians. All Rights Reserved.

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Insulin SecretionAIR (µU/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;104:787–794. 1 2 3 4 5 ©2005. American College of Physicians. All Rights Reserved.

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Natural History of Type 2Diabetes in Pima Indians Weyer C, et al. J Clin Invest. 1999;104:787–794. Acute Insulin Response (µU/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 50 150 200 300 100 250 ©2005. American College of Physicians. All Rights Reserved.

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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(%) 200 180 160 140 120 ©1998 PPS FPG HbA1c ©2005. American College of Physicians. All Rights Reserved.

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?-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 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.

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Trials to Prevent / Delay Progression From IGT to Type 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 XENDOS: orlistat ORIGIN: glargine insulin ACT NOW: pioglitazone TRIPOD = Troglitazone in Prevention of Diabetes Study; STOP-NIDDM = Study to Prevent Non–Insulin-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 with Initial Glargine Introduction. ©2005. American College of Physicians. All Rights Reserved.

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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 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 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.

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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. American College of Physicians. All Rights Reserved.

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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; 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 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 College of Physicians. All Rights Reserved.

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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 Reduction ©2005. American College of Physicians. All Rights Reserved.

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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 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.

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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.

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Study Interventions Eligible participants Randomized Standard lifestyle recommendations Intensive Lifestyle (n = 1079) Metformin (n = 1073) Placebo (n = 1082) ©2005. American College of Physicians. All Rights Reserved.

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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 Goals Metformin 850 mg twice daily ©2005. American College of Physicians. All Rights Reserved.

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Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Metformin , p<0.001 vs. Placebo) Incidence of Diabetes Risk reduction 31% by metformin 58% by lifestyle ©2005. American College of Physicians. All Rights Reserved.

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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.

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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.

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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 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 randomization ©2005. American College of Physicians. All Rights Reserved.

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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 (%) Lifestyle Placebo Metformin Risk reduction: 17%* by Metformin 41%# by Lifestyle Lifestyle vs. Metformin 29%# * p < 0.05; # p < 0.001 ©2005. American College of Physicians. All Rights Reserved.

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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 Troglitazone participants offered group lifestyle classes (less intensive than ILS group) and same follow-up as others Approved in USA from January 1997 to March 2000 ©2005. American College of Physicians. All Rights Reserved.

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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.\ ©2005. American College of Physicians. All Rights Reserved.

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STOP- NIDDM: Effect of Acarbose on the Probability of Remaining Free of CV Disease Probabilityof AnyCardiovascularEvent No. at risk Placebo 686 675 667 658 643 638 633 627 615 611 604 519 424 332 232 Acarbose 682 659 635 622 608 601 596 590 577 567 558 473 376 286 203 Chiasson J-L et al. JAMA. 2003;290:486-494. 49% reduction in RR ©2005. American College of Physicians. All Rights Reserved.

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Summary Worldwide epidemic of diabetes Metabolic Syndrome and IGT are more prevalent than diabetes Metabolic Syndrome, IGT and type 2 diabetes are known risk factors for cardiovascular disease Treating IGT may substantially reduce the progression to DM and potentially reduce the incidence of CV events Current strategies focus on reducing insulin resistance, and/or improving beta cell function Both Lifestyle Modification and Medications have been effective in reducing progression to DM in clinical trials, but their effectiveness in reducing CVD is not yet known ©2005. American College of Physicians. All Rights Reserved.

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Questions For Discussion Can Lifestyle Modification Interventions be implemented successfully? Can Lifestyle changes be sustained over long periods of time? Is Lifestyle Modification cost effective? What are the relative contributions of weight loss and increased physical activity to the beneficial effects? Should Lifestyle Modification be combined with Pharmacological Treatments to prevent type 2 diabetes and reduce CVD risk? ©2005. American College of Physicians. All Rights Reserved.

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C Nutrition Therapy, Exercise, Lifestyle Changes Nutrition therapy decrease fat content and total calories decrease saturated fat, substitute mono/polyunsats Low glycemic index CHOs Increase dietary fiber decrease salt for hypertension healthy diet weight reduction in obese patients Exercise increase energy expenditure withmoderate-intensity exercise Lifestyle changes to reduce cardiovascular risk factors(eg, smoking cessation) Training in self-management and SMBG ©1997 PPS ©2005. American College of Physicians. All Rights Reserved.

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There is much current interest in LOW CHO, LOW FAT and HIGH PROTEIN diets, but only limited data in humans to date. The new diabetic diet? 40% CHO:30% FAT: 30% PRO New Trends in Dietary Management ©2005. American College of Physicians. All Rights Reserved.

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DeFronzo RA. Diabetes. 1988;37:667-687. Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529. Blood glucose Insulin resistance 1 Intestine: glucose absorption 2 Muscle and adipose tissue:decreased glucose uptake 4 Liver: increased hepaticglucose output 3 Pancreas: impaired insulin secretion Insulinresistance C Causes of Hyperglycemia in Type 2 Diabetes ©1997 PPS ©2005. American College of Physicians. All Rights Reserved.

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Pharmacotherapy Tailored for the Multiple Defects of Type 2 Diabetes Type 2 Diabetes Sulfonylureas __________ Generalized insulin secretagogue ?-glucosidase Inhibitors ________ Delays CHO absorption Biguanide ________ Reduces hepatic Insulin resistance TZD’s ________ Reduce peripheral insulin resistance Meglitinides __________ Restore postprandial insulin patterns Phenylalanine Derivatives __________ Restore early postprandial insulin release Physiologic Insulin Replacement Therapy ©2005. American College of Physicians. All Rights Reserved.

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DeFronzo RA et al. N Engl J Med. 1995;333:541-549. *P<0.001 †P<0.001 glyburide-metformin vs glyburide‡P<0.001 metformin vs glyburide§P<0.01 metformin vs glyburide 40 ‡ ‡ Change infasting plasmaglucose (mg/dL) Diet + placebo Diet + metformin Metformin Metformin + glyburide Glyburide Week 20 0 -20 -40 -80 0 5 9 13 17 21 25 29 Week 0 5 9 13 17 21 25 29 20 0 -20 -40 -60 † † † ‡ ‡ § § ‡ † † † † † † * * * * * * * * * Effects of Metformin Monotherapy or Combination Therapy With Glyburide -60 C ©1998 PPS ©2005. American College of Physicians. All Rights Reserved.

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*P < 0.0001 vs placebo –1.6* –0.8* –0.7* +0.3 0.5 0 –0.5 –1.0 –1.5 –2.0 Change in HbA1c in Drug-Naïve Patients Mean Change in HbA1c (%) Horton ES. Diabetes Care. 2000;23(11):1660–1665. ©2005. American College of Physicians. All Rights Reserved.

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Mean Changes From Baseline in HbA1cin Patients Inadequately Controlled on Metformin* -0.1 -0.1 -0.4 -0.8 -1.4 0 –1.6 –1.4 –1.2 –1 –0.8 –0.6 –0.4 –0.2 0 HbA1c <8% on Metformin HbA1c 8–9.5% on Metformin HbA1c >9.5% on Metformin Placebo Nateglinide 120 mg Mean Change FromBaseline in HbA1c (%) *Metformin 1000 mg bid.Novartis data on file. ©2005. American College of Physicians. All Rights Reserved.

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Effects of Pioglitazone and Sulfonylurea on FBG and HbA1c Pioglitazone Package Insert. Schneider R et al. Diabetes. 1999;47(suppl 1):A106. Abstract. -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 FBG (mg/dL)changefrombaseline ©1999 PPS -60 -50 -40 -30 -20 -10 0 10 HbA1c(%)changefrombaseline *P?0.05 for comparison with placebo C Placebo + sulfonylurea Pioglitazone 15 mg + sulfonylurea Pioglitazone 30 mg + sulfonylurea ©2005. American College of Physicians. All Rights Reserved.

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Effects of Pioglitazone and Metformin on FBG and HbA1c Pioglitazone Package Insert. Egan J et al. Diabetes. 1999;47(suppl 1):A117. Abstract. -0.8 0.2 -0.8 -0.6 -0.4 -0.2 0.0 0.2 Placebo + metformin Pioglitazone 30 mg + metformin ©1999 PPS -5 -38 -55 -45 -35 -25 -15 -5 5 *P?0.05 for comparison with placebo * * C FBG (mg/dL)changefrombaseline HbA1c(%)changefrombaseline ©2005. American College of Physicians. All Rights Reserved.

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6.8 7.0 7.2 7.4 7.6 7.8 0 6 12 18 24 Glipizide Up-titration (n=106) Glipizide + Rosiglitazone 4 mg (n=59) Repeated measures analysis accounting for baseline A1c, treatment, visit, and treatment-visit interaction and the correlation among visits within a patient. Baseline values reflect the average baseline A1c across all treatments as estimated using this model. RESULT (Study 135). Data on file, GlaxoSmithKline. 0 Mean A1c (%) Months Early Addition of Rosiglitazone 4 mg to Low-dose SU: Durable Improvement in A1c up to 2 Years ADA A1c goal <7% ©2005. American College of Physicians. All Rights Reserved.

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Early Addition of Rosiglitazone 4 mg to Low-dose SU: More Patients Reach A1c Goal <7%† †Patients received Avandia® 4 mg QD plus glipizide 10 mg BID (n=59; baseline A1c 7.6%) versus up-titrated glipizide (n=106; baseline A1c 7.6%) in a 2-year, randomized, double-blind, parallel-group study. Values represent patients meeting goal at their last observation in the study. Based on the design of this study, patients may have received 4 mg or 8 mg Avandia in combination with glipizide. Doses of Avandia greater than 4 mg daily in combination with a sulfonylurea have not been approved. ‡A1c at last observation in study. GLIP=glipizide RESULT (Study 135). Data on file, GlaxoSmithKline. % of Patients Responded ‡ n=106 n=59 22% 56% Goal < 6.5% Goal <7% ©2005. American College of Physicians. All Rights Reserved.

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* Patients who received rosiglitazone 4 mg BID plus metformin 2.5 g/day for at least 30 months during a double-blind, randomized study (6 months duration) and/or its open-label extension. Results of this trial are biased because they include only those patients who elected to continue on rosiglitazone plus metformin for the full duration. Patients demonstrated sustained efficacy over time in these "completers.” Study/open label extensions: 093/113. Data on file, GlaxoSmithKline. Rosiglitazone 8 mg/day + Metformin (N = 88) Open-Label, 30-Month Completer Analysis* HbA1c(%) Rosiglitazone Added Rosiglitazone Added to Metformin :Long Term (HbA1c) Time (mo) ©2005. American College of Physicians. All Rights Reserved.

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*ADA A1c goal <7%, AACE A1C goal ?6.5%. †P<0.05. ‡Patients received Avandia® 8 mg/day plus metformin 1 g/day (n=322; baseline A1c 8.05%) versus maximum dose metformin (n=313; baseline A1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study. ITT without LOCF. EMPIRE (Study 284). Data on file, GlaxoSmithKline. Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin: More Patients Reach A1c Goal* vs. MET Monotherapy (2 g) 45% 55% † ©2005. American College of Physicians. All Rights Reserved.

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Insulin Therapy in Type 2 DM Basal insulin replacement: - Glargine insulin qd or bid - NPH bid - Detemir insulin bid? Bolus insulin for meals - Humalog or Novolog - Regular insulin Pre-mixed insulins - 70/30 or -75/25 mixtures bid or tid Insulin Pumps Inhaled insulin for meals? ©2005. American College of Physicians. All Rights Reserved.

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Incretins Peptide hormones secreted by enteroendocrine cells in the GI tract Modulate pancreatic islet secretions as part of the “enteroinsular axis” Other effects on nutrient homeostasis Two major incretins that affect glucose metabolism -GLP-1: glucagon-like peptide 1 -GIP: glucose-dependent insulinotropic peptide (gastric inhibitory polypeptide) ©2005. American College of Physicians. All Rights Reserved.

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Incretin Effect Normal Weight: Non-Diabetic Subjects Normal Weight: Diabetic Subjects Plasma Insulin Responses to Oral and Intravenous Glucose Data from: Perley M, et al. J Clin Invest 1967; 46:1954-1962 Oral Glucose Intravenous Glucose Oral Glucose Intravenous Glucose 60 Plasma Insulin (?U/mL) 30 0 0 60 120 180 30 90 150 0 60 120 180 30 90 150 90 Plasma Insulin (?U/mL) 60 30 0 90 Time (min) Time (min) ©2005. American College of Physicians. All Rights Reserved.

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Glucagon-Like Peptide-1 (GLP-1) Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723 Product of the proglucagon gene from intestinal L-cells Release is rapid in response to meals Potent insulinotropic hormone Impaired glucose tolerance (IGT) and type 2 diabetes manifest with lower plasma GLP-1 compared to healthy controls ©2005. American College of Physicians. All Rights Reserved.

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Postprandial GLP-1 Levels are Decreased in Subjects With IGT and Type 2 Diabetes Data from: Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723 20 15 10 5 0 0 60 120 180 240 Time (min) Mean (SE)GLP-1 (pmol/L) * * * * * * * * Meal ©2005. American College of Physicians. All Rights Reserved.

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