1. IDC Diabetes Update: Recent Research and Impact on Diabetes Management Type 1 DiabetesType 1 Diabetes –Post DCCT findings--improving glycemic control and preventing complications Type 2 DiabetesType 2 Diabetes –Impact of the United Kingdom Prospective Diabetes Study on Current Practice –Relationship between blood glucose, blood pressure dyslipidemia and complications Diabetes in PregnancyDiabetes in Pregnancy –New screening, diagnostic and treatment criteria (use of Glyburide) for GDM

2. IDC Epidemiology of Diabetes Interventions and Complications Trial 6-Year Follow-up 1375 Subjects Recruited Both original groups are now treated with the goal of HbA1c <7% 710 Conventionally Treated Patients HbA1c=9.2% Annual measurements at 28 sites 710 Intensively Treated Patients HbA1c=7.2%

3. IDC EDIC: Comparison of Baseline and Year 6 HbA1c 7.2 7.5 9.2 8.5 6 6.5 7 7.5 8 8.5 9 9.5 BaselineYear 6 Intensive Conventional HbA1c % Diabetes 48:383–390, 1999

4. IDC Risk of Complications Benefits of Lowering Hemoglobin A1c 0 4 8 12 16 6789101112 Hemoglobin A1c Relative Risk of Complications UKPDS 33: Lancet 1998; 352, 837-853. DCCT Study Group. N Engl J Med 329:977, 1993 120150180210240270300 Average Glucose

5. IDC DCCT and EDIC: Conclusions for Type 1 Diabetes HbA1c <7% because near normal blood glucose control prevents the development and progress of microvascular diseaseHbA1c <7% because near normal blood glucose control prevents the development and progress of microvascular disease Intensive insulin therapies can be utilized as they do not increase the risk of macrovascular diseaseIntensive insulin therapies can be utilized as they do not increase the risk of macrovascular disease Any lowering of blood glucose is important since there is a continuous relationship between glucose lowering and reduction in the risk of complicationsAny lowering of blood glucose is important since there is a continuous relationship between glucose lowering and reduction in the risk of complications

6. IDC Type 2 Diabetes: Controversies Does intensive glycemic control in Type 2 diabetes reduce micro and macrovascular complications?Does intensive glycemic control in Type 2 diabetes reduce micro and macrovascular complications? Are there advantages or disadvantages to sulfonylureas, insulin or metformin?Are there advantages or disadvantages to sulfonylureas, insulin or metformin? –? Increased cardiovascular risk with insulin or SU –Is metformin advantageous in those with obesity? Does aggressive lowering of blood pressure reduce the risk of secondary complications?Does aggressive lowering of blood pressure reduce the risk of secondary complications?

7. IDC Designed in 1976Designed in 1976 A 20-year, multicenter (23), prospective, randomized, interventional trialA 20-year, multicenter (23), prospective, randomized, interventional trial Recruited 5102 newly diagnosed type 2 diabetes patientsRecruited 5102 newly diagnosed type 2 diabetes patients –FPG >108 mg/dL (6 mmol/L) on two occasions Mean duration of follow-up: 11 yearsMean duration of follow-up: 11 years UKPDS: Study Overview UKPDS Group: Lancet 1998; 352, 837-853.

8. IDC UKPDS: Glucose Control Study 5102 patients treated with diet (3 months) Conventional therapy (n=1138) Initial therapy - medical nutrition Target FPG < 270 mg/dL (13.5 mmol/L) 4209 patients randomized (82%) Intensive therapy=3071 *Initial drug monotherapy Target FPG < 108mg/dL (6 mmol/L) Metformin Overweight only n=342Sulfonylureas Initial therapy n=1573Insulin Single-multi injection n=1156 * These therapies were combined or changed to maintain target

9. IDC UKPDS: Conclusions From Intensive Glucose Control Study Intensive glucose control achieved HbA1c lowering of ~ 1.0% at 10 yearsIntensive glucose control achieved HbA1c lowering of ~ 1.0% at 10 years –Mean Hb A1c 7.9%  7.0% Intensive glucose control significantly reduced clinical complicationsIntensive glucose control significantly reduced clinical complications –Reduced microvascular complications by 25% Glycemic control deteriorated over time regardless of therapyGlycemic control deteriorated over time regardless of therapy

10. IDC 6 7 8 9 03691215 HbA 1c (%) (%) Years from randomization Conventional Intensive 6.2% upper limit of normal range Insulin, Sulfonylurea Metformin Intensive Treatment versus Conventional Therapy for Type 2 Diabetes: UK Prospective Diabetes Study Mean 7.9% Mean 7.0%

11. IDC UKPDS: Effect of Treatment on Microvascular Endpoints UKPDS Group. Lancet. 1998;352:837-853. Years from randomization Patients with events Cumulative risk reduction of 25% when intensive treatment is compared to conventional P=0.0099 P=0.0099 0% 10% 20% 03691215 Intensive Intensive Conventional 25% 15% 5%

12. IDC UKPDS: Outcomes Intensive Glucose Control Study Relative Risk* %  12  16  25  21  24  33 *Compared with conventional therapy. P Value 0.0290.0520.00990.0150.046<0.001 Outcome Measure Any diabetes endpoint Myocardial infarction Microvascular disease Retinopathy progression Cataract extraction Microalbuminuria UKPDS Group. Lancet. 1998;352:837-853.

13. IDC Intensive therapy for Type 2 diabetesIntensive therapy for Type 2 diabetes –Lowered risk of microvascular complications –Sulfonylureas and insulin DO NOT increase cardiovascular mortality Intensive therapy results in:Intensive therapy results in: –Increased risk of mild hypoglycemia (Severe episodes rare) –Associated with significant increase in weight (~6.8 lbs) No evidence of glycemic thresholdNo evidence of glycemic threshold –Benefits of intensive glycemic control outweigh the risk of hypoglycemia UKPDS: Clinical Observations Intensive Glucose Control Study UKPDS Group. Lancet. 1998;352:837-853.

14. IDC UKPDS: Myocardial Infarction in Metformin Study 0% 10% 20% 30% 35% 03691215 Proportion of patients with events Years from randomization Conventional (n=411) Intensive (n=951) Metformin (n=342) Metformin vs Conventional P=0.010 Metformin vs Conventional P=0.010 UKPDS Group. Lancet. 1998;352:854-865.

15. IDC UKPDS: Conclusions Metformin Therapy in Overweight Patients Metformin therapy may be preferable in overweight individualsMetformin therapy may be preferable in overweight individuals –Comparable glycemic control –Achieved with limited weight gain and less hypoglycemia Potential benefit of metformin on CVD riskPotential benefit of metformin on CVD risk –Lower risk of myocardial infarction in those treated with metformin monotherapy –Benefit related to treatment of insulin resistance?

16. IDC Achieving Sustained Glycemic Control in Type 2 Diabetes Treatment Priorities After UKPDS Type 2 Diabetes - A Progressive DiseaseType 2 Diabetes - A Progressive Disease –Glucose control deteriorated over time –Insulin resistance and insulin deficiency Selection of Therapy Selection of Therapy –Numerous treatment options available –Therapy must be selected to “fit” individual patient needs and should change to adapt to disease progression

17. IDC Pathogenesis of Type 2 Diabetes Insulin Resistance and Insulin Deficiency DeFronzo RA. Diabetes. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Robertson RP. Diabetes. 43:1085, 1994. Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777. InsulinResistanceInsulinResistance InsulinDeficiencyInsulinDeficiency Type 2 Diabetes

18. IDC Natural History of Type 2 Diabetes Years of Diabetes Glucose Relative Measure of insulin /insulin action Insulin Resistance Insulin Level Fasting Glucose Beta cell failure Post Meal Glucose © International Diabetes Center Adapted from: DeFronzo RA. Diabetes. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Robertson RP. Diabetes. 43:1085, 1994. Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777. At risk for Diabetes normal

19. IDC Confirmation of the Natural History of Type 2 Diabetes: UKPDS 6 7 8 9 03691215 HbA 1c (%) (%) Conventional Intensive Increasingly intensive therapies were required to maintain glucose control over timeIncreasingly intensive therapies were required to maintain glucose control over time Multi-drug therapy or multi-dose insulin was required in a majority of patients to maintain glucose controlMulti-drug therapy or multi-dose insulin was required in a majority of patients to maintain glucose control

20. IDC © International Diabetes Center Adapted from: DeFronzo RA. Diabetes. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Robertson RP. Diabetes. 43:1085, 1994. Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777. Lifestyle SURepaglinide Insulin Insulin MetforminThiazolidinediones Years of Diabetes Glucose Relative Measure of insulin /insulin action Insulin Resistance Insulin Level Fasting Glucose Beta cell failure Post Meal Glucose At risk for Diabetes normal

21. IDC UKPDS: Risk Factors for Coronary Artery Disease in Type 2 Diabetes Identified 5 major risk factors for CAD: Dyslipidemia (High LDL, Low HDL) HyperglycemiaHypertensionSmoking Turner, RC et al. BMJ 316:823-8, 1998

22. IDC UKPDS: Intensive Blood Pressure Control in Type 2 Diabetes Goals: to determine whether: 1.Tight blood pressure control policy can reduce morbidity and mortality in Type 2 diabetic patients 2.ACE inhibitor (captopril) or Beta-blocker (atenolol) is advantageous in reducing the risk of development of clinical complications

23. IDC Treatment Outcomes Start Finish Less tight control: 160/94 mm Hg 154/87 mm Hg Tight control: 161/94 mm Hg 144/82 mm Hg Average difference: ----  10/5 mm Hg Start Finish Less tight control: 160/94 mm Hg 154/87 mm Hg Tight control: 161/94 mm Hg 144/82 mm Hg Average difference: ----  10/5 mm Hg UKPDS: Intensive Blood Pressure Control Study UKPDS Group. BMJ. 1998;317:703-713.

24. IDC UKPDS: Intensive Blood Pressure Control Study UKPDS Group. BMJ. 1998;317:703-713. Risk reduction*P value Any diabetes-related endpoint 24%0.0046 Diabetes-related deaths 32%0.019 Myocardial infarction 21%NS Heart failure 56%0.0043 Stroke 44%0.013 Microvascular disease 37%0.0092 *Tight vs less tight control.

25. IDC UKPDS: Treatment of Hypertension ACE inhibitor (captopril) and beta-blocker (atenolol) were equally effective in reducing the risk of secondary complicationsACE inhibitor (captopril) and beta-blocker (atenolol) were equally effective in reducing the risk of secondary complications Continuous relationship between systolic BP and diabetes related complications above 130 mm HgContinuous relationship between systolic BP and diabetes related complications above 130 mm Hg

26. IDC Type 2 Diabetes: Potential Benefit of Combined Blood Pressure and Glucose Control (UKPDS) 0 2 4 6 8 10 12 1 2 3 4 HbA1c BP Micro and Macrovascular Complications Risk Adapted from UKPDS 35: Lancet. 1998;352:837-853 UKPDS 38: BMJ 317, 703-713, 1998 UKPDS 32: BMJ 316:823-8, 1998

27. IDC Implications of UKPDS Priorities of Care Intensive glycemic control in Type 2 diabetesIntensive glycemic control in Type 2 diabetes –ESSENTIAL to reduce risk of microvascular disease –DOES NOT increase risk of macrovascular disease –Continuous relationship of glucose with complications Macrovascular disease preventionMacrovascular disease prevention –Requires treatment of cardiovascular risk factors including hypertension and dyslipidemia

28. IDC Diabetes Self Management Skills Medical Nutrition Therapy & Activity Plan Patient Education Glucose Monitoring Diabetes Self Management Skills Medical Nutrition Therapy & Activity Plan Patient Education Glucose Monitoring Type 2 Diabetes Fasting BG > 126 mg/dL Casual BG > 200 mg/dL Type 2 Diabetes Fasting BG > 126 mg/dL Casual BG > 200 mg/dL HyperglycemiaHyperglycemia Lipid Disorders HypertensionHypertensionComplicationsComplications Other Components of Care Other Components of Care Systematic Approach to Management of Type 2 Diabetes

29. IDC Understanding GDM The Role of Insulin Resistance Weeks of Pregnancy Glucose Relative Measure of insulin /insulin action Insulin Resistance Insulin Level Fasting Glucose Post Meal Glucose © International Diabetes Center

30. IDC Screening For GDM Guidelines All women by the 26th gestational weekAll women by the 26th gestational week At risk women at first pre-natal visit: age, multi-parity, previous GDM, genetic, obesityAt risk women at first pre-natal visit: age, multi-parity, previous GDM, genetic, obesity 1 hour post-50 gm challenge >140 mg/dl (7.8 mmol/l)1 hour post-50 gm challenge >140 mg/dl (7.8 mmol/l) If suspected use SMBGIf suspected use SMBGGuidelines All women by the 26th gestational weekAll women by the 26th gestational week At risk women at first pre-natal visit: age, multi-parity, previous GDM, genetic, obesityAt risk women at first pre-natal visit: age, multi-parity, previous GDM, genetic, obesity 1 hour post-50 gm challenge >140 mg/dl (7.8 mmol/l)1 hour post-50 gm challenge >140 mg/dl (7.8 mmol/l) If suspected use SMBGIf suspected use SMBG

31. IDC Diagnosis 75 gm or 100 gm glucose challenge (OGTT)75 gm or 100 gm glucose challenge (OGTT) 75 gm: 2hr > 140 mg/dl75 gm: 2hr > 140 mg/dl 100 gm: fasting 105 mg/dl100 gm: fasting 105 mg/dl 1 hr 190 mg/dl 2 hr 165 mg/dl 3 hr 145 mg/dl > 2 abnormal value > 2 abnormal value 75 gm or 100 gm glucose challenge (OGTT)75 gm or 100 gm glucose challenge (OGTT) 75 gm: 2hr > 140 mg/dl75 gm: 2hr > 140 mg/dl 100 gm: fasting 105 mg/dl100 gm: fasting 105 mg/dl 1 hr 190 mg/dl 2 hr 165 mg/dl 3 hr 145 mg/dl > 2 abnormal value > 2 abnormal value

32. IDC 5 Adverse Outcomes 15 Undiagnosed GDM 0 Positive 250 not screened 2 Adverse outcomes 15 GDM 62 Positive 250 Screened 500 Conventional 3 Adverse outcomes 31 GDM 125 Positive 500 Screened 500 Intensive 1000 Pregnancies Comparison of Intensive and Conventional Diagnostic Approaches SDM reduces adverse perinatal outcome by 58% Mazze RS. Mayo Clin Proc 1992 Oct;67(10):995-1002

33. IDC Treatment Guidelines FPG target 70-90mg/dl (<5mmol/L)FPG target 70-90mg/dl (<5mmol/L) CPG target <120mg/dl (<6.7mmol/L)CPG target <120mg/dl (<6.7mmol/L) SMBG all patientsSMBG all patients

34. IDC Overview of GDM Master DecisionPath Insulin Stage 3A* R/N – 0 – R – N Insulin Stage 3A* R/N – 0 – R – N Insulin Stage 2* R/N – 0 – R/N – 0 Insulin Stage 2* R/N – 0 – R/N – 0 Insulin Stage 4A* R – R – R – N Insulin Stage 4A* R – R – R – N Fasting< 95 mg/dl (5.2 mmol/l) Food Plan & Exercise Stage* Fasting> 95 mg/dl *Reported not to pass the placental barrier Langer, ADA, 1999

35. IDC Summary: Gestational Diabetes All pregnant women should be screenedAll pregnant women should be screened Tight glycemic controlTight glycemic control

36. IDC Diabetes Update: Recent Research and Impact on Care Type 1:Type 1: –Blood glucose control directly related to development of both micro and macrovascular complications Type 2:Type 2: –Blood glucose control directly related to development of both micro and macrovascular complications Gestational Diabetes:Gestational Diabetes: –Adverse perinatal outcome associated with blood glucose control; target prevention of development of type 2 diabetes