1. Update on EDIC: Epidemiology of Diabetes Interventions and Complications Study Charlotte McDonald, MD, MSc, FRCPC Associate Professor, Division of Endocrinology, Department of Medicine, UWO

2. DCCT/EDIC 30th Anniversary Symposium Contributions and Progress DCCT/EDIC Research Group June 22, 2013 DCCT/EDIC

3. Acknowledgements EDIC Executive Committee Patricia Cleary, MS John Lachin, ScD Catherine Cowie, PhD David Nathan, MD Saul Genuth, MD Rose Gubitosi-Klug, MD, PhD Bernard Zinman, MD Meg Bayless, BSN, RN, CDE, CCRC Gayle Lorenzi, RN, CDE 30 th Anniversary Slides David M. Nathan, M.D. Co-Chair Retinopathy: Lloyd Paul Aiello, MD, PhD PI, Joslin Diabetes Center Nephropathy: Ian H. de Boer, MD Investigator, University of Washington Neuropathy: Catherine Martin, MS, RN, BC-ADM, CDE Study Coordinator, University of Michigan Cardiology: John M. Lachin, Sc.D. Principal Investigator DCCT/EDIC Data Coordinating Center,The Biostatistics Center, The George Washington University Rose A. Gubitosi-Klug, MD, PhD Principal Investigator DCCT/EDIC Clinical Coordinating Center

4. EDIC TEAM: UWO John Dupre, MD, FRCP, FRCPC, FACP Principal Investigator DCCT/EDIC University of Western Ontario Judy Harth, RN and Marsha Driscoll, RN: EDIC Study Coordinators UWO Debra Nielsen Robarts Research Institute

5. EDIC TEAM: UWO DCCT/EDIC John Dupre, MD, FRCP, FRCPC, FACP Principal Investigator DCCT/EDIC University of Western Ontario Research Reports: 219 Other Peer Reviewed Publications: 91 Abstracts: 250 Total Publications: 560

6. DCCT/EDIC Timeline 1978 1982 1983 1989 1993 1994 2005 2013 2016 DCCT NationalCommissionRFANationalCommission PlanningRFA Feasibility PlanningRFA Recruitment Feasibility DCCT end EDIC start DCCT end 10 years EDIC 20 years DCCT/EDIC N=1,441 ages 13 to 39 29 centers US and Canada Diabetes duration 1 - 15 years

7. l CLINICAL CENTERS 1983-93 DCCT/EDIC

8. Discovery of Insulin (1921-1922) Banting and Best Insulin prevented acute death Chronic, incurable illness Most develop end-organ complications

9. Insulin Era: 1930-1970 Visual impairment (legal) 14% Blindness (total) 16% Renal failure 22% Stroke 10% Amputation 12% Myocardial infarction 21% Mortality increased 2-6 fold compared with age-matched non-diabetic population Long-term Complications: Steno Hospital 31% Diabetologia 1978;14:363 Death with or from hypoglycaemia was more common than death in ketoacidotic coma. Clinical manifestations of late diabetic complications were considerably less common in patients who were still alive after >40 years of diabetes than in patients who died before their fortieth year of diabetes.

10. DCCT: Major Study Questions Primary prevention: Will intensive therapy prevent the development of retinopathy Secondary Intervention: Will intensive therapy reduce the progression of retinopathy compared with conventional therapy?

11. Study Cohorts Primary prevention (n= 726): 1-5 years duration 1-5 years duration No retinopathy or microalbuminuria No retinopathy or microalbuminuria Secondary intervention (n= 715): 1-15 years duration > 1 microaneurysm, 1 microaneurysm, < severe NPDR < 200 mg albumin excretion/24 h < 200 mg albumin excretion/24 h Age 13-40

12. DCCT Glycemic Results Intensive Regimen >3 daily injections or CSII (pump) >4 SMBG Pre-meal BG (3.9-6.7 mmol/L) Post-meal (<10 mmol/L) DCCT Research Group NEJM 1993;342:381 2% HbA1c <6.05%

13. Completeness of Follow-up DCCT DCCT Baseline Study End (1993) Baseline Study End (1993) Number 1441 1422 Percent of 100 99 DCCT cohort

14. DCCT Retinopathy Results: > 3 Step Change Primary Prevention Secondary Intervention 76% 54% DCCT Research Group NEJM 1993;342:381

15. Reduction in Complications: Intensive vs Conventional DCCT Research Group NEJM 1993;342:381 Percent Reduction Retinopathy Nephropathy Neuropathy Development 3-step progression Severe NPDR Microalbuminuria Albuminuria Clinical

16. Summary Achieved mean HbA1c substantially (2%) lower than conventional therapy, albeit not in the non-diabetic range, with consistent major beneficial effects on early microvascular complications Achieved mean HbA1c substantially (2%) lower than conventional therapy, albeit not in the non-diabetic range, with consistent major beneficial effects on early microvascular complications Intensive Therapy

17. Relationship between Glycemia and Complications DCCT Research Group Diabetes 1995;44:968 0 2 4 6 8 10 12 14 16 Mean HbA1c (%) During DCCT 5678910111213 Intensive Rate per 100 PYR Risk Gradient: ~44 % reduction in risk per 10% lower HbA 1c Conventional Risk of Retinopathy Progression

18. Risk of Severe Hypoglycemia Rate of Severe hypoglycemia Rate of Coma or Seizure RR= 3.3 RR= 3.0 Diabetes 1997;46:271-86 Per 100 Pt-Yr 3-fold increase hypoglycemia, including coma /seizure mean wt gain 4.6 kg

19. 0 2 4 6 8 10 12 14 16 Mean HbA1c (%) During DCCT 5678910111213 Intensive Rate per 100 PYR Risk Gradient: ~44 % reduction in risk per 10% lower HbA 1c Conventional Risk of Retinopathy Progression vs Mean HbA1c during DCCT Current Hemoglobin A 1c (%) Rate per 100 PYR 5678910111213 0 20 40 60 80 100 Intensive Conventional Risk of Severe Hypoglycemia

20. Effect of INT vs CONV Therapy on Residual Insulin Secretion At baseline 303 subjects with stimulated C-peptide 0.2-0.5 pmol/L & duration 1-5 years Ann Int Med 1998;128:517-23 Intensive Conventional Although insulin secretion decreased in all subjects over time, intensive therapy reduced rate of decline.

21. Major Scientific and Clinical Results of DCCT Salutary effect of intensive therapy on early microvascular and neurologic complicationsSalutary effect of intensive therapy on early microvascular and neurologic complications Established association and primacy of glycemia and complicationsEstablished association and primacy of glycemia and complications Identified risks (hypoglycemia/weight gain) and costs and contrasted them with benefitsIdentified risks (hypoglycemia/weight gain) and costs and contrasted them with benefits No adverse effects of INT on quality-of-life or cognitive functionNo adverse effects of INT on quality-of-life or cognitive function 75 publications and ~150 abstracts75 publications and ~150 abstracts

22. Epidemiology of Diabetes Interventions and Complications A Long-term Observational Study of the Diabetes Control and Complications Trial Cohort DCCT/EDIC DCCT cohort too young (34 y at study end) and too brief duration of DM (12 y at end) to be at risk for CAD or more severe microvascular complications EDIC would allow study of macrovascular and more severe microvascular complications

23. Major Objective To examine the longer-term effects of Intensive vs Conventional therapy implemented during the DCCT on the development and progression of more advanced stages of retinopathy, nephropathy, and neuropathy, and of CVD. EDIC Research Group Diabetes Care 1999;22:99 DCCT/EDIC

24. Completeness of Follow-up DCCT EDIC DCCT EDIC Baseline Study End Baseline (1993) (1994) Baseline Study End Baseline (1993) (1994) Number 1441 1422 1394 Percent of 100 99 96 DCCT cohort DCCT/EDIC

25. Metabolic Results: Median HbA1c DCCT Intervention DCCT Intervention 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 EDIC Intensive EDIC mean 7.9% * * * * * P< 0.05 DCCT DCCT/EDICTraining 1993- 1994 At the end of the DCCT, all participants were offered training in intensive therapy and The clinical care of the DCCT participants was returned to their own health care providers

26. Metabolic Results: Median HbA1c DCCT Intervention DCCT Intervention S t u d y Y e a r 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 EDIC Observation EDIC Observation EDICConventional EDIC mean 8.0% Intensive EDIC mean 7.9% Training * * * * * P< 0.05 DCCT DCCT/EDIC

27. % Reduction in Risk with Intensive Therapy % Reduction in Risk with Intensive Therapy DCCT DCCTRetinopathy 3-step worsening 52 3-step worsening 52 Proliferative 47 Proliferative 47 Macular edema 26 Macular edema 26 Laser Therapy 56 Laser Therapy 56Nephropathy Microalbuminuria (>40mg/24h) 39 Microalbuminuria (>40mg/24h) 39 Albuminuria (>300 mg/24h) 54 Albuminuria (>300 mg/24h) 54 Effect of DCCT Intensive Therapy after 4 Years of EDIC Follow-up DCCT/EDIC Research Group N Engl J Med 2000; 342:381-9 DCCT/EDIC Discovery of Metabolic Memory EDIC Year 4* 63 63 55 55 73 73 62 62 53 53 84 84 * In subjects free of complication at end of DCCT * In subjects free of complication at end of DCCT Metabolic memory appears to persist for at least 10 years after end of DCCT for retinopathy, nephropathy, and neuropathy

28. Conventional Intensive Non-Fatal MI, Stroke or CVD Death Cardiovascular Events 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96 Years from Study Entry 0.00 0.02 0.04 0.06 0.08 0.10 0.12 Cumulative Incidence Risk reduction 57% 95% CI: 12, 79 Log-rank P = 0.018 DCCT/EDIC Research Group N Engl J Med 2005; 353:2643-53 Prior to 2005, we demonstrated reduction in atherosclerosis (carotid and coronary) in intensive therapy and association with HbA1c DCCT/EDIC

29. Completeness of Follow-up DCCT EDIC DCCT EDIC Baseline Study End Baseline Year 11 Year 18 Baseline Study End Baseline Year 11 Year 18 (1993) (1994) (2005) (2012) (1993) (1994) (2005) (2012) Number 1441 1422 1394 1340 1272 Percent of 100 99 96 93* 88 + DCCT cohort DCCT cohort DCCT/EDIC *96% of surviving cohort + 95% of surviving cohort

30. Durability of intensive therapy effect including metabolic memoryDurability of intensive therapy effect including metabolic memory Beneficial effect of Intensive therapy on longer-term clinical outcomesBeneficial effect of Intensive therapy on longer-term clinical outcomes -More advanced complications -Atherosclerosis and CVD events Safety-cognitive function unaffected despite hypoglycemiaSafety-cognitive function unaffected despite hypoglycemia Major Scientific and Clinical Results of EDIC DCCT/EDIC

31. Population-based Proliferative retinopathy Nephropathy CVD DCCT Intensive Therapy Long-term Outcomes of Type 1 Diabetes Pittsburgh EDC DCCT/EDIC Arch Int Med 2009;169:1307 20 44 19 8 12 8 30-year Cumulative Incidence ~1980-2008 DCCT/EDIC The frequencies of serious complications in patients with T1DM, especially when treated intensively, are lower than that reported historically.

32. Prevalence (%) of Severe Complications Complication Blindness 30 Renal failure 22 Amputation 12 Steno Steno 1978 1978 Arch Int Med 2009;169:1307 *<20/200 either eye † SeCr > 2, dialysis, or transplantation + All were of toes except one BKA DCCT INT 2008 1* † 1 † + 1 + Diabetologia 1978;14:363

33. DCCT Clues to Metabolic Memory 53% increased risk in retinopathy progression for every 1% higher screening A1c, suggesting effect of prior glycemia 3 to 4 year delay in demonstration of a beneficial effect of INT versus CONV therapy in primary prevention cohort Retinopathy

34. EDIC Year Cumulative Incidence % Arch Ophthal 2008 126:1707-1715. Further Retinopathy Progression over 10 years of EDIC from the Level at DCCT Closeout Adjusted For DCCT Closeout Level CONV INT 53% Risk Reduction P < 0.0001 0178234 56910 0 20 30 40 50 60 DCCT/EDIC

35. Benefits of DCCT Intensive Therapy on Microvascular Outcomes During EDIC Percent Explained By Group Differences in DCCT HbA1c Further Retinopathy Progression: at 4 years 70% 97.7% at 10 years 53% 89.3% at 18 years 46% 86.7% % Risk % Outcome Reduction Explained DCCT/EDIC

36. Retinopathy Update Intensive therapy reduced development and progression of early retinopathy during the DCCT INT had a profound reduction in risk of further progression during EDIC (metabolic memory) Further EDIC follow-up has demonstrated a consistent beneficial effect on severe eye disease Even though the risk reduction has decreased with time, the effect is still substantial after 18 years of EDIC follow-up DCCT/EDIC Summary

37. During EDIC, there was a major (48%) reduction of risk of ocular surgery in the original INT group In the original INT group, the incidence of severe retinal outcomes was reduced by 50% over the DCCT/EDIC period. DCCT/EDIC Retinopathy Update Summary

38. 1-2 3-4 5-6 7-8 0 5 10 15 20 25 Conventional Intensive Cumulative Incidence (%) 57% risk reduction p < 0.0001 EDIC Year JAMA 2003; 290:2159-2167 Cumulative Incidence of Microalbuminuria During EDIC Years 1-8 EDIC

39. 0 2 4 6 8 10 12 1 - 23 - 45 - 67 - 8 Conventional Intensive Cumulative Incidence (%) 84% risk reduction p < 0.0001 EDIC Year Cumulative Incidence of Macroalbuminuria during EDIC JAMA 2003; 290:2159-2167 Years 1-8 EDIC

40. Reduction of Risk for Albuminuria with Intensive Diabetes Therapy Proportion 99% explained by DCCT mean HbA1c 91%100% 98% 99%100% Summary DCCT EDIC Y 1-8 EDIC Y 1-8 EDIC Y 1-18 EDIC Y 1-18 DCCT/EDIC

41. Cumulative Incidence of Hypertension Arch Intern Med 2008; 168:1867-1873 DCCT/EDIC

42. Cumulative Incidence of Impaired GFR NEJM 2011 50% risk reduction P=0.006 Sustained eGFR <60 ml/min/1.73m 2 NEJM 2011; 365:2366-2376 DCCT/EDIC

43. Intensive therapy also reduced the risk of more severe kidney disease Intensive24 13 8 Conventional 4639 23 16 P-value 0.0060.0450.088 0.098 DCCT/EDIC

44. Effects of Intensive Therapy on Kidney Disease During the DCCT, intensive therapy reduced the risks of developing micro- and macro-albuminuria Over long-term EDIC follow-up: -The benefits on new albuminuria persisted (“metabolic memory”) -Development of hypertension delayed -Glomerular filtration rate preserved Effects mediated by level of glycemia Summary DCCT/EDIC

45. Effects of Intensive Therapy on Kidney Disease Conclusion DCCT/EDIC Early intensive diabetes therapy is effective for preventing or delaying kidney disease in type 1 diabetes

46. Peripheral Neuropathy Assessments DCCT Neurological history and physical examination Electrodiagnostic studies of median (motor and sensory), sural (sensory) and peroneal (motor) nerves, Measured at baseline, 5 years and or study end. EDIC Michigan Neuropathy Screening Instrument (MNSI) performed annually DCCT assessment once at EDIC year 13/14 Vibration perception threshold testing once at EDIC year 13/14 DCCT/EDIC

47. Neurologic Outcomes Abnormal exam consistent with peripheral sensory neuropathy and Abnormal nerve conduction in at least 2 peripheral nerves (or abnormal autonomic finding*) * Not used in EDIC definition Confirmed Clinical Neuropathy (CCN) DCCT/EDIC

48. Confirmed Clinical Neuropathy Percent * * * p < 0.001 Prevalence DCCT/EDIC DCCT: 64% RRR with INT EDIC 13/14: incr prevalence INT + Conv 30% RR with prior INT, NS after adjustment for age/ht/close out NC NB time b/w measurements 13-20 yrs

49. Reduction of Incidence of Confirmed Clinical Neuropathy with Intensive Therapy RR (95% CI) DCCT64% (45-76) EDIC30% (7-48) Mean A1c was associated with increased risk in both DCCT and EDIC DCCT/EDIC

50. Neurologic Outcomes Abnormal Autonomic Response R-R Variation < 15 OR R-R Variation < 20 AND Valsalva ratio < 1.5 OR Orthostatic hypotension Cardiac Autonomic Neuropathy DCCT/EDIC

51. INT CONV * p < 0.01 ** p < 0.05 Percent Prevalence DCCT/EDIC

52. Reduction of Incidence of Cardiac Autonomic Neuropathy with Intensive Therapy RR (95% CI) DCCT31% (7-49) EDIC24% (0.1-41) Mean A1c was associated with increased risk during both DCCT and EDIC 78% of treatment group effect explained by differences in A1c. DCCT/EDIC

53. Severe Neuropathic Outcomes Ulcers (EDIC) and Amputations (DCCT/EDIC) Amputations Risk reduction 28% P=0.40 Ulcers Risk reduction 48% P = 0.0018 Percent DCCT/EDIC Amputations: 56 events in 31 subjects LE Ulcers: 185 events/97 subjects

54. Erectile Dysfunction * *p< 0.001 DCCT/EDIC Prevalence EDIC Yr 10 J Urol 2011;185:1828

55. Effect of Glycemia on Risk of Erectile Dysfunction A1c Primary74% p < 0.0001 Secondary97% p < 0.0001 Increased risk for ED per 10% higher DCCT/EDIC mean HbA1c: DCCT/EDIC A1c of men w/o ED 1% lower than those with ED

56. Neuropathy Findings Intensive therapy reduced risk of developing Confirmed Clinical Neuropathy (CCN) by 64% and of Cardiac Autonomic Neuropathy (CAN) by 31% at DCCT end. Risk of developing CCN by EDIC year 14 reduced by 30% in former INT subjects (OR 0.70; 95% CI 0.52-0.93). Risk of developing CAN by EDIC year 14 reduced by 31% (OR 0.69 95% CI 0.51-0.93) in former INT subjects. Summary DCCT/EDIC

57. Neuropathy Findings Risk of developing ED reduced by 67% in former INT subjects (secondary intervention cohort) Risk of developing ulcers reduced by 48% in former INT Development of neurologic complications strongly associated with DCCT HbA1c levels Summary DCCT/EDIC

58. TAKE A BREAK!

59. Cardiovascular Update John M. Lachin, Sc.D. DCCT/EDIC Principal Investigator DCCT/EDIC Data Coordinating Center The Biostatistics Center The George Washington University

60. Cardiovascular Events in DCCT Events / Patients Am J Cardiol 1995; 75:894-903 ConventionalIntensive Non-fatal MI or stroke, silent MI, revascularization, confirmed angina 20 / 81 / 1 Fatal CV or sudden death 12 Total 21 / 93 / 3 Too few subjects for conclusive analysis

61. Cardiovascular Outcomes Carotid artery IMT by ultrasound at years 1, 6 and 12 Coronary artery calcification by computed tomography at ~year 8 Cardiac structure and Function by MRI at year 15 Cardiovascular disease events over the DCCT/EDIC combined DCCT/EDIC EDIC

62. Common Carotid IMT AllIntensiveConventional Year 1 Year 6 p = 0.012 N Eng J Med 2003; 348:2294 IMT (mm) EDIC

63. Factorp-value Age< 0.0001 DCCT mean HbA1c (females) 0.687 DCCT mean HbA1c (males) 0.024 Systolic blood pressure< 0.0001 LDL/HDL ratio 0.031 Duration of Type 1 diabetes 0.022 Cigarette smoking 0.014 Gender, triglycerides, overweight and microalbuminuria not significantly associated with IMT Risk Factors for Common Carotid IMT Full model R 2 = 25.8 % A1c explained 96% by yr 6 Multivariate Model EDIC N Eng J Med 2003; 348:2294

64. Progression of Common Carotid IMT Diabetes 2011; 60:607-613 EDIC Least Squares Means ? metabolic amnesia?

65. Mean Treatment-Related Difference in the Relation between the Estimated Mean Intima–Media Thickness and Age. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2003;348:2294-2303.

66. Coronary Artery Calcification at Year 8 0 2 4 6 8 10 12 Primary Prevention Secondary Intervention Intensive Conventional Percent p = 0.026 p = 0.063 Overall 50% Reduction in Odds p < 0.005 Diabetes 2006; 55:3556 EDIC Percent with Agatston Score > 200

67. Change in Common Carotid IMT at yr 6 95% at yr 12 96% Coronary Artery Calcification CAC > 200 86% Treatment Group Differences in Measures of Atherosclerosis Percent Outcome Explained Diabetes 2003, 2006, 2011 EDIC Percent Explained by DCCT HbA1c

68. Conclusions Initial DCCT treatments have effects on atherosclerosis 6 - 12 y after end of randomized treatments. The benefit of intensive therapy -increases with attained age -greater in the primary than secondary cohort. The benefit of intensive therapy is largely explained by the difference in DCCT HbA1c. DCCT/EDIC Atherosclerosis

69. CVD events defined a priori -Major Cardiovascular Events  Non-fatal myocardial infarction or stroke  Cardiovascular death -Silent myocardial infarction on ECG -Confirmed angina -Revascularization- angioplasty, stent, or bypass All CVD events adjudicated, masked to treatment assignment and HbA1c levels Clinical Cardiovascular Disease NEJM 2005; 353: 2643 DCCT/EDIC

70. Time to first of any CVD event Pre-planned analysis when 50 conventional group cases occurred 85% power to detect a 50% reduction in risk of CVD events 50 case landmark reached in 2005 Primary Outcome and Analysis DCCT/EDIC NEJM 2005; 353: 2643 CVD Events

71. Conventional Intensive Total 98 / 52 46 / 31 p = 0.007 Total Cardiovascular Events Events / Patients DCCT/EDIC NEJM 2005; 353: 2643

72. Cumulative Incidence Years from Study Entry Cumulative Incidence of Any (First) Cardiovascular Event 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Risk reduction 42% 95% CI: 9, 63 Log-rank P = 0.016 0.12 0.10 0.08 0.06 0.04 0.02 0.00 Conventional Intensive 52 31 DCCT/EDIC NEJM 2005; 353: 2643

73. Conventional Intensive MI 16 / 15 7 / 7 Stroke5 / 5 1 / 1 CVD death9 / 9 3 / 3 Any one 30 / 25 11 / 11 Cardiovascular Events Events / Patients DCCT/EDIC NEJM 2005; 353: 2643

74. Conventional Intensive Cumulative Incidence of Non-Fatal MI, Stroke or CVD Death Risk reduction 57% 95% CI: 12, 79 Log-rank P = 0.018 Cumulative Incidence 0.12 0.10 0.08 0.06 0.04 0.02 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years from Study Entry 25 11 DCCT/EDIC NEJM 2005; 353: 2643

75. Conventional Intensive Silent MI 21 / 18 7 / 7 Angina 22 / 18 11 / 11 Revascularization 25 / 20 17 / 11 Cardiovascular Events Events / Patients DCCT/EDIC NEJM 2005; 353: 2643

76. Treatment Group Risk Effect Reduction P Baseline Adjusted 47 0.005 Explanation of Treatment Group Effect on CVD Events DCCT/EDIC NEJM 2005; 353: 2643

77. Treatment Group Risk Effect Reduction P Baseline Adjusted 47 0.005 Explanation of Treatment Group Effect on CVD Events DCCT/EDIC NEJM 2005; 353: 2643 Albuminuria 42 0.016 29 Mean HbA1c 16 0.61 97 during DCCT Microalbuminuria 38 0.03 45 Adjusted for: % Group Effect Explained

78. Effect of DCCT Mean HbA1c on Risk of CVD Events Risk Reduction (95% CI)P DCCT Mean HbA1c per 10% decrease21% (9, 30)<0.001 DCCT/EDIC NEJM 2005; 353: 2643

79. Benefits of intensive therapy on CVD continue through 2012. Risk factor analyses for major CVD clinical events forthcoming after 100 CVD cases have occurred in conventional group. Anticipated in next few years. CVD Update DCCT/EDIC

80. Landmark of 50 conventional group deaths reached Manuscript in preparation Results embargoed until publication No excess mortality risk in the former DCCT intensive therapy group Mortality DCCT/EDIC

81. cMRI performed in EDIC years 14-16 (~2008) 1017 (81%) evaluated of 1259 available 741 with gadolinium delayed enhancement for detection of scars Subjects with renal dysfunction not given gadolinium for potential safety concern Cardiac Structure and Function Circulation 2011; 124:1737 EDIC Study Population

82. Left ventricular structure and function -Volumes -Mass -Ventricular remodeling Aortic distensibility Presence of scars (in subset without renal dysfunction) Cardiac Structure and Function Circulation 2011; 124:1737 EDIC cMRI Outcomes

83. Left ventricle: -No significant difference between intensive versus conventional groups -Worse among males, with increasing age and blood pressure -Worse with higher mean DCCT/EDIC HbA1c, after adjusting for other factors Cardiac Structure and Function Circulation 2011; 124:1737 Diabetes 2013; [epub] EDIC

84. Aortic stiffness: -No significant difference between intensive versus conventional groups -Worse with increasing age, blood pressure, lipids, and with microalbuminuria -Worse with higher mean DCCT/EDIC HbA1c, after adjusting for other factors Cardiac Structure Diabetes Care 2013; March 8 [epub] Diabetes 2013; March 21 [epub] EDIC

85. Association with DCCT mean HbA1c Mean, SDWorseβ, SEp = Ejection Fraction, %62, 6↓-0.02, 0.150.90 LV Mass, g/m 2 139, 33↑1.57, 0.520.003 LV mass/EDV, mg/mL1.0, 0.17↑0.02, 0.004<0.001 Ln Aortic Distensibility, mm Hg-1 (inverse of stiffness) 0.60, 0.51↓-0.05, 0.01<0.001 Circulation 2011; 124:1737 Diabetes 2013; [epub] DCCT/EDIC Cardiac Structure and Function

86. 32 / 741 (4.3%) overall -21 patients had no prior history of clinical MI -7 of these were typical ischemic scars, 14 non-ischemic -Modifiable risk factors: HTN and low HDL -Elimination of subjects with renal dysfunction from scar assessment eliminated high risk sub-group Cardiac Structure Myocardial Scars Circulation 2011; 124:1737 DCCT/EDIC

87. No differences between DCCT intensive versus conventional groups in cMRI measures of cardiac structure and function. Strong association with the history of glycemia over DCCT and EDIC combined. Cardiac Structure and Function DCCT/EDIC Conclusions

88. The long-term beneficial effects of intensive therapy on CVD in the DCCT are: largely mediated by changes in glycemia during the DCCT mediated in part by reduction in the incidence of albuminuria DCCT/EDIC Atherosclerosis and Cardiac Events Conclusions

89. 6.5 y of intensive therapy aimed at achieving near normoglycemia decreased: Progression of atherosclerosis as measured by IMT and CAC Aggregate CVD risk by 42% Major CVD events by 57%. DCCT/EDIC Summary Atherosclerosis and Cardiac Events

90. DCCT/EDIC In the DCCT T1DM population, intensive glycemic therapy was highly effective in decreasing the risk of cardiovascular disease Summary Atherosclerosis and Cardiac Events

91. Cheiroarthropathy Defined as history of carpal tunnel syndrome, adhesive capsulitis, Dupuytren’s contracture, flexor tenosynovitis (“trigger finger”) and/or prayer sign on examination DCCT/EDIC

92. Design Cross sectional analysis at EDIC yrs. 18/19Cross sectional analysis at EDIC yrs. 18/19 Targeted medical history and standardized physical exam by certified staffTargeted medical history and standardized physical exam by certified staff Self-administered questionnaireSelf-administered questionnaire DCCT/EDIC

93. Data Collection HistoryHistory Physical examPhysical exam –Prayer sign –Goniometry of shoulders Function measured with Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaireFunction measured with Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire –Self-administered, 30 item, validated –5 point scale, total score range (0-100) DCCT/EDIC

94. Physical Assessment Visual assessment for presence of positive prayer signVisual assessment for presence of positive prayer sign Shoulder flexion measured by goniometryShoulder flexion measured by goniometry Subjects with deformities, old fractures, recent shoulder surgery, or stroke affecting upper extremities were excluded from measurementsSubjects with deformities, old fractures, recent shoulder surgery, or stroke affecting upper extremities were excluded from measurements DCCT/EDIC

95. Prayer sign Normal DCCT/EDIC

96. Physical Examination Goniometry of Shoulder DCCT/EDIC

97. Data slides Removed pending publication DCCT/EDIC

98. Recommendations and Future Directions Rose A. Gubitosi-Klug, MD, PhD Principal Investigator DCCT/EDIC Clinical Coordinating Center DCCT/EDIC

99. DCCT/EDIC Conclusions Chronic glycemia and duration of diabetes are the major factors in the development and progression of diabetes-specific complications in Type 1 diabetes. Intensive therapy that achieves lower glycemia is highly effective in reducing all complications, including severe disease. Lower HbA1c is better.

100. DCCT/EDIC Recommendation Early intervention is most effective; if intensive therapy is delayed the momentum of complications is more difficult to slow.

101. Future Directions Decreasing effect of prior control? Metabolic Memory over time - Microvascular disease - Cardiovascular Disease Etiology- epigenetic changes, AGE formation, genetics, other? DCCT/EDIC

102. DCCT/EDIC Ancillary Studies and Collaborations DCCT/EDIC Core University of Toronto Genetics Medical University of South Carolina CVD-Program Project Obesity, T2DM and Int. Therapy University of Washington (Brunzell) Monnier Weiss Schaumberg Repository-old Repository new URO-EDIC 1 CVD Project Univ. Oklahoma R 01 IMT JDRF Cardiac MRI Johns Hopkins CVD Biomarkers Cleveland Clinic Neurobehavioral Joslin (Jacobson) 2007-2012 R 01 Dermal AGEs SCOUT Epigenetics City of Hope CAC URO-EDIC 2 Haptoglobin GlycatedAlbumin

103. More DCCT/EDIC Ancillary Studies and Collaborations DCCT/EDIC Core University of Toronto Genetics Medical University of South Carolina CVD-Program Project Obesity, T2DM and Int. Therapy University of Washington (Brunzell) Monnier Weiss Schaumberg Repository-old Repository new URO-EDIC 1 CVD Project Univ. Oklahoma R 01 IMT JDRF Cardiac MRI Johns Hopkins CVD Biomarkers Cleveland Clinic Neurobehavioral Joslin (Jacobson) R 01 Dermal AGEs SCOUT Epigenetics City of Hope CAC URO-EDIC 2 Haptoglobin GlycatedAlbumin Hearing Impairment Residual C-peptide Gastro

104. Effect of INT vs CONV Therapy on Residual Insulin Secretion Ann Int Med 1998;128:517-23 Intensive Conventional

105. Effects of Preserved C-Peptide Intensively treated Secretors vs Non-secretors Ann Int Med 1998;128:517-23 7.1 6.6 HbA1c % Secretors Non-secretors 2.5 1.4 4.7 2.0 17 7 Retin. Renal Hypo. 3-step >40 mg/24h coma or seizure Rate per 100 pt-yr 7.1 6.6 HbA1c %

106. Upcoming Studies DCCT/EDIC Questions: –Is there residual  -cell function after an average diabetes duration of 30 years? –What factors influence residual  -cell function? –What is the physiologic significance? –What is effect on risk for complications? Residual C-peptide

107. Residual C-peptide: Poster # 1618 Pilot Study Results- 2012 58 subjects Selected based on near normal HbA1c during DCCT/EDIC and/or above average C-peptide at DCCT baseline MMTT (mixed meal TT) Sensitive c-pep assay n=48n=10 DCCT/EDIC

108. DCCT/EDIC Protocol –MMTT in the full EDIC cohort –Evaluation of samples by three ultrasensitive assays Outcomes of interest –HbA1c over time/insulin dose –Hypoglycemia –Mediators/risk factors –Long-term complications Residual C-peptide: Full Cohort Upcoming Studies

109. Question: –Is there hearing impairment in T1DM? –If so, does it correlate with neuropathy, microvascular disease, cheiroarthropathy? –Relationship with HbA1c (prior DCCT treatment), other risk factors? Protocol: –Standardized hearing study across all 27 EDIC centers with central reading center DCCT/EDIC Upcoming Studies Hearing Impairment Hearing impairment is more common in T2DM than in non-diabetic population

110. Gastric Emptying Question: –What is the prevalence of disturbances in gastric emptying? –How does this impact glycemic control? Protocol: –Pilot Study, 7 EDIC centers, 80 participants – 13 C-Spirulina gastric emptying breath test DCCT/EDIC Upcoming Studies

111. DCCT/EDIC 30th Anniversary Symposium Contributions and Progress DCCT/EDIC On behalf of the DCCT/EDIC Research Group Thank you for your attention