DCCT Diabetes Control & Complications Trial

DCCT Diabetes Control & Complications Trial A. Vinik MD, PhD, FCP, MACP, FACE, Καθηγητής και Αντιπρόεδρος για την Έρευνα, Ιατρική Σχολή Ανατολικής Βιρτζίνια, Κέντρο Ενδοκρινολογικών και Μεταβολικών Νοσημάτων, Ερευνητική και Νευροενδοκρινολογική Μονάδα, Βιρτζίνια, ΗΠΑ 30 ο Επετειακό Πανελλήνιο Συνέδριο Διαβητολογική Εταιρεία Βόρειας Ελλάδας

The DCCT The DCCT,1983 to 1993 and funded by the NIDDK. 1,441 volunteers, 13 to 39y, type 1 DM >1<15y, 29 medical centers in the United States and Canada.. They also were required to have no, or only early signs of, diabetic eye disease. The study compared the effects of standard control of blood glucose versus intensive control (A1c <6%) on the complications of diabetes. EDIC ( epidemiology of DM and its complications (1993-) assessing the incidence and predictors of CVD events such as heart attack, stroke, or needed heart surgery, diabetic complications related to the eye, kidney, and nerves.

DCCT/EDIC Study Design

Study Time Line of the DCCT/EDIC Study National Commission RFA DCCT Planning Feasibility DCCT end EDIC start EDIC Recruitment 1978 1982 1983 1989 1993 1994 2005 2013 DCCT 10 years EDIC 20 years Nathan et al. Diabetes 2013; 62:3976-3986

Intensive DCCT Interventions CSII or MDI (3 or More Injections/day) SMBG (4 or more/day) Target: A1c 6.05% Conventional Insulin (1-2 Injections/day) SMBG But Not To Adjust Rx Clinical Well-being Target: A1c < 13.11%

Glycated Hemoglobin (Percent) DCCT Intervention A1c During DCCT 11 Conventional DCCT mean 9.1% 10 9 8 7 6 Intensive DCCT mean 7.2% 5 0 1 2 3 4 5 6 7 8 9 Study Year

Cumulative Incidence (%) 100% DCCT Retinopathy Progression Primary Prevention Cohort 80% 60% Conventional Group 40% 20% p<0.001 Intensive Group 0% 0 1 2 3 4 5 6 7 8 9 Years DCCT. NEJM 1993; 329:977

Cumulative Incidence (%) DCCT Retinopathy Progression Secondary Intervention Cohort 100% 80% 60% 40% p<0.001 Conventional Group 20% Intensive Group 0% 0 1 2 3 4 5 6 7 8 9 Years DCCT. NEJM 1993; 329:977

DCCT: Absolute Risk of Sustained Retinopathy Progression by A1c and Treatment Assignment Conventional treatment Intensive treatment Rate/100 personyears 16 14 12 10 8 6 4 2 0 5 6 7 8 9 10 11 12 13 Mean A1c (%) during study 16 14 12 10 8 6 4 2 0 5 6 7 8 9 10 11 12 13 Mean A1c (%) during study 44% lowering of risk for every 10% lowering of A1c DCCT Research Group. Diabetes. 1995;44:968-983.

DCCT: Absolute Risk of Sustained Retinopathy Progression by Years of Follow-up & Treatment 24 20 Rate/100 personyears 16 12 8 4 Conventional treatment Intensive treatment 0 1 2 3 4 5 6 Time during study (y) 7 8 9 DCCT Research Group. Diabetes. 1995;44:968-983.

Rate per 100 Patient-Years DCCT: Absolute Risk of Sustained Retinopathy by A1c and Years of Follow-Up Conventional Therapy Intensive Therapy 24 Mean A1c: 11% 10% 24 20 9% 20 16 16 12 12 Mean A1c: 8 8% 8 9% 4 0 0 7% 4 8% 7% 0 6% 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Time During Study (years) DCCT Research Group. Diabetes. 1995;44:968-983.

Study Time Line of the DCCT/EDIC Study National Commission RFA DCCT Planning Feasibility DCCT end EDIC start EDIC Recruitment 1978 1982 1983 1989 1993 1994 2005 2013 DCCT 10 years EDIC 20 years Nathan et al. Diabetes 2013; 62:3976-3986

EDIC Epidemiology of Diabetes Interventions & Complications

Glycated Hemoglobin (Percent) A1c During DCCT & EDIC DCCT Intervention EDIC Observation 11 Conventional DCCT mean 9.1% Training 10 Conventional EDIC mean 8.0% 9 8 7 6 5 Intensive DCCT mean 7.2% Study year Intensive EDIC mean 8.0% 0 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Nathan et al. Diabetes 2013; 62:3976-3986

Cumulative incidence 0.0 0.1 0.2 0.3 0.4 0.5 Further Three-step Progression of Retinopathy From DCCT Close-out through EDIC Year 8 Risk reduction with intensive therapy: 63% p <.0001 Conventional Intensive 0 1 2 3 4 5 6 7 8 EDIC year JAMA 2002; 287:2563-2569

Clinic vs Real-world Data: Incidence of Proliferative Retinopathy (DCCT-EDIC/EDC) Cumulative Incidence (%) 20 18 15 13 10 8 5 3 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 Diabetes Duration (years) Cumulative incidence of proliferative retinopathy or worse DCCT Conventional EDC therapy DCCT Intensive therapy DCCT/EDIC Research Group. Arch Intern Med 2009;69:1307 16

Nephropathy

Percentage of Patients DCCT: Microalbuminuria & Macroalbuminuria Primary Prevention Cohort 30 25 Conventional Intensive 20 15 Microalbuminuria > 40 mg/24 h P< 0.04 10 5 Albuminuria 300 mg/24 h P= 0.4 0 0 1 2 3 4 5 6 7 8 9 Year of Study DCCT (1993) NEJM 329:977-986.

DCCT: Microalbuminuria and Macroalbuminuria Secondary Intervention Cohort Percentage of Patients 50 40 Conventional Intensive 30 Microalbuminuria 40 mg/24 h P= 0.001 20 10 P= 0.01 Albuminuria 300 mg/24 h 0 0 1 2 3 4 5 6 7 8 9 Year of Study DCCT (1993) NEJM 329:977-986.

Cumulative Incidence (%) Cumulative Incidence of New Microalbuminuria > 40 mg/24 h During EDIC 20 57% risk reduction p <.0001 Conventional 15 10 Intensive 5 0 1-2 3-4 5-6 7-8 EDIC Year JAMA 2003; 290:2159-2167

Cumulative Incidence (%) Cumulative Incidence of New Clinical Albuminuria > 300 mg/24 h During EDIC 12 10 8 6 4 2 84% risk reduction p <.0001 Conventional Intensive 0 1-2 3-4 5-6 7-8 EDIC Year JAMA 2003; 290:2159-2167

Cumulative Incidence of an Impaired Glomerular Filtration Rate, According to Treatment Group. The DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-2376

Estimated GFR over Time. The DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-2376

Cumulative incidence, % Clinic vs Real-world Data: Incidence of Nephropathy (DCCT-EDIC/EDC) 20 18 15 13 10 8 5 DCCT Conventional therapy EDC DCCT Intensive therapy 3 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 Diabetes duration, years Nephropathy defined as albumin excretion rate 300 mg/24 h, serum Cr 2 mg/dl, dialysis or renal transplant DCCT/EDIC Research Group. Arch Intern Med 2009; 169:1307 1316.

Cardiovascular Disease

Cumulative Incidence of Any Predefined CV Outcome Cumulative Incidence of the First of Any of the Predefined CVD Outcomes 0.12 0.10 0.08 0.06 Risk reduction 42% 95% CI: 9 63 Log-rank p=0.016 Conventional treatment 0.04 0.02 Intensive treatment 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 Since Entry No. at Risk Intensive 705 683 629 113 Conventional 714 688 618 92 Nathan DM, et al. N Engl J Med 2005;353;2643 53

Cumulative Incidence of Non-fatal MI, Stroke, or Death from CVD Cumulative Incidence of the First Occurrence of Non-fatal MI, Stroke, or Death from CVD 0.12 0.10 0.08 0.06 0.04 0.02 Risk reduction 57% 95% CI: 12 79 Log-rank p=0.018 Conventional treatment Intensive treatment 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 No. at Risk Years Since Entry Intensive 705 686 640 118 Conventional 721 694 637 96 Nathan DM, et al. N Engl J Med 2005;353;2643 53

Cumulative CV outcomes up to 30 years in DCCT/EDIC First of any of the predefined CVD outcomes DCCT-EDIC Group. Diabetes Care 2016; 39:686-693

Cumulative CV outcomes up to 30 years in DCCT/EDIC First occurrence of MACE DCCT-EDIC Group. Diabetes Care 2016; 39:686-693

Cumulative Mortality, Proportion DCCT-EDIC Mortality Cumulative mortality by treatment group 0.12 0.10 0.08 HR 0.67 (0.46 0.99) p=0.045 Conventional treatment 0.06 0.04 0.02 Intensive treatment Course 2 0 0 5 10 15 20 Time Since DCCT Randomizaion, y No. at risk Conventional 730 726 721 712 693 476 Intensive 711 706 697 694 985 501 25 30 JAMA 2015;313:45-53.

Neuropathy

Intensive treatment reduction (%) in cumulative incidence of complications during DCCT, during EDIC (further progression, adjusting for level of complications at DCCT end), and during DCCT/EDIC combined. Nathan et al. Diabetes 2013;62:3976-3986

Flow diagram of DCCT/EDIC subject participation in CAN and DPN assessments at EDIC year 13/14. *Percentage based on the original number of EDIC participants (n = 1,375). Percentage based on number of active EDIC participants at year 13/14 (n = 1,274). Percentages shown for R-R variation and Valsalva ratio are based on number of EDIC participants with CAN test at EDIC year 13/14 (n = 1,226). Martin C L et al. Dia Care 2014;37:31-38 Copyright 2011 American Diabetes Association, Inc.

% with DPN DCCT/EDIC: Reduced incidence of DPN following previous intensive vs standard insulin therapy in type 1 diabetic patients at year 13-14 ( metabolic memory ) 40 35 30 25 20 15 10 5 0 35 30 25 20 15 10 5 DCCT Baseline Intensive Standard * DCCT End * EDIC Year 13-14 *p<0.05 Albers et al., Diabetes Care, 2010

DCCT/EDIC Summary and Conclusions DCCT Study Findings Intensive blood glucose control reduces risk of eye disease 76% reduced risk kidney disease 50% reduced risk nerve disease 60% reduced risk EDIC Study Findings Intensive blood glucose control reduces risk of any cardiovascular disease event 42% reduced risk nonfatal heart attack, stroke, or death from cardiovascular events Metabolic Memory suggests that treatment should start as early as possible

Conclusion Early glycemic control is important Could self-perpetuating pathways be initiated with higher A1c? If you operate under a certain level, are you below the radar screen?

The DCCT/EDIC core investigations have been the center of a diverse array of supplemental studies and collaborations over the past 30 years. Gubitosi-Klug R A, and for the DCCT/EDIC Research Group Dia Care 2014;37:44-49 Copyright 2011 American Diabetes Association, Inc.