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

Update on EDIC: Epidemiology of Diabetes Interventions and

Complications Study

Charlotte McDonald, MD, MSc, FRCPC

Associate Professor,

Division of Endocrinology,

Department of Medicine,

UWO

DCCT/EDIC 30th Anniversary Symposium Contributions and Progress

DCCT/EDIC Research Group

June 22, 2013

DCCT/EDIC

AcknowledgementsEDIC 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

30th 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

EDIC TEAM: UWOJohn 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

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

DCCT/EDICTimeline

1978 1982 1983 1989 1993 1994 2005 2013 2016

DCCT

NationalCommission

RFA

NationalCommission

PlanningRFA

FeasibilityPlanning

RFA

Recruitment

FeasibilityDCCTend

EDICstart

DCCTend

10 years

EDIC

EDIC20 years

DCCT/EDIC

• N=1,441• ages 13 to 39 • 29 centers US and Canada • Diabetes duration 1 - 15

years

lll

l

ll

l

ll

ll

l

l

ll

l

l

l

l

lll

llll ll

l

CLINICAL CENTERS1983-93

l

DCCT/EDIC

Discovery of Insulin(1921-1922)

Banting and Best

• Insulin prevented acute death• Chronic, incurable illness• Most develop end-organ complications

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 withage-matched non-diabetic population

Long-term Complications: Steno Hospital

31%

Diabetologia1978;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.

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?

Study Cohorts

Primary prevention (n= 726): 1-5 years duration No retinopathy or microalbuminuria

Secondary intervention (n= 715): 1-15 years duration> 1 microaneurysm, < severe NPDR

< 200 mg albumin excretion/24 h

Age 13-40

DCCTGlycemic 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 GroupNEJM 1993;342:381

2%

• HbA1c <6.05%

Completeness of Follow-up

DCCT Baseline Study End

(1993)

Number 1441 1422

Percent of 100 99 DCCT cohort

DCCTRetinopathy Results: > 3 Step Change

Primary Prevention Secondary Intervention

76%

54%


Reduction in Complications: Intensive vs Conventional


Series1

0 10 20 30 40 50 60 70 80

Percent Reduction

Retinopathy

Nephropathy

Neuropathy

Development

3-step progression

Severe NPDR

Microalbuminuria

Albuminuria

Clinical

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

Intensive Therapy

Relationship between Glycemiaand Complications

DCCT Research GroupDiabetes 1995;44:968

0

2

4

6

8

10

12

14

16

Mean HbA1c (%) During DCCT5 6 7 8 9 10 11 12 13

IntensiveR

ate

pe

r 1

00 P

YR Risk Gradient:

~44 % reduction in riskper 10% lower HbA1c

Conventional

Risk of Retinopathy Progression

Risk of Severe Hypoglycemia

0

10

20

30

40

50

60

70

CONV

INT

Rate of Severe hypoglycemia

Rate ofComa or Seizure

RR=3.3

RR=3.0

Diabetes1997;46:271-86

Per 100

Pt-Yr3-fold increase

hypoglycemia, including coma /seizure

mean wt gain 4.6 kg

0

2

4

6

8

10

12

14

16

Mean HbA1c (%) During DCCT5 6 7 8 9 10 11 12 13

Intensive

Ra

te p

er

100

PY

R

Risk Gradient:~44 % reduction in risk

per 10% lower HbA1c Conventional

Risk of Retinopathy

Progression vs Mean HbA1c during DCCT

Current Hemoglobin A1c (%)

Rat

e p

er 1

00 P

YR

5 6 7 8 9 10 11 12 130

20

40

60

80

100

Intensive

Conventional

Risk of Severe

Hypoglycemia

Effect of INT vs CONV Therapy on Residual Insulin Secretion

At baseline303 subjects

withstimulatedC-peptide

0.2-0.5 pmol/L& duration1-5 years

Ann Int Med 1998;128:517-23

Intensive

Conventional

Although insulin secretiondecreased in all subjects over

time, intensive therapy reducedrate of decline.

Major Scientific and Clinical Results of DCCT

• Salutary effect of intensive therapy on early microvascular and neurologic complications

• Established association and primacy of glycemia and complications

• Identified risks (hypoglycemia/weight gain) and costs and contrasted them with benefits

• No adverse effects of INT on quality-of-life or cognitive function

• 75 publications and ~150 abstracts

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

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 GroupDiabetes Care 1999;22:99 DCCT/EDIC


DCCT EDIC Baseline Study End Baseline

(1993) (1994)

Number 1441 1422 1394

Percent of 100 99 96 DCCT cohort

DCCT/EDIC

Metabolic Results: Median HbA1c

DCCT Intervention

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

EDIC

IntensiveEDIC mean 7.9%

* * * * * P< 0.05

DCCT

DCCT/EDIC

Training

1993-1994

At the end of the DCCT, allparticipants were offered

training in intensive therapy

and

The clinical care of the DCCT participants was returned to

their own health care providers

Metabolic Results: Median HbA1c

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

ConventionalEDIC mean 8.0%

IntensiveEDIC mean 7.9%

Training

* * * * * P< 0.05

DCCT

DCCT/EDIC

% Reduction in Risk with Intensive Therapy

DCCT

Retinopathy

3-step worsening 52

Proliferative 47

Macular edema 26

Laser Therapy 56

Nephropathy

Microalbuminuria (>40mg/24h) 39

Albuminuria (>300 mg/24h) 54

Effect of DCCT Intensive Therapyafter 4 Years of EDIC Follow-up

DCCT/EDIC Research GroupN Engl J Med 2000; 342:381-9

DCCT/EDIC

Discovery of Metabolic Memory

EDIC Year 4*

63

55

73

62

53

84

*In subjects free of complication at end of DCCT

Metabolic memory appears to persist for at least 10 years after end of DCCT forretinopathy, nephropathy, and neuropathy

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

Cu

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den

ce

Risk reduction 57% 95% CI: 12, 79Log-rank P = 0.018

DCCT/EDIC Research GroupN 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


DCCT EDIC Baseline Study End Baseline Year 11 Year

18 (1993) (1994) (2005)

(2012)

Number 1441 1422 1394 1340 1272

Percent of 100 99 96 93* 88+

DCCT cohortDCCT/EDIC

*96% of surviving cohort+95% of surviving cohort

• Durability of intensive therapy effect including metabolic memory

• Beneficial effect of Intensive therapy on longer-term clinical outcomes- More advanced complications- Atherosclerosis and CVD events

• Safety-cognitive function unaffected despite hypoglycemia

Major Scientific and Clinical Results of EDIC

DCCT/EDIC

0

10

20

30

40

50

60

0 5 10 15 20 25 30 35

Diabetes Duration (Years)C

um

ula

tive

In

cid

ence

(%

)

0

10

20

30

40

50

60

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

Duration of Diabetes (Years)

Population-based

Proliferativeretinopathy

Nephropathy

CVD

DCCT Intensive Therapy

Long-term Outcomes of Type 1 DiabetesPittsburgh EDC

DCCT/EDICArch Int Med 2009;169:1307

20

44

19

812 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.

Prevalence (%) of Severe Complications

Complication

Blindness 30

Renal failure 22

Amputation 12

Steno 1978

Arch Int Med 2009;169:1307

*<20/200 either eye † SeCr > 2, dialysis, or transplantation +All were of toes except one BKA

DCCT INT2008

1*

1†

1+

Diabetologia1978;14:363

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

EDIC Year

Cu

mu

lati

ve In

cid

ence

%

Arch Ophthal 2008126:1707-1715.

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

0 1 7 82 3 4 5 6 9 10

010

2030

4050

60

DCCT/EDIC

Benefits of DCCT Intensive Therapy onMicrovascular 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

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

• 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 UpdateSummary

1-2 3-4 5-6 7-8 0

5

10

15

20

25

Conventional

Intensive

Cu

mu

lati

ve I

nci

den

ce (

%)

57% risk reductionp < 0.0001

EDIC YearJAMA 2003; 290:2159-2167

Cumulative Incidence of Microalbuminuria During EDIC

Years 1-8

EDIC

0

2

4

6

8

10

12

1 - 2 3 - 4 5 - 6 7 - 8

Conventional

IntensiveCu

mu

lati

ve I

nci

den

ce (

%)

84% risk reductionp < 0.0001

EDIC Year

Cumulative Incidence of Macroalbuminuria during EDIC

JAMA 2003; 290:2159-2167

Years 1-8

EDIC

Reduction of Risk for Albuminuria with Intensive Diabetes Therapy

AER ≥40 mg/d AER ≥300 mg/d0

10

20

30

40

50

60

70

80

90

100

Ris

k r

ed

uc

tio

n (

%)

Proportion 99% explained by DCCT mean HbA1c

91% 100% 98% 99% 100%

Summary

DCCT DCCTEDICY 1-8

EDICY 1-8

EDICY 1-18

EDICY 1-18

DCCT/EDIC

Cumulative Incidence of Hypertension

Arch Intern Med 2008; 168:1867-1873 DCCT/EDIC

Cumulative Incidence of Impaired GFR

NEJM 2011

50% riskreductionP=0.006

Sustained eGFR <60 ml/min/1.73m2

NEJM 2011; 365:2366-2376 DCCT/EDIC

Intensive therapy also reduced the risk of more severe kidney disease

eGFR <60* eGFR <45 eGFR<30 ESRD0

10

20

30

40

50

60

70

80

90

100R

isk

red

uct

ion

(%

)

Intensive 24 24 13 8 Conventional 46 39 23 16P-value 0.006 0.045 0.088 0.098 DCCT/EDIC

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

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

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

Confirmed Clinical Neuropathy

DCCT Base DCCT Yr 5 EDIC Yr 13/140

5

10

15

20

25

30

35

40

INT CONV

Per

cen

t

*

*

* 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

Reduction of Incidence of Confirmed Clinical Neuropathy with Intensive Therapy

RR (95% CI)DCCT 64% (45-76)

EDIC 30% (7-48)

Mean A1c was associated with increased risk in both DCCT and EDIC

DCCT/EDIC

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

Cardiac Autonomic Neuropathy

Baseline DCCT END EDIC 13/14 EDIC 16/170

5

10

15

20

25

30

35

40

45

**

*

**

INT

CONV

* p < 0.01 ** p < 0.05

Per

cen

tPrevalence

DCCT/EDIC

Reduction of Incidence of Cardiac Autonomic Neuropathy with Intensive Therapy

RR (95% CI)DCCT 31% (7-49)

EDIC 24% (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

Severe Neuropathic Outcomes Ulcers (EDIC) and Amputations (DCCT/EDIC)

AmputationsRisk reduction 28% P=0.40

UlcersRisk reduction 48%P = 0.0018

Pe

rce

nt

DCCT/EDICAmputations: 56 events in 31 subjectsLE Ulcers: 185 events/97 subjects

Erectile Dysfunction

Primary Secondary0%

5%

10%

15%

20%

25%

30%

35%

INT

CONV

*

*p< 0.001 DCCT/EDIC

Prevalence EDIC Yr 10

J Urol2011;185:1828

Effect of Glycemia on Risk of Erectile Dysfunction

Primary Secondary7.4%

7.6%

7.8%

8.0%

8.2%

8.4%

8.6%

8.8%

No ED

ED

A1

c

Primary 74% p < 0.0001

Secondary 97% p < 0.0001

Increased risk for ED per 10% higher DCCT/EDIC mean HbA1c:

DCCT/EDICA1c of men w/o ED 1% lower than those with ED

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

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

TAKE A BREAK!

Cardiovascular Update

John M. Lachin, Sc.D.

DCCT/EDIC

Principal Investigator DCCT/EDIC Data Coordinating Center

The Biostatistics CenterThe George Washington University

Cardiovascular Events in DCCTEvents / Patients

Am J Cardiol1995; 75:894-903

Conventional IntensiveNon-fatal MI or stroke, silent

MI, revascularization, confirmed angina

20 / 8 1 / 1

Fatal CV or sudden death 1 2Total 21 / 9 3 / 3

Too few subjects for conclusive analysis

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

Common Carotid IMT

0.55

0.56

0.57

0.58

0.59

0.6

0.61

0.62

0.63

All Intensive Conventional

Year 1 Year 6

p = 0.012

N Eng J Med2003; 348:2294

IMT

(m

m)

EDIC

Factor p-value

Age < 0.0001

DCCT mean HbA1c (females) 0.687

DCCT mean HbA1c (males) 0.024

Systolic blood pressure < 0.0001

LDL/HDL ratio 0.031Duration of Type 1 diabetes 0.022Cigarette smoking 0.014

Gender, triglycerides, overweight and microalbuminuria not significantly associated with IMT

Risk Factors for Common Carotid IMT

Full model R2 = 25.8 %A1c explained 96% by yr 6

Multivariate Model

EDICN Eng J Med2003; 348:2294

0.614

0.650

0.701

0.630

0.687

0.560

0.580

0.600

0.620

0.640

0.660

0.680

0.700

0.720

Year 1 Year 6 Year 12

Co

mm

on

ca

roti

d I

MT

(m

m)

EDIC Year

Conventional

Intensive

p < 0.0001

p = 0.048

Progression of Common Carotid IMT

Diabetes 2011; 60:607-613 EDIC

Least Squares Means

? metabolic amnesia?

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.

Coronary Artery Calcification at Year 8

0

2

4

6

8

10

12

PrimaryPrevention

SecondaryIntervention

IntensiveConventional

Per

cen

t

p = 0.026

p = 0.063 Overall50% Reduction

in Oddsp < 0.005

Diabetes 2006; 55:3556 EDIC

Percent with Agatston Score > 200

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

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

• 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

• 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/EDICNEJM 2005; 353: 2643

CVD Events

Conventional Intensive

Total 98 / 52 46 / 31

p = 0.007

Total Cardiovascular EventsEvents / Patients


Cu

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ce


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


0.12

0.10

0.08

0.06

0.04

0.02

0.00

Conventional

Intensive

52

31



MI 16 / 15 7 / 7

Stroke 5 / 5 1 / 1

CVD death 9 / 9 3 / 3

Any one 30 / 25 11 / 11

Cardiovascular EventsEvents / Patients


Conventional

Intensive

Cumulative Incidence of Non-Fatal MI, Stroke or CVD Death


Cu

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den

ce

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


25

11



Silent MI 21 / 18 7 / 7

Angina 22 / 18 11 / 11

Revascularization 25 / 20 17 / 11

Cardiovascular EventsEvents / Patients


Treatment Group Risk Effect Reduction P

Baseline Adjusted 47 0.005

Explanation of Treatment Group Effect on CVD Events


Treatment Group Risk Effect Reduction P

Baseline Adjusted 47 0.005

Explanation of Treatment Group Effect on CVD Events


Albuminuria 42 0.016 29

Mean HbA1c 16 0.61 97 during DCCT

Microalbuminuria 38 0.03 45

Adjusted for:

% GroupEffect

Explained

Effect of DCCT Mean HbA1c on Risk of CVD Events

Risk Reduction(95% CI) P

DCCT Mean HbA1c per 10% decrease 21% (9, 30) <0.001


• 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

• 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

• 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

• Left ventricular structure and function- Volumes- Mass- Ventricular remodeling

• Aortic distensibility

• Presence of scars (in subset without renal dysfunction)


Circulation 2011; 124:1737 EDIC

cMRI Outcomes

• 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


Circulation 2011; 124:1737 Diabetes 2013; [epub]

EDIC

• 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

• 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 StructureMyocardial Scars

Circulation 2011; 124:1737 DCCT/EDIC

• 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.


DCCT/EDIC

Conclusions

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 EventsConclusions

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

DCCT/EDIC

In the DCCT T1DM population, intensive glycemic therapy was

highly effective in decreasing the riskof cardiovascular disease

Summary

Atherosclerosis and Cardiac Events

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

Design

• Cross sectional analysis at EDIC yrs. 18/19• Targeted medical history and standardized

physical exam by certified staff• Self-administered questionnaire

DCCT/EDIC

Data Collection• History • Physical exam

–Prayer sign–Goniometry of shoulders

• Function 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

Physical Assessment

• Visual assessment for presence of positive prayer sign

• Shoulder flexion measured by goniometry

• Subjects with deformities, old fractures, recent shoulder surgery, or stroke affecting upper extremities were excluded from measurements

DCCT/EDIC

Prayer signNormal

DCCT/EDIC

Physical ExaminationGoniometry of Shoulder

DCCT/EDIC

Data slides Removed pending publication

DCCT/EDIC

Recommendations and Future Directions

Rose A. Gubitosi-Klug, MD, PhDPrincipal Investigator

DCCT/EDIC Clinical Coordinating Center

DCCT/EDIC

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.

DCCT/EDIC

Recommendation

• Early intervention is most effective; if intensive therapy is delayed the momentum of complications is more difficult to slow.

Future Directions• Decreasing effect of prior control?

Metabolic Memory over time- Microvascular disease- Cardiovascular Disease

• Etiology- epigenetic changes,

AGE formation, genetics, other?

DCCT/EDIC

DCCT/EDIC Ancillary Studies and Collaborations

DCCT/EDIC Core

University of TorontoGenetics

Medical University ofSouth Carolina

CVD-Program Project

Obesity, T2DM and Int. TherapyUniversity of Washington (Brunzell)

MonnierWeissSchaumbergRepository-oldRepository new

URO-EDIC 1

CVD ProjectUniv. Oklahoma

R 01

R 01IMT

JDRF

Cardiac MRIJohns Hopkins

CVD BiomarkersCleveland Clinic

NeurobehavioralJoslin (Jacobson)

2007-2012

R 01R 01

R 01

Dermal AGEsSCOUT

EpigeneticsCity of Hope

CAC

URO-EDIC 2Haptoglobin

GlycatedAlbumin

More DCCT/EDIC Ancillary Studies and Collaborations

DCCT/EDIC Core

University of TorontoGenetics

Medical University ofSouth Carolina

CVD-Program Project

Obesity, T2DM and Int. TherapyUniversity of Washington (Brunzell)

MonnierWeissSchaumbergRepository-oldRepository new

URO-EDIC 1

CVD ProjectUniv. Oklahoma

R 01

R 01IMT

JDRF

Cardiac MRIJohns Hopkins

CVD BiomarkersCleveland Clinic

NeurobehavioralJoslin (Jacobson)

R 01R 01

R 01

Dermal AGEsSCOUT

EpigeneticsCity of Hope

CAC

URO-EDIC 2Haptoglobin

GlycatedAlbumin

Hearing Impairment

ResidualC-peptide

Gastro

Effect of INT vs CONV Therapy on Residual Insulin Secretion

Ann Int Med 1998;128:517-23

Intensive

Conventional

Effects of Preserved C-PeptideIntensively treated Secretors vs Non-secretors

Ann Int Med 1998;128:517-23

Series15

5.5

6

6.5

7

7.5

7.1 6.6

HbA1c

%

Secretors

Non-secretors

0

2

4

6

8

10

12

14

16

18

2.5 1.44.7 2.0

17 7

Retin. Renal Hypo. 3-step >40 mg/24h coma or seizure

Rateper

100 pt-yr

Series15

5.5

6

6.5

7

7.5

7.1 6.6

HbA1c

%

Upcoming Studies

DCCT/EDIC

• Questions: –Is there residual b-cell function after an

average diabetes duration of 30 years?–What factors influence residual b-cell

function? –What is the physiologic significance?–What is effect on risk for complications?

Residual C-peptide

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=48 n=10

DCCT/EDIC

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

• 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 StudiesHearing Impairment

Hearing impairment is more common in T2DM than in non-diabetic population

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– 13C-Spirulina gastric emptying breath test

DCCT/EDIC

Upcoming Studies

DCCT/EDIC 30th Anniversary Symposium Contributions and Progress

DCCT/EDIC

On behalf of the DCCT/EDIC Research GroupThank you for your attention

Documents

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