New Therapies - the Department of Medicine at the University of

Report
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
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
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: 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
EDIC TEAM: UWO
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/EDIC
DCCT/EDIC
Timeline
National
Commission
RFA
Planning
Feasibility
DCCT EDIC
end start
•
•
•
•
N=1,441
ages 13 to 39
29 centers US and Canada
Diabetes duration 1 - 15
years
EDIC
Recruitment
1978 1982 1983
1989 1993 1994
DCCT
10 years
2005
2013 2016
EDIC
20 years
DCCT/EDIC
CLINICAL CENTERS
1983-93
l
l
ll
l
l l
l
l
l
l
l l
l
l
ll l
l
ll
l l
l
l
l
l
l
l
l
DCCT/EDIC
Discovery of Insulin
(1921-1922)
• Insulin prevented acute death
• Chronic, incurable illness
• Most develop end-organ complications
Banting and Best
Insulin Era: 1930-1970
Long-term Complications: Steno Hospital
impairment
(legal)
14%
•Visual
Death
with or from
hypoglycaemia
was more
common than death in ketoacidotic coma. 31%
Blindness (total)
16%
Renal failure
22%
• Clinical manifestations of late diabetic
complications were considerably10%
less
Stroke
common in patients who were still alive after
Amputation
12% who
>40 years of diabetes than in patients
died before their fortieth year of diabetes.
Myocardial infarction
21%
Mortality increased 2-6 fold compared with
age-matched non-diabetic population
Diabetologia
1978;14:363
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
Age 13-40
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
Intensive Regimen
• >3 daily injections
or CSII (pump)
DCCT
Glycemic Results
• >4 SMBG
• Pre-meal BG
(3.9-6.7 mmol/L)
• Post-meal
(<10 mmol/L)
• HbA1c <6.05%
DCCT Research Group
NEJM 1993;342:381
2%
Completeness of Follow-up
DCCT
Baseline Study End
(1993)
Number
Percent of
DCCT cohort
1441
1422
100
99
DCCT
Retinopathy Results: > 3 Step Change
Primary Prevention
Secondary Intervention
54%
76%
DCCT Research Group
NEJM 1993;342:381
Reduction in Complications:
Intensive vs Conventional
Development
Retinopathy
3-step progression
Severe NPDR
Nephropathy Microalbuminuria
Albuminuria
Neuropathy
Clinical
0
DCCT Research Group
NEJM 1993;342:381
20
40
Percent Reduction
60
80
Summary
Intensive Therapy
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
Relationship between Glycemia
and Complications
Risk of Retinopathy Progression
16
Intensive
Rate per 100 PYR
14
Risk Gradient:
~44 % reduction in risk
per 10% lower HbA1c
12
10
8
Conventional
6
4
2
0
5
DCCT Research Group
Diabetes 1995;44:968
6
7
8
9
10
11
Mean HbA1c (%) During DCCT
12
13
Risk of Severe Hypoglycemia
70
60
50
40
Per
100 30
Pt-Yr
RR=
3.3
CONV
INT
20
RR=
3.0
10
0
Diabetes
1997;46:271-86
Rate of
Severe hypoglycemia
Rate of
Coma or
Seizure
3-fold increase
hypoglycemia,
including coma
/seizure
mean wt gain 4.6 kg
16
14
Rate per 100 PYR
Risk of
Retinopathy
Progression vs
Mean HbA1c
during DCCT
Intensive
12
Risk Gradient:
~44 % reduction in risk
per 10% lower HbA1c
10
8
Conventional
6
4
2
0
5
6
Risk of
Severe
Hypoglycemia
Rate per 100 PYR
100
80
7
8
9
10
11
12
Mean HbA1c (%) During DCCT
13
Intensive
60
40
20
Conventional
0
5
6
7
8
9
10
11
Current Hemoglobin A1c (%)
12
13
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
Although insulin secretion
decreased in all subjects over
time, intensive therapy reduced
rate of decline.
Intensive
Conventional
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 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
DCCT/EDIC
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
Completeness of Follow-up
Number
DCCT
EDIC
Baseline Study End
(1993)
Baseline
(1994)
1441
Percent of
100
DCCT cohort
1422
1394
99
96
DCCT/EDIC
Metabolic Results: Median HbA1c
DCCT Intervention Training
At the end of the DCCT, all
participants were offered
training in intensive therapy
* * * *
*
P< 0.05
and
DCCT
19931 2
1994
3
The clinical
Intensive care of the DCCT
EDIC meanwas
7.9% returned to
participants
their own health care
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
providers
EDIC
DCCT/EDIC
Metabolic Results: Median HbA1c
DCCT Intervention Training
EDIC Observation
Conventional
EDIC mean 8.0%
* * * *
*
P< 0.05
Intensive
EDIC mean 7.9%
1
2
3
4
5
6
7
DCCT
8
9
10
11
12
13
14
15
16 17 18
EDIC
Study Year
DCCT/EDIC
Effect of DCCT Intensive Therapy
after 4 Years of EDIC Follow-up
Discovery of Metabolic Memory
% Reduction in Risk with Intensive Therapy
DCCT
EDIC Year 4*
Retinopathy
3-step worsening
52
Metabolic memory appears
to persist 63
Proliferative
47
55
for at least 10 years after end of DCCT for
Macular edema
26
73
retinopathy,
nephropathy,
and
neuropathy
Laser Therapy
56
62
Nephropathy
Microalbuminuria (>40mg/24h)
39
53
Albuminuria (>300 mg/24h)
54
84
*In subjects free of complication at end of DCCT
DCCT/EDIC Research Group
DCCT/EDIC
N Engl J Med 2000; 342:381-9
Cardiovascular Events
Non-Fatal MI, Stroke or CVD Death
Prior to 2005, we demonstrated reduction in
atherosclerosis (carotid and coronary) in
intensive therapy and association with HbA1c
Cumulative Incidence
0.12
0.10
0.08
Risk reduction 57%
95% CI: 12, 79
Log-rank P = 0.018
0.06
0.04
0.02
Conventional
Intensive
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
Number at Risk
Intensive: 705
Conventional: 721
DCCT/EDIC Research Group
N Engl J Med 2005; 353:2643-53
686
694
640
637
118
96
DCCT/EDIC
Completeness of Follow-up
DCCT
EDIC
Baseline Study End
(1993)
Number
1441
Percent of
100
DCCT cohort
1422
99
Baseline
(1994)
Year 11
(2005)
Year 18
(2012)
1394
1340
1272
93*
+
96
88
*96% of surviving cohort
+
95% of surviving cohort
DCCT/EDIC
Major Scientific and Clinical
Results of EDIC
• 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
DCCT/EDIC
Long-term Outcomes of Type 1 Diabetes
Pittsburgh EDC
Population-based
50
40
30
20
Proliferative
frequenciesretinopathy
of serious
60
50
The
complications
in patients
44
with T1DM, especially
when40treated intensively, are
30
lower than that
historically.
19reported
Nephropathy
20
12CVD
10
Cumulative Incidence (%)
60
DCCT Intensive Therapy
20
8
8
10
0
0
0
5
10
15
20
25
30
35
Diabetes Duration (Years)
Duration of Diabetes (Years)
DCCT/EDIC
Arch Int Med 2009;169:1307
30-year Cumulative Incidence
DCCT/EDIC
~1980-2008
Prevalence (%) of Severe Complications
Complication
Blindness
Steno
1978
30
DCCT INT
2008
1*
Renal failure
22
1†
Amputation
12
1+
Diabetologia
1978;14:363
*<20/200 either eye
† SeCr > 2, dialysis, or transplantation
+All were of toes except one BKA
Arch Int Med
2009;169:1307
DCCT Clues to Metabolic Memory
Retinopathy
• 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
Further Retinopathy Progression over 10 years of
EDIC from the Level at DCCT Closeout
60
CONV
30
40
50
53% Risk Reduction
P < 0.0001
10
20
INT
0
Cumulative Incidence %
Adjusted For DCCT Closeout Level
0
Arch Ophthal 2008
126:1707-1715.
1
2
3
4
5
6
EDIC Year
7
8
9
10
DCCT/EDIC
Benefits of DCCT Intensive Therapy on
Microvascular Outcomes During EDIC
Percent Explained By Group Differences
in DCCT HbA1c
Outcome
Further Retinopathy
Progression:
at 4 years
at 10 years
at 18 years
% Risk
Reduction
70%
53%
46%
%
Explained
97.7%
89.3%
86.7%
DCCT/EDIC
Retinopathy Update
Summary
• 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
Retinopathy Update
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
Cumulative Incidence (%)
25
Cumulative Incidence of
Microalbuminuria During EDIC
Years 1-8
20
15
Conventional
57% risk reduction
p < 0.0001
10
Intensive
5
0
JAMA 2003;
290:2159-2167
1-2
3-4
5-6
EDIC Year
7-8
EDIC
Cumulative Incidence (%)
Cumulative Incidence of
Macroalbuminuria during EDIC
12
10
8
Years 1-8
84% risk reduction
p < 0.0001
Conventional
6
4
2
Intensive
0
1-2
3-4
5-6
7-8
EDIC Year
JAMA 2003;
290:2159-2167
EDIC
Reduction of Risk for Albuminuria
with Intensive Diabetes Therapy
Risk reduction (%)
Summary
100
90
80
70
60
50
40
30
20
10
0
EDIC EDIC
DCCT Y 1-8 Y 1-18
EDIC EDIC
DCCT Y 1-8 Y 1-18
AER ≥40 mg/d
AER ≥300 mg/d
Proportion
99%
explained by
DCCT mean HbA1c
91%
100%
98%
99% 100%
DCCT/EDIC
Cumulative Incidence of Hypertension
Arch Intern Med 2008; 168:1867-1873
DCCT/EDIC
Cumulative Incidence of Impaired GFR
Sustained eGFR <60 ml/min/1.73m2
50% risk
reduction
P=0.006
NEJM 2011;
2011 365:2366-2376
DCCT/EDIC
Risk reduction (%)
Intensive therapy also reduced the
risk of more severe kidney disease
100
90
80
70
60
50
40
30
20
10
0
eGFR <60*
Intensive
Conventional
P-value
eGFR <45
24
46
24
39
0.006
0.045
eGFR<30
13
23
0.088
ESRD
8
16
0.098
DCCT/EDIC
Effects of Intensive Therapy
on Kidney Disease
Summary
• 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
DCCT/EDIC
Effects of Intensive Therapy
on Kidney Disease
Conclusion
Early intensive diabetes therapy is
effective for preventing or delaying
kidney disease in type 1 diabetes
DCCT/EDIC
Neurologic Outcomes
Confirmed Clinical Neuropathy (CCN)
• 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
DCCT/EDIC
Confirmed Clinical Neuropathy
Prevalence
40
35
•
INT
CONV
Percent
30
•
*
25
•
20
15
•
*
10
5
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
0
DCCT Base
DCCT Yr 5
* p < 0.001
EDIC Yr 13/14
DCCT/EDIC
Reduction of Incidence of Confirmed
Clinical Neuropathy with Intensive Therapy
DCCT
RR (95% CI)
64% (45-76)
EDIC
30% (7-48)
Mean A1c was associated with increased risk
in both DCCT and EDIC
DCCT/EDIC
Neurologic Outcomes
Cardiac Autonomic Neuropathy
Abnormal Autonomic Response
• R-R Variation < 15
OR
• R-R Variation < 20 AND
Valsalva ratio < 1.5
OR
• Orthostatic hypotension
DCCT/EDIC
Cardiac Autonomic Neuropathy
Prevalence
45
40
35
Percent
*
INT
CONV
30
**
25
20
15
10
**
5
0
Baseline
DCCT END
* p < 0.01
EDIC 13/14
** p < 0.05
EDIC 16/17
DCCT/EDIC
Reduction of Incidence of Cardiac Autonomic
Neuropathy with Intensive Therapy
DCCT
RR (95% CI)
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)
Amputations
Risk reduction 28%
P=0.40
12
Percent
10
8
Amputations
6
Ulcers
4
2
Ulcers
Risk reduction 48%
P = 0.0018
0
INT
CONV
Amputations: 56 events in 31 subjects
LE Ulcers: 185 events/97 subjects
DCCT/EDIC
Erectile Dysfunction
Prevalence EDIC Yr 10
35%
30%
INT
CONV
25%
20%
*
15%
10%
5%
0%
Primary
J Urol
2011;185:1828
Secondary
*p< 0.001
DCCT/EDIC
Effect of Glycemia on
Risk of Erectile Dysfunction
8.8%
8.6%
A1c
8.4%
No ED
8.2%
ED
8.0%
7.8%
Increased risk for ED per
10% higher DCCT/EDIC
mean HbA1c:
Primary
74% p < 0.0001
Secondary 97% p < 0.0001
7.6%
7.4%
Primary
Secondary
A1c of men w/o ED 1% lower
than those with ED
DCCT/EDIC
Neuropathy Findings
Summary
• 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.
DCCT/EDIC
Neuropathy Findings
Summary
• 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
DCCT/EDIC
TAKE A BREAK!
Cardiovascular Update
John M. Lachin, Sc.D.
Principal Investigator
DCCT/EDIC Data Coordinating Center
The Biostatistics Center
The George Washington University
DCCT/EDIC
Cardiovascular Events in DCCT
Events / Patients
Non-fatal MI or stroke, silent
MI, revascularization,
confirmed angina
Fatal CV or sudden death
Total
Conventional
20 / 8
Intensive
1/1
1
21 / 9
2
3/3
Too few subjects for conclusive analysis
Am J Cardiol
1995; 75:894-903
Cardiovascular Outcomes
EDIC
• 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
Common Carotid IMT
0.63
p = 0.012
0.62
IMT (mm)
0.61
0.6
0.59
0.58
0.57
0.56
0.55
N Eng J Med
2003; 348:2294
All
Year 1
Intensive
Conventional
Year 6
EDIC
Risk Factors for Common Carotid IMT
Multivariate Model
Factor
Age
p-value
< 0.0001
DCCT mean HbA1c (females)
0.687
DCCT mean HbA1c (males)
0.024
Systolic blood pressure
LDL/HDL ratio
Duration of Type 1 diabetes
Cigarette smoking
< 0.0001
0.031
0.022
0.014
Gender, triglycerides, overweight and microalbuminuria
not significantly associated with IMT
N Eng J Med
2003; 348:2294
Full model R2 = 25.8 %
A1c explained 96% by yr 6
EDIC
Progression of Common Carotid IMT
Least Squares Means
Common carotid IMT (mm)
0.720
0.701
0.700
0.687
0.680
Conventional
p = 0.048
0.660
0.650
0.640
0.630
0.620
0.614
Intensive
p < 0.0001
0.600
? metabolic amnesia?
0.580
0.560
Year 1
Year 6
Year 12
EDIC Year
Diabetes 2011; 60:607-613
EDIC
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
Percent with Agatston Score > 200
12
Intensive
Conventional
Percent
10
p = 0.063
8
6
4
Overall
50% Reduction
in Odds
p < 0.005
p = 0.026
2
0
Diabetes 2006; 55:3556
Primary
Prevention
Secondary
Intervention
EDIC
Treatment Group Differences in
Measures of Atherosclerosis
Percent Explained by DCCT HbA1c
Outcome
Change in Common Carotid IMT
at yr 6
at yr 12
Coronary Artery Calcification
CAC > 200
Diabetes 2003, 2006, 2011
Percent
Explained
95%
96%
86%
EDIC
Conclusions
Atherosclerosis
• 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
Clinical Cardiovascular Disease
• 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
NEJM 2005; 353: 2643
DCCT/EDIC
Primary Outcome and Analysis
CVD Events
• 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
NEJM 2005; 353: 2643
DCCT/EDIC
Total Cardiovascular Events
Events / Patients
Total
Conventional
98 / 52
Intensive
46 / 31
p = 0.007
NEJM 2005; 353: 2643
DCCT/EDIC
Cumulative Incidence of Any (First)
Cardiovascular Event
Cumulative Incidence
0.12
Risk reduction 42%
95% CI: 9, 63
Log-rank P = 0.016
0.10
0.08
52
Conventional
31
0.06
0.04
Intensive
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
NEJM 2005; 353: 2643
DCCT/EDIC
Cardiovascular Events
Events / Patients
MI
Conventional Intensive
16 / 15
7/ 7
Stroke
5/ 5
1/ 1
CVD death
9/ 9
3/ 3
30 / 25
11 / 11
Any one
NEJM 2005; 353: 2643
DCCT/EDIC
Cumulative Incidence of Non-Fatal MI,
Stroke or CVD Death
Cumulative Incidence
0.12
Risk reduction 57%
95% CI: 12, 79
Log-rank P = 0.018
0.10
0.08
0.06
Conventional
25
0.04
Intensive 11
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
NEJM 2005; 353: 2643
DCCT/EDIC
Cardiovascular Events
Events / Patients
Silent MI
Angina
Conventional Intensive
21 / 18
7/ 7
22 / 18
11 / 11
Revascularization 25 / 20
17 / 11
NEJM 2005; 353: 2643
DCCT/EDIC
Explanation of Treatment Group Effect
on CVD Events
Treatment Group
Effect
Baseline Adjusted
NEJM 2005; 353: 2643
Risk
Reduction
47
P
0.005
DCCT/EDIC
Explanation of Treatment Group Effect
on CVD Events
Treatment Group
Effect
Baseline Adjusted
Risk
Reduction
P
% Group
Effect
Explained
47
0.005
Microalbuminuria
38
0.03
45
Albuminuria
42
0.016
29
Mean HbA1c
during DCCT
16
0.61
97
Adjusted for:
NEJM 2005; 353: 2643
DCCT/EDIC
Effect of DCCT Mean HbA1c on Risk
of CVD Events
DCCT Mean HbA1c
per 10% decrease
NEJM 2005; 353: 2643
Risk Reduction
(95% CI)
P
21% (9, 30)
<0.001
DCCT/EDIC
CVD Update
• 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.
DCCT/EDIC
Mortality
• 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
DCCT/EDIC
Cardiac Structure and Function
Study Population
• 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
Circulation 2011; 124:1737
EDIC
Cardiac Structure and Function
cMRI Outcomes
• Left ventricular structure and function
- Volumes
- Mass
- Ventricular remodeling
• Aortic distensibility
• Presence of scars (in subset without renal
dysfunction)
Circulation 2011; 124:1737
EDIC
Cardiac Structure and Function
• 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
Cardiac Structure
• 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
Diabetes Care 2013; March 8 [epub]
Diabetes 2013; March 21 [epub]
EDIC
Cardiac Structure
Myocardial Scars
• 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
Circulation 2011; 124:1737
DCCT/EDIC
Cardiac Structure and Function
Conclusions
• 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
Atherosclerosis and Cardiac Events
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 Events
Summary
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
Atherosclerosis and Cardiac Events
Summary
In the DCCT T1DM population,
intensive glycemic therapy was
highly effective in decreasing the risk
of cardiovascular disease
DCCT/EDIC
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
Normal
Prayer
sign
DCCT/EDIC
Physical Examination
Goniometry of Shoulder
DCCT/EDIC
Data slides Removed
pending publication
DCCT/EDIC
Recommendations and
Future Directions
Rose A. Gubitosi-Klug, MD, PhD
Principal Investigator
DCCT/EDIC Clinical Coordinating Center
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.
DCCT/EDIC
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
CVD Project
Univ. Oklahoma
Medical University of
South Carolina
CVD-Program Project
Obesity, T2DM and Int. Therapy
University of Washington (Brunzell)
IMT
URO-EDIC 1
Monnier
Weiss
Schaumberg
Repository-old
Repository new
DCCT/EDIC Core
Glycated
Albumin
R 01
CAC
R 01 Neurobehavioral
Joslin (Jacobson)
R 01
R 01
Dermal AGEs
SCOUT
Epigenetics
City of Hope
R 01
Haptoglobin
University of Toronto
Genetics
URO-EDIC 2
CVD Biomarkers
Cleveland Clinic
Cardiac MRI
Johns Hopkins
2007-2012
More DCCT/EDIC Ancillary Studies
and Collaborations
CVD Project
Univ. Oklahoma
Medical University of
South Carolina
CVD-Program Project
Obesity, T2DM and Int. Therapy
University of Washington (Brunzell)
IMT
URO-EDIC 1
Monnier
Weiss
Schaumberg
Repository-old
Repository new
CAC
R 01
Dermal AGEs
SCOUT
DCCT/EDIC Core
R 01 Neurobehavioral
Glycated
Albumin
R 01
R 01
Gastro
Joslin (Jacobson)
Epigenetics
City of Hope
R 01
Haptoglobin
University of Toronto
Genetics
URO-EDIC 2
CVD Biomarkers
Cleveland Clinic
Hearing
Impairment
Cardiac MRI
Johns Hopkins
Residual
C-peptide
Effect of INT vs CONV Therapy on
Residual Insulin Secretion
Intensive
Conventional
Ann Int Med
1998;128:517-23
Effects of Preserved C-Peptide
Intensively treated Secretors vs Non-secretors
18
16
7.5
7.5
%
7
7
6.5
6.5
6
14
%
7.1 6.6
6
5.5
5.5
5
5
HbA1c
12
Rate
per 10
100 pt-yr 8
7.1 66.6
2
0
4.7 2.0
HbA1c Retin.
Secretors
Non-secretors
Ann Int Med
1998;128:517-23
17 7
4
3-step
2.5 1.4
Renal
Hypo.
>40 mg/24h
coma or
seizure
Upcoming Studies
Residual C-peptide
• 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?
DCCT/EDIC
Residual C-peptide:
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
Poster # 1618
n=48
n=10
DCCT/EDIC
Upcoming Studies
Residual C-peptide: Full Cohort
• 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
DCCT/EDIC
Upcoming Studies
Hearing Impairment
Hearing impairment is more common in T2DM
than in non-diabetic population
• 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
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
DCCT/EDIC
30th Anniversary Symposium
Contributions and Progress
On behalf of the
DCCT/EDIC Research Group
Thank you for your attention
DCCT/EDIC

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