Slide 1

Report
Reducing Risk in Type 1 Diabetes
– A Practical Approach
Jay S Skyler
on behalf of the
Global Partnership for Effective Diabetes Management
This slideset was developed in 2009 with support from GlaxoSmithKline
Global Partnership for Effective Diabetes Management:
Identifying and addressing gaps in T1DM care
• There are considerable gaps in care of adults
with T1DM:
– High proportion continue to develop complications
– Majority do not achieve glycemic goals
– Patients face many challenges e.g. insulin dose
adjustment, hypoglycaemia, impact on daily life
Aschner P, et al. Int J Clin Pract 2009: in press.
Global Partnership for Effective Diabetes Management:
Identifying and addressing gaps in T1DM care
• The Global Partnership has developed
practical guidance to improve care in T1DM
by addressing:
– management of hyperglycemia
– insulin therapy
– management of CV risk factors
– psychological aspects
– team approach to care
Aschner P, et al. Int J Clin Pract 2009: in press.
Importance of management
of hyperglycemia
DCCT: Early intensive therapy reduced the incidence of
retinopathy and microalbuminuria in T1DM
Cumulative incidence of
retinopathy progression
Cumulative incidence of
microalbuminuria
54% risk reduction*
60
50
40
Patients (%)
50
Patients (%)
39% risk reduction*
60
Conventional
30
20
Intensive
10
40
Conventional
30
20
Intensive
10
0
0
0
1
2
3
4
5
6
Time (years)
7
8
9
0
1
2
3
4
5
6
7
8
9
Time (years)
*Intensive vs conventional treatment
Median HbA1c during 6.5 year follow-up period: intensive group, 7.3%; conventional group, 9.1%. N = 1441
DCCT Research Group. N Engl J Med 1993; 329:977–986.
Copyright 1993 Massachusetts Medical Society. All rights reserved.
Cumulative incidence of retinopathy over
10 years in EDIC following DCCT: the ‘legacy effect’
Cumulative incidence, %
60
Conventional
Intensive
53% risk reduction with intensive therapy,
95% CI, 43%–61%; P <.001
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
10
HbA1c (%)
12
10
8
+
+
++ ++ ++ ++ ++ ++ ++ ++ ++ ++
Conventional
Intensive
6
P <.001
<.001 <.001
DCCT 1
closeout
2
.002
.08
.12
.12
.64
.84
.36
.01
3
4
5
6
7
8
9
10
EDIC study year
Error bars are 95% CI. N = 1211
White NH, et al. Arch Ophthalmol 2008; 126:1707–1715.
Copyright © 2008 American Medical Association. All rights reserved.
Cumulative incidence of
non-fatal MI, stroke or
death from CVD
DCCT/EDIC: glycemic control reduces
macrovascular complications in T1DM
0.06
57% risk reduction in non-fatal MI, stroke or CVD death*
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
DCCT (intervention period)
EDIC (observational follow-up)
Years
*Intensive vs conventional treatment. N = 1441
DCCT/EDIC Study Research Group. N Engl J Med 2005; 353:2643–2653.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
Cumulative incidence, %
Clinic vs ‘real-world’ data: incidence of
proliferative retinopathy (DCCT-EDIC/EDC)
70
EDC
DCCT – Conventional therapy
60
DCCT – Intensive therapy
50
40
30
20
10
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/EDIC Research Group. Arch Intern Med 2009; 169:1307–1316.
Copyright © 2009 American Medical Association. All rights reserved.
Clinic vs ‘real-world’ data: incidence of
nephropathy (DCCT-EDIC/EDC)
40
EDC
DCCT – Conventional therapy
Cumulative incidence, %
35
DCCT – Intensive therapy
30
25
20
15
10
5
0
1
3
5
7
9
11
13 15 17 19 21 23
25 27
29
Diabetes duration, years
Nephropathy was defined as albumin excretion rate ≥ 300 mg/24 h,
serum creatinine ≥ 2 mg/dl, or dialysis or renal transplant
DCCT/EDIC Research Group. Arch Intern Med 2009; 169:1307–1316.
Copyright © 2009 American Medical Association. All rights reserved.
Clinic vs ‘real-world’ data: incidence of
CVD (DCCT-EDIC/EDC)
20
EDC
DCCT – Conventional therapy
Cumulative incidence, %
18
DCCT – Intensive therapy
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
CVD was defined as: non-fatal myocardial infarction or stroke, CVD
death, subclinical MI, angina, angioplasty or coronary artery bypass
DCCT/EDIC Research Group. Arch Intern Med 2009; 169:1307–1316.
Copyright © 2009 American Medical Association. All rights reserved.
Management of
hyperglycemia
Glycemic targets for individuals with T1DM
Characteristic
ADA
CDA
IDF
NICE (UK)
< 7.0%
≤ 7.0%
6.2–7.5%
≤ 6.5–7.5%
Fasting⁄
preprandial glucose,
mg⁄dl (mmol/l)
70–130
(3.9–7.2)
72–126
(4.0–7.0)
91–120
(5.1–6.5)
72–144
(4.0–8.0)
Postprandial glucose,
mg⁄dl (mmol/l)
< 180*
(< 10.0)
90–180†
(5.0–10.0)
136–160‡
(7.6–9.0)
< 180‡
(< 10.0)
HbA1c
ADA = American Diabetes Association; CDA = Canadian Diabetes Association; IDF = International Diabetes Federation; NICE = National Institute
for Health and Clinical Excellence
The CDA guidelines note that HbA1c goals and strategies must be tailored to the individual with diabetes, with consideration given to individual risk
factors.
ADA and CDA glycaemic targets are for type 1 and type 2 diabetes.
* Peak postprandial capillary plasma glucose.
† 90–144 mg/dl (5.0–8.0 mmol/l) if HbA1c target not being met.
‡ Capillary postprandial glucose 1–2 h after meal.
ADA. Diabetes Care 2009; 32(Suppl. 1):S13–S61. CDA. Can J Diabetes 2008; 32(Suppl. 1):S1–S201. IDF. Desktop guide
to Type 1 (insulin-dependent) diabetes, 1998; Brussels: IDF. NICE. Clinical Guideline 15. 2004; London, UK: NICE.
Majority of patients with T1DM do not reach
glycemic targets
Percentage not reaching
HbA1c target (%)
100
90
80
70
60
81%
83%
87%
74%
50
40
30
20
10
0
UK1
HbA1c > 7.5%
DCCT-EDIC
Intensive
EDC
DCCT-EDIC
Conventional
US2
HbA1c > 7.0%
1. Calvert M, et al. BMJ 2009; 338:b1870.
2. DCCT/EDIC Study Research Group. Arch Intern Med 2009; 169:1307–1316.
Managing hyperglycemia in type 1 diabetes
The Global Partnership recommends:
Aim for as good glycemic control as possible while minimizing
the risk of hypoglycemia
Ensure regular and appropriate
monitoring for complications
Aschner P, et al. Int J Clin Pract 2009: in press.
Insulin therapy
Intensive insulin therapy using a basal-bolus
approach: considered best treatment in T1DM
• Intensive insulin therapy using a basal-bolus approach,
whether as multiple daily injections or pump therapy, is
considered best treatment for individuals with T1DM
regardless of age
– Provides greater glycemic control, reduces risk of
complications, preserves β-cell function (DCCT)1-3
• Choice of insulin/mode of delivery should be guided by
factors such as:
– hypoglycemia, age, lifestyle, general health, motivation, ability
for self-management and diet, availability/accessibility
1. DCCT Research Study Group. N Engl J Med 1993; 329:977–986.
2. DCCT/EDIC Research Study Group. N Engl J Med 2005; 353:2643–2653.
3. DCCT Research Study Group. Ann Intern Med 1998; 128:517–523.
DCCT: C-peptide levels decrease with
increasing duration of T1DM
0.6
Basal C-peptide
Stimulated C-peptide
C-peptide (nmol/L)
0.5
0.4
0.3
0.2
0.1
0
1
2
3 4
5 6 7 8 9 10 11 12 13 14 15
Duration of T1DM (years)
Mean ± SEM basal (solid) and stimulated (stripes) C-peptide levels shown for 610 patients,
mean age 25 years (range 13–39 years). C-peptide levels measured following meal challenge
Reproduced with permission from DCCT Research Study Group. J Clin Endocrinol Metab 1987; 65:30–36.
DCCT: Intensive therapy preserves residual
β-cell function
1
Probability of maintaining
C-peptide > 0.2 pmol/mL
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Intensive therapy
0.2
0.1
Conventional therapy
0
Eligibility
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Number of patients in each treatment group who were evaluated
Intensive
138
131
80
53
32
8
2
Conventional
165
150
63
32
22
3
0
DCCT Research Study Group. Ann Intern Med 1998; 128:517–523.
Copyright © 1998 American Medical Association. All rights reserved.
HbA1c in T1DM is better with continuous
subcutaneous insulin infusion (CSII)
Study
SMD (random (95% CI)
Weight (%)
SMD (95% CI)
Berg 1998
Ciavarella 1985
DeVries 2002
Ziegler 1990
Oslo Study 1985–1988
Chiasson 1984
Hanaire-Broutin 2000
Home 1982
Hoogma 2006
Saurbrey 1988
Schiffrin 1982
Scmitz 1989
7.90
4.46
10.17
9.67
7.90
7.21
10.41
6.62
12.35
8.60
8.10
6.62
-0.92 (-1.64, -0.20)
-3.19 (-4.43, -1.95)
-0.81 (-1.28, -0.35)
0.16 (-0.36, 0.68)
-0.29 (-1.01, 0.42)
0.33 (-0.47, 1.13)
-0.56 (-1.00, -0.12)
-0.84 (-1.72, 0.04)
-0.22 (-0.40, -0.04)
0.00 (-0.64, 0.64)
-0.41 (-1.10, 0.28)
-1.36 (-2.24, -0.48)
Total (95% CI)
100.00
-0.55 (-0.87, -0.22)
-5.00 -4.00 -3.00 -2.00 -1.00
Favors CSII
0 1.00
2.00
Favors MDI
Jeitler K, et al. Diabetologia 2008; 51:941–951.
Incidence of severe hypoglycemia is reduced
with CSII
Study
Severe hypoglycemia rate ratio
Bode (poor control)
Bode (good control)
Kaderman
Maniatis
Rizvi
Litton
Linkeschova
Bruttomesso
Rudolph, Hirsch
Plotnik
Cohen
Hunger-Dathe
Weintrob
Weinzimer
McMahon
Siegel-Czarkowski
Alemzadeh
Mack-Fogg
Sciaffini
Rodrigues
Lepore
Hoogma
Overall (l 2 = 84.2%, P = 0.00)
0.5
Favors MDI
1.0
2.0
5.0
10
Favors CSII
Weight (%)
SMD (95% CI)
5.84
4.66
5.11
3.34
3.26
2.19
5.23
5.07
5.87
5.13
2.04
5.75
3.04
6.03
5.60
2.17
3.58
5.40
3.61
5.75
5.61
5.73
100.00
5.55 (3.57, 8.61)
10.50 (4.24, 26.01)
6.47 (3.09, 13.55)
1.29 (0.31, 5.42)
8.00 (1.84, 34.79)
5.75 (0.72, 45.97)
13.92 (6.95, 27.86)
3.44 (1.62, 7.33)
3.81 (2.49, 5.84)
2.18 (1.05, 4.52)
4.69 (0.52, 41.98)
3.62 (2.23, 5.85)
3.00 (0.62, 14.44)
2.11 (1.50, 2.96)
2.89 (1.67, 4.98)
7.07 (0.87, 57.46)
2.51 (0.67, 9.47)
2.09 (1.12, 3.92)
1.25 (0.34, 4.65)
35.41 (29.94, 57.15)
3.50 (2.04, 6.01)
2.50 (1.53, 4.08)
4.19 (2.86, 6.13)
25
Pickup JC & Sutton AJ. Diabet Med 2008; 25:765–774.
Reprinted by permission of John Wiley & Sons, Inc.
Initiation of insulin
The Global Partnership recommends:
Initiate basal-bolus regimen
as early as possible
Provide all patients with a
structured educational
programme at initiation of
insulin and thereafter
Aschner P, et al. Int J Clin Pract 2009: in press.
Adjusting insulin dosages: practical barriers
facing individuals with T1DM
• Patients must adjust insulin doses in response to many
factors to minimize risk of hypo- or hyperglycemia:
– carbohydrate intake, lifestyle, exercise, intercurrent illness
• Modification of insulin dosages based on diet and exercise
should be considered an essential part of patient education
– adapted to local diet and lifestyle
• Patients may not know the effect of factors such as exercise
or alcohol on glucose levels and need for appropriate
adjustment of insulin therapy
– 64% of patients with T1DM do not achieve recommended
physical activity levels due to barriers such as fear of
hypoglycaemia1,2
1. Brazeau AS, et al. Diabetes Care 2008; 31:2108–2109.
2. Plotnikoff RC, et al. Med Sci Sports Exerc 2006; 38:1526–1534.
Modification of insulin dosages based on
diet and exercise: DTTP study
HbA1c
Severe hypoglycemic
episodes
(events per patient-year)
10
HbA1c (%)
Severe hypoglycemia
9
8
7
6
5
Baseline
0.7
0.6
0.5
0.4
0.3
0.2
0.1
1 year
Mean difference: –0.7%
(95% CI –0.9 to –0.6%, P < 0.0001)
0
Baseline
1 year
Mean difference: −0.21 events per patient-year
(95% CI −0.32 to −0.11, P = 0.0001)
Dusseldorf Diabetes Treatment and Teaching Programme (DTTP): N = 9,583.
Samann A, et al. Diabetologia 2005; 48:1965–1970.
Precipitating causes of DKA
Precipitating factor
Percentage of cases
Infection
28–43%
Omission/reduction of insulin dose
13–45%
First presentation of diabetes
10–20%
Myocardial infarction
No cause identified
1%
<40%
Wallace TM & Matthews DR. QJM 2004; 97:773–780.
Reprinted by permission of Oxford University Press.
Self-monitoring blood glucose (SMBG):
a fundamental aspect of insulin therapy
• SMBG is so fundamental that insulin therapy should
always comprise insulin therapy plus SMBG
• Despite clear benefits, up to 64% of patients do not
regularly self-monitor1
• Barriers include patient motivation, psychological
barriers, cost, socioeconomic status, education
• Patients should receive appropriate training in
SMBG when insulin therapy is initiated and
periodically thereafter
1. DCCT/EDIC Research Study Group. Arch Intern Med 2009; 169:1307–1316.
SMBG ≥ 3-times per day associated with
better glycemic control in T1DM
Estimated HbA1c (%)
9.5
9.0
8.5
8.0
7.5
7.0
No utilization Less than
daily
Daily
At least
3x daily
Adjusted HbA1c by strip use (average strips per day)
Reproduced from Karter AJ, et al. Am J Med 2001; 111:1–9.
Copyright 2001 with permission from Elsevier.
HbA1c (%)
JDRF study: Sustained HbA1c lowering in
T1DM patients with HbA1c >7.0% using CGM
Treatment time (months)
JDRF CGM Study Group. Diabetes Care 2009; 32: 2047–2049.
HbA1c (%)
JDRF study: Maintained HbA1c with less hypoglycemia
in T1DM patients with HbA1c < 7.0% using CGM
Treatment time (months)
JDRF CGM Study Group. Diabetes Care 2009; 32: 2047–2049.
Self-monitoring of blood glucose
The Global Partnership recommends:
Ensure that self-monitoring is universally adopted
as an integral part of insulin therapy
Aschner P, et al. Int J Clin Pract 2009: in press.
Hypoglycemia: can affect many aspects of
care in T1DM
• In DCCT, severe hypoglycemia three times higher with intensive
vs conventional therapy1,2
• Almost one-third of patients who experience severe hypoglycemia
have a second episode within 4 months2
• Almost half of severe hypoglycemic episodes occur at night1
• Risk factors include strict glycemic control, prior episode of severe
hypoglycemia, longer duration of diabetes, autonomic neuropathy,
hypoglycemia unawareness
• In the DCCT, intensively treated patients with greater residual
β-cell function had a significantly lower rate of hypoglycemia vs
those with less/no residual β-cell function3
1. DCCT Research Study Group. Am J Med 1991; 90:450–459. 2. DCCT Research Group.
Diabetes 1997; 46:271–286. 3. Steffes M, et al. Diabetes Care 2003; 26:832–836.
DCCT: Risk of severe hypoglycemia versus
HbA1c in intensive and conventional groups
100
Rate per 100 years
80
60
40
20
Intensive
Conventional
0
5
6
7
8
9
10
11
12
13
14
HbA1c (%) during study
N = 1,441
DCCT Research Study Group. Diabetes 1997; 46:271–286.
Copyright 1997 American Diabetes Association. Reprinted with permission from The American Diabetes Association.
Incidence of hypoglycemia in the DCCT
Rate of hypoglycemia ± SE
per 100 participant-years*
14.0
12.0
10.0
8.0
6.0
4.0
2.0
0
Undetectable
Minimal
Baseline-only Sustained
Stimulated C-peptide group
*Both treatment groups (intensive and conventional therapy). Undetectable  0.03 nmol/L; minimal 0.04–0.20 nmol/L;
baseline-only (> 0.2 nmol/L at baseline, < 0.2 nmol/L thereafter); sustained (> 0.2 nmol/L at baseline and  1 year later).
Rates were compared (horizontally) between stimulated C-peptide groups. Rates between all groups were significantly
different (P < 0.05), except comparison between minimal and baseline-only group
Steffes M, et al. Diabetes Care 2003; 26:832–836.
Copyright 2003 American Diabetes Association. Reprinted with permission from The American Diabetes Association.
Effect of impaired awareness of hypoglycemia
in T1DM
100
2.5
80
2.0
60
1.5
40
1.0
20
0.5
0
0.0
Percentage
Number of events per year
Subjects (%)
Awareness of hypoglycemia:
Normal
Impaired
Events
Geddes J, et al. Diabetic Med 2008; 25:501–504.
Hypoglycemia
The Global Partnership recommends:
Provide education about prevention, recognition and
treatment of hypoglycemia at initiation of insulin therapy
and thereafter
Aschner P, et al. Int J Clin Pract 2009: in press.
Management of
CV risk factors
Higher absolute risk of CVD in T1DM at
younger age in men and women
MEN
WOMEN
Absolute CVD risk per 1000 person-years
Absolute CVD risk per 1000 person-years
T1DM
Without diabetes
T1DM
Without
diabetes
≤35 years
0.8 (0.4-1.6)
0.07 (0.02-0.2)
0.5 (0.2-1.3)
0.05 (0.01-0.2)
35-45 years
4.8 (3.2-7.1)
1.1 (0.8-1.6)
3.5 (2.1-6.1)
0.2 (0.09-0.6)
45-55 years
10.6 (7.3-15.2)
3.6 (2.8-4.7)
10.2 (6.7-15.5)
1.1 (0.6-1.9)
65-75 years
35.2 (21.6-57.5)
15.3 (11.3-20.8)
38.7 (24.1-62.3)
4.9 (2.8-8.4)
122.2 (69.4-215.2) 34.2 (23.1-50.6)
87.3 (39.2-194.3)
28.2 (18.0-44.2)
>75 years
Soedamah-Muthu SS, et al. Diabetes Care 2006; 29:798–804.
Copyright 2006 American Diabetes Association. Reprinted with permission from The American Diabetes Association.
Blood pressure, lipid and aspirin therapy
Study
SBP
mmHg
LDL-C
mmol/L (mg/dL)
On statins, %
On aspirin, %
ACCORD1,4
127/67
2.35 (91)
88
76
ADVANCE2,4
136/74
2.64 (102)
47
56
VADT3,4
127/68
2.07 (80)
84
87
SBP = systolic blood pressure; LDL-C = LDL-cholesterol
1. ACCORD Study Group. N Engl J Med 2008; 358:2545–2559.
2. ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560–2572.
3. Duckworth W, et al. N Engl J Med 2009; 360:129–139.
Managing cardiovascular risk factors
Patients with T1DM of
≥ 15 years’ duration and
aged >30 should be
considered at high risk of CVD
CDA. Can J Diabetes 2008; 32(Suppl. 1):S1–S201.
Other risk factors
The Global Partnership recommends:
Manage all CV risk factors
Aschner P, et al. Int J Clin Pract 2009: in press.
Psychological aspects
Depressive symptoms significantly related to
HbA1c in T1DM
Significant positive relationship between
BDI score and HbA1c
12
(r = 0.44, P < 0.02)
HbA1c (%)
11
10
9
8
7
6
0
5
10 15 20
Beck Depression Inventory (BDI) score
BDI score ≥16 indicates possible clinical depression
Reproduced with permission from Van Tilburg MA, et al. Psychosom Med 2001; 63:551–555.
Disordered eating behavior associated with higher risk
of retinopathy & nephropathy in young women with
T1DM
Diabetic retinopathy at
follow-up*
Abnormal urinary
albumin excretion
at follow-up
86% (6/7)
43% (3/7)
Moderately disordered
43% (6/14)
20% (3/15)
Nondisordered
24% (12/50)
18% (9/50)
Disordered-eating status
at baseline
Highly disordered
Values are % (n with complications/total n)
Mean age at baseline (±SD): 15±2 years (range 12–18)
Rydall AC, et al. N Engl J Med 1997; 336:1849–1854.
Copyright 1997 Massachusetts Medical Society. All rights reserved.
Psychological aspects of type 1 diabetes
The Global Partnership recommends:
Explore psychological issues associated with type 1
diabetes and treat/refer, as appropriate
Aschner P, et al. Int J Clin Pract 2009: in press.
Team approach to care
A multidisciplinary approach to care
• Many complexities involved in treating patients with T1DM
• Adopting a team approach that involves a broad range of
disciplines is essential
• Where possible, team should include: patient, diabetes
specialist, primary care physician, nurse, dietitian, podiatrist
and psychologist/psychiatrist, as well as family and friends.
• All members of the team should work together to ensure
continuity of care
Aschner P, et al. Int J Clin Pract 2009: in press.
A team approach to diabetes care
The Global Partnership recommends:
Adopt a multidisciplinary
team approach with shared
goals and recommendations
Aschner P, et al. Int J Clin Pract 2009: in press.
Practical recommendations for the
management of adults with T1DM
• Aim for as good glycemic control as possible while
minimizing the risk of hypoglycemia
• Ensure regular and appropriate monitoring for
complications
• Initiate basal-bolus regimen as early as possible
• Provide all patients with a structured educational
programme at initiation of insulin and thereafter
• Ensure that self-monitoring is universally adopted as
an integral part of insulin therapy
Aschner P, et al. Int J Clin Pract 2009: in press.
Practical recommendations for the
management of adults with T1DM
• Provide education about prevention, recognition and
treatment of hypoglycaemia at initiation of insulin
therapy and thereafter
• Manage all CV risk factors
• Explore psychological issues associated with T1DM
and treat/refer, as appropriate
• Adopt a multidisciplinary team approach with shared
goals and recommendations
Aschner P, et al. Int J Clin Pract 2009: in press.

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