Transcript Translating Clinical Trials Into Clinical Practice

Translating Clinical Trials Into
Clinical Practice
Cliff Bailey
on behalf of the
Global Partnership for Effective Diabetes Management
This slideset was developed in 2009 with support from GlaxoSmithKline
Translating clinical trials into clinical
practice
• Importance of good glycemic control
– More trials, more evidence
• Type 1: DCCT/EDIC
• Type 2: UKPDS, Steno-2, ADVANCE, VADT,
ACCORD, meta-analyses
• Guidelines and targets
• The 10 steps: treading carefully
• Recommendations for managing type 2 diabetes
Translating clinical trials into clinical
practice
• Importance of good glycemic control
– More trials, more evidence
• Type 1: DCCT/EDIC
• Type 2: UKPDS, Steno-2, ADVANCE, VADT,
ACCORD, meta-analyses
• Guidelines and targets
• The 10 steps: treading carefully
• Recommendations for managing type 2 diabetes
DCCT: intensive control reduces
complications in type 1 diabetes
Conventional versus intensive
insulin therapy (n = 1,441)
11
9
8
P < 0.001
7
6
Intensive treatment
(n = 711)
0
0
1
2
3
4
5
6
7
8
9
10
Reduction (%)
Conventional treatment
(n = 730)
10
HbA1c (%)
0
20
39%
40
54%
54%
60%
60
76%
80
Year of study
*Subdivided to primary and secondary prevention of retinopathy. Age 27 years, HbA 1c 8.8%.
Insulin dose (U/kg/d) 0.62 (primary), 0.71 (secondary).
DCCT Research Group. N Engl J Med 1993; 329:977–986.
DCCT/EDIC: long-term follow-up and
legacy effect
Glucose
similar
BUT CV
events
still
higher
HbA1C (%)
9
Conventional treatment
8
Intensive treatment
7
0
Cumulative incidence of
non-fatal MI, stroke or
death from CVD
1
0.06
Years
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
DCCT (intervention period)
EDIC (observational follow-up)
57% risk reduction in non-fatal MI, stroke or CVD death*
0.04
0.02
Conventional
treatment
Intensive
treatment
0
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)
*Intensive vs conventional treatment.
Years
DCCT Research Group. N Engl J Med 1993; 329:977–986.
Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.
Copyright Massachusetts Medical Society.
Translating clinical trials into clinical
practice
• Importance of good glycemic control
– More trials, more evidence
• Type 1: DCCT/EDIC
• Type 2: UKPDS, Steno-2, ADVANCE, VADT,
ACCORD, meta-analyses
• Guidelines and targets
• The 10 steps: treading carefully
• Recommendations for managing type 2 diabetes
Median HbA1C (%)
9
Conventional
8
Intensive
7
6.2% = upper limit of normal range
6
0
0
5
10
15
Relative risk reduction (%)
UKPDS: intensive control reduces
complications in type 2 diabetes
0
6%
–5
–10
12%
–15
P = 0.029
P = 0.44
16%
P = 0.052
–20
–25
–30
25%
P = 0.0099
UKPDS randomized years
Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853.
Copyright 1998 with permission from Elsevier.
UKPDS: long-term follow-up and legacy
effect
UKPDS
Active
Median HbA1c (%)
10
9
UKPDS
Follow-up
Conventional
Biochemical
data no
longer
collected
8
Intensive
7
6
0
1977
5
10
15
5
1997
10
2007
Relative risk reduction (%)
Intervention
ends
0
–5
9%
–10 P = 0.040
13%
15%
–15
P = 0.007
P = 0.014
–20
24%
–25
P = 0.001
–30
Years from randomization
Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.
Holman RR, et al. N Engl J Med 2008; 359:1577–1589.
Copyright © 2008. Reprinted by permission of SAGE.
Predictions from VADT: impact of bad
glycemic legacy
After entering VADT intensive
treatment arm
Before entering VADT intensive treatment arm
9.5
9.0
HbA1c (%)
Drives risk of
complications
Generation of a
‘bad glycemic
legacy’
8.5
8.0
7.5
7.0
6.5
6.0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Time since diagnosis (years)
Del Prato S. Diabetologia 2009; 52:1219–1226.
Reproduced with kind permission of Springer Science and Business Media.
Meta-analysis: impact of intensive glucose
control on coronary heart disease* events
Intensive treatment/standard
treatment
Odds ratio
(95% CI)
Odds ratio
(95% CI)
Participants
Events
UKPDS
3,071/1549
426/259
0.75 (0.54–1.04)
PROactive
2,605/2633
164/202
0.81 (0.65–1.00)
ADVANCE
5,571/5,569
310/337
0.92 (0.78–1.07)
892/899
77/90
0.85 (0.62–1.17)
5,128/5123
205/248
0.82 (0.68–0.99)
17,267/15,773
1,182/1,136
0.85 (0.77–0.93)
VADT
ACCORD
Overall
0.4
0.6
0.8
Intensive treatment better
1.0
1.2
1.4
1.6 1.8 2.0
Standard treatment better
*Included non-fatal myocardial infarction and death from all cardiac mortality.
Reproduced from Ray KK, et al. Lancet 2009; 373:1765–1772.
Copyright 1998 with permission from Elsevier.
?
ACCORD
Translating
Into
Clinical
Practice
Trials
ADVANCE
DCCT/EDIC
?
STENO-2
VADT
?
UKPDS
?
Translating clinical trials into clinical
practice
• Importance of good glycemic control
– More trials, more evidence
• Type 1: DCCT/EDIC
• Type 2: UKPDS, Steno-2, ADVANCE, VADT,
ACCORD, meta-analyses
• Guidelines and targets
• The 10 steps: treading carefully
• Recommendations for managing type 2 diabetes
HbA1c targets generally 6.5–7% when safe and appropriate
CDA (Canada)
HbA1c  7%
ADA (US)
HbA1c < 7%
AACE (US)
HbA1c  6.5%
NICE (UK)
HbA1c 6.5%/7.5%
Joint British
Societies (JBS 2)
HbA1c < 6.5%
APPG (Asia-Pacific)
HbA1c  6.5%
IDF (Europe)
HbA1c  6.5%
Australia
HbA1c  7%
ALAD (Latin America)
HbA1c < 6–7%
ADA. Diabetes Care 2009; 32(Suppl 1):S13–S61; American Association of Clinical Endocrinologists. Endocr Pract 2007; 13(Suppl. 1):1–68. IDF. Global
guideline for type 2 diabetes, IDF 2005. Available at: http://www.idf.org/Global_guideline. JBS2. Heart 2005; 91(Suppl. V):1–52. European Diabetes
Policy Group. Diabet Med 1999; 16:716–730. CDA. Can J Diabetes 2008; 32(Suppl. 1):S1–S201. NICE. 2009. Available at:
http://www.nice.org.uk/nicemedia/pdf/CG87ShortGuideline.pdf; ALAD. Rev Assoc Lat Diab 2000; Suppl. 1. Asian-Pacific Policy Group. Practical Targets
and Treatments (3rd Edn). Available at: http://www.idf.org/webdata/docs/T2D_practical_tt.pdf. NSW Health Department. The Principles of Diabetes Care
and Guidelines for the Clinical Management of Diabetes Mellitus in Adults. NSW Health Department 1996.
Current management often fails to
achieve glycemic targets
China
Latin America
Europe
(CODIC-2)1
HbA1c < 7.5%
(DEAL)3
HbA1c <7%
(CODE-2)5
HbA1c < 6.5%
32%
68%

31%
43%
57%
Canada
(DICE)2
HbA1c  7%

69%
US

(NHANES)4
HbA1c < 7%
37%
51%
49%

63%

1. Xingbao C. Chinese Health Economics 2003. Ling T. China Diabetic Journal 2003. 2. Harris SB, et al. Diabetes Res Clin Pract 2005; 70:90–97.
3. Lopez Stewart G, et al. Rev Panam Salud Publica 2007; 22:12–20. 4. Saydah SH, et al. JAMA 2004; 291:335–342.
5. Liebl A, et al. Diabetologia 2002; 45:S23–S28.
Translating clinical trials into clinical
practice
• Importance of good glycemic control
– More trials, more evidence
• Type 1: DCCT/EDIC
• Type 2: UKPDS, Steno-2, ADVANCE, VADT,
ACCORD, meta-analyses
• Guidelines and targets
• The 10 steps: treading carefully
• Recommendations for managing type 2 diabetes
Evolution of the ten steps to good
glucose control
www.effectivediabetesmanagement.com
Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.
Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.
Ten steps: reconsidering targets
Aim for good glycemic control, e.g. HbA1c
6.5–7%* when safe and appropriate
6.5–7%
Treat to achieve appropriate target HbA1c
within 6 months of diagnosis
After 3 months, if patients are not at target
HbA1c, consider combination therapy
Consider initiating combination therapy or
insulin for patients with HbA1c > 9%
*Or fasting/pre-prandial plasma glucose 110–130 mg/dl (6.0–7.2 mmol/l) where assessment of HbA1c
is not possible.
Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.
Ten steps: taking a multifactorial
approach
Appropriately manage all cardiovascular risk
factors
Implement a multidisciplinary team approach
that encourages patient self-management,
education and self-care, with shared
responsibilities to achieve goals
Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.
Ten steps: targeting the underlying
pathophysiology of type 2 diabetes
Address the underlying pathophysiology
of diabetes, including the treatment of
β-cell dysfunction and insulin resistance

 

IR
Use combinations of antihyperglycemic agents
with complementary mechanisms of action
Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.
Ten steps: monitoring regularly
Monitor HbA1c every 3 months
in addition to appropriate
glucose self-monitoring
Refer all newly diagnosed patients to a unit
specializing in diabetes care where possible
Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.
Translating clinical trials into clinical
practice
• Importance of good glycemic control
– More trials, more evidence
• Type 1: DCCT/EDIC
• Type 2: UKPDS, Steno-2, ADVANCE, VADT,
ACCORD, meta-analyses
• Guidelines and targets
• The 10 steps: treading carefully
• Recommendations for managing type 2 diabetes
Glycemic control: how intensive?
• Aim for:
–
HbA1c < 7% for younger, healthier, newly diagnosed
patients with compatible lifestyle, no
contraindications and no signs of hypoglycemia
• Consider lower (< 6.5%) if easy and safe
• Individualize
–
–
Existing guidelines are appropriate if applied
flexibly to fit individual circumstances
Type 2 diabetes is heterogeneous and progressive,
with multivariable pathogenic routes (treating a
moving target)
Glycemic control: how intensive?
• Early and durable
–
To avoid a vascular legacy of ‘hyperglycemic
memory’
• Intensive enough, but safely
–
–
To minimize complications without causing
hypoglycemic events
And to be practicable without undue imposition
• Integrated
–
Within a comprehensive program to reduce
cardiovascular risk