translating clinical trials into clinical practice cliff bailey on behalf of the global partnership...
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Translating Clinical Trials Into Clinical Practice
Cliff Baileyon 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
*Subdivided to primary and secondary prevention of retinopathy. Age 27 years, HbA1c 8.8%.Insulin dose (U/kg/d) 0.62 (primary), 0.71 (secondary).
Conventional versus intensive insulin therapy (n = 1,441)
Mic
ro-
a
lbum
inur
ia
Nep
hrop
athy
Ret
inop
athy
*
0
20
40
60
80
Red
uct
ion
(%
)
Neu
ropa
thy
76%
60%
54%
39%
54%
0
0 1 2 3 4 5 6 7 8 9 10
Year of study
Hb
A1c
(%
)
Conventional treatment (n = 730)
Intensive treatment (n = 711)
P < 0.001
6
7
8
9
10
11
DCCT Research Group. N Engl J Med 1993; 329:977–986.
57% risk reduction in non-fatal MI, stroke or CVD death*
Intensivetreatment
Cu
mu
lati
ve i
nci
de
nce
o
f n
on
-fat
al M
I, s
tro
ke o
r d
eath
fro
m C
VD
Conventionaltreatment
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years
0.06
0.04
0.02
0
DCCT (intervention period) EDIC (observational follow-up)
*Intensive vs conventional treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986.Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.
0
7
1 6
Hb
A1
C (
%)
9
8
2 3 4 5 7 8 9
Conventional treatment
Intensive treatment
11 12 13 14 15 16 1710DCCT (intervention period)
YearsEDIC (observational follow-up)
DCCT/EDIC: long-term follow-up and legacy effect
Glucose similar BUT CV events
still higher
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
Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853.
UKPDS randomized years
06
7
8
9
0 5 10 15
Conventional
Intensive
6.2% = upper limit of normal rangeMe
dia
n H
bA
1C (
%)
UKPDS: intensive control reduces complications in type 2 diabetes
All-
caus
e
mor
talit
y
Any
dia
bete
s-
rela
ted
end
poin
tM
icro
vasc
ular
dise
ase
Myo
card
ial
infa
rctio
n
–30
–25
–20
–15
–10
–5
0
Re
lati
ve
ris
k r
edu
cti
on
(%
)
12%
25%
16%
6%
P = 0.029
P = 0.0099
P = 0.052
P = 0.44
Copyright 1998 with permission from Elsevier.
–30
–25
–20
–15
–10
–5
0
Rel
ativ
e ri
sk r
edu
ctio
n (
%)
All-
caus
e
mor
talit
y
Any
dia
bete
s-
rela
ted
end
poin
tM
yoca
rdia
l
infa
rctio
n
Mic
rova
scul
ar
dise
ase
9%
24%
15%
13%P = 0.040
P = 0.001
P = 0.014 P = 0.007
UKPDS: long-term follow-up and legacy effect
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.
10
9
8
7
6
0 5 10 15 5 10 1977 1997 2007 Years from randomization
UKPDS
Active
Conventional
Intensive
Intervention ends UKPDS
Follow-up
Med
ian
Hb
A1c
(%)
Biochemical data no longer
collected
Copyright © 2008. Reprinted by permission of SAGE.
Predictions from VADT: impact of bad glycemic legacy
Del Prato S. Diabetologia 2009; 52:1219–1226.
Time since diagnosis (years)
Hb
A1
c (%
)
1 2 3 8 9 12 1364 5 10 11 14 157 16 17
9.0
8.5
8.0
7.5
7.0
6.5
6.0
9.5 Drives risk ofcomplications
Before entering VADT intensive treatment arm After entering VADT intensivetreatment arm
Generation of a‘bad glycemic
legacy’
Reproduced with kind permission of Springer Science and Business Media.
Meta-analysis: impact of intensive glucose control on coronary heart disease* events
Reproduced from Ray KK, et al. Lancet 2009; 373:1765–1772.
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)
VADT 892/899 77/90 0.85 (0.62–1.17)
ACCORD 5,128/5123 205/248 0.82 (0.68–0.99)
Overall 17,267/15,773 1,182/1,136 0.85 (0.77–0.93)
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Intensive treatment better Standard treatment better
*Included non-fatal myocardial infarction and death from all cardiac mortality.
Copyright 1998 with permission from Elsevier.
Clinical Trials
Translating
Clinical Practice
Into
ACCORD
ADVANCE
VADT UKPDS
STENO-2
DCCT/EDIC
?
?
?
?
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
ADA (US)
HbA1c < 7%
IDF (Europe)
HbA1c 6.5%
CDA (Canada)
HbA1c 7%
NICE (UK)
HbA1c 6.5%/7.5%
AACE (US)
HbA1c 6.5% ALAD (Latin America)
HbA1c < 6–7%
APPG (Asia-Pacific)
HbA1c 6.5%
Australia
HbA1c 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.
Joint British Societies (JBS 2)
HbA1c < 6.5%
Current management often fails to achieve glycemic targets
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.
US(NHANES)4
HbA1c < 7%
37%
63%
Europe(CODE-2)5
HbA1c < 6.5%
31%
69%Canada(DICE)2
HbA1c 7%
51%
49%
China(CODIC-2)1
HbA1c < 7.5%
68%32%
Latin America(DEAL)3
HbA1c <7%
43%
57%
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
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.www.effectivediabetesmanagement.com
Ten steps: reconsidering targets
Aim for good glycemic control, e.g. HbA1c 6.5–7%* when safe and appropriate
*Or fasting/pre-prandial plasma glucose 110–130 mg/dl (6.0–7.2 mmol/l) where assessment of HbA 1c is not possible.
6.5–7%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%
Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.
Ten steps: taking a multifactorial approach
Appropriately manage all cardiovascular risk factors HbA1c
FPG TC
LDLHDL
TGsSBP
DBPABPM
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
IRIR
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