practical implementation of the advance results in real life davide carvalho centro hospitalar s....
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Practical implementation of the Practical implementation of the ADVANCE results in real lifeADVANCE results in real life
Davide CarvalhoDavide CarvalhoCentro Hospitalar S. João, Centro Hospitalar S. João,
University of Porto Medical School , University of Porto Medical School , PortugalPortugal
1212thth Meeting of the Mediterranean Group for the Study Meeting of the Mediterranean Group for the Study of Diabetes (MGSD)of Diabetes (MGSD)
Casablanca, April 29, 2011Casablanca, April 29, 2011
Outline
What have we learned with ADVANCE trial?What have we learned with ADVANCE trial?
Why the other Glycemic intensive control trials didn’t achieve Why the other Glycemic intensive control trials didn’t achieve the aims ?the aims ?
How to translate in clinical practice the results of ADVANCE How to translate in clinical practice the results of ADVANCE TrialTrial
Diabetic vascular complications:what is the A1c target?
Previous studies:Previous studies:DCCT (1993) and UKPDS (1998) showed that a tighter DCCT (1993) and UKPDS (1998) showed that a tighter control of A1c helps to prevent diabetic complicationscontrol of A1c helps to prevent diabetic complications
But the intention of these trials was to targetnormal Blood Glucose and not A1c
What have we learned with ADVANCE trial?A1c progressive and sustained reduction
Gliclazide MR at the dose of 120 mg in 70% of patientsADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
Mean HbA1c
at final visit
Mea
n Hb
A1c
(%)
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Follow-up (Months)0 6 12 18 24 30 36 42 48 54 60 66
7.3 %
6.5%
Δ 0.67% (95% CI 0.64 – 0.70); p<0.0001
StandardIntensive (Gliclazide MR)
What have we learned with ADVANCE trial?
Progressive and sustained blood glucose control Progressive and sustained blood glucose control (6.5% of A1c)(6.5% of A1c)
Reduction of serious complications Reduction of serious complications (-10% primary endpoint)(-10% primary endpoint)
Kidney protection Kidney protection (-21% nephropathy, regression to (-21% nephropathy, regression to normoalbuminuria)normoalbuminuria)
Reduction of CV risk markers Reduction of CV risk markers (-30% in albuminuria)(-30% in albuminuria)
Trend toward CV mortality reduction Trend toward CV mortality reduction (-12%)(-12%)
Safe and weight neutralSafe and weight neutralADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
What have we learned with ADVANCE trial?Efficient glycemic control whatever the patient profile
Gliclazide MR always provides an efficient glycemic control Gliclazide MR always provides an efficient glycemic control
ADVANCE Collaborative Group. IDF Annual Meeting, 2009. Canada, Montreal. Posters
Zoungas Diabetes Care 2009
1.02
0.820.84
0.680.6
0.8
1.0
1.2
P for interaction=0.93
RRR 33%P=0.005
Pre
tera
x
DIA
MIC
RO
N M
R
1.02
0.820.84
0.680.6
0.8
1.0
1.2
P for interaction=0.93
RRR 33%P=0.005
Pre
tera
x
DIA
MIC
RO
N M
R
1.14
1.02
0.89
0.870.7
0.9
1.1
1.3
P for interaction=0.62
1.14
1.02
0.89
0.87
RRR 24%P=0.04
Pre
tera
x
DIA
MIC
RO
N M
R
1.14
1.02
0.89
0.870.7
0.9
1.1
1.3
P for interaction=0.62
1.14
1.02
0.89
0.87
RRR 24%P=0.04
Pre
tera
x
DIA
MIC
RO
N M
RCardiovascular death is reduced
by 24% (p=0.04)Renal disease is reduced
by 33% (p=0.005)
What have we learned with ADVANCE trial?Interaction data
Multifactorial treatments including routineblood pressure lowering and intensive glucose control
are indicated for all patients with type 2 diabetes
What have we learned with ADVANCE trial?Conclusions on Joint effects
The effects of the 2 treatments were independent The effects of the 2 treatments were independent of one another for all clinical outcomes of one another for all clinical outcomes
Where both treatments had a significant effect, Where both treatments had a significant effect, these effects were fully additive these effects were fully additive
Where only one treatment had a significant effect, Where only one treatment had a significant effect, the second treatment preserved that effectthe second treatment preserved that effect
Outline
What have we learned with ADVANCE trial?What have we learned with ADVANCE trial?
Why the other glycaemic intensive control trials didn’t achieve Why the other glycaemic intensive control trials didn’t achieve the aims ?the aims ?
How to translate in clinical pratice the results of ADVANCE TrialHow to translate in clinical pratice the results of ADVANCE Trial
ACCORD, ADVANCE and VADT trials Similarities and differences
ACCORD ADVANCE VADTNo. of participants 10,251 11,140 1,791Age of participants (years) 62 66 60Participants – men, (%) 62 58 97Diabetes Duration at begining (years) 10 8 11.5Baseline A1C ,% 8.1 7.2 9.4Participants with previous CV events (%)
35 32 40
Follow-up,(years) 3.4 5.0 6Results, intensive vs. standard
A1C, % 6.4 vs. 7.5 6.5 vs. 7.3* 6.9 vs. 8.4 Death from any cause, % 5.0 vs. 4.0 8.9 vs. 9.6 NA Death from CV events, % 2.6 vs. 1.8 4.5 vs. 5.2 2.1 vs. 1.7 Non-fatal MI % 3.6 vs. 4.6 2.7 vs. 2.8 6.1 vs. 6.3 Non-fatal Stroke, % 1.3 vs. 1.2 3.8 vs. 3.8 2.0 vs. 3.1 New or worsening Nephropaty, % NA 4.1 vs. 5.2 NA Severe/Major hypoglycemias , % 10.5 vs. 3.5 2.7 vs. 1.5 21.1 vs. 9.7Weight gain, kg 3.5 vs. 0.4 0.7 vs. - 0.0 NA* Mean A1c
Morbidity-mortality study:ACCORD (2008)
Morbidity-mortality study in type 2 diabetic patient Morbidity-mortality study in type 2 diabetic patient aiming at HbAaiming at HbA1c1c 6%6%
Increase in total mortality (HR 1.22, p=0.04)Increase in total mortality (HR 1.22, p=0.04)
Non significant reduction in the primary end pointNon significant reduction in the primary end point
Significant increase in cardiovascular mortalitySignificant increase in cardiovascular mortality
Reasons for increased mortality ? Reasons for increased mortality ? too sharp decrease in HbAtoo sharp decrease in HbA1c1c ? ?
hypoglycemic events ?hypoglycemic events ?adverse events related to the choice of drugs ? adverse events related to the choice of drugs ?
ACCORDACCORDvsvs
ADVANCE/ACCORD debate
ADVANCEADVANCE
ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ACCORD Study Group. Diabetes Care 2010; 33:983–990
Participants who were unable to reduce A1C after initiation of the intensive strategy and continued to have average A1C > 7% seemed to be at greater risk
ADVANCE: N Engl J Med 2008; 358, 2560-2572. ACCORD: N Engl J Med 2008; 358, 2545-2559. VADT: N Engl J Med 2009;360:129-39.
Standard Intensive
P<0.001 P<0,01P<0.001
100 patients/year
0.3 0.6
4.0
12.0
3
6
9
12
15
VADT3ACCORD2ADVANCE1
100 patients/year
1.0
0
100 patients/year
Severe
hypogly
cem
ic e
ven
ts
3
6
9
12
15
0
3
6
9
12
15
0
3.2
Standard Intensive Standard Intensive
Major hypoglycaemia was uncommon in ADVANCE and only reported in 231 patients among 11,140 followed for 5 years, 150 in intensive group and 81 in standard control group
ADVANCE, ACCORD and VADT trialsIncidence of severe hypoglycemic events according to the type of control
Severe
hypogly
cem
ic e
ven
ts
Severe
hypogly
cem
ic e
ven
ts
All cause mortality according to A1c in the ACCORD Trial
RIDDLE MC, et al .Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial. Diabetes Care 33:983–990, 2010
ACCORDHypoglycaemia and A1c
6
5
4
3
2
1
06.0 7.0 8.0 9.0
Updated average HbA1C
Inci
dence
per
100 p
ers
on
years
Standard therapyIntensive therapy
Adapted from Bonds D., data presented at ADA 2009
Kovatchev et al, J Clin Endocrinol Metab 2000;85:4287-92
Glycemic instability precedes severe hypoglycemia
48 h before Severe Hypoglycemia, glycemic instability increases
Different issues between ACCORD and ADVANCE
87 %
95 %
92 %
77%
92 %
74 %
17 %
40%
% of drugs prescribed
secretagogues
metformin
glitazones
insulin
16.2 %2.5 %Severe hypoglycemias
6.4 %6.4 %Median HbA1c
ACCORDADVANCE
Results at the end of follow up in the intensiveglucose lowering arms of ADVANCE and ACCORD studies
Gliclazide MR GlibenclamideGlimepiride
Outline
What have we learned with ADVANCE trial?What have we learned with ADVANCE trial?
Why the other Glycemic intensive control trials didn’t achieve Why the other Glycemic intensive control trials didn’t achieve the aims ?the aims ?
How to translate in clinical practice the results of ADVANCE How to translate in clinical practice the results of ADVANCE TrialTrial
How to translate in clinical practice the results of ADVANCE TrialPopulation representative of a daily practice
Baseline characteristics: Baseline characteristics: Age 66 yearsAge 66 years
HbAHbA1c1c 7.5% 7.5%
BMI 28 kg/mBMI 28 kg/m22
SBP 145 mm HgSBP 145 mm Hg
Duration of diabetes 8 yearsDuration of diabetes 8 years
Past history of macrovascular disease Past history of macrovascular disease 32%32% microvascular disease 10% microvascular disease 10%
How to translate in clinical practice the results of ADVANCE TrialIntensive glucose control (at start of the study)
Gliclazide MR—based therapy with a target HbA1C of 6.5% or less
HbA1c 6.5% (target level):Maintain current therapy
HbA1c 6.5%-7.5%Maintain or titrate up existing therapy
HbA1c 7.5% (Threshold level) Titrate up existing therapy and/or introduce additional therapy
Unrestricted use of other glucose-lowering agents (except sulfonylureas)
How to translate in clinical practice the results of ADVANCE TrialMethods for achieving intensive glucose control target
Additional drug treatmentsAdditional drug treatmentsIncrease dose of gliclazide MRIncrease dose of gliclazide MRAdd/increase dose of other oral agents (metformin, Add/increase dose of other oral agents (metformin,
thiazolidinedione, thiazolidinedione, -glucosidase inhibitor) -glucosidase inhibitor) Low-dose insulin (bedtime or mealtime)Low-dose insulin (bedtime or mealtime)Full-dose insulinFull-dose insulin
Additional non-drug interventionsAdditional non-drug interventions Home glucose monitoring, regular dietician review, more Home glucose monitoring, regular dietician review, more
frequent follow-up, etc frequent follow-up, etc
Gliclazide MR
Drug titration at physician’s discretion based on HbA1c and
FBG levels
No drugOther SUs Metformin
Initiation Add-onSwitch
Add other OADs
Add insulin
Progressively maximize the dose
70% of the patients
60 mg
90 mg
120 mg
30 mg
HbA1c target6.5%
ADVANCE intensive glucose control strategy
1. Guillausseau PJ and Greb W. Diabetes Metab. 2001;27:133-137 - 2. Schernthaner G, et al. Eur J Clin Invest. 2004;34:535-5423. data on file - 4. Satoh J, et al. Diabetes Res Clin Pract. 2005;70:291-297 - 5. O’Brien RC , et al. J Diabetes Complications.2000;14:201-206 - 6. Katakami N, et al. Diabetologia. 2004;47:1906-1913 - 7. Johnsen SP, et al. Am J Ther. 2006;13:134-140
Innovative formulation for an effective 24-hour coverageInnovative formulation for an effective 24-hour coveragein a single intake at breakfast in a single intake at breakfast 11
Effective and long-lasting glycemic control Effective and long-lasting glycemic control 2,3,42,3,4
Well tolerated even at higher doses Well tolerated even at higher doses 2,32,3
Antioxidant properties and direct vascular protection Antioxidant properties and direct vascular protection 5,6,75,6,7
How to translate in clinical practice the results of ADVANCE TrialRationale for the choice of Gliclazide MR
How to translate in clinical practice the results of ADVANCE Trial - Compliance
"Keep a watch also on the faults of the patients,
which often make them lie about the taking of things
prescribed.“
Hippocrate
A major issue in type 2 diabetes
How to translate in clinical practice the results of ADVANCE TrialThe less the number of intake, the better the compliance
Guillausseau PJ, Diabetes Metab 2003
Practical implementation of the ADVANCE results in real life Conclusions
A pragmatic approach to glucose controlA pragmatic approach to glucose control
Intensified Glucose Control maintained in the long termIntensified Glucose Control maintained in the long term
Reduced serious complications, primarily renal diseaseReduced serious complications, primarily renal disease
With low rates of hypoglycemia and no weight gainWith low rates of hypoglycemia and no weight gain
Thanks to the full range of doses up to 120 mg dailyThanks to the full range of doses up to 120 mg daily
An intensive regimen based on Gliclazide MR is a suitabletreatment for routine implementation in daily clinical practice
Place of Gliclazide MR in practice