Transcript Slide set - MGSD - Mediterranean Group for the Study of Diabetes

Practical implementation of the
ADVANCE results in real life
Davide Carvalho
Centro Hospitalar S. João,
University of Porto Medical School ,
Portugal
12th Meeting of the Mediterranean Group for the Study
of Diabetes (MGSD)
Casablanca, April 29, 2011
Outline
What have we learned with ADVANCE trial?
Why the other Glycemic intensive control trials didn’t achieve
the aims ?
How to translate in clinical practice the results of ADVANCE
Trial
Diabetic vascular complications:
what is the A1c target?
Previous studies:
DCCT (1993) and UKPDS (1998) showed that a tighter
control of A1c helps to prevent diabetic complications
But the intention of these trials was to target
normal Blood Glucose and not A1c
What have we learned with ADVANCE trial?
A1c progressive and sustained reduction
10.0
Standard
Intensive (Gliclazide MR)
9.5
Mean HbA1c (%)
9.0
8.5
Δ 0.67% (95% CI 0.64 – 0.70); p<0.0001
8.0
Mean HbA1c
at final visit
7.5
7.3 %
7.0
6.5
6.5%
6.0
5.5
5.0
0
6
12
18
24 30 36 42 48
Follow-up (Months)
54
60
66
Gliclazide MR at the dose of 120 mg in 70% of patients
ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
What have we learned with ADVANCE trial?
Progressive and sustained blood glucose control
(6.5% of A1c)
Reduction of serious complications (-10% primary endpoint)
Kidney protection (-21% nephropathy, regression to
normoalbuminuria)
Reduction of CV risk markers (-30% in albuminuria)
Trend toward CV mortality reduction (-12%)
Safe and weight neutral
ADVANCE 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
ADVANCE Collaborative Group. IDF Annual Meeting, 2009. Canada, Montreal. Posters
What have we learned with ADVANCE trial?
Interaction data
Renal disease is reduced
by 33% (p=0.005)
Zoungas Diabetes Care 2009
Cardiovascular death is reduced
by 24% (p=0.04)
What have we learned with ADVANCE trial?
Conclusions on Joint effects
The effects of the 2 treatments were independent
of one another for all clinical outcomes
Where both treatments had a significant effect,
these effects were fully additive
Where only one treatment had a significant effect,
the second treatment preserved that effect
Multifactorial treatments including routine
blood pressure lowering and intensive glucose control
are indicated for all patients with type 2 diabetes
Outline
What have we learned with ADVANCE trial?
Why the other glycaemic intensive control trials didn’t achieve
the aims ?
How to translate in clinical pratice the results of ADVANCE Trial
ACCORD, ADVANCE and VADT trials
Similarities and differences
No. of participants
Age of participants (years)
Participants – men, (%)
Diabetes Duration at begining (years)
Baseline A1C ,%
Participants with previous CV events (%)
Follow-up,(years)
Results, intensive vs. standard
A1C, %
Death from any cause, %
Death from CV events, %
Non-fatal MI %
Non-fatal Stroke, %
New or worsening Nephropaty, %
Severe/Major hypoglycemias , %
Weight gain, kg
ACCORD
10,251
62
62
10
8.1
35
3.4
ADVANCE
11,140
66
58
8
7.2
32
5.0
VADT
1,791
60
97
11.5
9.4
40
6
6.4 vs. 7.5
5.0 vs. 4.0
2.6 vs. 1.8
3.6 vs. 4.6
1.3 vs. 1.2
NA
10.5 vs. 3.5
3.5 vs. 0.4
6.5 vs. 7.3*
8.9 vs. 9.6
4.5 vs. 5.2
2.7 vs. 2.8
3.8 vs. 3.8
4.1 vs. 5.2
2.7 vs. 1.5
0.7 vs. - 0.0
6.9 vs. 8.4
NA
2.1 vs. 1.7
6.1 vs. 6.3
2.0 vs. 3.1
NA
21.1 vs. 9.7
NA
* Mean A1c
Morbidity-mortality study:
ACCORD (2008)
Morbidity-mortality study in type 2 diabetic patient
aiming at HbA1c 6%
Increase in total mortality (HR 1.22, p=0.04)
Non significant reduction in the primary end point
Significant increase in cardiovascular mortality
Reasons for increased mortality ?
too sharp decrease in HbA1c ?
hypoglycemic events ?
adverse events related to the choice of drugs ?
ADVANCE/ACCORD debate
ADVANCE
vs
ACCORD
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 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
ADVANCE, ACCORD and VADT trials
Incidence of severe hypoglycemic events according to the type of control
ADVANCE1
ACCORD2
100 patients/year
100 patients/year
100 patients/year
12
9
6
3
15
12
9
6
3.2
3
1.0
Severe hypoglycemic events
15
Severe hypoglycemic events
15
Severe hypoglycemic events
VADT3
12.0
12
9
6
4.0
3
0.6
0.3
0
0
0
Standard
Intensive
P<0.001
Standard
Intensive
P<0.001
Standard Intensive
P<0,01
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: 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.
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
ACCORD
Hypoglycaemia and A1c
Standard therapy
Intensive therapy
Incidence per 100 person years
6
5
4
3
2
1
0
6.0
7.0
8.0
Updated average HbA1C
Adapted from Bonds D., data presented at ADA 2009
9.0
Glycemic instability precedes severe hypoglycemia
48 h before Severe
Hypoglycemia,
glycemic instability
increases
Kovatchev et al, J Clin Endocrinol Metab 2000;85:4287-92
Different issues between ACCORD and ADVANCE
Results at the end of follow up in the intensive
glucose lowering arms of ADVANCE and ACCORD studies
ADVANCE
ACCORD
Median HbA1c
6.4 %
6.4 %
Severe hypoglycemias
2.5 %
16.2 %
% of drugs prescribed
secretagogues
metformin
glitazones
insulin
92 %
74 %
17 %
40%
Gliclazide MR
87 %
95 %
92 %
77%
Glibenclamide
Glimepiride
Outline
What have we learned with ADVANCE trial?
Why the other Glycemic intensive control trials didn’t achieve
the aims ?
How to translate in clinical practice the results of ADVANCE
Trial
How to translate in clinical practice the results of ADVANCE Trial
Population representative of a daily practice
Baseline characteristics:
Age 66 years
HbA1c 7.5%
BMI 28 kg/m2
SBP 145 mm Hg
Duration of diabetes 8 years
Past history of macrovascular disease 32%
microvascular disease 10%
How to translate in clinical practice the results of ADVANCE Trial
Intensive 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 Trial
Methods for achieving intensive glucose control target
Additional drug treatments
Increase dose of gliclazide MR
Add/increase dose of other oral agents (metformin,
thiazolidinedione, -glucosidase inhibitor)
Low-dose insulin (bedtime or mealtime)
Full-dose insulin
Additional non-drug interventions
Home glucose monitoring, regular dietician review, more
frequent follow-up, etc
ADVANCE intensive glucose control
strategy
Other SUs
No drug
Initiation
Switch
Metformin
Add-on
Gliclazide MR
30 mg
Drug titration at physician’s discretion
based on HbA1c and FBG levels
60 mg
Progressively maximize the dose
90 mg
HbA1c target
6.5%
120 mg
Add other OADs
Add insulin
70% of the patients
How to translate in clinical practice the results of ADVANCE Trial
Rationale for the choice of Gliclazide MR
Innovative formulation for an effective 24-hour coverage
in a single intake at breakfast 1
Effective and long-lasting glycemic control 2,3,4
Well tolerated even at higher doses 2,3
Antioxidant properties and direct vascular protection 5,6,7
1. Guillausseau PJ and Greb W. Diabetes Metab. 2001;27:133-137 - 2. Schernthaner G, et al. Eur J Clin Invest. 2004;34:535-542
3. 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
How to translate in clinical practice the results of
ADVANCE Trial - Compliance
A major issue in type 2 diabetes
"Keep a watch also on the faults of the patients,
which often make them lie about the taking of things
prescribed.“
Hippocrate
How to translate in clinical practice the results of ADVANCE Trial
The less the number of intake, the better the compliance
Guillausseau PJ, Diabetes Metab 2003
Practical implementation of the ADVANCE results in real life
Conclusions
Place of Gliclazide MR in practice
A pragmatic approach to glucose control
Intensified Glucose Control maintained in the long term
Reduced serious complications, primarily renal disease
With low rates of hypoglycemia and no weight gain
Thanks to the full range of doses up to 120 mg daily
An intensive regimen based on Gliclazide MR is a suitable
treatment for routine implementation in daily clinical practice