12 th meeting of the mediterranean group for the study of diabetes mgsd casablanca april 29 2011
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Practical implementation of the ADVANCE results in real life Davide Carvalho Centro Hospitalar S. João, University of Porto Medical School , Portugal. 12 th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD) Casablanca, April 29, 2011. Outline.

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12 th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD) Casablanca, April 29, 2011

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12 th meeting of the mediterranean group for the study of diabetes mgsd casablanca april 29 2011

Practicalimplementation of the ADVANCE results in real lifeDavide CarvalhoCentro Hospitalar S. João, University of Porto MedicalSchool , Portugal

12th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD)

Casablanca, April 29, 2011


Outline

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 a 1c target

Diabetic vascular complications:what is the A1ctarget?

Previousstudies:DCCT (1993) and UKPDS (1998) showedthat a tighter control of A1c helps to preventdiabetic complications

But the intention of these trials was to targetnormal Blood Glucose and not A1c


What have we learned with advance trial a 1c progressive and sustained reduction

What have we learned with ADVANCE trial?A1cprogressive and sustained reduction

10.0

Standard

Intensive (Gliclazide MR)

9.5

9.0

8.5

Δ 0.67% (95% CI 0.64 – 0.70); p<0.0001

Mean HbA1cat final visit

8.0

Mean HbA1c (%)

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

54

60

66

Follow-up (Months)

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

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

What have we learned with ADVANCE trial?Efficient glycemic control whatever the patient profile

  • Gliclazide MR alwaysprovides an efficient glycemic control

ADVANCE Collaborative Group.IDF Annual Meeting, 2009. Canada, Montreal. Posters


What have we learned with advance trial interaction data

What have we learned with ADVANCE trial?Interaction data

Cardiovascular death is reduced by 24% (p=0.04)

Renal disease is reduced by 33% (p=0.005)

Zoungas Diabetes Care 2009


What have we learned with advance trial conclusions on joint effects

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 routineblood pressure lowering and intensive glucose controlare indicated for all patients with type 2 diabetes


Outline1

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

ACCORD, ADVANCE and VADT trials Similarities and differences

* Mean A1c


Morbidity mortality study accord 2008

Morbidity-mortality study:ACCORD (2008)

Morbidity-mortalitystudy in type 2 diabetic patient aimingat HbA1c6%

Increase in total mortality (HR 1.22, p=0.04)

Non significantreduction in the primary end point

Significantincrease in cardiovascularmortality

Reasons for increasedmortality ?

toosharpdecrease in HbA1c ?

hypoglycemicevents ?

adverse eventsrelated to the choice of drugs ?


Advance accord debate

ADVANCE

ACCORD

vs

ADVANCE/ACCORD debate

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

ACCORD Study Group.Diabetes Care 2010; 33:983–990

ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.

ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

ADVANCE, ACCORD and VADT trialsIncidence of severe hypoglycemic events according to the type of control

ADVANCE1

ACCORD2

VADT3

100 patients/year

100 patients/year

100 patients/year

15

15

15

12.0

12

12

12

9

9

9

Severe hypoglycemic events

Severe hypoglycemic events

Severe hypoglycemic events

6

6

6

4.0

3.2

3

3

3

1.0

0.6

0.3

0

0

0

Standard

Intensive

Standard

Intensive

Standard

Intensive

P<0.001

P<0.001

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

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 a 1c

ACCORDHypoglycaemia and A1c

Standard therapy

Intensive therapy

6

5

4

Incidence per 100 person years

3

2

1

0

6.0

7.0

8.0

9.0

Updated average HbA1C

Adapted from Bonds D., data presented at ADA 2009


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

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

Different issues between ACCORD and ADVANCE

ADVANCE

ACCORD

Median HbA1c

6.4 %

6.4 %

Severe hypoglycemias

2.5 %

16.2 %

% of drugs prescribed

secretagogues

metformin

glitazones

insulin

87 %

95 %

92 %

77%

92 %

74 %

17 %

40%

Results at the end of follow up in the intensiveglucose lowering arms of ADVANCE and ACCORD studies

Glibenclamide

Glimepiride

Gliclazide MR


Outline2

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


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

How to translate in clinical practice the results of ADVANCE TrialPopulation 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

Pasthistory of macrovasculardisease 32%microvasculardisease 10%


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

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)


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

How to translate in clinical practice the results of ADVANCE TrialMethods 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

30 mg

60 mg

90 mg

70% of the patients

120 mg

ADVANCE intensive glucose control strategy

Other SUs

Metformin

No drug

Initiation

Add-on

Switch

Gliclazide MR

Drug titration at physician’s discretion based on HbA1c and FBG levels

Progressively maximize the dose

HbA1c target6.5%

Add other OADs

Add insulin


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

Innovative formulation for an effective 24-hour coveragein 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

How to translate in clinical practice the results of ADVANCE Trial

Rationale for the choice of Gliclazide MR

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


How to translate in clinical practice the results of advance trial compliance

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


Practical implementation of the advance results in real life davide carvalho centro hospitalar s jo o university of

How to translate in clinical practice the results of ADVANCE Trial

The less the number of intake, the better the compliance

GuillausseauPJ, Diabetes Metab 2003


Practical implementation of the advance results in real life conclusions

Practical implementation of the ADVANCE results in real life Conclusions

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

Place of Gliclazide MR in practice

An intensive regimen based on Gliclazide MR is a suitabletreatment for routine implementation in daily clinical practice


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