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