ueda2012 advance trial-d.salah

ADVANCE trial : the ADVANCE trial : the present and the futurepresent and the future

Salah SHELBAYA, MDSalah SHELBAYA, MDProfessor of Diabetology, Professor of Diabetology,

Ain Shams UniversityAin Shams University

OutlineOutline

ADVANCEADVANCE in the context of megatrials. in the context of megatrials.

Lessons from Lessons from ADVANCEADVANCE trial. trial.

Gliclazide MR, Gliclazide MR, the best treatment strategy.the best treatment strategy.

ADVANCEADVANCE what’s next?what’s next?

Global projections for Diabetes 2007-2030Global projections for Diabetes 2007-2030

A worldwide increasing epidemic over the upcoming yearsA worldwide increasing epidemic over the upcoming years

+54%+54%

IDF, Diabetes Atlas, 4th edition, 2009

438 million diabetics438 million diabetics

2/3 of People With Diabetes Die of CVD2/3 of People With Diabetes Die of CVD

Adapted from Alexander CM, Antonello S Pract Diabet 2002;21:21-28.

Among people with diabetes, macro-vascular complications (including CHD, stroke & peripheral

vascular disease) are the leading causes of morbidity and mortality.

67%

CHD, stroke & peripheral vascular disease.Other.

Causes of mortality in diabetics

In the context of megatrialsIn the context of megatrials

Megatrials in diabetesMegatrials in diabetes

1998 June 2008 Sept 2008 2009

UKPDSUKPDSN=3867N=3867

ACCORDACCORDN=10,251N=10,251

ADVANCEADVANCEN=11,240N=11,240

UKPDSUKPDSLong-term follow-upLong-term follow-up

VADT VADT N=1791N=1791

CONTROLmeta-analysisN=27,049

The UKPDSThe UKPDS

The UKPDSThe UKPDS

The main effect in the UKPDS was the reduction of The main effect in the UKPDS was the reduction of microvascular complications by 25% mainly due to the microvascular complications by 25% mainly due to the

reduction in retinopathy “need for retinal reduction in retinopathy “need for retinal photocoagulation”photocoagulation”

UKPDS Group. Lancet. 1998;352:837-853

The ACCORD trialThe ACCORD trial

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

+35%

ACCORD trial was prematurely interrupted because of excess mortality among intensively treated patients

CONTROL meta-analysisCONTROL meta-analysis

Only ADVANCE decreases overall and cardiovascular mortality.Only ADVANCE decreases overall and cardiovascular mortality.

Turnbull FM. Diabetologia. Epub Aug 5 2009

Evidence-based medicine shaped the new IDF algorithmEvidence-based medicine shaped the new IDF algorithm

www.idf.org/treatment-algorithm-people-type-2-diabetes

ADVANCEADVANCE the largest trial in T2DMthe largest trial in T2DM

ADVANCEADVANCE the largest trial in T2DMthe largest trial in T2DM

11 140 patients, 215 centers, 20 countries11 140 patients, 215 centers, 20 countries

Study designStudy design

Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.

HbA1c target6.5%

11.140 patients

Intensive glycemic controlIntensive glycemic control

DIAMICRON MR

Preterax Placebo

Standard glycemic controlStandard glycemic control

STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


DIAMICRON MRIntensive glycemic controlIntensive glycemic control

DIAMICRON MR

Preterax PlaceboPreterax Placebo


STANDARD

Preterax Placebo


STANDARDStandard glycemic controlStandard glycemic control

STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


DIAMICRON MRIntensive glycemic controlIntensive glycemic control

DIAMICRON MR

Preterax PlaceboPreterax Placebo


STANDARD

Preterax Placebo


STANDARDStandard glycemic controlStandard glycemic control

STANDARD

Preterax Placebo

(same BP control)

Intensive

glycemic

control

Standard

glycemic

control

Local targets 7%

Gliclazide MRGliclazide MR

Inclusion criteriaInclusion criteria

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 32%Past history of macrovascular disease 32%

Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.

LESSONS fromLESSONS from

Progressive and tight glycemic controlProgressive and tight glycemic control

Sustained over 5 years

ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

Gliclazide MR at the dose of 120 mg

In 70% of patients


Tight HbATight HbA1c1c control control

50.250.281.1%81.1%<< 7%7%

28.8%28.8%64.9%64.9%<< 6.5%6.5%

8.4%8.4%21.3%21.3%<< 6%6%

4372437244994499AllAllStandardStandardIntensiveIntensive

50.250.281.1%81.1%<< 7%7%

28.8%28.8%64.9%64.9%<< 6.5%6.5%

8.4%8.4%21.3%21.3%<< 6%6%


No. & % of patientsNo. & % of patients

50.250.281.1%81.1%<< 7%7%

28.8%28.8%64.9%64.9%<< 6.5%6.5%

8.4%8.4%21.3%21.3%<< 6%6%


50.250.2 %%81.1%81.1%<< 7%7%

28.8%28.8%64.9%64.9%<< 6.5%6.5%

8.4%8.4%21.3%21.3%<< 6%6%


No. & % of patientsNo. & % of patients


Whatever the age at entryWhatever the age at entry

Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133

Whatever the duration of the diseaseWhatever the duration of the disease


Whatever the baseline of the BMIWhatever the baseline of the BMI


Whatever the HbAWhatever the HbA1C1C at baseline at baseline


10%10% Significant Significant reduction in the reduction in the combined risk of combined risk of

micro- and micro- and macrovascular macrovascular

eventsevents

Protection from serious complicationsProtection from serious complications



Gliclazide MR : unique renal protection.Gliclazide MR : unique renal protection.


Gliclazide MR : Gliclazide MR : unique renal protection.unique renal protection.

NNT: we need to treat 15 diabetic patients to make 1 NNT: we need to treat 15 diabetic patients to make 1 patient regain the normal range of albuminuria.patient regain the normal range of albuminuria.

ADVANCE Collaborative Group. EASD Congress 2010. Stockholm,Sweden. Abstract

Gliclazide MR : Gliclazide MR : unique renal protection.unique renal protection.20 mg/l200 mg/l

albuminuria

Macroalbuminuria

Normal range of albuminuria

Majority of these patients

*versus standard treatment group

Microalbuminuria

20% more patients regressed to normal range vs standard treatment

(P=0.0002)

ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication

New results EASD 2011New results EASD 2011

The ADVANCE Collaborative Group. EASD Annual Meeting, 2011. Portugal, Lisbon. Abstract.


20% of people with diabetes die of renal disease.20% of people with diabetes die of renal disease. 50% of patients in dialysis units have diabetes.50% of patients in dialysis units have diabetes. Albuminuria is a major predictor of ESRD, CVD & death.Albuminuria is a major predictor of ESRD, CVD & death.

Key resultsRisk of CVD predicted by albuminuriaRisk of CVD predicted by albuminuria


Cardiovascular death 253 289 12% (-4 to 26)

All deaths 498 533 7% (-6 to 17)

Non-cardiovascular death 245 244 0% (-20 to 16)

Number of patients with eventIntensive Standard(n=5,571) (n=5,569)

Relative riskreduction (95%CI)

FavorsIntensive

FavorsStandard

Hazard ratio

0.5 1.0 2.0Cardiovascular MortalityCardiovascular Mortality

-12%-12%P=0.12P=0.12

Gliclazide MR : Gliclazide MR : unique cardioprotection.unique cardioprotection.

Gliclazide MR Gliclazide MR : the lowest rate of hypoglycemia: the lowest rate of hypoglycemia

ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. The UKPDS Group (33). Lancet. 1998;352:837-853

Maximal dose of Gliclazide MR

In 70% of patients



ACCORD ADVANCEADVANCE VADT

Severe hypoglycemia in intensive arm [% part. with ≥ 1 episodes] 16.2% 2.7%2.7% 21.2%

Gliclazide MR Gliclazide MR : strict weight neutrality: strict weight neutrality




CONTROL Group. Diabetologia. 2009, August 6. Epub ahead of print.


There was no weight gain in the intensive group patients. On the contrary there was some weight loss in intensive group patients

with BMI 25-30 & ≥ 30.


Weight loss of 1.6 Kg in Gliclazide MR based intensive glucose control “for patients not taking Insulin or TZDs”

The ADVANCE Collaborative Group. Diabetes Res Clin. Pract. Epub ahead of print.

Gliclazide MRGliclazide MR, the best , the best treatment strategy. treatment strategy.

Modified Release formulationModified Release formulation

Francillard M EUGMS 2001. Reaven GM Diabetes 1988

Restores physiological insulin secretionRestores physiological insulin secretion

Gregorio F et al. Diabetes Res Clin Prac. 1992;18:197-206.


Satoh J, Takahashi Y, Takizawa Y et al. Diabetes Research and Clinical Practice, 2005.

0

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GLICLAZIDEGLICLAZIDE

8

14.5x2Double the time needed to start insulin therapyDouble the time needed to start insulin therapy

Gliclazide MRGliclazide MR Protects Protects ββ-Cells-Cells

Gliclazide MR Gliclazide MR reduces the risk of deathreduces the risk of death


Al Sifri S et al. Int J Clin Pract. 2011;11,1132-1140


What’s next?What’s next?

Megatrials in diabetesMegatrials in diabetes

1998 June 2008 Sept 2008 2009

UKPDSUKPDSN=3867N=3867

ACCORDACCORDN=10,251N=10,251

ADVANCEADVANCEN=11,240N=11,240

UKPDSUKPDSLong-term follow-upLong-term follow-up

VADT VADT N=1791N=1791

CONTROLmeta-analysisN=27,049

ADVANCE-ONADVANCE-ON

UKPDS 10 years follow up UKPDS 10 years follow up (Total of 25 years)(Total of 25 years)

Persistence of RRR in microvascular disease.

Significant RR for macrovascular related deaths.

““Intensive glucose control may Intensive glucose control may have a legacy effect...have a legacy effect...

This may explain why the This may explain why the macrovascular and mortality macrovascular and mortality benefits of intensive glucose benefits of intensive glucose lowering may take several lowering may take several

years to become apparent.”years to become apparent.”

““Intensive glucose control may Intensive glucose control may have a legacy effect...have a legacy effect...

This may explain why the This may explain why the macrovascular and mortality macrovascular and mortality benefits of intensive glucose benefits of intensive glucose lowering may take several lowering may take several

years to become apparent.”years to become apparent.”

Professor J. Chalmers,Professor J. Chalmers,Chairman of the ADVANCE Study Management Chairman of the ADVANCE Study Management GroupGroup

RecruitmentRecruitment

Primary end points:Primary end points:1.1. Death from any cause.Death from any cause.2.2. Major macrovascular events: Major macrovascular events:

nonfatal myocardial infarction. nonfatal myocardial infarction. nonfatal stroke. nonfatal stroke. Cardiovascular death.Cardiovascular death.

ADVANCE ON recruitment progress; August 2011

ConclusionConclusion

Tight glycemic control using Gliclazide MR, Tight glycemic control using Gliclazide MR, based treatment strategybased treatment strategy

Superior glycemic control.Superior glycemic control.

Preservation of the Preservation of the ββ- cell of the pancreas.- cell of the pancreas.

Unique Cardioprotection.Unique Cardioprotection.

Unique neproprotection.Unique neproprotection.

Excellent safety.Excellent safety.

Thank youThank you

ueda2012 advance trial-d.salah

Health & Medicine

advanceadvance trial

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ukpdsukpds n

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accordaccord n

t2dmthe largest trial

control metaanalysis

n engl j