ADVANCE ADVANCE-ON

ADVANCE este un real avans

Profesor Dr. N. HÂNCU

Universitatea de Medicina si Farmacie

“Iuliu Hațieganu”

Cluj-Napoca

Primul Congres naţional cu participare internaţională al Societăţii Endocrinologilor din Republica Moldova

09-11 octombrie 2014, Chişinău, Republica Moldova

Structură

• Studiul ADVANCE

• Control glicemic

• Control ponderal

• Hipoglicemii

• Complicații micro și macrovasculare

• Meta-analize

• Cancerul

• Risk- engine

• Concluzii ADVANCE

• ADVANCE-ON braț glicemic

• Mesaj final

Ales pentru studiul ADVANCE (Action in Diabetes and Vascular Disease: Preterax and

Diamicron MR Controlled Evaluation)

Cel mai mare studiu clinic desfăşurat vreodată în diabet

A urmărit 11.140 pacienţi cu DZ 2

Obiectiv:

“Tratamentul antiHT împreună cu un control glicemic mai riguros decât în mod obişnuit reduc riscul la toţi adulţii cu DZ 2?”

Pacienţii sunt în continuare evaluaţi prin studiul

ADVANCE-ON (2014)

2–4 tablete o dată pe zi

6 săptămâni de run-in ;

regim de reducere a TA

cu Noliprel

Înrolare

Randomizare

N > 10 000

Terapie optimală

+

Noliprel

+

Control glicemic intensiv

Diaprel MR

(n=2500)

Terapie optimală

+

Noliprel

+

Control glicemic standard (n=2500)

Terapie optimală

+

Placebo

+

Control glicemic

intensiv

Diaprel MR

(n=2500)

Terapie optimală

+

Placebo

+

Control glicemic

standard

(n=2500)

Finalul folow-up-ului (4.5 ani în medie)

Design-ul studiului

Demonstraţiile studiului ADVANCE

s-a obtinut un control glicemic intensiv (A1c≤6.5%), preponderent cu 120 mg

gliclazid la care s-a asociat în funcţie de necesar insulină şi metformin:

Fără hipoglicemii

Fără creştere în greutate

Fără creşterea mortalităţii

Cu beneficii semnificativ statistice pe nefropatie, inclusiv administrare în

insuficienţa renală stadiul 3

Cu beneficii macrovasculare (nesemnificativ statistic)

demonstrează corelaţia între patologia orală şi RCV

STUDIUL A FOST TERMINAT CONFORM PROTOCOLULUI,

DEOSEBINDU-SE NET DE ACCORD ŞI VADT

CONFIRMAT: control glicemic eficient

• 81% dintre pacienti: HbA1c 7%

ADVANCE Collaborative Group. Diabetes Res Clin Pract. 2010. 89:126-133

CONFIRMAT: Reducere eficientă a HbA1c indiferent de vechimea bolii

ADVANCE Collaborative Group. Diabetes Res Clin Pract. 2010. 89:126-133

Gliclazid este relativ selectivpentru receptorii SUR1 ;I prin aceasta au o specificitate pentru canalele KATP din celulele beta pancreatice, fata de canalele din miocard si celulele musculare netede

Actioneaza numai cand este nevoie (previne hipoglicemiile)

Actiune antiaterogena

HoldenSE, CurrieCJ Diabetes, Obesity nd Metabolism.

2014;16(10) - october

Particularitatea gliclazid

A. Avogaro. Diabetes, Obesity and Metabolism 14 (Suppl. 1): 14–19, 2012

The metabolic and cardiovascular effects of gliclazide

Conclusions:

Effective glycaemic control was associated with treatment intensification at lower HbA1c levels at all stages of the disease course and in both arms of the ADVANCE trial.

Plasma CRP, fibrinogen, and IL-6 levels were determined in a case-cohort study (n = 3,865) nested within the 11,140 men and women with type 2 diabetes and baseline CVD or risk factors in the ADVANCE Study.

All three biomarkers of inflammation were associated with an increased risk of macrovascular events and death in analyses adjusted for age, sex, and treatment groups.

After further adjustment, only IL-6 was an independent predictor of macrovascular events

Siguranţă remarcabilă

Cel mai mic risc de hipoglicemii 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

120 mg Diaprel

MR la 70% dintre

pacienţi !

Conclusions: this study shows that weight gain is not merely due to intensification of treatment, but is also related to HbA1c level and smoking status Moreover, insulin and thiazolidinedione use was associated with substantial weight gain, while sulphonylurea use produced only minimal weight gain and metformin use minimal weight loss It is important for clinicians to understand the differential effects on weight of different treatment strategies for type 2 diabetes.

S.van Dieren et al. Diabetes, Obesity and Metabolism 14: 464–469, 2012

kg

Weight gain in several trials of intensive glucose–lowering strategies

The different patterns in these trials might be explained, at least in part, by the fact that considerably more patients received insulin in the intensive treatment arms of ACCORD and VADT compared to ADVANCE as well as the higher baseline HbA1c levels in these studies

ADVANCE: rezultate

Reducere cu 21% a

evenimentelor renale (P=0.006)

Reducere cu 9% a

microalbuminuriei (P=0.018)

Reducere cu 30% a

macroalbuminuriei (P<0.001)

ADVANCE Collaborative Group. N Engl J Med 2008;

358:2560-72

Normalizarea albuminuriei

Normalizarea albuminuriei: 20% dintre pacienţi !

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

Rezultate noi

EASD 2010

Courtesy from JAMA 2008

ADVANCE vs ACCORD

ACCORD

ADVANCE vs ACCORD

PROGRESIV

ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.

AGRESIV vs

ADVANCE vs ACCORD

Diaprel MR 91%

Insulină 40%

TZD 17%

Metformin 74%

Glimepirid 78%

Insulină 77%

TZD 91%

Metformin 95%

vs

ADVANCE ACCORD

Diferenţe evidente în ceea ce priveşte strategia şi medicaţia folosită

ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.

PROGRESIV AGRESIV vs

Metaanaliza CONTROL

J. Chalmers, H. Gerstein, W. Duckworth, R. Holmann

Control glicemic intensiv şi efecte macrovasculare în DZ 2

ADVANCE ACCORD VADT UKPDS

Turnbull FM. Diabetologia. 2009;52:2288-2298

CONTROL

Numai în ADVANCE: reducerea mortalităţii de toate cauzele, inclusiv cardiovasculară

Metaanaliza CONTROL

Turnbull FM. Diabetologia. Epub Aug 5 2009

Conclusions/interpretation In patients with T2DM, HbA1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5% There was no evidence of lower risks below these levels but neither was there clear evidence of harm. Above these thresholds, the risks increased significantly:

every 1% higher HbA1c level was associated with: a 38% higher risk of a macrovascular event a 40% higher risk of a microvascular event a 38% higher risk of death

all p<0.0001

P. Hamet. Diabetes, Obesity and Metabolism 14 (Suppl. 1): 20–29, 2012.

Combined effects of routine blood pressure lowering and intensive glucose control strategy on the incidence of death

from any cause

Conclusions/interpretations • More intensive glucose control achieved with a regimen that included greater use of gliclazide, insulin, metformin and other agents, did not affect the risk of cancer events or death in patients with type 2 diabetes

P. Hamet. Diabetes, Obesity and Metabolism 14 (Suppl. 1): 20–29, 2012.

Schema for estimating the 4-year risk of cardiovascular disease by the ADVANCE model equation

…Trialuri relaţionate cu controlul

glicemic

Gra

du

l d

e e

ntu

zia

sm

cu

care

este

perc

ep

ut

Timp

UGDP

UKPDS

PROactive

PROactive

(Nissen)

ADOPT

RECORD

ACCORD

Adapted from David Matthews, Oxford University, UK

Presentation in Paris, April 2008

2014

Trialuri relaţionate cu controlul glicemic. Perspective: ADVANCE-ON

Obiectiv primar: Efectele pe termen lung al unui control glicemic intensiv cu Diaprel MR

comparativ cu controlul glicemic standard privind:

– Decesul de orice cauză

– Evenimente macrovasculare majore (IM nonfatal, AVC non fatal, deces de cauza cardiovasculara)

Obiectiv secundar:

Deces de orice cauză cardiovasculară

Target: HbA1c ≤6.5%

Trialuri relaţionate cu controlul glicemic. Perspective: ADVANCE-ON

Participanţi: din studiul ADVANCE, 11.140 pacienţi cu risc crescut din 213 centre

Urmărire: 5 ani de la ultima vizită din ADVANCE, follow up documentat anual

Primul follow up documentat: 2010

Rezultate: 2014!

ADVANCE-ON Glucose arm results

1. Context

2. Design

3. Results

4. Communication plan

Agenda

Diabetes morbidity and mortality comparing those with and without diabetes

Hyperglycemia and diabetes complications

Sarwar N et al. Lancet. 2010;375:2215-2222

HR adjusted for age, sex, smoking status, SBP and BMI

Context

NEJM sept 2014

In 2014, preventing ESRD remains the main challenge for type 2 diabetic patients

Part of ESRD among of all type 2 diabetes complications

Context

N Engl J Med 2014;370:1514-23

UKPDS Clinical benefits of glucose control with metformin sustained over the long term

Context

HbA1c

↘ All Cause Mortality ↘ Myocardial Infarction

↘ All Cause Mortality ↘ Myocardial Infarction

Metformin

Conventional therapy

NEJM sept 2014

• Lowering HbA1c at 7.4% is beneficial to prevent diabetes complications

• Benefits can be sustained together with a continuous effort in lowering HbA1c

• Metformin is an effective drug within this strategy (=> Guidelines and WHO list)

Lessons learned from UKPDS

Context

Can we go further than UKPDS…

… with a lower HbA1c target?

… by adding new treatments to metformin?

NEJM sept 2014

Study ACCORD n=10 251

VADT n=1 791

ADVANCE n=11 140

HbA1c targets (intensive vs. Standard)

6.4% vs. 7.5% 6.9% vs. 8.4% 6.5% vs. 7.3%

Intensive group treatments

Glimepiride Metformin TZD Insulin

78% 95% 91% 77%

Glimepiride Metformin TZD Insulin

53% 60% 37% 67%

Gliclazide MR Metformin TZD Insulin

91% 74% 17% 40%

Primary endpoint (CV composite)

-10% P=0.16

-13% P=0.12

-6% P=0.12

CV mortality +39% P=0.02

+25% P=NS

-12% P=0.12

Mortality (all cause)

+22% P=0.04

+6.5% P=NS

-7% P=0.28

ESRD -9% P=NS

-36% P=NS

-65% P=0.017

Morbidity-mortality trials

Context

NEJM sept 2014

Last patient last visit: February 2014

Post-trial observational study

Cease randomization of treatments

Primary outcomes: All cause death – Macrovascular events

Secondary outcomes: Retinopathy – Renal mortality – Requirement for renal transplant or dialysis

Design

NEJM sept 2014

During the post-trial, the HbA1c control was not maintained in the intensive group

Results

HbA1c control over the years

Follow-up (years)

Standard

Intensive

Me

an H

bA

1c

(%)

6.0

6.5

7.0

7.5

8.0

8.5

9.0

0 6 12 18 24 30 36 42 48 54 60 66

7.4

7.2

7.3

6.5

7.3

7.3

5 10

NEJM sept 2014

Results C

um

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tive

incid

en

ce

(%

)

0

5

10

15

20

25

Follow-up (years)0 2 4 6 8 10

No. at RiskIntensiveStandard

5571 5414 5197 4125 3772 28225569 5412 5190 4050 3693 2697

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0 2 4 6 8 10 0 2 4 6

A: Death from any cause

Follow-up (years)

D: Death from any cause (post trial)

E: Major macrovascular events (post trial)B: Major macrovascular events

C: Cardiovascular death F: Cardiovascular death (post trial)

No. at RiskIntensiveStandard

No. at RiskIntensiveStandard

HR: 1.00 (0.92, 1.08)

P=0.91

StandardIntensive

HR: 1.05 (0.94, 1.17)

P=0.40

HR: 1.00 (0.92, 1.08)

P=0.93

HR: 1.06 (0.94, 1.20)

P=0.36

HR: 0.97 (0.86, 1.10)

P=0.63

HR: 1.10 (0.91, 1.32)

P=0.32

Cum

ula

tive

incid

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ce

(%

)

0

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0 2 4 6 8 10 0 2 4 6

A: Death from any cause

Follow-up (years)

D: Death from any cause (post trial)

E: Major macrovascular events (post trial)B: Major macrovascular events

C: Cardiovascular death F: Cardiovascular death (post trial)

No. at RiskIntensiveStandard

No. at RiskIntensiveStandard

HR: 1.00 (0.92, 1.08)

P=0.91

StandardIntensive

HR: 1.05 (0.94, 1.17)

P=0.40

HR: 1.00 (0.92, 1.08)

P=0.93

HR: 1.06 (0.94, 1.20)

P=0.36

HR: 0.97 (0.86, 1.10)

P=0.63

HR: 1.10 (0.91, 1.32)

P=0.32

Primary outcomes

All cause death Macrovascular events

Lowering HbA1c to 6.5% for 5 years, using regimen including gliclazide MR, leads to complete safety over 10 years

NEJM sept 2014

Cardiovascular death

Results

Lowering HbA1c to 6.5% for 5 years, using regimen including gliclazide MR, leads to complete cardiovascular safety over 10 years

-3% (NS)

-12% (NS)

NEJM sept 2014

Lowering HbA1c to 6.5% for 5 years, using regimen including gliclazide MR, leads to further renal protection over 10 years

End Stage Renal Disease (renal transplant or dialysis)

Results

-65%

NEJM sept 2014

Use of treatments

Results

Lowering HbA1c to 6.5% for 5 years, using regimen including gliclazide MR, doesn’t induce pancreatic exhaustion

NEJM sept 2014

Endpoints UKPDS Follow-up ADVANCE-ON

Myocardial infarction 14.8 6.7

Death from any cause 25.9 20.7

ADVANCE-ON: a major progress in type 2 diabetes management

Results

• UKPDS follow-up vs. ADVANCE-ON: event/year/1000 patients

• ADVANCE-ON: unique ESRD risk reduction

Diabetes duration (end of trial)

20 years 18.4 years

NEJM sept 2014

Diamicron MR 60 preserves the heart and protects the kidney over 10 years

• ADVANCE-ON reinforces the importance of effectively and lastingly lowering HbA1c with Diamicron MR 60 at 6.5% to prevent ESRD with total cardiovascular safety

• ADVANCE-ON values the effective management of diabetes mellitus by practionners

• Following UKPDS, the ADVANCE-ON results emphasize the WHO guidelines, which recommend both metformin and gliclazide as the only two oral essential treatments for diabetics

Take home messages

NEJM sept 2014

WHAT DOES IT MEAN FOR CLINICIANS?

1. Is a legacy effect supported by ADVANCE-ON? Yes

2. Do the results change our HbA1c targets? No 3. Do the results change our perspective on the

medical treatment of patients with type 2 diabetes?

Yes

Busko M– ADVANCE-ON: Tight BP Control Lingers, Tight HbA1c Doesn’t. Medscape 22 sep 2014.

Conslusions:

Application of these two regimens to all patients with type 2 diabetes alive today would save around 4 million lives over the next 5 years.

Chalmers J. ADVANCE – Protection against cardiovascular and renal disease in type 2 diabetes. Ed Wolters Kluwer, 2010