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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
ula
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
Cu
mu
lative
in
cid
en
ce
(%
)
0
5
10
15
20
25
Follow-up (years)
5571 5273 4942 3881 3448 24485569 5253 4940 3774 3359 2363
Cu
mu
lative
incid
ence
(%
)
0
5
10
15
20
25
Follow-up (years)0 2 4 6 8 10
5571 5402 5188 4125 3772 28225569 5399 5179 4050 3693 2697
Cu
mu
lative
in
cid
en
ce
(%
)
0
5
10
15
20
25
Follow-up (years)0 2 4 6
5060 3987 3214 13675022 3923 3115 1263
Cu
mu
lative in
cid
ence
(%
)
0
5
10
15
20
25
4782 3702 2868 12014737 3627 2777 1119
Cu
mu
lative
in
cid
en
ce
(%
)
0
5
10
15
20
25
Follow-up (years)0 2 4 6
5060 3987 3214 13675022 3923 3115 1263
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
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
Cu
mu
lative
in
cid
en
ce
(%
)0
5
10
15
20
25
Follow-up (years)
5571 5273 4942 3881 3448 24485569 5253 4940 3774 3359 2363
Cu
mu
lative
incid
ence
(%
)
0
5
10
15
20
25
Follow-up (years)0 2 4 6 8 10
5571 5402 5188 4125 3772 28225569 5399 5179 4050 3693 2697
Cu
mu
lative
in
cid
en
ce
(%
)
0
5
10
15
20
25
Follow-up (years)0 2 4 6
5060 3987 3214 13675022 3923 3115 1263
Cu
mu
lative in
cid
ence
(%
)
0
5
10
15
20
25
4782 3702 2868 12014737 3627 2777 1119
Cu
mu
lative
in
cid
en
ce
(%
)
0
5
10
15
20
25
Follow-up (years)0 2 4 6
5060 3987 3214 13675022 3923 3115 1263
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