J.R.G. JUANATEY C.H.U.Santiago
José R. José R. González JuanateyGonzález JuanateyHospital Hospital Clínico UniversitarioClínico Universitario de Santiago de de Santiago de CompostelaCompostela
Valoración de los Últimos Resultados CVCs en Relación con el Control de la
Diabetes
J.R.G. JUANATEY C.H.U.Santiago
Control Glucémico en la Cardiopatía Isquémica
Diabetes y Cardiopatía Isquémica
Control Glucémico en Diabéticos con CI
Fármacos antidiabéticos en Pacientes con CI
Prevención integral
J.R.G. JUANATEY C.H.U.Santiago
ACUTE CORONARY SYNDROME AND DIABETES
3 (10%) treated with OAD at discharge2 (6,7%) treated with insulin at discharge
219 patients
Estudio DM-Barbanza
MORTALIDAD BRUTA
8,3
12%
0%DM
8,8
5,16%
CI ECV
10,7
8,1
6,2
Total VP EMV
Enfermedad cardiovascular previaSeguimiento medio: 44,6 meses109 pacientes perdidos GonzGonzáálezlez--JuanateyJuanatey JRJR et alet al (Grupo BARBANZA)(Grupo BARBANZA). . RevRev EspEsp CardiolCardiol 20082008
Estudio DM-Barbanza
EXITUS Y/O INGRESO CV
20,2
40%
0%DM
26,3
10,3
20%
CI ECV
32,2 33,9
14,8
Total VP EMV
Seguimiento medio: 44,6 meses109 pacientes perdidos
Enfermedad cardiovascular previa
GonzGonzáálezlez--JuanateyJuanatey JRJR et alet al (Grupo BARBANZA)(Grupo BARBANZA). . RevRev EspEsp CardiolCardiol 20082008
EMV
VP
ECV
CI
DM
2,12 (1,17-3,83)3,53 (1,35-9,19)2,43 (0,66-8,89)
1,46 (0,81-2,60)0,76 (0,18-3,29)1,84 (0,51-6,61)
2,51 (1,28-4,92)1,97 (0,45-8,67)5,58 (1,88-16-53)
2,48 (1,51-4,07)6,01 (2,92-7,45)2,45 (0,80-7,45)
OR (IC-95%)
Estudio DM-BarbanzaRiesgo de eventos y mortalidadEnf previa
65 74 81 2 30
Cardiopatía isquémica Enf. cerebrovascularEnf cardiovascular
GonzGonzáálezlez--JuanateyJuanatey JRJR et alet al (Grupo BARBANZA)(Grupo BARBANZA). . RevRev EspEsp CardiolCardiol 20082008
Estudio DM-Barbanza
Determinantes de mortalidad
1,08 1,05-1,11
2,15 1,12-4,14
3,40 1,76-6,56
0,48 0,25-0,93
OR IC-95%
Edad
Enf CV
Diuréticos
IECA/ARA
4 50 2 31
GonzGonzáálezlez--JuanateyJuanatey JRJR et alet al (Grupo BARBANZA)(Grupo BARBANZA). . RevRev EspEsp CardiolCardiol 20082008
J.R.G. JUANATEY C.H.U.Santiago
Glucose andMortality in ACS
Patients
Non-diabetic Patients
Diabetic Patients
Fasting glucose: dotted lines
Admission glucose: solid lines
J.R.G. JUANATEY C.H.U.Santiago
Non-diabetic Patients
Diabetic Patients
Time (years)A
UC
Glucose and Mortality in ACS Patients
Fasting glucose: dotted lines
Admission glucose: solid lines
Time (years)
AU
C
Fasting glucose: dotted lines
Admission glucose: solid lines
J.R.G. JUANATEY C.H.U.Santiago
Control Glucémico en la Cardiopatía Isquémica
Diabetes y Cardiopatía Isquémica
Control Glucémico en Diabéticos con CI
Fármacos antidiabéticos en Pacientes con CI
Prevención integral
J.R.G. JUANATEY C.H.U.Santiago
Objetivos Glicémicos para el Cuidado de Pacientes con Diabetes Recomendados por Varias Organizaciones
Organización HbA1c (%) FPG (mmol/L)PG post-prandial(mmol/L)
ADA < 7 ≤ 6,7 (120) Nada
IDF-Europa ≤ 6,5 ≤ 6,0 (108) ≤ 7,5 (135)
AACE ≤ 6,5 ≤6,0 (108) ≤ 7,8 (140)
ESC/EASD Eur Heart J 2007;28:88-136
J.R.G. JUANATEY C.H.U.Santiago
STATEMENT OF ADA, ACC y AHA (ADVANCE, ACCORD, VADT)
• Microvacular Dis.: HbA1c < 7 % (ACC/AHA 1 A)• Macrovascular Dis: HbA1c < 7 % (ACC/AHA IIb A)
– Individualization:– “Lowering A1c to below 7 %” in pactients without risk of
hypoglycemia, patients with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. (ACC/AHA IIa C)
– “Less stringent A1c goal” for patients with a history ofsevere hypoglycemia, limited life expectancy, advancedmicrovascular or macrovascular complications, comorbidconditions, long-standing diabetes. (ACC/AHA IIa C)
Circulation 2009; 119: 0-0
J.R.G. JUANATEY C.H.U.Santiago
Objetivos de Tratamiento en Pacientes con Diabetes Tipo 2. Guias Europeas Prevención-07
Unidad Objetivo
HbA1C(DCCT) HbA1C (%) ≤ 6,5 si es posible
ayunas/preprandialmmol/L (mg/dL)
<6,0 (110) si es posible
postprandialmmol/L (mg/dL)
< 7,5 (135) si es posible
Presión arterial mmHg ≤ 130/80
Colesterol total mmol/L (mg/dL)mmol/L (mg/dL)
< 4,5 (175)< 4,0 (155) si es
posible
Colesterol LDL mmol/L (mg/dL)mmol/L (mg/dL)
< 2,5 (100)< 2,0 (80) si es
posible
Glucosa en plasma
J.R.G. JUANATEY C.H.U.Santiago
Effects of Intensive Glucose Lowering in Type 2 Diabetes
Years
Gly
cate
dH
emog
lobi
n (%
)Yea
rs
Standard therapy
Intensive therapy
0 1 2 3 4 5 6 0
9.0
7.0
7.5
6.0
6.5
8.5
8.0
Median Glycated Hemoglobin Levels at Each Study Visit
I bars denote interquartileranges
No. at Risk
Standard 5019 4774 4588 3186 1744 455 436
Intensive 5119 4768 4585 3165 1706 476 471
The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59
J.R.G. JUANATEY C.H.U.Santiago
Effects of Intensive Glucose Lowering in Type 2 DiabetesKaplan-Meier Curves for the Primary Outcome and Death from Any Cause
Intensive therapy
Standard therapy
Standard therapy
Intensive therapy
Years Years
Patie
nts
with
Eve
nts
(%)
Patie
nts
with
Eve
nts
(%)
0 1 2 3 4 5 6 0 1 2 3 4 5 6
0
25
20
15
5
5
0
25
20
15
5
5
Primary Outcome Death from Any cause
No. atRisk
No. at Risk
Intensive therapy
5128 4843 4390 2839 1337 475
440
448 Intensive therapy
5128 4972 48803 3250 17484 523 506
Standard therapy
5123 4827 4262 2702 1186 395 Standard therapy
5123 4971 4700 3180 1642 499 480
The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59
J.R.G. JUANATEY C.H.U.Santiago
Effects of Intensive Glucose Lowering in Type 2 DiabetesHazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups
Intensive Therapy Better Standard Therapy Better
0.8 1.2 1.6
Hazard RatioSubgroup No. of Patients
No. of Events
Total 10,251 723
Previous cardiovascular event
No 6,643 330
Yes 3,608 393
Sex
Female 3,952 212
Male 6,299 511
Age at baseline
<65 yr 6,779 383
≥65 yr 3,472 340
Glycated hemoglobin at baseline
≤8.0% 4,868 284
>8.0% 5,360 438
Race
Nonwhite 3,647 222
White 6,604 501
The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59
Data regarding glycated haemoglobin levels and baseline are presented for 10,288 patients because a baseline level was not available for 23 patients. Horizontal bars represent the 95% confidence interval, and vertical dashed lines indicate the overall hazard ratio. The sine of each square is proportional to the number of patients
0.93
0.15
0.19
0.92
0.53
P Value
J.R.G. JUANATEY C.H.U.Santiago
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes
Months of Follow-up
Mea
n G
lyca
ted
Hem
oglo
bin
(%)
0 6 12 18 24 30 36 42 48 54 60 66
Standard control
Intensive control
10.0
9.5
9.0
0.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
P<0.001
Months of Follow-up
Mea
n Fa
stin
g B
lood
glu
cose
(mm
ol/li
ter)
0 6 12 18 24 30 36 42 48 54 60 66
Standard control
Intensive control
10.0
9.5
9.0
0.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
P<0.001
Glucose Control at baseline and during Follow-up, According to Glucose-Control Strategy
ValueStandard 7.32 7.30 7.29 7.29 7.31 7.33 7.29
Intensive 7.01 6.93 6.70 6.53 6.50 6.52 6.53 6.556.516.477.17Intensive
7.747.927.848.15Standard
Level
The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72
J.R.G. JUANATEY C.H.U.Santiago
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 DiabetesCumulative incidences of Events, According to Glucose-Control Strategy
Major Macrovascular EventsCombined Major Macrovascular and Microvascular Events
25
15
10
5
0
20
Months of Follow-up
Cum
ulat
ive
Inci
denc
e (%
)
Intensive control
Standard control
P=0.32
0 6 12 18 24 30 36 42 48 54 60 66
Intensive control
Standard control
P=0.01
0 6 12 18 24 30 36 42 48 54 60 66
Months of Follow-up
Cum
ulat
ive
Inci
denc
e (%
)
25
15
10
5
0
20
Intensive 5570 5457 5369 5256 5100 4957 4867 4756 4599 4044 1883 447
Standard 5569 5448 5342 5240 5065 4903 4808 4703 4545 3992 1921 470
No. at Risk
Intensive 5570 5494 5428 5338 5256 5176 5097 5005 4927 4396 2071 486
Standard 5569 5486 5413 5330 5237 5163 5084 4995 4922 4385 2108 509
No. at Risk
Roy D. et al. N Engl J Med 2008;358:2667-77.
J.R.G. JUANATEY C.H.U.Santiago
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 DiabetesCumulative incidences of Events, According to Glucose-Control Strategy
Death from Any CauseMajor Microvascular Events
25
15
10
5
0
20
Months of Follow-up
Cum
ulat
ive
Inci
denc
e (%
)
Intensive control
Standard control
P=0.28
0 6 12 18 24 30 36 42 48 54 60 66
Intensive control
Standard control
P=0.01
0 6 12 18 24 30 36 42 48 54 60 66
Months of Follow-up
Cum
ulat
ive
Inci
denc
e (%
)
25
15
10
5
0
20
Intensive 5571 5495 5430 5358 5233 5120 5055 4968 4824 4258 1992 473
Standard 5569 5498 5431 5353 5207 5069 4995 4911 4764 4204 2024 494
No. at Risk
Intensive 5571 5533 5490 5444 5411 5361 5312 5246 5189 4653 2211 523
Standard 5569 5537 5503 5445 5399 5354 5301 5237 5178 4643 2240 544
No. at Risk
Denis Roy et al. N Engl J Med 2008;358:2667-77
J.R.G. JUANATEY C.H.U.Santiago
Intensive Glycemic Control in the ACCORD and ADVANCE TrialsDifferences between the ACCORD and ADVANCE Studies
Outcome (intensive vs. standard) ACCORD ADVANCE
Median glycated hemoglobin at study end (%) 6.4 vs. 7.5 † 6.4 vs. 7.0 †
From any cause (%) 5.0 vs. 4.0 † 8.9 vs. 9.6
From cardiovascular causes (%)Death
2.6 vs. 1.8 † 4.5 vs. 5.2
Nonfatal myocardial infarction (%) 3.6 vs. 4.6 † 2.7 vs. 2.8
Nonfatal stroke (%) 1.3 vs. 1.2 † 3.8 vs. 3.8
Major hypoglycemia requiring assistance (ACCORD), or severe hypoglycemia (ADVANCE) (%/yr) 3.1 vs. 1.0 † 0.7 vs. 0.4
Weight gain (kg) 3.5 vs. 0.4 0.0 vs. -1.0 †
Current smoking (%) 10 vs. 10 8 vs. 8
†The comparison of the intervention with the standard therapy was significant.
Dluhy RG et al. N Engl J Med 2008;358:2630-33
J.R.G. JUANATEY C.H.U.Santiago
Glucose Control and Vascular Complications in Veterans with Type 2 DiabetesChanges in Median Glycated Hemoglobin Levels from Baseline through 78 Months
Gly
cate
dH
emog
lobi
n (%
)
Months
Standard therapy
Intensive therapy
Duckworth W. et al. N Engl J Med 2009;360:129-39The vertical bars represent interquartile ranges
No. at Risk
Standard therapy 899 811 812 759 760 727 727 707 688 667 644 472 329 225
Intensive therapy 892 801 805 763 754 729 706 692 668 661 639 489 340 223
J.R.G. JUANATEY C.H.U.Santiago
Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
Kaplan–Meier Curves for the Time until the First Occurrence of a Primary or Secondary Outcome
Primary Outcome Death from Cardiovascular Causes
Prob
abili
ty o
f Sur
viva
l
Years
Standard therapy
Intensive therapy
P=0.14
Standard therapy
Intensive therapy
Prob
abili
ty o
f Sur
viva
l
Years
P=0.26
No. at Risk
Standard therapy 899 770 693 637 570 471 240 55 0
Intensive therapy 892 774 707 639 582 510 252 62 0 085337646713746786828892Intensive therapy
075320635724767797833899Standard therapy
No. at Risk
Duckworth W. et al. N Engl J Med 2009;360:129-39
J.R.G. JUANATEY C.H.U.Santiago
Glucose Control and Vascular Complications in Veterans with Type 2 DiabetesHypoglycemic Episodes** P<0.001 for all differences between the two groups
Variable Standard Therapy(N = 899)
Intensive Therapy(N = 892)
no./100 patient-yr
Episodes with impaired consciousness 3 9Episodes with complete loss of consciousness 1 3Nocturnal episodes 44 152
With symptoms 383 1333Without symptoms 49 233
Relieved by food or sugar intake 421 1516Measurement of blood glucose during episode 348 1392With documented blood glucose <50 mg/dl (2.8 mmol/liter) 52 203
Total episodes
Duckworth W. et al. N Engl J Med 2009;360:129-39
J.R.G. JUANATEY C.H.U.Santiago
Glucose and Long-term Mortality in ACS Patients
Fasting glucose (mg/dL)
Log
Haz
ard
Rat
io Ref.= 107
Admission glucose (mg/dL)
Log
Haz
ard
Rat
io
Ref.= 110
J.R.G. JUANATEY C.H.U.Santiago
Glucose and Long-term Mortality in ACS PatientsNon-diabetic Patients
Diabetic Patients
Fasting glucose (mg/dL)Lo
g H
azar
d R
atio
Ref.= 106
Fasting glucose (mg/dL)
Log
Haz
ard
Rat
io
Ref.= 111
J.R.G. JUANATEY C.H.U.Santiago
Non-diabetic Patients Glucose and Long-term Mortality in
ACS Patients
Fasting glucose (mg/dL)
Diabetic Patients
Fasting glucose (mg/dL)
J.R.G. JUANATEY C.H.U.Santiago
Control Glucémico en la Cardiopatía Isquémica
Diabetes y Cardiopatía Isquémica
Control Glucémico en Diabéticos con CI
Fármacos antidiabéticos en Pacientes con CI
Prevención integral
J.R.G. JUANATEY C.H.U.Santiago
FDA News
FDA Decision Nov 14To date, no oral anti-diabetes drug has beenconclusively shown to reduce cardiovascular risk. Consequently, the agency also will be requesting that labeling of all approvedoral anti-diabetes drugs contain languagedescribing the lack of data showing thisbenefit.
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html
J.R.G. JUANATEY C.H.U.Santiago
TRATAMIENTO CON INSULINA Y SUPERVIVENCIA TRAS IAM
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
0000 11 22 33 44 55
ControlControl44%44%
TratamientoTratamiento IntensivoIntensivoCon Con InsulinaInsulina
33%33%
Seguimiento Seguimiento ((añosaños))
Mor
talid
adM
orta
lidad
IAM < 24hIAM < 24hN=620 N=620 GlucemiaGlucemia > 11 > 11 mmolmmol/l/lIntensivoIntensivo::InfusiónInfusión InsulinaInsulina (100%)(100%)Seguida Seguida de sc (87%)de sc (87%)Control:Control:Practica clínicaPractica clínica43% 43% insulinainsulina sc
n = 620n = 620p < 0.01p < 0.01
sc
DIGAMIDIGAMIBMJ 1997;314:1512BMJ 1997;314:1512
J.R.G. JUANATEY C.H.U.Santiago
05
1015202530354045
0 0,5 1 1,5 2 2,5 3
Estudio DIGAMI II.
Malmberg, k, et al Eur Heart j. 2005;206:650-661
Grupo 1 474 367 299 254 202 154 87170 91
80119225145
Grupo 2 473 381 317 261Grupo 3 306 241 214 175
Nº de riesgo Años
%
Grupo 1 vs Grupo 3IR= 1,22 (0,95-1,56) P=0,115
Grupo 1Grupo 2Grupo 3
J.R.G. JUANATEY C.H.U.Santiago
Estudio DIGAMI II. Control Metabólico
24 H 8 6 12 18 24 30 36
20
15
10
5
0
Basal24 H 8 6 12 18 24 30
20
15
10
5
0Basal 36
meses
Malmberg, k, et al Eur Heart J. 2005;206:650-661
J.R.G. JUANATEY C.H.U.Santiago
TRATAMIENTO INTENSIVOTRATAMIENTO INTENSIVO
RECOMENDACIRECOMENDACIÓÓNN CLASECLASE NIVELNIVELControl Control estricto estricto de de glucosa glucosa concon II BBinsulina perfusiinsulina perfusióón mejora mortalidadn mejora mortalidady y morbilidad morbilidad de de pacientes sometidospacientes sometidosa a cirugcirugíía carda cardííacaaca
Control Control estrictoestricto de de glucosaglucosa concon II AAinsulina perfusiinsulina perfusióón mejora mortalidadn mejora mortalidady y morbilidadmorbilidad de de pacientes crpacientes crííticosticos
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. Eur Heart J 2007; 28, 88–136
J.R.G. JUANATEY C.H.U.Santiago
Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy
Algorithm for the metabolic management of type 2 diabetes
Nathan DM et al. Diabetes Care 2008; 31:1-11
Tier 1: Well-valited core therapies
At diagnosis:
Lifestyle
+ Metformin
STEP 1
Tier 2: Less well validated therapies
STEP 2 STEP 3
Lifestyle + Metformin
+ Basal insulin
Lifestyle + Metformin
+ Sulfonylurea
Lifestyle + Metformin+ Intensive
insulin
Lifestyle + Metformin
+ PioglitazoneNo hypoglycemiaOedema/chfBone loss
Lifestyle + Metformin
+ GLP-1 agonistNo hypoglycemiaWeight lossNausea/vomiting
Lifestyle + Metformin
+ Pioglitazone+ Sulfonylurea
Lifestyle + Metformin
+ Basal insulin
J.R.G. JUANATEY C.H.U.Santiago Terapia intensiva con insulina más metformina con o sin glitazonac
Hemoglobina Glicosilada ≥ 7%
Sia
Intervención estilo de vida más Metformina
Manejo Metabólico de la Diabetes Tipo 2Diagnosis
Natham DM et al Diabetología 2006;49:1711-21.
Diabetología 2007. DOI 10.1007/s00125-007-0873-z
No Hemoglobina Glicosilada ≥ 7%
Añadir sulfonilurea(menos cara)
Añadir glitazonab
(no Hipoglucemia)Añadir insulina basal
(más efectiva)
Hemoglobina Glicosilada ≥ 7%
Hemoglobina Glicosilada ≥ 7%
Hemoglobina Glicosilada ≥ 7%
Sia
Sia Sia
No No No
Intensificar terapia insulina Añadir glitazonas b,c Añadir insulina basal Añadir sulfonilureac
Hemoglobina Glicosilada ≥ 7%
Sia
No
Sia
Añadir insulina basal o Intensificar terapia insulina
a analizar HbA1c cada 3meses hasta < 7% y entonces cada 6 meses; basociado con aumento riesgo de retención fluidos, IC y fracturas.
Rosiglitazona, y probablemente no pioglitazona, se asocia a mayor
riesgo de IM; c aunque se pueden usar los tres la intensificación de
insulina es mas eficaz y económica
J.R.G. JUANATEY C.H.U.Santiago
New Drugs for the Treatment of DiabetesPart II: Incretin-Based Therapy and Beyond
Proposed antihyperglycemicstrategy in the patient with T2DM and
CAD
HbA1c ≥ 7.0%
Metformin HbA1c < 7.0%
HbA1c < 7.0%
HbA1c < 7.0%
HbA1c ≥ 7.0%
HbA1c ≥ 7.0%
HbA1c ≥ 7.0%
+ Pioglitazone
+ Secretagogue, α-glucosidase inhibitor,
Sitaglipin, or Exenatide
Insulin
Inzucchi SE et al. Circulation. 2008;117:574-584.
J.R.G. JUANATEY C.H.U.Santiago
New Drugs for the Treatment of DiabetesPart II: Incretin-Based Therapy and Beyond
Proposed antihyperglycemicstrategy in the patient
with T2DM and HFHbA1c < 7.0%
HbA1c < 7.0%
HbA1c ≥ 7.0%
HbA1c ≥ 7.0%
HbA1c ≥ 7.0%
+ Exenatide, Sitaglipin, or
α-glucosidase inhibitor
Insulin
Secretagogue, (and/or Metformin)
Inzucchi SE et al. Circulation. 2008;117:574-584.
J.R.G. JUANATEY C.H.U.Santiago
Tasas de Infarto de Miocardio y de Mortalidad Cardiovascular
Nissen S, et al. N Engl J Med 2007;356
MORTALIDAD CARDIOVASCULAR
Pequeños EnsayosDREAMADOPTGlobal
44/10280 (0.43)15/2635 (0.57)27/1456 (1.85)
22/6105 (0.36)9/2634 (0.34)
41/2895 (1.44)
25/6557 (0.38)12/2365 (0.51)
2/1456 (0.14)
Pequeños EnsayosDREAMADOPTGlobal
nº eventos/nº total (%)
7/3700 (0.19)10/2634 (0.38)
5/2854 (0.18)
1.45 (0.88 -2.39)1.65 (0.74 – 3.68)1.33 (0.80 – 2.21)1.43 (1.03 – 1.98)
2.40 (1.17 – 4.91)1.20 (0.52 – 2.78)0.80 (0.17 – 3.86)1.64 (0.98 – 2.74)
0.150.220.270.03
0.020.670.780.06
Rosiglitazona Odds Ratio(IC 95%)Estudio
GrupoControl p
INFARTO DE MIOCARDIO
J.R.G. JUANATEY C.H.U.Santiago
“The Rosiglitazone Story. Lessons from and FDA Advisory Committee Meeting”WellPoint Observational Study
Fármaco Nº Pactotal IAM
Nº de enferm
Incidencia por
100000 pac/año
IR (IC 95%) Valor P
Rosiglitazona 22050 212 0,73 1,029(0,886-1,194) 0,710
Pioglitazona 23768 232 0,74 1,044(0,905-1,205) 0,553
Otros antidiabéticos orales
120771 866 0,72 1,000
Rosen C J N Engl J Med 2007
J.R.G. JUANATEY C.H.U.Santiago
Riesgo de Enfermedades Cardiovasculares a Largo Plazo con Rosiglitazona
0,1 1 10
A favor Rosiglitazona
A favor Control
Riesgo relativo (95% IC)
Mortalidad Cardiovascular
Fuente Rosiglitazona Control Peso % Riesgo relativo (IC 95%)
Kahn et al, 2006 5/1456(0,3) 12/2895(0,4) 11,83 0,83(0,29-2,35)
Dargie et al, 2007 5/110(4,5) 4/114(3,6) 5,79 1,30(0,36-4,70)
Gerstein et al , 2006 12/2635(0,5) 10/2634(0,4) 14,73 1,20(0,52-2,77)
Home et al, 2007 37/2220(1,7) 46/2227(2,1) 67,65 0,81(0,53-1,24)
Total (IC 95%) 6421 7870 100,00 0,90(0,63-1,26)
Total enfermedades: 59 (rosiglitazona), 72 (control)Test de heterogeneidad; χ2
3= 1,03 (P=0,79), I2=0%Tests efecto total; Z=0,63 (P=0,53)
Rosiglitazona Nº de enf. /Total (%)
Singh S et al JAMA 2007,10:1189-1195
J.R.G. JUANATEY C.H.U.Santiago
VariableGrupo
Rosiglitazona(N=2220)
Grupo control
(N=2227)IR (IC 95%)
Enfermedades adjudicadas nº pacientes
Objetivo primario 217 202 1,08(0,89-1,31) 0,43
MuerteCausas CV 29 35 0,83(0,51-1,36) 0,46Cq causa 74 80 0,93(0,67-1,27) 0,63
IAM 43 37 1,16(0,75-1,81) 0,50IC Congestiva 38 17 2,24(1,27-3,97) 0,006Muerte por causas CV, IAM e ictus
93 96 0,97(0,73-1,29) 0,83
Valor P
Rosiglitazona y Riesgo CVC. Un Análisis Intermedio del Estudio RECORD.
Home P D et al, N Engl J Med 2007;357-1
J.R.G. JUANATEY C.H.U.Santiago
Estudio ProACTIVE.Muerte, IM (incluso Silente) o Ictus
0,0
0,05
0,10
0,15
0 6 12 18 24 30 36
Episodios
Nº enferm Estimación 3-añosPlacebo 358/2633 14,4%Pioglitazona 301/2605 12,3%
IR IC 95% PPioglitazonavs placebo 0,841 0,722-1,981 0,0273
5238 5102 4991 4877 4752 4651 786(256)N Riesgo:
Tiempo desde la randomización (meses)
J.R.G. JUANATEY C.H.U.Santiago
VariableGrupo
Rosiglitazona(N=2220)
Grupo control
(N=2227)IR (IC 95%)
Enfermedades adjudicadas nº pacientes
Objetivo primario 217 202 1,08(0,89-1,31) 0,43
MuerteCausas CV 29 35 0,83(0,51-1,36) 0,46Cq causa 74 80 0,93(0,67-1,27) 0,63
IAM 43 37 1,16(0,75-1,81) 0,50IC Congestiva 38 17 2,24(1,27-3,97) 0,006Muerte por causas CV, IAM e ictus
93 96 0,97(0,73-1,29) 0,83
Valor P
Rosiglitazona y Riesgo CVC. Un Análisis Intermedio del Estudio RECORD.
Home P D et al, N Engl J Med 2007;357-1
J.R.G. JUANATEY C.H.U.Santiago
The Effect of Pioglitazone on Recurrent Myocardial Infarction in 2,445 Patients With Type 2 Diabetes and Previous Myocardial InfarctionTime to Fatal/Nonfatal MI (Excluding Silent MI)
0 6 12 18 24 30 36
2445 2387 2337 2293 2245 2199 399 (139)
Time from Randomization (months)
Kap
lan-
Mei
er E
vent
Rat
e
0.0
0.02
0.04
0.06
0.08
0.10
N at Risk:
HR 95% CI p value
0.72 0.52, 0.99 0.045pioglitazonevs placebo
pioglitazone (65/1230)
placebo (88/1215)
The solid line represents the pioglitazone group; the dashed Iine represents the placebo group. CI = confidence interval; HR = hazard ratio.
Erdmann E et al. Journal of the American College of Cardiology; Vol. 49, No.17, 2007
J.R.G. JUANATEY C.H.U.Santiago
Comparison of Cardiovascular Outcomes in Elderly Patients With Diabetes Who Initiated Rosiglitazone vs Pioglitazone TherapyAssociations of New Pioglitazone vs New Rosiglitazone Use and Subsequent Clinical Outcomes (On-Drug Exposure Models)
IRR (95% CI)Exposure* No. of
PatientsNo. of Events
Event Rates per 1000
Person-Years Crude AdjustedPioglitazone 14 260 885 59.7
Rosiglitazone 14 101 984 69.2 1.17 (1.06-1.28) 1.15 (1.05-1.26)
Pioglitazone 14 260 363 24.7
Rosiglitazone 14 101 374 26.5 1.10 (0.95-1.27) 1.08 (0.93-1.25)
Pioglitazone 14 260 614 42.0
Rosiglitazone 14 101 645 46.0 1.12 (1.00-1.25) 1.13 (1.01-1.26)
Pioglitazone 3009 317 127.5
Rosiglitazone 3163 320 129.4 1.01 (0.87-1.18) 1.04 (0.89-1.22)
Pioglitazone 11 251 297 24.5
Rosiglitazone 10 938 325 28.1 1.19 (1.02-1.40) 1.21 (1.03-1.42)No prior CHF
Prior CHF
Hospitalization for CHF
MI
All-cause mortality
CHF, congestive heart failure; CI, confidence interval; IRR, incidence rate ratio; MI, myocardial infarction.
*Pioglitazone is pioglitazone hydrochloride and rosiglitazone is rosiglitazone maleate.
Winkelmayer WC et al. Arch Intern Med. 2008;168:2368-2375
J.R.G. JUANATEY C.H.U.Santiago
Glitazonas. ¿Efecto de Clase?
J.R.G. JUANATEY C.H.U.Santiago
Glitazonas. ¿Efecto de Clase?
J.R.G. JUANATEY C.H.U.Santiago
10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. UKPDS Follow-upMean Glycated Hemoglobin Levels
A BGly
cate
dH
emog
lobi
n (%
)
Gly
cate
dH
emog
lobi
n (%
)Conventional therapy
Conventional therapy
Metformin
Sulfonylurea–insulin
Glycated hemoglobin levels for patients who were originally assigned to receive either sulfonylurea–insulin or conventional therapy (Panel A) or metformin or conventional therapy (Panel B) are shown.
Holman RR et al. N Engl J Med 2008;359
J.R.G. JUANATEY C.H.U.Santiago
10-Year Follow-up of Intensive Glucose Control in Type 2 DiabetesKaplan–Meier Curves for Four Prespecified Aggregate Clinical OutcomesAny Diabetes-Related End Point Any Diabetes-Related End Point
A BConventional
therapyConventional
therapy
Metformin
Sulfonylurea–insulin
Prop
ortio
n w
ith E
vent
Years since Randomization
P=0.04 P=0.01
Prop
ortio
n w
ith E
vent
Years since Randomization
No. at Risk
Conventional therapy 1138 913 679 370 104 5Sulfonylurea–insulin 2729 2270 1692 933 277 32 144
132
762236300342Metformin
245255333411Conventional therapy
No. at Risk
The proportions of patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D) or who died from any cause (Panels E and F) are shown for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group.
Holman RR et al. N Engl J Med 2008;359
J.R.G. JUANATEY C.H.U.Santiago
10-Year Follow-up of Intensive Glucose Control in Type 2 DiabetesKaplan–Meier Curves for Four Prespecified Aggregate Clinical OutcomesMyocardial Infarction Myocardial Infarction
C D
Conventional therapy
Conventional therapy
MetforminSulfonylurea–insulin
Prop
ortio
n w
ith E
vent
Years since Randomization
P=0.01 P=0.005
Prop
ortio
n w
ith E
vent
Years since Randomization
No. at Risk
Conventional therapy 1138 1013 857 578 221 20Sulfonylurea–insulin 2729 2488 2097 1459 577 66 214
213
16106274317342Metformin
495311360411Conventional therapy
No. at Risk
The proportions of patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D) or who died from any cause (Panels E and F) are shown for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group.
Rury R. Holman et al. N Engl J Med 2008;359
J.R.G. JUANATEY C.H.U.Santiago
10-Year Follow-up of Intensive Glucose Control in Type 2 DiabetesKaplan–Meier Curves for Four Prespecified Aggregate Clinical OutcomesDeath from Any Cause Death from Any Cause
E F
Conventional therapy
Conventional therapy
MetforminSulfonylurea–insulin
Prop
ortio
n w
ith E
vent
Years since Randomization
P=0.006 P=0.002
Prop
ortio
n w
ith E
vent
Years since Randomization
No. at Risk
Conventional therapy 1138 1066 939 665 270 28Sulfonylurea–insulin 2279 2573 2276 1675 680 83 239
246
11124296328342Metformin
7116345387411Conventional therapy
No. at Risk
The proportions of patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D) or who died from any cause (Panels E and F) are shown for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group.
Rury R. Holman et al. N Engl J Med 2008;359
J.R.G. JUANATEY C.H.U.Santiago
Efecto de metformina, glitazonas o ambas sobre la mortalidad después de IAM
No sensibilizante insulina1.00 Thiazolidinedionas
MetforminaAmbos
0.95
Sup
ervi
venc
ia
0.90
0.85
0.800 50 100 150 200 250 300 350
Días tras alta
24,953 diabéticos, seguimiento tras IAM.
SE Inzucchi et al. Diabetes Care 2005; 28:1680–1689
J.R.G. JUANATEY C.H.U.Santiago
GlitazonasGlitazonas ((RosiglitazonaRosiglitazona) ) y y Riesgo CVCRiesgo CVC
... y Finalmente ¿Qué Hacer?... y Finalmente ¿Qué Hacer?
¿Qué dicen las Agencias Regulatorias?
J.R.G. JUANATEY C.H.U.Santiago
FDA News
FDA Decision Nov 14• At this time, FDA has concluded that there isn't
enough evidence to indicate that the risks ofheart attacks or death are different betweenAvandia and some other oral type 2 diabetes treatments. Therefore, FDA has requested thatGSK conduct a new long-term study to evaluatethe potential cardiovascular risk of Avandia, compared to an active control agent. GSK has agreed to conduct the study and FDA will ensureit is initiated promptly.
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html
J.R.G. JUANATEY C.H.U.Santiago
emeA. European Medicines Agency.Press Office
emeA. Recomendación, 24 de EneroAgencia Española de Medicamentos y Productos Sanitarios (28.I.2008)
1. Contraindicación para uso en pacientes con SCA.2. Especial precaución en pacientes cocardiopatía isquémica y arteriopatía periférica sintomática.3. En la ficha técnica se mencionará que no existen datos definitivos sobre el incremento de riesgo de cardiopatía isquémica
J.R.G. JUANATEY C.H.U.Santiago
ADOPT
DREAM CANOE
NAVIGATOR
ACT-NOW
I Glucosa
DMT2
ECV
2005 20072006 2008 20102009
Ensayos Clínicos en el “Continuum Metabólico”
RECORD APPROACH
BARI-2D
VADT
ACCORD
Años 2011
Comparing the effects of insulin-sparing versus insulin-providing therapy on progression of CAD
Determining whether intensive glycemic control benefits CVD
The effects of rosiglitazone in combination with metformin or sulfonylurea on CVD outcomes
and progression of diabetes
Comparing the effects of RSG, MET and glyburideon metabolic and clinical outcomes in type 2 diabetes
Can rosiglitazone and/or ramiprilprevent or reduce the incidence of
diabetes in individuals with IGT or IFG
The effects of treatment strategy on CVD mortality
Can Avandamet prevent progression from
IGT to T2DM?
Can nateglinide and valsartan reduce progression to T2DM and
CV outcomes?
Can pioglitazone reduce conversion from IGT to T2DM?
Effects of rosiglitazoneversus glipizide on
atherosclerosis in T2DM
ROSI vs PIO vs PCB
Gerstein HC, et al. Diabetologia 2004; 47:1519–1527. Viberti G, et al. Diabetes Care 2002; 25:1737–1743. Home PD, et al. Diabetologia 2005; 48:1726–1735. Sobel BE, et al. Circulation 2003; 108:500.
Abraira C, et al. J Diabetes Complications 2003; 17:314–322. http://www.accordtrial.org
J.R.G. JUANATEY C.H.U.Santiago
Control Glucémico en la Cardiopatía Isquémica
Diabetes y Cardiopatía Isquémica
Control Glucémico en Diabéticos con CI
Fármacos antidiabéticos en Pacientes con CI
Prevención integral
J.R.G. JUANATEY C.H.U.Santiago
Effect of a Multifactorial Intervention on Mortality in Type 2 DiabetesChanges in Selected Risk Factors during the Interventional Study and Follow-up Period
0
10
20
30
40
50
60
70
80
90
100
GlycatedHemoglobin
<6,5%
Cholesterol<175 mg/dl
Triglycerides<150mg/dl
Systolic bloodPressure <130
mm Hg
DiastolicBlood
Presssure<80 mm Hg
Patie
nts
(%)
Intensive therapy Conventional therapy
P=0.31
P=0.35 P=0.005
P=0.27
P=0.14
Shows the percentage of patients in each group in whom the treatment goals for the intensive-therapy group were reached at the end of the study. Only one patient (in the intensive-therapy group) reached all five treatment goals at the end of follow-up. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the val-ues for triglycerides to millimoles per liter, multiply by 0.01129. LDL denotes low-density lipoprotein.
Gaede P et al. N Engl J Med 2008; 358:580-91.
J.R.G. JUANATEY C.H.U.Santiago
Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes
Kaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group
Years of Follow-up
Cum
ulat
ive
Inci
denc
e of
Any
C
ardi
ovas
cula
r Eve
nt (%
) Conventional therapy
Intensive therapy
0 1 2 3 4 5 6 7 8 9 10 11 12 13
80
5040302010
7060
0
Years of Follow-upCum
ulat
ive
Inci
denc
e of
Dea
th (%
)
Intensive therapy
0 1 2 3 4 5 6 7 8 9 10 11 12 13
80
5040302010
7060
0
Conventional therapy
No. At Risk
80 78 75 72 65 62 57 39 Conventional therapy 80 72 65 61 56 50 47 31
80 80 77 69 63 51 43 30 Intensive therapy 80 70 60 46 38 29 25 14
A B
Gaede P. et al. N Engl J Med 2008; 358:580-91
J.R.G. JUANATEY C.H.U.Santiago
Effect of a Multifactorial Intervention on Mortality in Type 2 DiabetesKaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group
Years of Follow-up
Cum
ulat
ive
Inci
denc
e of
Any
C
ardi
ovas
cula
r Eve
nt (%
) Conventional therapy
Intensive therapy
0 1 2 3 4 5 6 7 8 9 10 11 12 13
80
5040302010
7060
0
Years of Follow-upCum
ulat
ive
Inci
denc
e of
Dea
th (%
)
Intensive therapy
0 1 2 3 4 5 6 7 8 9 10 11 12 13
80
5040302010
7060
0
Conventional therapy
No. At Risk
80 78 75 72 65 62 57 39 Conventional therapy 80 72 65 61 56 50 47 31
80 80 77 69 63 51 43 30 Intensive therapy 80 70 60 46 38 29 25 14
A B
Gaede p. et al. N Engl J Med 2008; 358:580-91
J.R.G. JUANATEY C.H.U.Santiago
Effect of a Multifactorial Intervention on Mortality in Type 2 DiabetesKaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group
0
5
10
15
20
25
30
35
40D
eath
from
Car
diov
ascu
lar
Cau
ses
Stro
ke
Myo
card
ial
Infa
rctio
n
CA
BG
PCI
Rev
ascu
lariz
atio
n
Am
puta
tion
No.
of C
ardi
ovas
cula
r Eve
nts
Intensive therapy Conventional therapy
Shows the number of events for each component of the composite end point.Gaede P et al. N Engl J Med 2008; 358:580-91.
J.R.G. JUANATEY C.H.U.Santiago
Effect of a Multifactorial Intervention on Mortality in Type 2 DiabetesPatients with Development or Progression of Diabetic Nephropathy, Retinopathy, Autonomic Neuropathy, and Peripheral Neuropathy
0
10
20
30
40
50
60
At 4 Yr At 8 Yr Post-Trial At 13 Yr
No.
of P
atie
nts
Intensive therapy Conventional therapy
0
10
20
30
40
50
60
At 4 Yr At 8 Yr Post-Trial At 13 Yr
No.
of P
atie
nts
Intensive therapy Conventional therapy
0
10
20
30
40
50
60
At 4 Yr At 8 Yr Post-Trial At 13 Yr
No.
of P
atie
nts
Intensive therapy Conventional therapy
Nephropathy Retinopathy
Autonomic Neuropathy
0
10
20
30
40
50
60
At 4 Yr At 8 Yr Post-Trial At 13 Yr
No. o
f Pat
ient
s
Intensive therapy Conventional therapy
Peripheral Neuropathy
Gaede P. et al. N Engl J Med 2008; 358:580-91.
J.R.G. JUANATEY C.H.U.Santiago
Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in DiabetesCategorical Changes in Left Ventricular Mass Index And Intimal Medial Thickness by Treatment Group
Intimal medial thickness
0
20
40
60
80
StandardTreatment (n=230)
AggressiveTreatment (n=224)
Patie
nts,
% Decrease (improved)
No change
Increase (w orsened)
Left ventricular mass index
0
20
40
60
80
StandardTreatment
(n=200)
AggressiveTreatment
(n=202)
Patie
nts,
% Decrease (improved)
No change
Increase (w orsened)
For intimal medial thickness, n=454; P value <.001. For left ventricular mass index, n=402; P value=.17. The "no change" category was defined as ±0.01 mm for intimal medial thickness or ±0.05 gm/m2.7 for left ventricular mass index. P is for trend by each treatment group for intimalmedial thickness and left ventricular mass index.
Howard BV et al. JAMA, April 9, 2008;, Vol 299 1678-1689
J.R.G. JUANATEY C.H.U.Santiago
ADVACNCE.Cardiovascular death
Annual event rate %Hazard ratios
Standard
Intensive
Placebo
Per-Ind
1.14
1.02
0.89
0.870.7
0.9
1.1
1.3BP armAll participants 18% (2 to 32)
Standard 22% (0 to 40)
Intensive 14% (-11 to 34)
Hazard ratio0.5 1.0 2.0
Relative riskreduction (95% CI)
FavoursPer-Ind
FavoursPlacebo
All participants 7% (-11 to 23)Placebo 11% (-14 to 30)
Per-Ind 2% (-28 to 25)
Relative riskreduction (95% CI)
FavoursIntensive
FavoursStandard
Hazard ratio
0.5 1.0 2.0
Glucose arm
1.14
1.02
0.89
0.87
RRR 24%, P=0.04
BPGlucose
P for interaction=0.62
J.R.G. JUANATEY C.H.U.Santiago
Aspirina ClopidogrelTiclopidina
Hipertensión
Terapia Antiaterosclerótica en Diabetes
Agregación y Activación Plaquetaria
Aterosclerosis
HiperglicemiaInsulinorresistencia
Insulina Metformina
TiazolidinedionasSulfonilureasSecretagogos
Nonsulfonilureas
IECAsARA II
β-bloqueantesCalcioantagonistas
Diuréticos
EstatinasFibratos
Tiazolidinedionas?
ModificacionesEstilo de VidaDislipemia
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