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Transcript of LIPID LOWERING IN T2D (The Lower the Better?) CONS… TARGETING HARD CVD END POINTS Charles SAAB MD...
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LIPID LOWERING IN T2DLIPID LOWERING IN T2D(The Lower the Better?)(The Lower the Better?)
CONS…CONS…TARGETING HARD CVD END POINTSTARGETING HARD CVD END POINTS
Charles SAAB MDCharles SAAB MD
Consultant EndocrinologistConsultant Endocrinologist
DCRP Sacre-Coeur University Hospital-LebanonDCRP Sacre-Coeur University Hospital-Lebanon
MGSD-CASABLANCA April 2011MGSD-CASABLANCA April 2011
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WHAT IS THE BEST WAY TO AVOID
INJURIES IF A CAR ACCIDENT OCCURES???
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BEST IS NOT TO LET ACCIDENTS
HAPPENS
AVOID INJURIES
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"The growth of knowledge depends entirely on
disagreement“
Karl R. Popper (28 juillet 1902 à Vienne, Autriche - 17 septembre 1994 à Londres
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DIABETES AND STATIN TTTDIABETES AND STATIN TTTIS IT FOR ALL??IS IT FOR ALL??
YES THE EARLIER THE BETTERYES THE EARLIER THE BETTERINDEPENDENTLY OF LDL LEVELSINDEPENDENTLY OF LDL LEVELS
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24% SE 2.6reduction(P<0.00001)
Baseline STATIN PLACEBO Risk ratio and 95% CIfeature (10269) (10267) STATIN better STATIN worse
Het =0.8c 2
3
0.4 0.6 0.8 1.0 1.2 1.4
LDL (mg/dL)
<100 285 360
100 < 130 670 881
1087 1365130
ALL PATIENTS 2042 2606
(19.9%) (25.4%)
Simvastatin: Vascular Event by LDL
Heart Protection Study: Lancet 2002
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IS CVD ONLY AN LDL MATTER??
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1.00
0.99
0.98
0.97
0.96
0 0 2 4 6 8Years of follow-up
Low CRP-low LDL
Low CRP-high LDL
High CRP-low LDL
High CRP-high LDL
Ridker et al. N Engl J Med 2002;347:1157–65
Pro
bab
ilit
y o
f ev
ent-
free
su
rviv
al
Median LDL 124 mg/dLMedian CRP 1.5 mg/L
CV Event-free Survival Using Combined CRP and LDL-C Measurements
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IDEAL
The Incremental decrease in Endpoints through Aggressive
Lipid Lowering Trial
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IDEAL Study: IDEAL Study: Effect of Treatment on LDL-CEffect of Treatment on LDL-C
Mean LDL-C = 104 mg/dL
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445.
0
70
80
90
100
110
120
130
BaselineWeek 12Year 1 Year 2 Year 3 Year 4 Year 5
LD
L-C
(m
g/d
L)
Atorvastatin 80mg
Simvastatin 20mg
Mean LDL-C = 81 mg/dL
99.8 mg/dl
80 mg/dl
102 mg/dl
79.1 mg/dl
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Copyright restrictions may apply.
`NS
NS
NS
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0
2
4
6
8
10
12
14
16
Barter PJ et al. J Am Coll Cardiol 2006;47:492–499. | Waters DD et al. J Am Coll Cardiol 2006;48:1793–1799.
Major Cardiovascular Events Major Cardiovascular Events According to On-treatment HDL-C: According to On-treatment HDL-C: Treating to New Targets (TNT) TrialTreating to New Targets (TNT) Trial
%
Atorvastatin 10 mgAtorvastatin 10 mg Atorvastatin 80 mgAtorvastatin 80 mgMean LDL-C73 mg/dL
Mean LDL-C99 mg/dL
On-treatment HDL-C (mg/dL)
<40 <40>40-50 >40-50 >50-60 >60>60>50-60
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Major coronary events
50
40
30
20
10
0
0.5(19)
1.0(38)
1.5(58)
2.0(77)
-10
Major vascular events
Reduction in LDL-C mmol/L (mg/dL)
50
40
30
20
10
-10
0
0.5(19)
1.0(38)
1.5(58)
2.0(77)
Reduction in LDL-C mmol/L (mg/dL)
Pro
port
ion
al re
du
cti
on
in
even
t ra
te (
%
SE)
Pro
port
ion
al re
du
cti
on
in
even
t ra
te (
%
SE)
CTT Collaborators. Lancet 2005;366:1267–1278.
Relationship Between Proportional Reduction in Events and Mean LDL-C Reduction at 1 Year
90056 PATIENTS
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a = Statin trials. Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855–1862.
Non
fata
l MI a
nd C
HD
Dea
th
Rel
ativ
e R
isk
Red
uctio
n, %
–20
100
80
60
40
20
0
LDL-C Reduction, %
25 3015 35 4020
LondonOsloMRCLos AngelesUpjohnLRC NHLBIPOSCH4Sa
WOSCOPSa
CAREa
LIPIDa
AF/TexCapsa
HPSa
ALERTa
PROSPERa
ASCOT-LLAa
CARDSa
Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis
Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis
National heart lung blood institute
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Goals for Management of LDL in Patients With Diabetes
Guidelines
LDL-C Goal
Diabetes With CVDa Diabetes Without CVD
ESC/EASD 2007
<70 mg/dL(<1.8 mmol/L)
<97 mg/dL(<2.5 mmol/L)
ADA/AHA/ACC 2007
<70 mg/dL(<1.8 mmol/L)
<100 mg/dL(<2.6 mmol/L)
JBS2 2005 <77 mg/dLb
(<2.0 mmol/L)<77 mg/dLb
(<2.0 mmol/L)
NCEP ATP III 2004
<70 mg/dL(<1.8 mmol/L)
<100 mg/dL(<2.6 mmol/L)
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TTCT/CC CT CC p-value*
n 342 219 211 11
chd present 81 71 70 1 0.033
BMI (kg/m²) 22.1±1.5 22.9±1.3 22.9±1.1 23.1±1.1 0.023
Cholesterol (mg/dl) 270.5±51.2 266.2±89.4 266.4±93.2 262±64.5 ns
LDL 183±46.8 189±54.8 194±53.9 174.6±62.5 ns
HDL 65.5±20.6 53.5±16 54±16 58.2±17.8 0.004
VLDL 22±13.2 23±8.8 23.4±8.8 19.2±4.8 ns
Triglycerides (mg/dl)
112±115.4 118±181.6 118.9±84.5 96.4±23.8 ns
Apo B (mg/dl) 100±22.6 103.3±21.1 103±11.1 111.5±9.8 ns
Apo A1 (mg/dl) 159±26.8 161±24.3 161.1±13.3 159±22.1 ns
Lp(a) (mg/dl) 6±4.2 12±14.1 12.1±8.8 10.7±3.4 ns
ROLE OF GENOTYPE IN CHD
Link E, et al, for the SEARCH Collaborative Group. N Engl J Med 2008;359:789–799. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
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Estimated Cumulative Risk of Myopathy Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of SimvastatinAssociated with Taking 80 mg of Simvastatin
Cumulative No. and Percentages with Myopathy
Year 1 Year 5
GenotypePopulationFrequency no. %
Attributable to genotype no. % of total no. %
Attributable to genotype no. % of total
TT 0.730 12 0.34 0 0 21 0.63 0 0
CT 0.249 17 1.38 12.8 75 32 2.83 24.9 78
CC 0.021 16 15.25 15.6 98 19 18.55 18.4 97
All genotypes 1.000 45 0.91 28.4 63 72 1.56 43.3 60
0
5
10
15
20C
um
ula
tive P
erc
enta
ge o
f Pati
ents
Who H
ave H
ad
a
Myop
ath
y
0 1 2 3 4 5 6
Years since Starting 80 mg of Simvastatin
CC genotype
CT genotype
TT genotype
Link E, et al, for the SEARCH Collaborative Group. N Engl J Med 2008;359:789–799. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
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Slide SourceLipids Online Slide Librarywww.lipidsonline.org
SMOKER EATERNO SPORTHTNOBESEMULTIPLE STROKESSTATIN= 0..DEATH AT WHAT AGE?
DEATH = 91 YO
NO SMOKING !!!!!!LEANJOGGING EVERY DAYHTN=0NO CVD NO DIABETESFIRST MI AT WHAT AGE???
FIRST MI = 50 YO
1874-1965
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Slide Source:Lipids Online Slide Librarywww.lipidsonline.org
WHAT ELSE?? IN T2D LIPID WHAT ELSE?? IN T2D LIPID PROFIL????PROFIL????
CONTROVERSIES IN ACCORD (study)
BP/??
GLUCOSE/??
LIPIDS/??– HDL SHOULD BE INCREASED?– TG SHOULD BE DECREASED?
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Baseline lipids – mg/dLSimvastatin + Fenofibrate
(n=2,765)
Simvastatin(n=2,753)
Overall(n=5,518)
Mean total cholesterol 174.7 175.7 175.2
Mean LDL-C 100.0 101.1 100.6
Mean HDL-C 38.0 38.2 38.1
Median TG 164 160 162
Baseline Characteristics – Lipids
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
ACCORD LipidACCORD Lipid
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Results Results LDL-C target levels were achieved
in both groups
ACCORD LipidACCORD Lipid
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
0 1 2 3 4 5 6 7
No. of PatientsFenofibratePlacebo
Mean
LD
L C
hole
stero
l (m
g/d
L)
Years
LDL-C
27472735
25932591
25052484
24172375
23612364
14771480
796801
248243
0
60
80
100
120
Placebo
Fenofibrate
Lipid levels at study close
Lipid levels at study closeSimvastatin + Fenofibrate
(n=2,765)
Simvastatin(n=2,753)
p value
Mean LDL-C (mg/dL) 81.1 80.0 p=0.16
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RESULTS RESULTS There was a significant improvement
in TG and HDL-C in the combination group
ACCORD LipidACCORD Lipid
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
0 1 2 3 4 5 6 7
No. of PatientsFenofibratePlacebo
Mean
HD
L C
hole
stero
l (m
g/d
L)
Years
HDL-C
27472735
25932591
25052484
24172375
23612364
14771480
796801
248243
037
38
39
40
41
42
43
Placebo
Fenofibrate
0 1 2 3 4 5 6 7
No. of PatientsFenofibratePlacebo
Med
ian T
rig
lyce
rides
(mg
/dL)
Years
Triglycerides
27472735
25932591
25052484
24172375
23612364
14781480
796801
248243
0100
120
140
160 Placebo
Fenofibrate
Lipid levels at study closeSimvastatin + Fenofibrate
(n=2,765)
Simvastatin(n=2,753)
p value
Mean HDL-C (mg/dL) 41.2 40.5 p=0.01
Median triglycerides (mg/dL) 122.0 144.0 p=0.001
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RESULTS Primary endpoint
Major CV events (overall population)
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
ACCORD LipidACCORD Lipid
0
20
40
60
80
100
Pro
port
ion w
ith E
vent
(%)
0 1 2 3 4 5 6 7 8
27652753
26442634
25652528
24852442
19811979
11601161
412395
249245
137131
No. At RiskFenofibratePlacebo
Years
0.92 (95% CI 0.79-1.08),p=0.32
0
10
20
0 1 2 3 4 5 6 7 8
Placebo
Fenofibrate
Major CV events defined as CV death, nonfatal MI and nonfatal stroke
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MY TAILOR IS RICH
LIPID LOWERING SHOULD TARGET EACH T2D PATIENT RISK THE EARLIEST AND NOT TO THE LOWEST