LIPID LOWERING IN T2D
(The Lower the Better?)
CONS…
TARGETING HARD CVD END POINTS
Charles SAAB MD
Consultant Endocrinologist
DCRP Sacre-Coeur University Hospital-Lebanon
MGSD-CASABLANCA April 2011
WHAT IS THE BEST WAY TO
AVOID
INJURIES IF A CAR
ACCIDENT OCCURES???
BEST IS NOT TO
LET ACCIDENTS
HAPPENS
AVOID INJURIES
"The growth of knowledge
depends entirely on
disagreement“
Karl R. Popper
(28 juillet 1902 à Vienne, Autriche - 17 septembre 1994 à Londres
DIABETES AND STATIN TTT
IS IT FOR ALL??
YES THE EARLIER THE BETTER
INDEPENDENTLY OF LDL LEVELS
Simvastatin: Vascular Event by LDL
Baseline
feature
STATIN
(10269)
PLACEBO
(10267)
Risk ratio and 95% CI
STATIN better
STATIN worse
LDL (mg/dL)
<100
285
360
100 < 130
670
881
130
1087
1365
ALL PATIENTS
2042
2606
(19.9%)
2
Het c 3 =0.8
24% SE 2.6
reduction
(P<0.00001)
(25.4%)
0.4
0.6
0.8
1.0
1.2
1.4
Heart Protection Study: Lancet 2002
IS CVD
ONLY AN LDL MATTER??
CV Event-free Survival Using Combined CRP
and LDL-C Measurements
Probability of event-free survival
1.00
Low CRP-low LDL
0.99
Low CRP-high LDL
0.98
High CRP-low LDL
0.97
Median LDL 124 mg/dL
Median CRP 1.5 mg/L
0.96
High CRP-high LDL
0
0
2
4
Years of follow-up
6
8
Ridker et al. N Engl J Med 2002;347:1157–65
IDEAL
The Incremental decrease in
Endpoints through Aggressive
Lipid Lowering Trial
IDEAL Study:
Effect of Treatment on LDL-C
Atorvastatin 80mg
Simvastatin 20mg
130
LDL-C (mg/dL)
120
110
Mean LDL-C = 104 mg/dL
102 mg/dl
100
90
99.8 mg/dl
Mean LDL-C = 81 mg/dL
80
70
0
79.1 mg/dl
80 mg/dl
BaselineWeek 12 Year 1 Year 2 Year 3 Year 4 Year 5
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445.
`NS
NS
NS
Copyright restrictions may apply.
Major Cardiovascular Events
According to On-treatment HDL-C:
Treating to New Targets (TNT) Trial
16
14
12
Atorvastatin 10 mg
Mean LDL-C
99 mg/dL
Atorvastatin 80 mg
Mean LDL-C
73 mg/dL
%
10
8
6
4
2
0
<40 >40-50 >50-60 >60
<40 >40-50 >50-60 >60
On-treatment HDL-C (mg/dL)
Barter PJ et al. J Am Coll Cardiol 2006;47:492499. | Waters DD et al. J Am
Coll Cardiol 2006;48:17931799.
Relationship Between Proportional Reduction in
Events and Mean LDL-C Reduction at 1 Year
Proportional reduction in event rate (%SE)
Major coronary events
50
40
30
20
10
0
-10
0.5
1.0
(19) (38)
1.5
(58)
Reduction in
LDL-C mmol/L (mg/dL)
2.0
(77)
Proportional reduction in event rate (%SE)
90056 PATIENTS
Major vascular events
50
40
30
20
10
0
-10
0.5
(19)
1.0
(38)
1.5
(58)
2.0
(77)
Reduction in
LDL-C mmol/L (mg/dL)
CTT Collaborators. Lancet 2005;366:1267–1278.
Nonfatal MI and CHD Death
Relative Risk Reduction, %
Correlation Between LDL-C Lowering and Decreased CHD Risk According
to Treatment Modality in a Meta-Regression Analysis
100
National heart lung blood institute
80
60
40
20
0
–20
15
20
25
30
LDL-C Reduction, %
a = Statin trials.
Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855–
1862.
35
40
London
Oslo
MRC
Los Angeles
Upjohn
LRC
NHLBI
POSCH
4Sa
WOSCOPSa
CAREa
LIPIDa
AF/TexCapsa
HPSa
ALERTa
PROSPERa
ASCOT-LLAa
CARDSa
Goals for Management of LDL in Patients With
Diabetes
Guidelines
ESC/EASD
2007
LDL-C Goal
Diabetes With CVDa Diabetes Without
CVD
<70 mg/dL
<97 mg/dL
(<1.8 mmol/L)
(<2.5 mmol/L)
ADA/AHA/AC
C 2007
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
JBS2 2005
<77 mg/dLb
<77 mg/dLb
(<2.0 mmol/L)
(<2.0 mmol/L)
<70 mg/dL
<100 mg/dL
(<1.8 mmol/L)
(<2.6 mmol/L)
NCEP ATP III
2004
ROLE OF GENOTYPE IN CHD
TT
CT/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
262±64.5
ns
Cholesterol (mg/dl)
270.5±51.2 266.2±89.4 266.4±93.2
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
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.
Estimated Cumulative Risk of Myopathy
Associated with Taking 80 mg of Simvastatin
Cumulative Percentage of
Patients Who Have Had a
Myopathy
20
CC genotype
15
10
5
CT genotype
0
TT genotype
0
1
2
3
4
5
Years since Starting 80 mg of Simvastatin
6
Cumulative No. and Percentages with Myopathy
Year 1
Population
Frequency
no.
%
TT
0.730
12
0.34
0
CT
0.249
17
1.38
CC
0.021
16
15.25
All genotypes
1.000
45
0.91
Genotype
Year 5
Attributable to genotype
no.
% of total
Attributable to genotype
no.
% of total
no.
%
0
21
0.63
0
0
12.8
75
32
2.83
24.9
78
15.6
98
19
18.55
18.4
97
28.4
63
72
1.56
43.3
60
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.
SMOKER
EATER
NO SPORT
HTN
OBESE
MULTIPLE STROKES
STATIN= 0..DEATH AT WHAT AGE?
NO SMOKING !!!!!!
LEAN
JOGGING EVERY DAY
HTN=0
NO CVD
NO DIABETES
FIRST MI AT WHAT AGE???
DEATH = 91 YO
FIRST MI = 50 YO
1874-1965
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
WHAT ELSE?? IN T2D LIPID
PROFIL????
CONTROVERSIES IN ACCORD (study)
BP/??
GLUCOSE/??
LIPIDS/??
– HDL SHOULD BE INCREASED?
– TG SHOULD BE DECREASED?
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Baseline Characteristics –
Lipids
Baseline lipids – mg/dL
Simvastatin +
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
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
ACCORD Lipid
Results
ACCORD Lipid
LDL-C target levels were achieved
in both groups
Simvastatin +
Fenofibrate
(n=2,765)
Lipid levels at study close
Simvastatin
(n=2,753)
p value
80.0
p=0.16
Lipid levels at study close
Mean LDL-C (mg/dL)
81.1
Mean LDL Cholesterol (mg/dL)
LDL-C
120
Placebo
100
80
Fenofibrate
60
0
0
No. of Patients
Fenofibrate
2747
Placebo
2735
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
1
2
3
4
5
6
7
2361
2364
1477
1480
796
801
248
243
Years
2593
2591
2505
2484
2417
2375
RESULTS
There was a significant improvement
in TG and HDL-C in the combination group
ACCORD Lipid
Simvastatin +
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
Triglycerides
43
42
Median Triglycerides (mg/dL)
HDL-C
Mean HDL Cholesterol (mg/dL)
Lipid levels at study close
Fenofibrate
41
40
39
38
Placebo
37
0
0
No. of Patients
Fenofibrate
2747
Placebo
2735
1
2
3
2593
2591
2505
2484
2417
2375
4
5
6
7
2361
2364
1477
1480
796
801
248
243
Years
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
Placebo
160
140
120
Fenofibrate
100
0
0
No. of Patients
Fenofibrate
2747
Placebo
2735
1
2
3
2593
2591
2505
2484
2417
2375
4
5
6
7
2361
2364
1478
1480
796
801
248
243
Years
RESULTS
ACCORD Lipid
Primary endpoint
Major CV events (overall population)
Proportion with Event (%)
100
20
80
Placebo
10
Fenofibrate
60
0
0
40
1
2
3
4
5
6
7
8
0.92 (95% CI 0.79-1.08),
p=0.32
20
0
0
No. At Risk
Fenofibrate
Placebo
1
2
3
4
5
6
7
8
249
245
137
131
Years
2765 2644 2565 2485 1981 1160 412
2753 2634 2528 2442 1979 1161 395
Major CV events defined as CV death, nonfatal MI and nonfatal stroke
ACCORD Study Group. N Engl J Med March 14, 2010. Epub.
MY TAILOR IS RICH
LIPID LOWERING SHOULD TARGET
EACH T2D PATIENT RISK THE EARLIEST
AND NOT TO THE LOWEST