Transcript Diovan Value Dossier

Lipids:
Is Lower Better For Diabetic Patients?
Prof. Samir Helmy Assaad -Khalil
Department of Internal Medicine
Unit of Diabetes, Lipidology & Metabolism
Alexandria University, Alexandria, Egypt
MGSD Morocco; Friday, April 29, 2011
Agenda
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
Epidemiological data
EBM derived from clinical trials
Evidence in patients with T2DM
What is Desirable Cholesterol?
Elevated Cholesterol Is a Risk Factor
for Cardiovascular Disease (CVD)
Elevated serum
cholesterol
is associated with
increased
risk of1–3
 CHD
 Reinfarction
 CVD



mortality4
All-cause
CHD
Stroke
MRFIT (N=350,977)4
50
CVD Mortality Ratea

40
30
20
10
0
<160
160–199
200–239
(4.13) (4.13–5.14) (5.17–6.18)
Serum Cholesterol,
mg/dL (mmol/L)
CHD=coronary heart disease; MRFIT=Multiple Risk Factor Intervention Trial.
1. Kannel WB. Am J Cardiol. 1995;76:69C–77C; 2. Anderson KM et al. JAMA. 1987;257:2176–2180; 3. Kannel WB et al. Ann Intern
Med. 1971;74:1–12; 4. Neaton JD et al. Arch Intern Med. 1992;152:1490–1500.
240
(6.20)
Age Adjusted 10-Year Death
Rates, % of Population
Correlation Between LDL-C & Cardiovascular
Mortality: The Framingham Study1
20
Men
Women
17.3
15
11.3
10.6
10
7.3
6.5
5
2.3
0
(n=11,142a) (n=15,835a)
(n=10,384a) (n=10,455a)
<130 mg/dL
130–159 mg/dL
≥160 mg/dL
(<3.4 mmol/L)
(3.4–4.11 mmol/L)
(≥4.14 mmol/L)
aNs
refer to person-years.
1. Wilson PWF et al. Circulation. 1998;97:1837–1847.
(n=8,628a)
(n=11,767a)
Log Linear Relationship Between LDL-C and
Relative Risk of CHD1
Relative Risk of CHD,
Log Scale
3.7
2.9
2.2
1.7
1.3
1.0
0
40
70
100
130
160
190
(1.0)
(1.8)
(2.6)
(3.4)
(4.1)
(4.9)
LDL-C, mg/dL (mmol/L)
CHD=coronary heart disease.
Log-linear relationship between LDL-C levels and relative risk of CHD. This relationship is consistent with a large body of
epidemiologic data and with data available from clinical trials of LDL-lowering therapy. These data suggest that for every 30 mg/dL
change in LDL-C, the relative risk of CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C=40 mg/dL.
1. Grundy SM et al. Circulation. 2004;110:227–239.
Reprinted with permission ©2004, American Heart Association, Inc.
Is Lower LDL-C Better?1
Relative Risk of CHD,
Log Scale
3.7
–30%
2.9
CHD risk
2.2
–30 mg/dL
1.7
1.3
1
40
70
100
130
160
190
(1.0)
(1.8)
(2.6)
(3.4)
(4.1)
(4.9)
LDL-C, mg/dL (mmol/L)
CHD=coronary heart disease.
1. Grundy SM et al. Circulation. 2004;110:227–239.
Reprinted with permission ©2004, American Heart Association, Inc.
Correlation Between LDL-C Lowering &
Decreased CHD Risk in Primary &
Secondary Prevention Trials With Statins1–3
30
Statin
Placebo
Event, %
25
20
15
PROVE-IT
(Atv)
5
IDEAL
(Atv)
TNT
(Atv
80 mg)
0
0
Secondary
Prevention
4S
NCEP 2004
10
4S
NCEP 2001
IDEAL CARE
(Sim)
LIPID
CARE
LIPID
TNT
(Atv 10 mg)
HPS PROVE-IT (Pra)
AFCAPS
ASCOT
HPS
WOSCOPS
AFCAPS
WOSCOPS
Primary
Prevention
ASCOT
40
60
80
100
120
140
160
180
200
(1.0)
(1.6)
(2.1)
(2.6)
(3.1)
(3.6)
(4.1)
(4.7)
(5.2)
Mean Treatment LDL-C at Follow-up, mg/dL (mmol/L)
Reproduced from Rosenson. (2004).1
CHD=coronary heart disease; Atv=atorvastatin; Pra=pravastatin; Sim=simvastatin; PROVE-IT=Pravastatin or AtorVastatin Evaluation
and Infection Therapy; IDEAL=Incremental Decrease in Endpoints through Aggressive Lipid Lowering; ASCOT=Anglo-Scandinavian
Cardiac Outcomes Trial; AFCAPS=Air Force Coronary Atherosclerosis Prevention Study; 4S=Scandinavian Simvastatin Survival Study;
CARE=Cholesterol And Recurrent Events Trial; HPS=Heart Protection Study; LIPID=Long-term Intervention with Pravastatin in
Ischaemic Disease; TNT=Treating to New Targets: WOSCOPS=West of Scotland Coronary Prevention Study.
1. Rosenson RS. Expert Opin Emerg Drugs. 2004;9(2):269–279; 2. LaRosa JC et al. N Engl J Med. 2005;352(14):1425–1435; 3. Pedersen
TR et al. JAMA. 2005;294(19):2437–2445.
Nonfatal MI and CHD Death
Relative Risk Reduction, %
Correlation Between LDL-C Lowering & Decreased CHD Risk
According to Treatment Modality in a Meta-Regression Analysis1,a
100
80
60
40
20
0
–20
15
20
25
30
LDL-C Reduction, %
35
40
London
Oslo
MRC
Los Angeles
Upjohn
LRC
NHLBI
POSCH
4Sb
WOSCOPSb
CAREb
LIPIDb
AF/TexCapsb
HPSb
ALERTb
PROSPERb
ASCOT-LLAb
CARDSb
Reprinted from Journal of the American College of Cardiology, 46(10), Robinson JG, Smith B, Maheshwari N, et al, Pleiotropic effects of statins: benefits
beyond cholesterol reduction? A meta-regression analysis, 1855–1862, Copyright © (2005), with permission from Elsevier.
CHD=coronary heart disease; MI=myocardial infarction; MRC=Medical Research Council; LRC=Lipid Research Clinics; NHLBI=National Heart, Lung, and Blood
Institute; POSCH=Program on the Surgical Control of the Hyperlipidemias; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland
Coronary Prevention Study; CARE=Cholesterol And Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease;
AF/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=Heart Protection Study; ALERT=Assessment of LEscol in Renal
Transplantation; PROSPER=PROspective Study of Pravastatin in the Elderly at Risk; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering
Arm; CARDS=Collaborative Atorvastatin Diabetes Study.
aAnalysis included 19 trials of high-risk primary prevention and secondary prevention (CHD, cardiovascular disease, renal transplant, diabetes) patients; bStatin
trials.
Robinson JG et al. J Am Coll Cardiol. 2005;46(10):1855–1862.
Relative Risk Reduction, %
Each LDL-C Reduction of 1 mmol/L (39 mg/dL)
Reduced CHD Risk by Over 20% in a MetaAnalysis1,a
0
CHD Eventsb
CHD Mortality
–25.5
–26.0
–26.5
–27.0
–26.6
–27.5
–28.0
–28.8
–28.0
CHD=coronary heart disease.
aMeta-analysis
of 62 randomized, controlled clinical studies that included 216,616 patients with CHD (secondary prevention),
without CHD (primary prevention), or with or without CHD.
bFatal or nonfatal myocardial infarction.
1. Gould AL et al. Clin Ther. 2007;29(5):778–794.
Each LDL-C Reduction of 1 mmol/L (39 mg/dL) Reduced Major
Coronary Eventsa by 23% in a Meta-Analysisb of Statin Trials1
Patients With Major
Coronary Events, %
12
P<0.001
Statin vs Control
10

9.8
7.4
8
6
Each 1 mmol/L
(39 mg/dL) reduction
also reduced

All-cause mortality
(P<0.0001)

CHD mortality
(P<0.0001)

Nonvascular mortality
(P=NS)
4
2
0
Pooled Statin Groups Pooled Controlc Groups
(n=45,054)
(n=45,002)
CHD=coronary heart disease.
aMajor
coronary event=nonfatal myocardial infarction or death due to CHD.
of 14 trials of patients with CHD (47%), history of diabetes (21%), and history of hypertension (55%).
cIn the 14 trials analyzed, the control group was placebo in 11 trials, lower statin doses in 1 trial, no treatment in 1 trial, and usual care in 1
trial.
bMeta-analysis
1. Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2005;366:1267–1278.
Reducing LDL-C by 1 mmol/L Continued to Reduce IHDa Risk
During Each Year of Treatment in a Meta Analysis1,b
Years of Treatment
Risk Reduction, %
0
Year 1
Year 2
Years 3–5
–10
–11
–20
–30
–24
–33
–40
IHD=ischemic heart disease.
aIHD
Year 6
and After
death and nonfatal myocardial infarction.
of 58 trials.
bMeta-analysis
1. Law MR et al. BMJ. 2003;326:1423–1427.
–36
The 4S Diabetes Sub-study
(n=202)
P=0.087
P=0.002
P=0.018
The Role of Lipid-lowering Therapy in Preventing CHD in
Patients with Type 2 Diabetes : A Meta-analysis
D.G. Karalis. Clin. Cardiol. 31, 6, 2008: 241–248
The Role of Lipid-lowering Therapy in Preventing CHD in
Patients with Type 2 Diabetes : A Meta-analysis (continued)
D.G. Karalis. Clin. Cardiol. 31, 6, 2008: 241–248
What Is the Ideal Level of LDL Cholesterol
An Ideal Level of LDL Cholesterol should
be between 40-70 mg/dL
“Normal” Plasma Cholesterol
Plasma cholesterol level mg/dl (mmol/l)
700
(18.0)
FH Homozygotes
Physiologic level for
plasma LDL-Cholesterol
as predicted from receptor studies
25 mg/dl (0.65mmol/l)
300
(7.7)
FH Heterozygotes
200
(5.2)
Guinea pig
150
(3.9)
Rat
Sheep
Cow
Rabbit
Camel
Pig
Normal Adults
100
(2.6)
50
(1.3)
0
Newborns
What is Desirable Cholesterol?
Evolution of NHLBI Supported Guidelines
Intensive LDL-C Goals for High Risk Patients
Recommended LDL-C treatment goals
ATP III
Update 20041
<100 mg/dL:
Patients with CHD or
CHD risk equivalents
(10 year risk >20%)1
<70 mg/dL:
Therapeutic option
for very high risk
patients1
AHA/ACC
guidelines
for patients with
CHD*,2
<100 mg/dL
<70 mg/dL
2006
Update
<100 mg/dL:
Goal for all patients
with CHD,2
<70 mg/dL:
A reasonable goal
for all patients with
CHD2
If it is not possible to attain LDL-C <70
mg/dL because of a high baseline LDL-C,
it generally is possible to achieve LDL-C
reductions of >50% with more intensive
LDL-C lowering therapy, including drug
combinations.
*And other forms of atherosclerotic disease.2
 Factors that place a patient at very high risk: established cardiovascular disease plus: multiple
major risk factors (especially diabetes); severe and poorly controlled risk factors (e.g.,
cigarette smoking); metabolic syndrome (triglycerides ≥200 mg/dL + nonHDL-C ≥130
mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1
1. Grundy SM et al. Circulation 2004;110:227239.
2. Smith SC Jr et al. Circulation 2006; 113:23632372.
The relationship between mean LDL-C and change in
percent
atheroma volume (PAV) in IVUS studies†
2
REVERSAL5
1.5
pravastatin
CAMELOT4
placebo
Change in
Percent
Atheroma
Volume*
(%)
1
ACTIVATE1
placebo
0.5
A-Plus2
REVERSAL5
placebo
Progression
atorvastatin
0
50
60
70
90
Mean LDL-C (mg/dL)
-0.5
-1
80
100
110
120
Regression
ASTEROID3
rosuvastatin
†ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but
included placebo arms who received background statin therapy (62%, 80% and 84% respectively).
*Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT
1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al. JAMA 2006;295 (13):15561565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080
Conclusion
 Epidemiological data
 Findings in other species
 EBM derived from clinical trials
 Evidence in patients with T2DM
 Studies aiming at regression of atheroma volume

All support the view of: “The
lower the
better in the context of lipids in patients with
diabetes”
Thank You!