Escolar Documentos
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Epidemiology of CVD
ACC/AHA & other Guidelines
Global perspective
Our Perspective
Story of Statins
The Galaxy Program
Conclusion
Epidemiology
of
CVD
Around the globe
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
cholesterol
History
Joseph Goldstein, who won the Nobel Prize for related work on cholesterol, said of Endo:
"The millions of people whose lives will be extended through statin therapy owe it all to Akira
Endo.”
Why are we giving statins?
High level of evidence was found that statins reduce total mortality in
individuals with a history of prior ASCVD events (e.g., secondary
prevention settings).
NLA 2015
National Lipid Association Recommendations forPatient-Centered
Management of Dyslipidemia Terry A. Jacobson and others published
in Journal of Clinical Lipidology
ADA 2014
American Diabetes Association. Standards of medical care in
diabetes.
KDIGO 2015
Kidney Disease Outcomes Quality Initiative
Evolution of guidelines
NCEP ACC/AHA
NCEP ATP III 2013
ATP II REVISED
1993 2004
Patient centered approach
rather than
one treatment fits all
What’s new in the
guideline…?
Who are to be
benefited
by Statins?
Individuals with
Individuals ≥ 21 years of age
clinical Atherosclerotic
with primary LDL-C ≥ 190
Cardiovascular Disease
mg/dl
(ASCVD)
Evaluate primary
for cause secondary
IIa
IB IB
B
Primary prevention in
patients with diabetes
Diabetes
LDLcholesterol
70-189 mg/dl
<40 yrs,
Ageyrs
40-75 >75yrs
High intensity
Moderate statins Balance between
Statins
intensity
statins with risk
ASCVDbenefits
and adverse effects
>7.5%
IIa
IA IIa B
C
LDLcholesterol
Patients without diabetes,primary prevention
70-189 mg/dl
>7.5
10 yr ASCVD risk estimate 5-7.5%
%
40-75 >75 40-75 >75
Ageyrs
of the patient yrs
yrs yrs
Assess
Moderate
Moderate to
to
Moderate risks
high intensity
high intensity
Assess intensity benefits
therapy
therapy risk, therapy
benefits
IIa
IA B
High- Moderate – and
Low Intensity Statin
Therapy
Clinical application by
Statin dose
STATINS
HIGH INTENSITY MODERATE INTENSITY LOW INTENSITY
THERAPY THERAPY THERAPY
Daily dose lowers LDL-C Daily dose lowers LDL –C Daily dose lowers LDL –C
on average,by on average,by <30%
approximately ≥50% approximately 30-50%
Atorvastatin (40) 80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg
Rosuvastatin 20 mg Rosuvastatin (5) 10 mg Pravastatin 10-20 mg
Simvastatin 20-40 mg Lovastatin 20 mg
Pravastatin 40 (80) mg Fluvastatin 20-40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Side-effects and safety
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl
ubiquinones pyrophosphate
farnesyl pyrophosphate dolichols
cholesterol
Fluvastatin
Atorvastatin Rosuvastatin
Pravastatin
B M
Y
Lovastatin
Cerivastatin
Simvastatin
Rosuvastatin:
A new hydrophilic statin – single enantiomer
Statin Pharmacophore
Relative lipophilicity *
O Ca 2.0
(3R, 5S) HO
O cerivastatin
1.5
OH simvastatin
1.0 fluvastatin
F atorvastatin
C H3 0.5
0.0
C
N N rosuvastatin
H3 -0.5
H3C N pravastatin
-1.0
S C
H3 * log D at pH 7.4
O O
Buckett et al., (2000); Mc
Rosuvastatin:Hepatoselective
Cholesterol synthesis inhibited in hepatocytes at
1000-fold lower concentrations than fibroblasts
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
140
120
% of Control Fibroblasts IC50 = 331
Mean nM
100 Hepatocytes IC50= 0.2 nM
80
60
40
20
0
0 0.1 1 10 100 1000 10000
Concentration (nM) 100000
Buckett et al., (2000)
Cerivastatin: Non hepatoselective
Cholesterol synthesis inhibited in fibroblasts
and hepatocytes at similar concentrations
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
140
120
% of Control Fibroblasts IC 50= 1.3 nM
Mean
100
Hepatocytes IC50= 2.4
nM
80
60
40
20
0
0 0.01 0.1
1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
Rosuvastatin : X-Ray crystallography provides
molecular rationale for potent enzyme
inhibition
The rosuvastatin:
HMG-CoA reductase
complex has more
bonding interactions
than any other
statin
binding interaction
Arg568 and sulphone
Prava ***
44.1
100
*P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin
McTaggart et al., (2001)
Pharmacologic properties of Statins
Lipophilicity
-0.3 +4.1 +3.2 +4.3 -0.2 +4.7
(log P)
IC50(nm)
5 8 28 NA NA 11
Potency
20
Elimination, %
10 2 5 10 20 13
90 96 95 70 70 80
Urine
Feces
T homas N. Riley, PhD & Jack DeRuiter, PhD (2004)
Statin Dose Required to
Achieve 45–50% LDL-C Reduction
10 20 40 80 mg
Rosuvastatin
Atorvastatin
Simvastatin
10 20 40
mg mg mg
* † ‡
10 20 40 80
mg mg mg
mg Rosuvastatin
Atorvastatin
10 20 40 80 Simvastatin
mg mg mg mg Pravastatin
10
20 40
mg Rosuvastatin 10 mg (–46%)
mg mg
*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg
†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg
‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg
100%
P-values
***p<0.002
90% CRESTOR 10 mg
vs. atorvastatin
10 mg pravastatin
10, 20 & 49 mg and
80% * simvastatin 10, 20,
80 mg & 40 mg
% patients reaching LDL-C
70%
40 mg
10 mg
80 mg
60% Usual start doses
20 mg
50%
40 mg
10 mg
40%
20 mg
30%
goal*
20% 40 mg
10 mg
n=160
10% n= n= n= 20 mg
20
10
n=535 n=923
n=528
0
10 10 20
Dose (mg/day)
•high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L)
60 64
51
40 49
20
(%)
100 *
90 *
88
84 *
80
76
70 69
Patients 60 62
at goal
(%) 50
40
30
20
10
0
R10 A10 A20 S20 P40
*p<0.0001 (R10 vs A10, S20 & P40) 1998 European goal <3.0 mmol/l (116 mg/dl)
Patients 60
at goal
50
(%)
40
30
20
10
0
AD1o0se A(m10g) A20 A20 A20 S20 S20 P40 P40
R10 A10 R10 R20 A20 R10 S20 R10 P40
vs A10/A10;
vs
A20/A20;
10 vs S20/S20 and P40/R10 vs P40/P40)
al <3.0 mmol/l (116 mg/dl)
Pleiotropic Effects of Rosuvastatin
in Animal Models of Vascular Disease
eNOS, NO availability
leukocyte-endothelial interactions
superoxide, oxidative stress
Preservation of vascular function in
hypertension and insulin-
resistance
Protection against ischaemia-reperfusion
injury
Protection of kidney function and inhibition
of renal fibrosis and glomerulosclerosis
Statins – Therapeutic Ratio
Adverse Effects
Therapeutic
Effects i sk
R
fi t
Be ne
Muscle
Liver
Cardiovascular
protection Drug interactions
Rosuvastatin Tolerability and Safety –
Withdrawals due to Adverse Events
10
Percentage of patients with an adverse event
9 leading to withdrawal
8
7
6
Percentage of
5
4
patients
2.9% 3.2%
3 2.5% 2.5%
2
10-80 mg
10-40 mg 10-80 mg 10-40 mg
1
0
rosuvastatin atorvastatin simvastatin pravastatin
(n=3074) (n=2899) (n=1457) (n=1278)
1.5
1.0
(%)
0.5
0.0
20 30 40 50 60 70
LDL-C reduction (%)
Fatal cases of 19 3 14 0 6 31 0
rhabdomyolysis
No. of
prescriptions 99,197
81,364 116,145 37,392 140,360 9,815 10,100
dispensed since
marketing
began
(in thousands)
prescriptions)
*worldwide prescriptions
#Netherlands (MR ref state)
Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.
Rosuvastatin Tolerability and Safety
- Liver Effects
Elevations in liver transaminase levels are an infrequent
but recognized complication of treatment with statins
Incidence of clinically significant increases in serum
transaminases* with rosuvastatin 10–40 mg in clinical
trials was low (0.2%) which is similar to that seen with
other currently marketed statins1,2
As with other statins:
– liver function tests recommended
– caution in patients who consume excessive quantities of
alcohol and/or have a history of liver disease
– contraindicated in patients with active liver disease
2.0
1.5
1.0
0.5
(%)
0.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent elevation is elevation to >3 x ULN on 2 successive occasions
Contraindication:
• Cyclosporin – 7x increase in rosuvastatin AUC
• ANY fibrate with rosuvastatin 40 mg
Rosuvastatin: Limited drug-drug interactions
No clinically significant interactions seen or expected with:
• Fluconazole / Ketoconazole / Itracnoazole
• Fenofibrate
• Digoxin
• Drugs mediated by cytochrome P450 metabolism
Interactions with limited clinical significance:
• Oral contraceptive pill - ethinyl oestradiol and norgestrel levels Antacid - 50%
• rosuvastatin levels
• INR
Interactions resulting in not recommended for use:
Lifestyle modification
remains the foundation of
the management of blood
cholesterol.
THANK YO ALL!