CRE/006/FEB14-FEB15/BR

CRE/005/FEB14-FEB15/BR CRE/006/FEB14-FEB15/BR

Lipid Treatment
The Importance of Potential Statin in
Global burden of CVD due to atherosclerosis

Figure : Age-standardized deaths due to cardiovascular disease (rate per 100,000), 2004

Kelly et al., 2010. Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global
Health. National Academies Press (US);
Burden of atherosclerosis in South East Asia

Figure 1. Age-standardized death rates per 100 000 for stroke (left) and CHD (right) across countries in different regions of Asia in 2002. Middle Eastern countries ( ), Central
Asian countries (p), South Asian countries ( ), Southeast Asian countries (o),East Asian countries (1), and non-Asian countries (open bars). UAE indicates United Arab Emirates;
USA, United States of America;and UK, United Kingdom1.

China- Increase in the CHD rate from 46 per 100,000 men to 81 per 100,000 men and 26 per 100,000 to 35 per
100,000 women in 10 years2
India- 41% of urban male and and 37% female deaths due to CVD2
Singapore- CAD rate doubled in Singapore in the last 30 years 3
1. Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular Disease and Risk Factors in Asia: A Selected Review. Circulation.
2008;118(25):2702-2709.
2. Celermajer et al., Cardiovascular Disease in the Developing World Prevalences, Patterns, and the Potential of Early Disease
Detection. J Am Coll Cardiol 2012;60:1207–16 . 3. Enas et al., Dyslipidaemia among Indo-Asians strategies for identification and
management. British Journal of Diabetes & Vascular Disease 2005 5: 81
 Burden of CVD in Asia

1. http://www.pace-cme.org/d/175/cv-risk-and-lipids-in-asia Accessed 14th march 2014

New Paradigm: Multi-Risk Factor Approach

Traditional CVD New CVD risk New targets and

perspective perspective goals for therapy
Hypercholesterolemia

DM
Gender
Age Reduction of
Diabetes

total CVD risk

HTN

Hyper- HTN
cholesterol- is the primary
emia
goal
Organ
damage

Smoking

Multiple independent
Integrated identification and management of
risk factors (silo
risk factors contributing to CVD risk
approach)
(global approach)
CVD: Cardiovascular disease;
DM: Diabetes mellitus; HTN: Hypertension
Volpe M, et al. J Human Hypertens. 2008;22:154–157.
On-Treatment LDL-C is Closely Related to CHD
Events in Statin Trials – Lower is Better
30
4S - Placebo

25 Rx - Statin therapy
PRA – pravastatin Secondary Prevention
ATV - atorvastatin
4S - Rx
20

LIPID - Placebo
15
LIPID - Rx CARE - Placebo
CARE - Rx CORONA - Placebo
CORONA - Rx HPS - Placebo Primary Prevention
HPS - Rx TNT – ATV10
10 PROVE-IT - PRA
TNT – ATV80 WOSCOPS – Placebo
PROVE-IT – ATV AFCAPS - Placebo
6
5 AFCAPS - Rx WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx
0
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)
LDL-C achieved mg/dL (mmol/L)

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004; 9(2): 269-279
LaRosa JC et al. N Engl J Med 2005; 352: 1425-1435
On-Treatment LDL-C is Closely Related to Stroke Events
in Statin Trials – Lower is Better
Relationship between protection from stroke events and LDL-C reduction

1.2
GISSI
1.0 PROSPER
ALLHAT-LLT WOSCOPS

0.8 LIPID AFCAPS/TexCAPS

HPS ASCOT-LLA
4S
0.6 CARE

GREACE MIRACL
0.4

0.2
-10 -20 -30 -40 -50
Reduction in LDL-C (%)
Amarenco P, et al. Stroke 2004;35:2902-2909
 Relationship Between Proportional Reduction in
Events and Mean LDL-C Reduction at 1 Year
A prospective meta-analysis of data from 90,056 individuals from 14 statin trials

A 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a …..

…. 23% reduction in …. 21% reduction in
50 major coronary events 50 major vascular events

40 40
Proportional reduction in

Proportional reduction in
30
event rate (%SE)

30

event rate (%SE)

20 20

10 10

0 0
0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0
(19) (38) (58) (77) (19) (38) (58) (77)
-10 -10
Reduction in Reduction in
LDL-C mmol/L (mg/dL) LDL-C mmol/L (mg/dL)

CTT Collaborators. Lancet 2005;366:1267–1278.

 LDL Cholesterol
is
The Primary Target

in Dyslipedmia Treatment

NCEP ATP III 2003/ NCEP ATP III Update 2004

ADA/ACC Guideline Update for Secondary Prevention 2006
ESC/EAS Guidelines for the management of Dyslipidemias 2011
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults
 Who is at Risks?
European Society of
Cardiology Guidelines1 ACC/AHA Guidelines2

• Documented CVD
• DM (type 1 or 2) with one or more CV Patients with clinical ASCVD
Very high risk risk factors and/or target organ damage
• Severe CKD
• A calculated SCORE ≥10%.

•Markedly elevated single risk factors

•DM (type 1 or 2) but without CV risk Patients with primary elevation of LDL-C of >190 mg/dL
factors or target organ damage
High risk
•Moderate CKD
•SCORE of ≥5% and 10% for 10-year risk of
fatal CVD
Patients with diabetes aged 40-75 years with LDL-C of
70-189 mg/dL without clinical ASCVD
• Subjects are considered to be at
Moderate risk moderate risk when their SCORE is ≥1%
and <5% at 10 years
Patients without clinical ASCVD or diabetes with LDL-C of
70-189 mg/dL and estimated 10-year ASCVD risk of
>7.5%
• The low risk category applies to
Low risk
individuals with SCORE <1%.

ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease ; CKD, chronic
kidney disease; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; LDL-C, Low density lipoprotein- cholesterol;
SCORE, Systematic Coronary Risk Evaluation Project.

1. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635–1701.
2. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A
report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. 2013. Accessed December 16, 2013.
SCORE Chart: Assessment of Cardiovascular
Risk Score
10-year risk of fatal CVD is
based on risk factors: Age,
smoking, sex, systolic blood
pressure and total
cholesterol.

SCORE, Systematic Coronary Risk Evaluation Project; CVD, cardiovascular disease

European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635–1701
 10-year Atherosclerotic Cardiovascular Disease Using
Pooled Cohort Equations

Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in
adults: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. 2013. Accessed January 28, 2014.
 Cardiovascular Risk Reduction:
Recommendations of ESC Guidelines
• Smoking
cessation Lifestyle modification
• Dietary
modification
• Weight Management of comorbid
management
• Physical activity
conditions

Lipid-lowering drugs

ESC, European Society of Cardiology

European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635–1701
 Lipid-Lowering Medications: Statins have
maximum benefit
Medication Effect on LDL-C Effect on HDL-C Effect on TG Effect on Lp(a)

Statin ↓↓↓ ↑ (also depends ↓ ↔

on statins)
Bile acid ↓↓ ↔↑ ↑ ↔
sequestrants
Nicotinic acid ↓ ↑↑ ↓↓ ↓

Cholesterol ↓↓ ↔ ↔ ↔
absorption
inhibitor
Fibric acid ↓ ↑ ↓↓↓ ↔
derivatives

CIMT, carotid intima medial thickness; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp, Lipo protein; TG,
Triglycerides

Jellinger PS , Smith DA, Mehta AE, et al. AACE Guidelines. American association of clinical endocrinologists' guidelines for management
of dyslipidemia and prevention of atherosclerosis. https://www.aace.com/files/lipid-guidelines.pdf. Accessed on December 3, 2013.
 Recommendation for treatment target LDL-C
(ESC/EAS 2011)
Recommendation Class Level
VERY HIGH CV risk (established CVD, DM type 1 &2 I A
with target organ damage, severe CKD or SCORE
level > 10%) the LDL-C goal is < 70 mg/dl and or >
50% reduction when target level cannot be
reached

HIGH CV risk (markedly elevated single risk factor, a II a A

SCORE level > 5 to < 10%), an LDL-C goal < 100
mg/dl

MODERATE risk (SCORE level >1 to< 5), an LDL-C II a C

goal < 115 mg/dl
Guideline Approach To Decide Intensity Of Statin
(ACC/AHA 2013)
ASCVD Statin Benefit Groups
Heart healthy lifestyle habits are the foundation of ASCVD prevention. In individuals not receiving cholesterol-lowering
drug therapy, recalculate estimated 10-y ASCVD risk every 4-6 y in individuals aged 40-75 y without clinical ASCVD
or diabetes and with LDL–C 70-189 mg/dL.

Yes Age <75 y High-intensity statin (Moderate-intensity statin if not

candidate for high-intensity statin)
Yes Clinical
Adults age >21 y and a candidate for statin therapy ASCVD
Yes Age >75 y OR if not candidate for high-intensity statin
No Moderate-intensity statin

Definitions of High- and

Moderate-Intensity Statin Therapy LDL–C ≥190 Yes High-intensity statin (Moderate-intensity statin if not
mg/dL candidate for high-intensity statin)
High Moderate
No
Daily dose lowers Daily dose lowers
LDL–C by appox. LDL–C by appox.
≥50% 30% to <50% Yes Moderate-intensity statin

Yes Estimated 10-y ASCVD risk ≥7.5%*

High-intensity statin

Estimate 10-y ASCVD Risk

with Pooled Cohort Equations*

≥7.5% estimated Yes

10-y ASCVD risk Moderate-to-high intensity statin
and age 40-75 y
No

ASCVD prevention benefit of statin therapy may be less clear in other groups
In selected individuals, consider additional factors influencing ASCVD risk‡ and potential ASCVD risk benefits and adverse effects,
drug-drug interactions, and patient preferences for statin treatment

Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol. 2013.
 2013 ACC/AHA Guideline Recommendations for
Statin Therapy
ASCVD Statin Benefit Groups
Heart healthy lifestyle habits are the foundation of ASCVD prevention

Estimated 10-yr
Diabetes; age
Clinical ASCVD LDL-C ≥190 mg/dL ASCVD risk ≥7.5%†;
40-75 years*
age 40-75 years*
• High-Intensity statin • High-intensity statin • Moderate-intensity • Moderate- to high-
(age ≤75 years) statin intensity statin
• Moderate-intensity
• Moderate-intensity statin if not a • High-intensity statin if
statin if >75 years or candidate for high- estimated 10 year
not a candidate for intensity statin ASCVD risk ≥7.5%
high-intensity statin

ASCVD prevention benefit of statin therapy may be less clear in other groups . Consider additional factors
influencing ASCVD risk , potential ASCVD risk benefits and adverse effects, drug-drug interactions, and patient
preferences for statin treatment.

* With LDL-C of 70-189 mg/dL

† Estimated using the Pooled Cohort Risk Assessment Equations

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at:

http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.
 Intensity of Statin Therapy
High-Intensity Statin Moderate-Intensity Stain Low-Intensity Statin
Therapy Therapy Therapy

LDL–C ↓ ≥50% LDL–C ↓ 30% to <50% LDL–C ↓ <30%

Atorvastatin (40†)–80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg

Rosuvastatin 20 (40) 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
Fluvastatin 40 mg bid
Pitavastatin 2–4 mg

Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use
of cholesterol lowering drug therapies.

Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL
‡Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including
rhabdomyolysis.
Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at:
http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.
 Relative LDL-lowering efficacy of different
doses of statins

% decrease in
Rosuvastatin
Atorvastatin

Pitavastatin

Simvastatin
Pravastatin
Fluvastatin

Lovastatin

LDL-C
- 40 mg 1 mg 20 mg 20 mg - 10 mg 30%

10 mg 80 mg 2 mg 40 or 80 40 mg - 20 mg 38%
mg
20 mg - 4 mg 80 mg 80 mg 5 mg 40 mg 41%

40 mg - - - 10 mg 80 mg 47%

80 mg - - - 20 mg - 55%

- - - 40 mg - 63%

US FDA. Web site http://www.fda.gov/drugs/drugsafety/ucm256581.htm. Accessed on December 9, 2013.

Training Use Only
 Management of Hypercholesterolaemia
remains Sub-optimal: Pan-Asian CEPHEUS
• Survey conducted in eight Asian countries of 7281 patients on lipid-lowering
therapy for ≥3 months
– Only 34.9% of very high risk patients reached NCEP ATP III goal and it
was below from overall result
– 65.1% of very high risk patients did not reach NCEP ATP III goal

100
Patients (%) at

75.4 76
80
LDL-C goal

55.4
60 49.1
40 34.9

20
0

Overall Very-high High Moderate Lower

<70 mg/dL <100 mg/dL) <130 mg/dL <160 mg/dL
Risk category and NCEP ATP III goal

Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.
Percentage of Patients at LDL-C goals recommended
by the 2004 updated NCEP ATP III* guidelines
% of Patients at LDL-C goals recommended by 2004 updated NCEP ATP III* guidelines

• For patients in Hong Kong the treatment goal attainment rate was 82.9% while patients in other countries had
very low LDL-C attainment rate (31.3 – 52.7%).

Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.
 PAN-ASIAN CEPHEUS Study:
Follow-up of Patients not achieving LDL-C goals

• Follow-up of patients not achieving LDL-C goals

Other follow-up treatment (n=40) 1.7

Lifestyle modification (n=332) 13.7

Dose increased+additional medication (n=156) 6.4

Switched to another therapy (n=407) 16.8

Dose increased (n=618) 25.5

Same medication (n=871) 35.9

0 5 10 15 20 25 30 35 40
No. of patients (%)

Park JE, et al. Eur J Prev Cardiol. 2012;19(4):781-794..

 Statins: Mechanism of Action

Cholesterol
Apo B LDL receptor-mediated
synthesis LDL receptor VLDLR
(B-E receptor) Apo E and VLDL remnants
synthesis Apo B Serum LDL-C
Intracellular LDL
Cholesterol Serum VLDL remnants
Serum IDL

Hepatocyte Systemic
Circulation
Statins reduce hepatic cholesterol synthesis, lowering intracellular cholesterol,
which stimulates the upregulation of LDL receptor and increases the uptake of
non-HDL particles from the systemic circulation.

Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5(4):378-387.
 Relative lipophilicities of various statins

Pravastatin

More hydrophilic
CRESTOR

atorvastatin

Fluvastatin

More lipophilic
Simvastatin

Cerivastatin

1. Buckett L, Ballard P, Davidson R et al. Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versus non-hepatic cells. Poster presented at the
XIIth International Symposium on Atherosclerosis, Stockholm, Sweden, 25-29 June 2000.
2. Buckett L, Ballard P, Davidson R et al. Atherosclerosis 2000;151(1) 41 Abs MoP29:W6.
Differential Membrane Locations of Statins

Mason et al. Am J Cardiol. 2005;96(suppl):11F.

Hepatic metabolism of statins

Statin Principal CYP450 isoenzyme system

CRESTOR# CYP2C9 and CYP2C19

(minimal)
simvastatin CYP3A4

atorvastatin CYP3A4

fluvastatin CYP2C9

cerivastatin* CYP3A4 and CYP2C8

pravastatin None

# CRESTOR has minimal metabolism and no clinically significant CYP450 interactions

*cerivastatin has been withdrawn from all markets worldwide

Horsmans Y. Eur Heart J Suppl 1999;1(Suppl T):T7-T12.

 Pharmacokinetic Profile of Selected Statins

Rosuvastatin Atorvastatin Simvastatin Pravastatin

CYP450 3A4 No Yes Yes No
metabolism
Clinically significant No Yes Yes No
metabolites
Plasma clearance Dual renal/ Primarily Dual renal/ Dual renal/
hepatic hepatic hepatic hepatic
Relatively hydrophilic Yes No No Yes

Hepatoselective Yes Yes Yes Yes

Bioavailability (%) 20 14 <5 17

Elimination half-life* 19 14 1.9 77

(hours)
*Elimination t1/2 of drug and metabolites, if any.
CRESTOR (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. Atorvastatin Calcium
Prescribing Information 2002, Pfizer Inc, NY, NY; Simvastatin Prescribing Information, Merck & Co., Inc., Whitehouse Station, NJ;
Pravastatin Prescribing Information 2003, Bristol-Meyers Squibb Company, Princeton, NJ.

1. McTaggart F et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3- hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;
87(Suppl): 28B–32B;
2. Horsmans Y. Differential metabolism of statins: importance of drug-drug interactions. Eur Heart J 1999; 1(Suppl T): T7–T12.
3. Buckett L et al. Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versus non-hepatic cells. Atherosclerosis 2000; 151: 41 abs MoP29:W6
 Blasetto, 2003: Rosuva 5 mg Lowers LDL-C More Effectively
than Atorva 10 mg, Simva 20 mg & Prava 20 mg

Blasetto, Am J Cardiol 2003;91(suppl):3C–10C

High-risk Patients Achieving LDL-C <70 mg/dL
with different statins
VOYAGER Individual Patient Data Meta-analysis

VOYAGER, an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and
simvastatin
NA, not applicable; LDL-C, low-density lipoprotein cholesterol
Nicholls SJ et al. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus
simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol 2010; 105: 69–76
Change in LDL-C with Rosuvastatin and Atorvastatin
in High-Risk Patients
The RADAR Study
10 mg 20 mg 20 mg 40 mg 40 mg 80 mg

*
**
***
RADAR, Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport
*p<0.05, **p<0.01, ***p<0.0001 vs atorvastatin
Jukema JW et al. LDL-C/HDL-C ratio in subjects with cardiovascular disease and a low HDL-C: results of the RADAR (Rosuvastatin and Atorvastatin in
different Dosages And Reverse cholesterol transport) study. Curr Med Res Opin 2005; 21: 1865-1874
 Effect of Statins on HDL-C

↑ HDL-C with ↑ doses of rosuvastatin but

with ↑ doses of atorvastatin, HDL-C ↓

HDL-C, high-density lipoprotein cholesterol

Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the
VOYAGER Database. J Lipid Res. 2010;51(6):1546-53.
Impact of statin therapy in high risk patients
with diabetes
32,258 patients

LDL-C, low-density lipoprotein cholesterol

Karlson BW, Barter PJ, Palmer MK, Lundman P, Nicholls SJ. Comparison of the effects of different statins and doses on lipid levels in patients with
diabetes: results from VOYAGER. Nutr Metab Cardiovasc Dis. 2012;22(9):697-703.
 Risk-Benefit Profile of Rosuvastatin

ALT, alanine aminotransferase; LDL-C, low-density lipoprotein

Brewer HB. Benefit-Risk assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol. 2003;92(suppl):23–29.

 Key Takeaway Points
• Lower LDL-C levels are associated with lower CHD
mortality; the lower the better
• LDL cholesterol reduction achieved with starting doses may
be an important index of performance in clinical practice
• High doses of atorvastatin and rosuvastatin are
recommended in patients at a high-risk of developing CV
events
• An unmet need exists for medications which can reduce the
LDL-C at lower doses, increase HDL-C and reduce
triglycerides with good safety profile in the management of
dyslipidaemia
• Clinical trials indicate that rosuvastatin addresses these
unmet needs in the management of dyslipidaemia

CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol
Thank You