Optimal Dyslipidemia Management to Address

Cardiovascular Disease

M. Fitriandi B.
Why does it happen?

We spend most of our

People living in mostly
time deskbound.
capital city encounter
Average time spent ± 5
“traffic jam” almost
hours.
daily

Consume food contain

high carbohydrate, fat
and protein.

↑ Insulin Resistance &

↑ Hypertension. Dsylipidemia ↑ Central Obesity.
Source: Country statistic & global health estimates by WHO and UN Partner
http://who.int/gho/mortality_burden_disease/en/
 Metabolic Syndrome associates
with complexity
Endothelial
Complex Systemic
Dysfunction
Dyslipidemia Inflammation
TG, LDL
HDL

Disordered Insulin Athero-

Fibrinolysis Resistance sclerosis

Hypertension Visceral
Type 2 Diabetes Obesity

Pradhan AD et al. JAMA. 2001;286:327-334.

 The Global CVD Crisis
CVDs are the number 1 cause of death globally: more people die annually from
CVDs than from any other cause.

23.6 million
2030

WHO, data updated May 2017

Cardiovascular Diseases (CVDs) in Indonesia

ASCVD remains the leading cause of death in Indonesia CVDs account for 37% of total deaths2
(2005 – 2015)1

Source:
1. Institute for Health Metrics and Evaluation (IHME) 2015
8
2. Noncommunicable diseases Country Profile 2014. WHO 2014
CVD is #1 Cost Burden in Indonesia

P2JK Kemenkes RI
 Overview
Evolution of Lipid Management Guidelines
 Individuals with elevated LDL-C are at increased risk of CHD

Multiple Risk Factor Intervention Trial Framingham Study (n=5209)

(MRFIT) (n=361,662)
50
10-year CHD Death Rate

40
(Deaths per 1000)

30

20

10

0 150 200 250 300

Serum cholesterol (mg/dL)

Gotto AM Jr et al. Circulation. 1990;81:1721-1733.

Castelli WP. Am J Med. 1984;76:4-12.
Increased Relative Risk of CHD Associated With
Increasing LDL Levels

ARIC Study
4.50 Men

Relative Risk of CHD 2.85

1.80 Adjusted for age and race

12-year follow-up
n = 5432
1.15

0.75

2.35 2.85 3.35 3.85 4.35 4.85 (mmol/L)

91 110 130 149 168 188 (mg/dL)

LDL Cholesterol

Adapted from Sharrett AR, et al. Circulation. 2001;104:1108-1113.

 Multiple Studies Showed a Relationship Between LDL-C
Reduction & CHD Relative Risk

London WOSCOPS
100 Oslo CARE

Nonfatal MI and CHD death relative

MRC LIPID
Los Angeles AF/TexCAPS
80 Upjohn HPS
LRC ALERT
NHLBI PROSPER
POSCH ASCOT-LLA

risk reduction, %
60 4S CARDS

40

20

–20

15 20 25 30 35 40
LDL-C reduction, %
MI: Myocardial
MI = myocardial Infarction
infarction.

Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.

 Per 1.0 mmol/L (40 mg/dL) LDL-C reduction:

▪ 10% proportional reduction in all-cause mortality

▪ 20% proportional reduction in CAD death
▪The risk for major coronary events was reduced by 23%
▪The risk for stroke was reduced by 17%
Association Between Lowering LDL-C and Cardiovascular Risk
Reduction Among Different Therapeutic Interventions
A Systematic Review and Meta-analysis

A total of 312.175 participants (mean age, 62 years; 24%women;

mean baseline LDL-C level of 3.16 mmol/L [122.3mg/dL]) from 49 trials
with 39 645 major vascular eventswere included.

JAMA. 2016;316(12):1289-1297. doi:10.1001/jama.2016.13985

Per 1.0 mmol/L (40 mg/dL) LDL-C reduction:

▪ 23% proportional reduction in major vascular events
 Cardiovascular Event Reduction and Adverse Events Among Subjects Attaining Low-Density
Lipoprotein Cholesterol <50 mg/dl With Rosuvastatin
The JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)
(J Am Coll Cardiol 2011;57:1666–75)
Time to Occurrence of Major Cardiovascular Events According to Treatment
Group and Achieved LDL-C Concentrations
Lowering LDL-C Reduces Risk For Major CV Events
Meta-analysis of 8 Statin Trials (N=38.153)

Patients Who Achieved Very Low LDL-C Levels Had Lower Risk for Major CV Events
The Relationship Between Achieved LDL-C Level and Change in Percent Atheroma Volume
(Stronger LDL-C Reduction is Directly Related To Plaque Regression)
GLAGOV Study

1.0

Change in Percent Atheroma Volume, %

0.5

-0.5

-1.0

-1.5
10 20 30 40 50 60 70 80 90 100 110

On- Treatment LDL-C, mg/dL

Nicholls SJ, et al. JAMA. doi:10.1001/jama.2016.16951

Relationship Between LDL-C Levels and Change in Percent Atheroma Volume
for Several IVUS Trials

1.8
REVERSAL
CAMELOT pravastatin
Change in Percent Atheroma
placebo
1.2

ACTIVATE placebo
Volume

0.6 REVERSAL
atorvastatin A-Plus placebo
ILLUSTRATE ILLUSTRATE Progression
Torcetrapib Placebo
0

Regression
-0.6
ASTEROID
rosuvastatin
-1.2
50 60 70 80 90 100 110 120
Mean LDL-C (mg/dL)

Nissen SE et al. JAMA 2006

 Overview
The Most Potent Statin with Excellence Safety
 High, Moderate, and Low-Intensity Statin Therapy

High-intensity Moderate-intensity Low-intensity

statin therapy (mg) statin therapy (mg) statin therapy (mg)
Daily dose lowers Daily dose lowers Daily dose lowers
LDL-C on average, LDL-C on average, LDL-C on average,
by approx. ≥50% by approx. 30% to <50% by approx. <30%
Atorvastatin 40-80 Atorvastatin 10-20 Simvastatin 10
Rosuvastatin 20-40 Rosuvastatin 5-10 Pravastatin 10-20
Simvastatin 20-40 Lovastatin 20
Pravastatin 40-80 Fluvastatin 20-40
Lovastatin 40 Pitavastatin 1
Fluvastatin Xl 80
Fluvastatin 40 bid
Pitavastatin 2-4
Donald M. Lloyd-Jones DM, et al. JACC. 2016;68:92-125
Third Generation Statin
Highest-Potency Generation of Statins

Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353
Superiority of Rosuvastatin vs Other Statins
Powerful efficacy in all lipid parameters

Gotto AM, et al. HeartViews 2017.

Superiority of Rosuvastatin vs Other Statins
Powerful efficacy up to 62% start from very low dose 5 mg

*Avoid due to high risk of toxicity

Roberts WC. AM J Cardiolo 2004;93:808

Rosuva Safety – Liver Effects
ALT >3 × ULN: Frequency by LDL-C reduction1,2

1. Brewer H. Am J Cardiol 2003; 92(Suppl): 23K–29K

2. Davidson M. Exp Opin Drug Saf 2004; 3: 547–557
KDOQI 2007:
Dosing Adjustments of Medicines to Treat Lipid Disorders in CKD

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2);S1-S179.

KDIGO 2013:
Adjusment Dose Apply To All Statins, Including Atorvastatin

KDIGO, ISN 2013.

Intensive LDL-C-Lowering Treatment
with Rosuvastatin Does Not
Affect the Risk of Developing Renal
Insufficiency or Renal Failure
in Patients Who Do Not Have
Advanced, Pre-existing Renal Disease

Stein EA, et al. Atherosclerosis 2012.

 NOD: RISKS AND BENEFITS OF STATINS
• Per 255 patients treated with statin over 4 years :
Each 39mg/dl reduction in LDL-C vs control → 5.4 fewer CHD deaths
and nonfatal MI
Versus

• One case of NOD per 255 patients treated with statin over 4 years

Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
Lancet 2010; 375: 735-42.
Treatment-Emergent Adverse Events (per 100 Person-Year) by
Treatment Group and Attained LDL-C

J Am Coll Cardiol 2011;57:1666–75

 How To Explain
ROSUVASTATIN Superior Efficacy & Safety?
 Three Pillars Efficacy and Safety of RUSUFA

Fluorinated Phenyl Enhanced Binding Enthalpies Hydrophilic Nature of Rosuvastatin:

Group & for HMG-CoA Reductase : Eliminating Dependence on
Polar Methane Shorter Hydrogen Bond Length Metabolic Conversion to a
Sulphonamide Group and Involvement of Sulfonyl Groups Water-Soluble Molecule

Multiple Sites of Activity Strength of The Interaction Reduce the Number of

Against Between the Inhibitor Drug-Drug Interactions
HMG-CoA Reductase and Target Enzyme
Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353
Rosuvastatin is a Hydrophilic Statin and Not Metabolized by CYP3A4
Less Prone To Drug Interactions & Rhabdomyolysis

Ramosevac AC, et Al. Acta Pharm 2013

Among PCI Treated Patients:
Switching Atorvastatin to non CYP3A4-metabolized statin (Rosuvastatin)
Significantly decrease platelet reactivity and the prevalence of HPR*

*HPR = High Platelet Reactivity

Park Y, et al. European Heart Journal 2012
 Summary
• ASCVD is the leading global cause of death.
• The robust relationship between Cholesterol and ASCVD found in epidemiological
and observational studies, strongly implies that an elevated LDL-C is a powerful
risk factor.
• In term of CV-Risk reduction the evidence supports the premise that “lower is
better” when it comes to LDL-C goals.
• LDL-C is the primary target therapy in dyslipidemia guidelines.
• Statin intensity trials show clear benefit for high-intensity versus moderate-
intensity statins.
• Rosuvastatin, the third generation statin, has demonstrated good clinical efficacy
and safety in several clinical trials and post-marketing analysis.
• There is a linear association between absolute lowering of LDL C and CVD risk
reduction
 Why Rosuvastatin ?
Experience Always Make The Differences !

15 Years Helping Your High Risk Dyslipidemia Patients To LDL-C Goals

For Reduction of Cardiovascular Morbidity & Mortality

Schuster H, Exp Cardiv Rev Ther 2007

Are You Sure BE* always TE*?
WHY COMPROMISE?
Therapeutic Equivalence = Bioequivalence + Pharmaceutical Equivalence

*BE = Bioequivalence
1. Gherghiceanu Florentina, et al. Farmacia 2016
*TE = Therapeutic Equivalence 2. Definitions from FDA.Gov
Thank You

What Science Can Do