Dyslipidemia Management : Time To Act
ID-4046/January 2024
CASE 1
Physical examination:
• Blood pressure 120/80 mmHg.
• Other physical findings are non-remarkable.
• A 60-year old gentleman visit your office for
consulting his lipid profile.
• He was hypertensive, controlled with Lipid profile:
antihypertensive drugs
• Total Cholesterol 219 mg/dL,
• Not a smoker
• LDL-C 130 mg/dL,
• Not aware of diabetes
• HDL-C 38 mg/dL,
• No family history of CAD
• Triglyceride 180 mg/dL.
• History of ACS, 1 year ago
• Dyslipidemia, being treated with Atorvastatin Fasting blood glucose and liver enzymes are within
20 mg/day. normal limits.
What will you do first?
PERFORM RISK ASSESTMENT
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Step 1, Risk Assessment: RISK LEVEL
European Heart Journal (2019) 00, 178. doi:10.1093/eurheartj/ehz455
What is the risk stratification of this patient
Very High Risk
High Risk
Moderate Risk
Low Risk
CHD Risk Assessment
Based On SCORE System
Variable of the SCORE Chart
• Gender
• Age
• Systolic Blood Pressure
• Total Cholesterol
• HDL-C
• Smoking
Catapano AL, et al. Eur Heart J. 2016;37:2999-3058
High CVD Low CVD
Reiner Z, et al. Eur Heart J. 2011;32:1769-1818
What will you do NEXT ?
Identify LDL-C Goal
Is his LDL-C within the target range?
ESC 2019 Dyslipidemia Guideline1
New LDL- C target for very high risk (<55 mg/dL)
High-intensity statin is recommended (class IA) to prescribed up to
the highest tolerated dose to reach the goals Mach F, et al. European Heart Journal. 2019; 00: 1-78.
Treatment Target of LDL-C
Risk level LDL-C target (mg/dl)
Very high ↓≥50% and <55*
High ↓≥50% and <70
Moderate <100
Low <116
* <40 mg/dl may be considered for patients with ASCVD who experience a
second vascular event within 2 years
Mach F, et al. European Heart Journal. 2019; 00: 1-78.
Initiation of Treatment
DISCLAIMER: Crestor has not yet been approved by BPOM RI for primary prevention. The information should under no circumstances be regarded as a
recommendation for use of Crestor in Primary Prevention
Mach F, et al. European Heart Journal. 2019; 00: 1-78.
LDL-C : LOWER IS BETTER
LDL-C: Lower is Better
The Lower the LDL-C Level, the Better the Long-term Clinical Benefits
Achieved LDL-C levels
mmol/L <1.29 1.29 - <1.95 1.94 - <2.58 2.58 - <3.23 3.23 - <3.88 3.88 - <4.52 ≥4.52
cardiovascular events (adjusted HR*)
0%
Reduction rate in the risk for major
Series1
0%
-10%
-20%
-30% -29%
-36%
-40%
-42%
-44%
-50% -49%
-56%
-60%
This meta-analysis included 8 statin randomized controlled trials, and among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events
occurred in 5,387 study participants during follow-up (1 year). Definition of major cardiovascular events: fatal or nonfatal MI, fatal "other CHD", hospitalization for
unstable angina, or fatal or nonfatal stroke. * Analyses were adjusted for sex, age, smoking status, diabetes mellitus status, systolic blood pressure, HDL-C
Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5): 485-94.
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%
Baigent C, et al. Lancet 2010; 376(9753): 1670 - 81
Drugs Choice
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
LDL-C Reduction With Each Titration of Rosuvastatin, Atorvastatin, Simvastatin, or
Pravastatin
Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg)
Mean %
Change
in LDL-C
From
Untreated
Baseline
p<0.002 vs atorvastatin 10 mg; simvastatin 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
Jones PH et al. Am J Cardiol.. 2003;92:152–160
Rosuvastatin : Third Generation Statin1
Most potent statin to reduce LDL-C
Relative efficacy of statin-based therapies in LDL-C reduction2:
Adapted from FDA drug safety communication
1. Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353
2. FDA drug safety communication. Available in https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm 03/12/2018
Achieve Secondary Target in high and very high-risk
patients
Lipid Treatment target
LDL-C Primary target
Non-HDL-C or apoB Secondary target
HDL-C Not a target
Mach F, et al. European Heart Journal. 2019; 00: 1-78.
Recommendations for drug treatment of patients with high TG
DISCLAIMER: Crestor has not yet been approved by BPOM RI for primary prevention. The information should under no
circumstances be regarded as a recommendation for use of Crestor in Primary Prevention
Mach F, et al. European Heart Journal. 2019; 00: 1-78.
Mach F, et al. European Heart Journal. 2019; 00: 1-78.
Why Rosuvastatin?
First-Second-and Third-generation Statins
First Generation Second Generation Third Generation
• More efficacious in • Highly effective and
• Lowest potency
reducing LDL-c than potent : dubbed as
• Effective in reducing first- generation statins “super statins”
LDL-c, CV morbidity and • Used in both primary • Lower drug
mortality and secondary interactions because of
• Effective in secondary prevention hydrophillic nature and
prevention • >30% lowering of LDL-c action through an
• Used as alternates in with lower daily doses alternate metabolic
• Higher potential for pathway
patients who cannot • Used as alternatives in
tolerate more potent drug interactions than
first-generation but high-risk individuals
statins may be used safely developing statin
• Examples, pravastatin • Examples, atorvastatin intolerance
and fluvastatin and simvastatin • Example rosuvastatin
and pitavastatin
26 Maji D, et al. Indian J EndocrinolMetab. 2013;17(4):636-646.
Molecular Advantage of Crestor®:
With 4 Binding Sites to Potently Inhibit HMG-CoA Reductase
Binding sites of statins to HMG-CoA reductase
Crestor® Simvastatin Simvastatin
Atorvastatin
1, 2, 3 and 4 in the above figures are binding sites to HMG CoA reductase IC50 : Half-maximal Inhibitory Concentration
IC50 value: drug concentration required to inhibit half activity of HMG-CoA
reductase nM : nanomolar
27
Istvan ES, et al. Science. 2001; 292(5519): 1160-4. Structural Mechanism for Statin Inhibition of HMG-CoA Reductase.
Statin Metabolism: Many Similarities, Some Key Differences
Rosuvastatin is a Hydrophilic Statin and Not Metabolized by CYP3A4
Less Prone To Drug Interactions & Myalgia
Schachter M. 2004 Blackwell Publishing Fundamental & Clinical Pharmacology.2004;19: 117–125
DRUG INTERACTION ?
Rosuvastatin Is not Affected by the Genetic Polymorphisms of CYP3A4
CRESTOR® has no clinically significant drug interactions with erythromycin,
azole antifungals, fibrate, or digoxin which reduce the risk of Myopathy
and Rhabdomyolysis
CYP3A4 METABOLISM THROUGH THE MAIN METABOLIC PATHWAY
CRESTOR Atorvastatin Simvastatin
(Rosuvastatin)
CYP3A4 No Yes Yes
Metabolism
Main Metabolic 2C9 3A4 3A4
Pathway
29 1.Package
Bellosta S, et al. Safety ofinsert of Crestor®
Statins Focus on Clinical Pharmacokinetics and Drug InteractionsCirculation. 2004;109(Suppl III):III-50—III-57.
Significant reduction of LDL-C with loading Crestor 40 mg before PCI:
Lower incidence of short & long term death & others cardiovascular events
Change in LDL-cholesterol
*Control : no statin treatment before PCI
*Rosuvastatin: Crestor 40 loading before PCI Yun KH et al. Int J Cardiol. 2011;146:68-72.
Pharmacokinetic Interaction of Atorvastatin and Clopidogrel
31
Lau, Wei C., et al. Circulation, 2003; 107:32-37
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;33: 2151-2162
32
Rosuvastatin improves eGFR in patients with
moderate CKD
Adapted from: Vidt, D.G. et al. AM J Cardiol. 2006; 97: 1602-6
KDIGO 2013:
Adjusment Dose (in CKD Stage 3 above) Apply To All Statins,
Including Atorvastatin
34
KDIGO, Kidney International Supplements. 2013; 3: 271-279
Rosuvastatin Safety
Muscle Effects Liver Effects
Incidence of treatment-related myopathy with Incidence of clinically significant increases in serum
rosuvastatin (5-40 mg) in controlled clinical trials is transaminases with rosuvastatin (5-40 mg) in
low controlled clinical trials is low
1. Shepherd J, et al. Cardiology. 2007;107(4):433-43.
2. CRESTOR (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018.
3. Brewer HB Jr. Am J Cardiol. 2003;92(Suppl 4B):23K-29K.
4. Davidson MH. Exp Opin Drug Saf. 2004;3(6):547-557
Take Home Message
• Do Risk Assessment in managing dyslipidaemia
• Start early treatment with high intensity statins for very high risk and high risk patients
• It is recommended that a high-intensity statin is prescribed up to the highest tolerated
dose to reach the goals set for the specific level of risk (I A)
• Rosuvastatin 20 mg and 40 mg are high intensity statins, with excellence safety profile.
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