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Assessing Statin Therapy:
What are Their Differences?
Educational Partner: Saturday, June 23, 2012 New York, New York Session 5: Assessing Statin Therapy:
What are Their Differences?
Learning Objectives
1.
2.
3.
Recognize statin drug interactions and select appropriate therapies that will not carry an increased risk of adverse
events.
Apply evidence-based clinical study data into practice that demonstrates statins’ ability to modify both LDL-C and
HDL-C to optimize drug selection.
Evaluate the available safety data concerning statins, proteinuria, hyperglycemia, and dose reduction requirements
in patients with kidney failure and apply this knowledge to therapeutic risk/benefit analysis.
Faculty
Amit Khera, MD, MSc, FACC
Associate Professor
Director, Preventive Cardiology Program
Director, Cardiology Fellowship Training Program
University of Texas Southwestern Medical Center
Dallas, Texas
Amit Khera, MD, MSc, FACC, is an associate professor of medicine at the University of Texas, Southwestern Medical
School in Dallas, Texas, where he serves as director of the preventive cardiology program and program director for the
cardiology fellowship. He is also medical director of cardiac rehabilitation at University Hospital-St. Paul and Parkland
Memorial Hospital. His research interests include the primary and secondary prevention of coronary artery disease, focusing
on risk assessment and risk factor modification in those with premature and familial disease. Dr Khera received his
undergraduate degree in American history from the University of Pennsylvania, with magna cum laude honors. He obtained
his medical degree from Baylor College of Medicine, where he served as class president and was inducted into the Alpha
Omega Alpha honor medical society. Dr Khera completed an internal medicine residency at Brigham and Women’s
Hospital, Harvard Medical School, followed by a cardiology fellowship at the University of Texas, Southwestern Medical
Center. He also completed his masters degree in epidemiology at the Harvard School of Public Health.
Carl E. Orringer, MD, FACC, FNLA
Harrington Chair in Preventive Cardiovascular Medicine
University Hospitals Case Medical Center
Associate Professor of Medicine
Case Western Reserve University School of Medicine
Cleveland, Ohio
Carl E. Orringer, MD, FACC, FNLA, is associate professor of medicine at Case Western Reserve University School of
Medicine, where he is the Harrington Chair in Preventive Cardiovascular Medicine. He directs the preventive cardiovascular
medicine program, the lipid clinic and LDL apheresis program at the Harrington Heart and Vascular Institute at University
Hospitals Case Medical Center. Dr Orringer is a fellow of the American College of Cardiology, and of the National Lipid
Association, where he has been on the board of directors since 2009 and is currently the secretary. He is a past president and
a member of the board of directors of the Midwest Lipid Association. Dr Orringer served as program co-chairman for the
Midwest Lipid Association 2011 Annual Scientific Sessions. He has been an editorial reviewer and faculty contributor to the
National Lipid Association Self-Assessment Programs and to the Complex Lipid Management Self-Assessment Programs.
He served as faculty chair for the 2011 update of National Lipid Association Self-Assessment Programs and is faculty chair
for the 2013 revision of this educational program.
Session 5
Faculty Financial Disclosure Statements
The presenting faculty report the following:
Amit Khera, MD, MSc, FACC, has no financial relationship to disclose.
Carl E. Orringer, MD, FACC, FNLA, has no financial relationship to disclose.
Education Partner Financial Disclosure Statement
The content collaborators at Vindico Medical Education report the following:
Ronald Codario, MD, Medical Director, has no financial relationship to disclose.
Chris Rosenberg, Director of Medical Education, has no financial relationship to disclose.
Suggested Reading List
Asztalos BF, Horvath KV, McNamara JR, et al. Comparing the effects of five different statins on the HDL subpopulation
profiles of coronary heart disease patients. Atherosclerosis. 2002 Oct;164(2):361-369.
Kalaitzidis RG, Elisaf MS. The role of statins in chronic kidney disease. Am J Nephrol. 2011;34(3):195-202.
Masana L. Pitavastatin - from clinical trials to clinical practice. Atheroscler Suppl. 2010 Dec;11(3):15-22.
McKenney JM, Davidson MH, Jacobson TA, Guyton JR; for the National Lipid Association Statin Safety Assessment Task
Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am
J Cardiol. 2006 Apr 17;97(8A):89C-94C.
Sharp Collaborative Group. Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of
lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am Heart J. 2010
Nov;160:785-794.
Sukhija R, Prayaga S, Marashdeh M, et al. Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. J
Investig Med. 2009 Mar;57(3):495-499.
Talbert, RL. Safety issues with statin therapy. J Am Pharm Assoc. 2006;46(4):479-490.
Teramoto T, Shimano H, Yokote K, et al. Effects of pitavastatin (LIVALO Tablet) on high density lipoprotein cholesterol
(HDL-C) in hypercholesterolemia. Atheroscler Thromb. 2009 Oct;16(5):654-661.
US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose
limitations for Zocor (simvastatin) to reduce the risk of muscle injury.
http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm (Accessed December 1, 2011.)
Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J
Med. 2005 Jul 21;353:238-248.
Session 5
Drug List
Generic
Colesevelam
Ezetimibe
Fenofibrate
Fenofibric Acid
Gemfibrozil
Omega-3 acid ethyl esters
Niacin –ER
Atorvastatin
Fluvastatin
Fluvastatin – XL
Lovastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Simvastatin-ezetimibe
Trade
Welchol
Zetia
Antara, Lipofen,Lofibra,Tricor
Fibricor, Trilipix
Lopid
Lovaza
Niaspan
Lipitor
Lescol
Lescol XL
Mevacor
Livalo
Pravachol
Crestor
Zocor
Vytorin
Assessing Statin Therapy:
What are Their Differences?
Amit Khera, MD, MSc, FACC
Carl E. Orringer, MD
Pre ?
Pre ?
Which of the following statins is not
metabolized by cytochrome P-450 3A4 or
2C9?
Which of the following statements is false?
1.
2.
3.
4.
5.
1. Lower statin doses generally are less likely
to cause side effects
2. Gemfibrozil has no effect on pitavastatin
levels
3. Gemfibrozil has no effect on fluvastatin
levels
4. There were no cases of rhabdomyolysis
reported in the FIELD Trial with
statin/fenofibrate combinations
Atorvastatin
Rosuvastatin
Simvastatin
Fluvastatin
Pravastatin
Pre ?
When measured by AUC, which of the
following statins has the least drug
interaction with cyclosporine?
1.
2.
3.
4.
Statin Drug Interactions
and Special Populations
Pravastatin
Rosuvastatin
Atorvastatin
Fluvastatin
Amit Khera, MD, MSc, FACC
Associate Professor
Director, Preventive Cardiology Program
UT Southwestern Medical Center
1
Statin Basic
Pharmacological Principles
Disclosures
• No relevant financial relationships to
Relationship between drug dose and clinical utility, and adverse drug event
(ADE) is governed by 2 concepts:
disclose
•
PHARMACODYNAMICS
–
•
The study of biochemical and
physiological effects of drugs &
their mechanisms of actions
Operationally describes “what Rx
does to the body”
–
Receptor affinity and dynamics
–
Age/Genetic variations
–
Therapeutic Window
•
PHARMACOKINETICS:
•
Operationally describes “what the
body does to the drug”
•
Deals with dynamics of:
–
Bioavailability
–
Absorption (cholestyramine)
–
Distribution
–
Biotransformation
–
Elimination
Adapted from Goodman & Gilman, McGraw-Hill Pub.
Predominance of CYP450
System in Drug Metabolism
PK Mechanisms of Statin-drug
Interactions (SDI)
• METABOLISM: Induction &/or inhibition of:
– PHASE I ENZYMES (Redox reactions)


~75% of Drugs Metabolized Involve CYP450
Routes of Drug Metabolism
– PHASE II ENZYMES (Conjugation)

Sulfation: sulfotransferase (SULT)

Acetylation: N-acetyltransferase (NAT)
Glutathione conjugation (GST)
Methylation: methyltransferases (MT)
Glucuronidation: UDP-glucuronosyltransferase (UGT)



•
CYTOCHROME P450 (CYP450)
Group of related enzymes belonging
to super family of iron-containing heme
proteins (hemoproteins) located
in mitochondria/SER in liver, gut, etc.
•
Most catalyze oxidation of lipids,
steroidal hormones, and xenobiotics
(toxin/ Rx metabolism/bioactivation)
•
Monooxygenase reaction (inserting
one O atom into organic substrate
RH +O2+2H+2e >ROH +H20
•
Reduced P450s/CO absorb light
@ wavelengths ~450nm (Soret peak)
•
Many CYP 450 isoforms
FMO, MAO
Cytochrome P (CYP)450 3A4, 2D6, 1A2, 2C9
1. Guengerich FP. Chem Res Toxicol. 2008;21(1):70-83.
2. Williams JA, et al. Drug Metab Dispos. 2004;32(11):1201-1208.
FMO=flavin-containing monooxzgenase;MAO=monoamine oxidase.
NAT=N-acetyltransferase;UDT=uridine5`-diphosphate-glucufonyltransferase.
Shitara Y, et al. Annu Rev Pharmacol Toxicol. 2005;45:689-723.
Isoforms of CYP450 System
Involved in Drug Metabolism
Isoforms of CYP450 System
Involved in Statin Metabolism
~50% of CYP450 Metabolism Involves 3A4
Most Statins Use CYP 3A4 or CYP 2C9 Isoforms
Routes of Drug Metabolism
Most Utilized CYP450 Isoforms
Routes of Drug Metabolism
Most Utilized CYP450 Isoforms
Fluvastatin
Rosuvastatin (some)
Pitavastatin (minimal)
CYP450=cytochrome P450; FMO=flavin-containing monoxygenase; MAO=monoamine oxidase;
NAT=N-acetyltransferase; UGT=uridine 5'-diphosphate-glucuronosyltransferase.
1. Guengerich FP. Chem Res Toxicol. 2008;21(1):70-83.
2. Williams JA, et al. Drug Metab Dispos. 2004;32(11):1201-1208.
CYP450=cytochrome P450; FMO=flavin-containing monoxygenase; MAO=monoamine oxidase;
NAT=N-acetyltransferase; UGT=uridine 5'-diphosphate-glucuronosyltransferase.
1. Guengerich FP. Chem Res Toxicol. 2008;21(1):70-83.
2. Williams JA, et al. Drug Metab Dispos. 2004;32(11):1201-1208.
2
Simvastatin
Lovastatin
Atorvastatin
Select Inhibitors
of CYP450 3A4
Select Inhibitors
of CYP450 2C9
STRONG/MODERATE
WEAK/UNSPECIFIED
STRONG/MODERATE
WEAK/UNSPECIFIED
• Protease Inhibitors
• H2 antagonist - cimetidine
• Uricosuric
• H2 antagonist - cimetidine
–
Ritonavir, indinavir, nelfinavir
• Antiarrhythmic - amiodarone
• Macrolide antibiotics
–
• CCBs amlodipine, felodipine
Erythromycin, telithromycin,
clarithromycin
–
–
& St. John’s Wort
Budzinski, JW, et al. Phytomedicine. 2000;7(4):273-82
Kajbaf M, et al. Drug Metab Lett. 2011;5(1):30-9
Choi I, et al. Eur J Med Chem. 2009;44(6):2354-60
Lee SS, et al. Phytother Res. 2007;21(11):1096-9
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
Yang J, et al. Current Drug Metabolism. 2008;9(5):384-393
Kajbaf M, et al. Drug Metab Lett. 2011;5(1):30-9.
Lee CR, et al. Pharmacogenetics. 2002; 12:251-26
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
Gleeson MP, et al. J Comput Aided Mol Des. 2007;21(10-11):559-73
PK Mechanisms
of Statin-Drug Interactions
Competitive Glucuronidation:
Gemfibrozil & Fenofibrate vs. Statins
• METABOLISM: Induction &/or inhibition of:
– PHASE I ENZYMES (Redox reactions)
CYP450 3A4, 2D6, 1A2, 2C9
FMO, MAO
– PHASE II ENZYMES (Conjugation)

Sulfation: sulfotransferase (SULT)

Acetylation: N-acetyltransferase (NAT)
Glutathione conjugation (GST)
Methylation: methyltransferases (MT)
Glucuronidation: UDP – glucuronosyltransferase (UGT)



Most Statins Utilize UGT 1A1
and 1A3 for Metabolism
3000
Glucuronide Formation,pmol/min/mg

2000
Gemfibrozil
Fenofibrate
1000
50
Prueksaritanont T, et al. Drug Metab Dispos. 2002;30:1280-1287.
Gemfibrozil Increased Cerivastatin
Plasma Concentrations
Statin-fibrate Combination Therapy:
Pharmacokinetic Interactions
Cerivastatin Acid, ng/mL
10
Gemfibrozil
Doses:
Cerivastatin: 0.3 mg
Gemfibrozil: 600 mg BID
8
6
+ Gemfibrozil
2
+ Placebo
0
0
2
4
6
8
10
12
Time, h
Backman JT, et al. Clin Pharmacol Ther. 2002;72:685-691.
Fenofibrate Primarily Utilizes
UGT 1A9 and 2B7 for Metabolism
Gemfibrozil competitively competes with statins for UGT 1A1
and 1A3 and is potent inhibitor of CYP 2C9 and 2C8 and OA1B1.
Shitara Y, et al. Annu Rev Pharmacol Toxicol. 2005;45:689-723.
4
• Leukotriene antagonist - Zafirlukast
• Flavones
• Echinacea, Star Fruit, Milk Thistle
of grapefruit juice

• ChemoRx - teniposide
– Component of Ginkgo Biloba
Fluoxetine, norfluoxetine, fluvoxamine
–
• Bergamottin - constituent
• Antifungal - voriconazole
• Amentoflavone
• SSRIs
• Antiemetic - aprepitant
• Sertraline
– Sulfaphenazole
• Antineoplastics - imatinib
• Antidepressant- Nefazodone
• Probenecid
• Antibacterial
• PIs - saquinavir
Verapamil, diltiazem
• Lovastatin
– Losartan, irbesartan
Nevirapine, efavirenz, delavirdine
–
• Fenofibrate
• ARBs
• NNRTIs
• CCBs
sulfamethoxazole
• Fluvastatin
– Valproic acid
• Antibiotics - norfloxacin, ciprofloxacin
Ketoconazole, fluconazole, itraconazole
• Antibiotics: Chloramphenicol,
• Anticonvulsant
• Analgesic - buprenorphine
• Chloramphenicol
• Antiarrhythmic - amiodarone
Antifungal
– Fluconazole
• Cyclosporine
• Azole antifungals
– Benzbromarone
•
24
* Cerivastatin
withdrawn in 2001
Pravastatin
 in cmax
No effect*
Fluvastatin
No effect
Not available
Simvastatin
 cmax by 112%
No effect*
Cerivastatin
 cmax by 2-3 fold
No effect*
Rosuvastatin
 cmax by 2-fold
No effect*
Lovastatin
 AUC by 2-3 fold
No effect*
Pitavastatin
 Cmax by 31%
No effect*
Adapted from: Davidson MH. Am J Cardiol. 2002;90 (suppl):50K-60K.
* Significant
3
Fenofibrate
Rhabdomyolysis in Fibrate
Combination Therapy With Statins*
No. Cases Reported
per Million Prescriptions
10
Other Mechanisms
of Statin-Drug Interactions
• METABOLISM: Induction &/or inhibition of:
– HEPATIC UPTAKE:
8.6
9
8

7

Organic anion transporters (OAT)
Organic anion transporter polypeptides (OATP)

Na-dependent taurocholate cotransporter (NTCP)
6
5
15-Fold Increase
– ELIMINATION:
4
ACTIVE BILIARY SECRETION:

3
2
0.58
1
0
Fenofibrate
Gemfibrozil
*Excludes cases involving cerivastatin
Jones PH, et al. Am J Cardiol. 2005;95:120-122

MDR1-[P-glycoprotein (Pgp)]

Breast cancer resistance protein (BCRP)

Multidrug resistance proteins (MRP)
Shitara Y, et al. Annu Rev Pharmacol Toxicol. 2005;45:689-723.
Hepatic Statin
Transport Pathways
Selected Drug/Food Interactions
Increasing Statin Levels
Statin Membrane Transporters
Blood
OATP
1B1*
NTCP
OATP
1B3
OATP
2B1
Biotransformation
Of Statin
Bile
MDR1
(P-gp)**
MRP2**
Fold ↑ Statin AUC
by CYP3A4 Inhibitors
Hepatocyte
Erythromycin
Itraconazole
Clarithromycin
Statin Uptake (Influx)
BCRP***
Statin (metabolite) Exit (Efflux)
***SNPs in gene for ABCG2 increase response to rosuvastatin.
Bioavailabiliy
Half-life
(hr)
Active
Metabolites
Food
Effect
Lovastatin
5%
2-4
YES
50% inc
Simvastatin
5%
2-3
YES
NS
NO
?
6-15
< 1.5
1-4
Fluvastatin


()
2-4

()
Lovastatin
5-10
(4-12)
3-8
5-20
2-3
2-10
Pitavastatin
()
()
()
5
 1.5

Pravastatin

2

5-10
2



()
5-10
2
()
5-20
4-12
3-8
6-8
2-3
2-10
Selected Statin-Drug Interactions
Dosing Adjustments
Select Statin Pk Properties
1-3
Grapefruit
Juice
1.5-5
Magnitude of effects is expressed as fold increase of the statin AUC by various inhibitors. The doses of the
inhibitors, as well as the pharmacogenetic factors, can affect the extent of interaction in an individual patient.
An “approximately equal to” sign indicates practically unchanged, parentheses indicate estimation based on the
pharmacokinetic properties of the statin, and a question mark indicates not known or estimated.
AUC, Area under plasma statin concentration–time curve.
*Inhibitors of CYP2C9 increase the AUC of fluvastatin and rosuvastatin by less than 2-fold.
Neuvonen PJ, et al. Clin Pharmacol Ther. 2006;80:565-581.
1. Hirano M, et al. J Pharmacol Exp Ther. 2004;311(1):139-46.
2. Fujino H, et al. J Pharm Pharmacol. 2005;57(10):1305-1311.
3. Hirano M et al. Drug Metab Dispos. 2006;34:1229-36.
4. Corsini A, et al. Curr Med Res Opin. 2011;27(8):1551-62.
18%
Gemfibrozil
2-4
Simvastatin
**All statins except rosuvastatin/fluvastatin are substrates; Inhibitors include: cyclosporine, verapamil,
erythromycin, ketoconazole, itraconazole, quinidine, elacridar: Inducers: rifampicin, St. John’s Wort
Pravastatin
Cyclosporine
Atorvastatin
Rosuvastatin
*SNPs in gene SCLO1B1 affect statin plasma levels; Strong inhibitors include: gemfibrozil, rifampicin,
cyclosporine, erythromycin, clarithromycin, telithromycin, atazanavir, indinavir, ritonavir, saquinavir
Fold ↑ Statin AUC
by other agents
Verapamil
Diltiazem
Max. RecommendedStatin
Dose With Concomitant* Use
Atorvastatin
Fluvastatin
30% dec
Fluvastatin
6%
4.7
NO
NS
Atorvastatin
12%
15-30
YES
13% dec
Rosuvastatin
20%
21
Minor
20% inc
Pitavastatin
51%
13
NO
NS
Other Max. Statin Dose
or Adjustment Recommendations
Itraconazole;
Clarithromycin
Amlodipine;
Amiodarone
Verapamil
Diltiazem
20
NR
NR(?)
NR
Cyclosporine
Gemfibrozil
OTHER
AVOID
AVOID
Adj. Digoxin
NR
NR
20
AVOID
Fluconazole-20
Lovastatin
AVOID
Amio.-40
20
AVOID
AVOID
Danazol-20*
Pitavastatin
Erythro-1
NR
NR
AVOID
NR
Rifampin2**
Pravastatin
Clarithro-40
NR
NR
20
NR
Colchicine***
NR
NR
NR
5
AVOID(10)
Adj.Warfarin
AVOID
20
10
AVOID
AVOID
Ranolazine-20*
Rosuvastatin
Simvastatin
Maximum recommended doses are FDA approved from package inserts of respective statins.
NR= No recommendation
*Inhibitors of CYP 3A4 & CYP2C9 increase the AUC of adjusted agents
**Inhibits OATP1B1;Induces CYP3A4,2C9,MDR1,2
*** Interaction common with many statins
Corsini A, et al. Curr Med Res Opin. 2011;27(8):1551-62.
Adapted from Neuvonen PJ, et al. Clin Pharmacol Ther. 2006;80:565-581.
4
Coadministration of Statins
with Protease Inhibitors
Statins
Protease Inhibitors
Drug-Drug Interaction
Dosing Recommendation
Rosuvastatin
Darunavir; Saquinavir,
Fosamprenavir,
Lopinavir,
Tipranavir
Atazanavir
Atazanavir + Ritonavir
Lopinavir + Ritonavir
Possible increase in rosuvastatin concentration
Start 5 mg; Use lowest
possible dose
Inc. Rosuv. AUC 213% & Cmax by 6-fold
Inc. Rosuv. AUC 3-fold & Cmax 7-fold
Inc. Rosuv. AUC 2-fold & Cmax 5-fold
Limit dose to 10 mg
Limit dose to 10 mg
Limit dose to 10 mg
Atorvastatin
All Protease Inhibitors
Nelfinavir
Fosamprenavir+/-Ritonavir
Darunavir or Saquinqvir +
Tipranavir+ Ritonavir
Telaprevir
Increase atorvastatin concentration
Use lowest possible dose
Limit dose to 40 mg
Limit dose to 20mg
Limit dose to 20 mg
AVOID
AVOID
Pravastatin
Darunavir
Lopinavir+/-Ritonavir
Saquinavir
Darunavir/Ritonavir
Increases prava-concentration
Increases pravastatin -concentration
May decrease prava-concentration (~50%)
Inc. Pravastatin AUC 81% & Cmax 63%
Use lowest possible dose
No dose adjustment (FDA)
Pitavastatin
Atazanavir
Atazanavir+ Ritonavir
Darunavir+Ritanavir
Lopinavir+Ritonavir
31%increase in pitavastatin AUC
No dosage adjustements.
Contraindications removed
from 2/28/12 Pkg. insert
(v.4)/FDA
Simvastatin
or Lovastatin
All Protease Inhibitors inc.
Boceprevir or Telaprevir
Significant increases in simvastatin
or lovastatin concentrations
20-26% decrease in pitavastatin AUC.
20-26% decrease in pitavastatin AUC
Conclusions
• Knowledge of statin metabolism is crucial to
minimizing side effects with concomitant
therapies
• Lower statin doses generally are less likely to
cause side effects
• Remember to track ALL medications, herbs
and supplements taken by your patients
• Be aware of recent FDA dosing adjustments in
patients on CYP 450-3A4 drugs
No dose adjustment (FDA)
ALL Contraindicated
Kiser JJ, et al. J Acquir Immune Defic Syndr. 2008;47(5):570-8. Busti AJ, et al. J Cardiovasc Pharmacol.
2008;51(6):605-10; U.S. FDA Update. 3/1/12.
Disclosures
No relevant financial relationships to
disclose
Statin Intolerance and Side
Effects
Amit Khera, MD, MSc, FACC
Associate Professor
Director, Preventive Cardiology Program
UT Southwestern Medical Center
Drug Interactions
Increasing Statin Levels
Statin Safety
• Hepatic toxicity
Fold ↑ Statin AUC
by other agents
Fold ↑ Statin AUC
by CYP3A4 Inhibitors
• Muscle toxicity
Atorvastatin
• Toxicity more common in the elderly, frail,
or those with liver disease or renal
insufficiency
• Toxicity may be increased by certain other
meds (e.g., gemfibrozil, antifungals,
amiodarone, verapamil, macrolide antibiotics,
cyclosporine, certain antidepressants) or foods
(e.g., grapefruit juice)
Itraconazole
Erythromycin
Clarithromycin
Verapamil
Diltiazem
Cyclosporine
Gemfibrozil
2-4
1.5-5
?
6-15
< 1.5
Grapefruit
Juice
1-4
Fluvastatin


()
2-4

()
Lovastatin
5-10
(4-12)
3-8
5-20
2-3
2-10
Pitavastatin
()
()
()
5
 1.5

Pravastatin

2

5-10
2

Rosuvastatin
Simvastatin


()
5-10
2
()
5-20
4-12
3-8
6-8
2-3
2-10
Magnitude of effects is expressed as fold increase of the statin AUC by various inhibitors. The
doses of the inhibitors, as well as the pharmacogenetic factors, can affect the extent of
interaction in an individual patient. An “approximately equal to” sign indicates practically
unchanged, parentheses indicate estimation based on the pharmacokinetic properties of the
statin, and a question mark indicates not known or estimated.
AUC, Area under plasma statin concentration–time curve.
*Inhibitors of CYP2C9 increase the AUC of fluvastatin and rosuvastatin by less than 2-fold.
Neuvonen PJ, et al. Clin Pharmacol Ther. 2006;80:565-581.
5
All Statin Clinical Outcome Trials:
Effects on Cancer
Statins and Rhabdomyolysis
Treatment
Incidence of Rhabdomyolysis
per 10,000 patient-years
of therapy
Atorvastatin
Pravastatin
Simvastatin
Cerivastatin
0.54 (0.22-1.12)
0 (0-1.11)
0.49 (0.06-1.76)
5.34 (1.46-13.68)
In combination with statins
Gemfibrozil
Fenofibrate
• Relative risk of cancer per 1.0 mmol/L
(40 mg/dL) reduction in LDL-cholesterol
Cancer incidence
Treatment arm
Control arm
Relative risk
(95% CI)
More vs less statin
5 trials (n=39,612)
1466
1472
1.02 (0.89-1.18)
Statin vs Control
21 Trials
(n=129,526
3594
3592
1.00 (0.95-1.04)
All 26 trials
(n=169,138)
5060
5064
1.00 (0.96-1.04)
Comparison
3.70 (0.76-10.82)
0 (0-14.58)
CTT Collaborators. Lancet. 2010; 376:1670-1681.
Graham DJ, et al. JAMA. 2004;292:2585-2590
Withdrawal of Statins Because
of Elevated Liver Function Tests
Statins and the Liver
• LFT elevations > 3 times the ULN occur
• Withdrawal is recommended if LFTs are
with all statins
• Incidence at lower doses is < 1% and 2-3%
at 80 mg/day doses
• Almost always reversible with removal
of therapy
• Liver failure reports are extremely rare, similar
in frequency to that of general population,
and causality from statins not established
three times the upper limit of normal
• Physicians often stop statins for mild
LFT elevation
• Role of fatty liver
McKenney JM, et al. Am J Card. 2006; 97(8A):89c-94c
Statin Advisory: Risk Factors
for Statin-associated Myopathy
Statin Advisory:
Definitions of Muscle Toxicity
Concomitant meds or consumption of:
– Fibrates
– Nicotinic acid (rarely)
– Cyclosporine
– Azole antifungals
– Itraconazole, ketoconazole
– Macrolide antibiotics
– Erythromycin, clarithromycin
– HIV protease inhibitors
– Nefazodone (antidepressant)
– Verapamil
– Amiodarone
– Large quantities of grapefruit juice
(1 qt/d)
– Alcohol abuse
• Myopathy — a general term referring to any disease
of muscles; myopathies can be acquired or inherited
and can occur at birth or later in life
• Myalgia — muscle ache or weakness without creatine
kinase (CK) elevation
• Myositis — muscle symptoms with increased
CK levels
• Rhabdomyolysis — muscle symptoms with marked
CK elevation (10x the ULN) and creatinine elevation,
usually with brown urine and urinary myoglobin
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567-572.
Pasternak RC, et al. Circulation. 2002;106:1024-1028.
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:568-573.
Pasternak RC, et al. Circulation. 2002;106:1024-1028.
6
Other considerations
– Advanced age (especially
80 y; women more than
men)
– Small body frame, frailty
– Multisystem disease
(eg, chronic renal
insufficiency, especially due
to diabetes)
– Multiple medications
– Perioperative periods
Aggravating Factors
in Statin Myopathy
Statin Myopathy (continued)
• Vitamin D deficiency and statin-induced
•
•
•
•
• Link between hypothyroidism and statin
myalgias
One study by Ahmed W, et al suggests that
many patients improve with Vitamin D
supplementation while continuing their statin
therapy
Study not placebo controlled
Ongoing studies in progress
Review of the TNT study did not show a
difference in myalgia in those with low vitamin D
myopathy
• Additive risk has been reported in case
reports
• Potential for misdiagnosis with occult
hypothyroidism
Ahmed W, et al. Transl Res. 2009;153(1):11-16.
CoEnzyme Q10
(Ubiquinone)
Coenzyme Q10 and Statin Therapy
• More heat than light – 1 quality review published1
• Benefit for statin myalgia controversial
• 8 RCTs and 8 observational studies concluded that
•
•
•
•
• Issue of reduction in coenzyme Q10
statins ↓ circulating CoQ10 levels by 16-54%, BUT……
1 RCT and 1 observational study did not, AND……
Skeletal muscle CoQ10 levels were NOT consistently
lowered in 4 human studies
Minimal, inconclusive evidence regarding the effects of
statins on mitochondrial function
Only 2 small (44, 32 pts) RCTs of CoQ10 to prevent
statin-related mylagias: 1 negative2, 1 positive3
levels in patients on statins
• If patient feels better, no need to
proscribe
• CoQ10 carried on LDL particles
1.Marcoff L, et al. J Am Coll Cardiol. 2007;49:2231-2237.
2.Young JM, et al. Am J Cardiol. 2007;100:1400-1403.
3.Caso G, et al. Am J Cardiol. 2007;99:1409-1412.
Marcoff L, et al. JACC. 2007;49:2231-2237;
Palomaki A, et al. J Lipid Res. 1998;84:99-104
Statin Fibrate
Combination Therapy
Treatment Options
• Change to a different statin
• Cerivastatin/gemfibrozil combination had >4000
times the rhabdo rate compared to statin alone
• If the patient is high risk, try all statin options
• Other statins with gemfibrozil rates are 1 to 1.5
• Lower statin dose or consider twice weekly
per thousand pts treated
therapy (e.g., once or twice weekly rosuvastatin)
• Rhabdo rates with statin/fenofibrate combination
• Ezetemibe
are much lower with none reported in FIELD
• Bile acid sequestrants
• Rate of rhabdo is 33 times more for
• Niacin
statin/gemfibrozil combination compared
to statin/fenofibrate combination
• Add water soluble fiber and/or plant stanols
• Role of red yeast rice
Backes JM. The Annals of Pharmacotherapy. 2008;42(3):341-346.
Davidson MH, et al. Am J Card. 2007;99(6A):3C-18C
7
Association Between Incident Diabetes
and Baseline Age or BMI in Statin Trials
Placebo or
control
Statin
Events Rate Events Rate
ASCOT-LLA7
7773
154
11.9
134
10.5
Or
(95% Cl)
Weight
(%)
1.14 (0.89-14.6)
7.07%
HPS8
14573
335
9.2
293
8.0
JUPITER4
17802
270
16.0
216
12.8
1.26 (1.04-1.51) 11.32%
WOSCOPS5
5974
75
5.2
93
6.5
0.79 (0.58-1.10)
1.15 (0.98-1.35) 13.91%
4.24%
LIPID6
6997
126
6.0
138
6.6
0.91 (0.71-1.71)
6.53%
CORONA9
3534
100
20.9
88
18.5
1.14 (0.84-1.55)
4.65%
CORONA9
5023
165
20.5
127
15.8
1.32 (1.03-1.69)
6.94%
CORONA9
6086
172
10.8
164
10.1
1.07 (0.86-1.35)
8.03%
6211
72
4.5
74
4.6
0.98 (0.70-1.38)
3.76%
4S15
4242
198
17.3
193
16.8
1.03 (0.84-1.28)
8.88%
ALLHAT14
6087
238
16.4
212
14.4
1.15 (0.95-1.41) 10.23%
GISSI HF16
3378
225
34.8
215
32.1
1.10 (0.89-1.35)
9.50%
3460
96
27.5
105
30.6
0.89 (0.67-1.20)
4.94%
1.09 (1.02-4.17)
100%
AFCAPS/TEXCAPS18
GISSI PREV16
Overall (P=11.2% [95%Cl0-0-50.2%])
0.5
1.0
Odds Ratio (95%Cl)
n
Odds Ratio (95%Cl)
Incident Diabetes in Statin Trials
2.0
13 trials, N = 91,140
Sattar N, et al. Lancet. 2010;375:735-742.
1.6
1.4
1.2
JUPITER
MEGA
1.0
AFCAPS/
TexCAPS
0.8
0.6
0.0
WOSCOPS
55
ASCOT-LLA
4S
HPS
GISSI HF
LIPID
GISSI
PREVENZONE
60
65
75
PROSPER
CORONA
MEGA
4S
0.8
0.6
0.0
70
Mean age at baseline (years)
1.6
1.4
1.2
1.0
PROSPER
CORONA
ALLHAT-LLT
GISSI HF
24
35
JUPITER
ALLHAT-LLT
ASCOT-LLA
GISSI PREVENZONE
WOSCOPS
13 trials, N = 91,140
HPS
AFCAPS/TexCAPS
26
27
28
29
Mean body mass index at baseline (kg/m2)
Sattar N, et al. Lancet. 2010;375:735-742.
Conclusions
• Statin toxicity and side effects can be
•
•
•
•
reduced by avoiding concomitant therapy
that may increase risk
Lower statin doses generally are less
likely to cause side effects
Rule out underlying hypothyroidism
Vitamin D assessment may be
considered
Consider non-statin therapy if necessary
?
61-year-old male with a myocardial infarction 3 years ago,
Hepatitis C diagnosed 2 years ago (on no therapy):
currently on Simvastatin 40 mg daily, Amlodipine 10 mg od,
Lisinopril 10 mg od, Clopidogrel 75 mg od, aspirin 81 mg
daily presents with the following data:
•
•
•
•
•
LDL-C:
HDL-C:
Triglycerides:
TC:
Non-HDL-C:
115 mg/dL
26 mg/dL
177 mg/dL
176 mg/dL
150 mg/dL
•
•
•
•
•
•
What is your LDL-C goal for this patient?
1.
2.
3.
4.
Fasting glucose: 97 mg/dL
A1C:
6.0%
ALT:
94 mg/dL
AST:
118 mg/dL
GGT:
229 mg/dL
(Last LFTs were normal 6
months ago)
8
< 70 mg/dL
< 100 mg/dL
< 130 mg/dL
Unsure
?
Lipid Profile:
LDL-C: 115 mg/dL; HDL-C: 26 mg/dL; Triglycerides: 177 mg/dL;
TC: 176 mg/dL ; Non-HDL-C: 150 mg/dL (on simvastatin 40 mg OD)
67-year-old hypertensive female with type 2 diabetes for 10
years currently taking: pioglitazone 30 mg daily, metformin
1000 mg twice daily, sitagliptin 100 mg daily,
lisinopril/HCTZ 20/12.5 once daily, and aspirin 325 mg
daily. She states that she has developed leg cramps with
atorvastatin, simvastatin, rosuvastatin, and lovastatin. She
presents with the following data:
What lipid lowering therapy would you
add/institute?
1.
2.
3.
4.
5.
Change simvastatin to rosuvastatin 20 mg od
Change simvastatin to atorvastatin 40 mg od
Change simvastatin to pitavastatin 4 mg od
Add ezetimibe 10 mg od
Change simvastatin to fluvastatin XL 80 od
•
•
•
LDL-C:
145 mg/dL •
HDL-C:
32 mg/dL •
Triglycerides: 326 mg/dL •
TC:
242 mg/dL
Non-HDL-C: 210 mg/dL
A1C:
7.4%
?
Lipid Profile:
LDL-C: 145 mg/dL; HDL-C: 32 mg/dL; Triglycerides: 326 mg/dL
66-year-old white female with a history of hypertension,
coronary disease and renal insufficiency. She stopped
smoking in 2002. Her current medications are:
aspirin 81 mg, Amlodipine 5 mg od, Losartan/HCT 50/12.5
What lipid lowering therapy would you add/institute?
1.
2.
3.
4.
5.
6.
Laboratory Studies:
• TC:
237 mg/dL
• LDL-C:
156 mg/dL
• TG:
205 mg/dL
• HDL-C:
40 mg/dL
• Non-HDL-C: 197 mg/dL
Pitavastatin 2 mg OD
Fluvastatin XL 80 mg OD
Fenofibrate/Ezetimibe
Red Yeast Rice
Rosuvastatin 20 mg once weekly
Rosuvastatin 20 mg OW plus colesevelam daily
• HbA1C:
6.2%
• eGFR:
40 mL/min
• Urine microalbumin/creatinine
ratio:
55 mg/mmol
(elevated)
?
?
Lipid Profile:
TC: 237 mg/dL; LDL-C: 156 mg/dL; TG: 205 mg/dL; HDL-C: 40 mg/dL;
Non-HDL-C: 197 mg/dL
What is your LDL-C goal for this patient?
1.
2.
3.
4.
What lipid lowering therapy would you add/institute?
< 70 mg/dL
< 100 mg/dL
< 130 mg/dL
Unsure
1.
2.
3.
4.
5.
6.
9
Pitavastatin 1 mg OD
Fluvastatin XL 80 mg OD
Rosuvastatin 10 mg OD
Atorvastatin 10 mg OD
Simvastatin 40 mg OD
Pravastatin 40 mg OD
Disclosures
• No relevant financial relationships to disclose
Statins in CKD
Carl E. Orringer, MD
Harrington Chair in Preventive Cardiovascular Medicine
University Hospitals Case Medical Center Harrington Heart and
Vascular Institute
Associate Professor of Medicine
Case Western Reserve University School of Medicne
Cleveland, OH
Association of CKD and CV Events
in Community-Based Studies
Population
Number
of
patients
Definition of
CKD
CV endpoints
Unadjusted
CV hazard
ratio (95% CI)
Adjusted CV
hazard ratio
(95% CI)*
ARIC
15,350
eGFR: 15-59
ml/min/1.73m2
Fatal CHD, MI,
stroke, and cardiac
procedure
2.89
(2.22-3.77)
1.38
(1.08-1.87)
CHS
4893
eGFR: 15-59
ml/min/1.73m2
Cardiac death, MI,
PCTA, CABG, angina,
CHF, peripheral
vascular disease,
stroke, and TIA
2.29
(1.93-2.72)
1.31
(1.06-1.62)
FHS/FOS
men
2837
serum
creatinine: 136265
μmol/l
CHD CHF,
and ischemic
stroke
1.17
(0.88-1.57)
1.06
(0.79-1.43)
3386
serum
creatinine: 120265
μmol/l
CHD CHF,
and ischemic
stroke
2.19
(1.70-2.83)
1.04
(0.79-1.37)
FHS/FOS
women
Cardiovascular Event Rates in 2000
and 2001 (per 100 patient years)
Harper CR, et al. J Am Coll Cardiol. 2008;51:2375-2384.
Adapted from Foley RN, et al. J. Am Soc Nephrol. 2005;16:489-495.
Adapted from: van der Zee S, et al. Nat Rev Cardiol. 2009;6:580-589.
Analysis of CV Outcomes According to the
Presence of Chronic Kidney Disease
Chronic kidney disease as a coronary disease
equivalent – a comparison with diabetes over a decade
• Veterans with and without diabetes and with and
without CKD were prospectively recruited. A competing
Cox regression model was used to describe the risk of
myocardial infarction in the two groups (CKD and
diabetes) over a decade of follow-up
• CKD is associated with a risk of death similar to that of
established coronary artery disease and higher than
that of diabetes mellitus. CKD is associated with a risk
of MI that is at least as much as that from diabetes
mellitus. Among veterans, CKD appears to be a
coronary disease equivalent
No CKD eGFR 60-150 mi/min/1.73m2
eGFR 15-60 mi/min/1.73m2
0.0
van der Zee S, et al. Nat Rev Cardiol. 2009;6:580-589.
Weiner DE, et al. J Am Soc Nephrol. 2004;15:1307-1315.
Yalew T, et al. Clin J Am Soc Nephrol. 2011;Mar 10. [Epub ahead of print]; doi:10.2215/CJN.10271110.
10
Factors Affecting Serum
Creatinine Concentration
How to Interpret GFR
Average measured GFR by age in
people without CKD
Stages of chronic kidney disease
and clinical action plans
Frequently Asked Questions about GFR: Available at
www.kidney.org/professionals/kls/pdf/KBA_FAQs_AboutGFR.pdf
Accessed August 23, 2011.
Frequently Asked Questions about GFR: Available at www.kidney.org/professionals/kls/pdf/KBA_FAQs_AboutGFR.pdf
Accessed August 23, 2011.
ATP III Update 2004:
Pharmacologic Treatment
When is Assessment of GFR Important?
Risk Category
Initiate TLC
<70 mg/dL
(favored option)
70 mg/dL
≥70 mg/dL
High risk:
CHD or CHD risk equivalents
(10-year risk >20%)
<100 mg/dL
(optional goal: <70
mg/dL)
100 mg/dL
≥100 mg/dL
(<100 mg/dL:
consider drug
option)
Moderately high risk:
2+ risk factors
(10-year risk 10% to 20%)
<130 mg/dL*
130 mg/dL
≥130 mg/dL**
Moderate risk:
2+ risk factors (risk <10%)
<130 mg/dL
130 mg/dL
≥160 mg/dL
<160 mg/dL
160 mg/dL
Lower risk:
0-1 risk factor
*optional goal:
<100 mg/dL.
Frequently Asked Questions about GFR: Available at
www.kidney.org/professionals/kls/pdf/KBA_FAQs_AboutGFR.pdf
Accessed August 23, 2011.
≥190 mg/dL
**100-129 mg/dL
consider drug option
CRF=Cardiac Risk Factors. TLC=Therapeutic Lifestyle Changes
Adapted from: Grundy SM, et al. Circulation. 2004;110:227-239.
Mechanisms of
Dyslipidemia in CKD
Mechanism
Consider
Drug Therapy
LDL-C Goal
Very high risk:
ACS, or CHD w/ DM, multiple
CRF ? CKD
Percentage of Lipid Abnormalities
by Target Population
CKD Stage
TC
>240 mg/dL
LDL-C
>130 mg/dL
HDL-C
<35 mg/dL
TGs
>200 mg/dL
General
Population
20
40
15
15
CKD Stages
1-4 With NS
90
85
50
60
Decreased HDL
CKD Stages
1-4 NO NS
30
10
35
40
Decreased
Decreased HDL
CKD Stage 5
Hemodialysis
20
30
50
45
Decreased
Decreased HDL
CKD Stage 5
Peritoneal Dialysis
25
45
20
50
Change
Effects
Lipoprotein Lipase
Decreased
Increased TG and increased
lipid-poor LDL and HDL
ApoCII/ApoCIII Ratio
Decreased
Increased TG and LPL activity
VLDL Receptor
Decreased
Increased TG
CETP
Increased
ApoA-I
LCAT
LPL: lipoprotein lipase; CETP: cholesterol ester transfer protein; LCAT: lecithin cholesterol acyltransferase;
VLDL: very low-density lipoprotein
Harper CR, et al. J Am Coll Cardiol. 2008;51:2375-2384.
Adapted from: Vaziri ND. Am J Physiol Ren Physiol. 2005;290:F262–F272.
NS, nephrotic syndrome
Weiner DE, et al. J Gen Intern Med. 2004;19:1045-1052.
11
Summary of Trials with Lipid
Lowering Rx in CKD
Study
Population
CKD Level
Intervention +
Follow-up Period
Primary End Point
Results Summary
Pravastatin
Pooling Project
N = 19768
CKD = 4491
(22.8%)
eGFR 30-60
(Stage 3)
40 mg pravastatin
vs. placebo
5.2-year mean
follow-up
Cardiovascular events (MI,
coronary death, coronary
revascularization)
23% end point incidence reduction
(HR: 0.77; 95% CI: 0.68-0.86)
TNT sub-study
N = 1859 CKD
+ metabolic
syndrome
eGFR < 60
excluding
dialysis
(Stage 2-4)
80 mg atorvastatin
vs 10 mg
atorvastatin
5-year follow-up
Cardiovascular events
(death, nonfatal MI, fatal or
nonfatal stroke)
Combined sub-study populations:
33% events risk reduction in high
dose 80 mg atorvastatin group (HR:
0.68; 95% CI: 0.55-0.84; p=0.0003)
TNT sub-study
N = 954 CKD
+ obese
eGFR < 60
excluding
dialysis
(Stage 2-4)
80 mg atorvastatin
vs 10 mg
atorvastatin
5-year follow-up
Cardiovascular events
(death, nonfatal MI, fatal or
nonfatal stroke)
4D
N = 1255
eGFR < 15
(Stage 5)
Atorvastatin 20 mg
vs placebo
4-year follow-up
Cardiovascular death (nonfatal MI, stroke)
Non-significant 8% events risk
reduction (RR: 0.92; 95% CI: 0.771.1; p=0.37
AURORA
N = 2766
eGFR < 15
(Stage 5)
Rosuvastatin 10 mg
vs. placebo
3.2-year follow-up
Cardiovascular event
(death, non-fatal MI, nonfatal stroke)
Non-significant 9.9% events risk
reduction (HR: 0.96; 95% CI: 0.841.11; p=0.59
SHARP
N = 9270
6247 stage 2-4
3023 stage 5
Simvastatin 20 mg +
ezetimibe 10 mg vs
placebo
4.9 year follow-up
Major atherosclerotic event
(death, non-fatal MI, nonhemorrhagic stroke,
revascularization procedure)
Total population 17% end point risk
reduction (RR: 0.83; 95% CI 0.740.94; p=0.0021
ALERT
N = 2102
Renal
transplant
recipients
40-80 mg fluvastatin
vs. placebo
6-year follow-up
extended to 8 years
Major cardiac event (cardiac
death, non-fatal MI,
coronary intervention)
Non-significant primary end point
reduction p=0.139 at 6-year followup. After 2-year extension: RR:
0.79; 95% CI: 0.55-0.93; p=0.036
SHARP: Main Outcomes
• Key outcome
– Major atherosclerotic events (coronary death, MI,
non-haemorrhagic stroke, or any revascularization)
• Subsidiary outcomes
– Major vascular events (cardiac death, MI, any
stroke, or any revascularization)
– Components of major atherosclerotic events
• Main renal outcome
– End stage renal disease (dialysis or transplant)
Presented at American Society of Nephrology Meeting, November 20, 2010. Accessed at
http://www.ctsu.ox.ac.uk/~sharp/SHARP_slides.
CKD: Chronic kidney disease; eGFR: estimated glomular filtration rate; HR: hazard
ratio; RR: relative risk
Clin Lipidol. 2011; 6(6)
SHARP: Major
Atherosclerotic Events
Drug Dose Modification in CKD
• Statins: GFR 15-59 no dose reductions needed with
25
atorvastatin, simvastatin, or pravastatin; fluvastatin
not defined
• Non-statins: GFR 15-59 no dose modification required
for niacin, bile acid sequestrants, ezetimibe,
gemfibrozil, omega 3
• 25% dose reduction recommended for fenofibrate
• For gemfibrozil, the NLA recommends a dose of
600 mg/day for GFR 15-59 ml/min/1.73 m2 and
avoiding use for GFR 15 ml/min/1.73 m2
Proportion suffering event (%)
Risk ratio 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
20
Placebo
15
Eze/simv
10
5
0
0
1
2
3
4
5
Years of follow-up
NLA, National Lipid Association
Harper CR, et al. J Am Coll Cardiol.2008;51:2375-2384.
Presented at American Society of Nephrology Meeting, November 20, 2010. Accessed
at http://www.ctsu.ox.ac.uk/~sharp/SHARP_slides.
Proposed Treatment Algorithm for Lipid
Management in Patients With CKD
Management of Dyslipidemias in
Adults With Chronic Kidney Disease
Stage 3 to 5
Moderate-to-severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2)
• Elevated LDL-C
– Atorvastatin, add ezetimibe if not at LDL-C goal
– Fluvastatin, add ezetimibe if not at LDL-C goal
• Mixed dyslipidemia (not at non-HDL-C goal)
– Atorvastatin or fluvastatin, ezetimibe
– Fluvastatin, gemfibrozil 600 mg/day, ezetimibe if not at non-HDL-C goal
– Statin, omega-3 fatty acids, add ezetimibe if not at non-HDL-C goal
– Statin, fenofibrate 48 mg/day, add ezetimibe if not at non-HDL-C goal
• Very high triglycerides (triglyceride 500 mg/dL)
– Gemfibrozil 600 mg/day
– Omega-3 fatty acids 3-4 g/day
– Fenofibrate 48 mg/day
Consult product insert or the Physicians Desk Reference for safety and risk information.
Harper CR, et al. J Am Coll Cardiol.2008;51:2375-2384.
Dyslipidemia
Goal
Initiate
Increase
Alternative
TG ≥500 mg/dL
TG <500 mg/dL
TLC
TLC + fibrate or
niacin
Fibrate or
niacin
LDL 100-129
mg/dL
LDL <100 mg/dL
TLC
TLC + low- dose
statin
Bile acid
sequestrant
or niacin
LDL >130 mg/dL
LDL <100 mg/dL
TLC + low- dose
statin
TLC + maxdose statin
Bile acid
sequestrant
or niacin
TG ≥ 200 mg/dL
and non-HDL
≥ 130 mg/dL
Non-HDL <130
mg/dL
TLC + low- dose
statin
TLC + maxdose statin
Fibrate or
niacin
National Kidney Foundation. Available at: http://www.kidney.org/professionals/kls/pdf/Pharmacist_CPG.pdf
Accessed May 10, 2011.
Kidney Disease Outcomes Quality Initiative (K/DOQI) Group. Am J Kidney Dis. 2003;41(4 Suppl 3):S1-S91.
12
NKF Summary
Recommendations
•
•
•
•
•
•
Nephrology Referral
CKD is considered to be the HIGHEST RISK category
Drug therapy should be used for LDL-C of 100-129 mg/dL after
3 months of TLC
• eGFR <30ml/min, early referral improves dialysis survival
and allows earlier transplantation
• Heavy proteinuria with albumin/creatinine ratio>1000 mg/g
Initial drug therapy should be with a statin
Fibrates may be used in Stage 5 CKD for patients with
triglycerides ≥500 mg/dL and for patients with triglycerides
≥200 mg/dL with non-HDL cholesterol ≥130 mg/dL who do not
tolerate statins
Gemfibrozil may be the fibrate of choice for treatment of high
triglycerides in patients with CKD
Evaluation of lipids should occur at presentation of CKD, after a
change in status, and annually
• Resistant hypertension: above target on 3 or more meds
• Recurrent renal calculi
• Refractory Hyperkalemia K>5.5
• Rapid decline in kidney function
• Autoimmune disease
• Onset of kidney disease at young age (<30 years old)
Fleg JL, et al. J Am Coll Cardiol. 2008;52:2198-2205. National Kidney Foundation KDOQI Guidelines. Available at:
http://www.kidney.org/professionals/kdoqi/guidelines_lipids/i.htm#guidelines. Accessed May 10, 2011.
Adapted from “CHRONIC KIDNEY DISEASE QUICK REFERENCE GUIDE for the PRIMARY CARE PROVIDER”
(Derived from the National Kidney Foundation K-DOQI Clinical Guidelines)
De Coster C, et al. J Nephrol. 2010;23(4):399-407.
Statins Dose Adjustments
in CKD
Statin/Fibrate Combination Therapy:
Pharmacokinetic Interactions
GFR (ml/min/1.73m²)
Gemfibrozil
Fenofibrate
Statin
60–90
15–59
<15
Atorvastatin
↑ in Cmax by 2.7-fold
No effect
Atorvastatin
No
No
No
Simvastatin
↑ in Cmax by 2-fold
No effect
Fluvastatin
No
?
?
Reduce by 50% in patients with GFR
<30 ml/min/1.73m²
Pravastatin
↑ in Cmax by 1.8-fold
No effect
Pravastatin
No
No
No
Start at 10 mg/day for GFR
<60 ml/min/1.73m²
Rosuvastatin
↑ in Cmax by 2-fold
No effect
Rosuvastatin
No
5–10 mg
5–10 mg
Fluvastatin
No effect
No effect
Start at 5 mg/day for GFR
<30 ml/min/1.73m², do not exceed
10 mg/day
Lovastatin
↑ in Cmax by 2.8-fold
No effect
Simvastatin
No
↑ in Cmax by 2-3-fold
No effect
Reduce by 50% in
patients with GFR
<30 ml/min/1.73m²
Start at
5 mg/day
Cerivastatin
Lovastatin
No
↓ to 50%
↓ to 50%
Pitavastatin
↑ in Cmax 31%
No effect
Notes
Reduce to 50% in patients with GFR
<30 ml/min/1.73m²)
Pitavastatin
Backman JT, et al. Clin Pharmacol Ther. 2005;78:154-167.
Kyrklund C, et al. Clin Pharmacol Ther. 2001;69:340-345.
Pan WJ, et al. J Clin Pharmacol. 2000;40:316-323.
Backman JT, et al. Clin Pharmacol Ther. 2000;68:122-129.
Schneck DW, et al. Clin Pharmacol Ther. 2004;75:455-463.
Kyrklund C, et al. Clin Pharmacol Ther. 2003;73:538-544.
TriCor [package insert]. Abbott Laboratories;2004.
Adapted from K/DOQJ clinical practice guidelines K/DOQJ clinical practice guidelines for
management of dyslipidemias in patients with kidney disease (2003).
Backman JT, et al. Clin Pharmacol Ther. 2002;72:685-691.
Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K.
Martin PD, et al. Clin Ther. 2003;25:459-471.
Bergman AJ, et al. J Clin Pharmacol. 2004;44:1054-1062.
Livalo [package insert]. Montgomery, AL: Kowa
Pharmaceuticals America, Inc; 2010.
Abbott Laboratories. Data on file; 2005.
↓ = decrease; ? = not defined; CKD = chronic kidney disease; GFR = glomerular filtration rate
Kassimatis TI, et al. Pharmacol Ther. 2009;122(3):312-23
Post ?
Summary
Which of the following statins is not
metabolized by cytochrome P-450 3A4 or
2C9?
• CKD is associated with an increased risk of
CVD and a worse prognosis
• CKD is a CHD risk equivalent state
1.
2.
3.
4.
5.
• CKD is associated with low HDL-C, TG and
excessive # atherogenic particles
• Statin therapy reduces CVD except in dialysis
patients, where no benefit has been established
• Lipid medication dosage adjustment is often
required in patients with CKD
13
Atorvastatin
Rosuvastatin
Simvastatin
Fluvastatin
Pravastatin
Post ?
Post ?
When measured by AUC, which of the
following statins has the least drug
interaction with cyclosporine?
Which of the following statements is false?
1. Lower statin doses generally are less likely
to cause side effects
2. Gemfibrozil has no effect on pitavastatin
levels
3. Gemfibrozil has no effect on fluvastatin
levels
4. There were no cases of rhabdomyolysis
reported in the FIELD Trial with
statin/fenofibrate combinations
1.
2.
3.
4.
Questions & Answers
?
14
Pravastatin
Rosuvastatin
Atorvastatin
Fluvastatin