Assessing Statin Therapy: What are Their Differences?

Educational Partner: 

 

 

 

Saturday, June 23, 2012 

New York, New York 

Session 5

Session 5: Assessing Statin Therapy: What are Their Differences? Learning Objectives

1. Recognize statin drug interactions and select appropriate therapies that will not carry an increased risk of adverse events.

2. Apply evidence-based clinical study data into practice that demonstrates statins’ ability to modify both LDL-C and HDL-C to optimize drug selection.

3. 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.

1

Generic TradeColesevelam WelcholEzetimibe ZetiaFenofibrate Antara, Lipofen,Lofibra,TricorFenofibric Acid Fibricor, TrilipixGemfibrozil LopidOmega-3 acid ethyl esters LovazaNiacin –ER NiaspanAtorvastatin LipitorFluvastatin LescolFluvastatin – XL Lescol XLLovastatin MevacorPitavastatin LivaloPravastatin PravacholRosuvastatin CrestorSimvastatin ZocorSimvastatin-ezetimibe Vytorin

Drug List

Assessing Statin Therapy: What are Their Differences?Amit Khera, MD, MSc, FACCCarl E. Orringer, MD

Which of the following statins is notmetabolized by cytochrome P-450 3A4 or 2C9?

1. Atorvastatin2. Rosuvastatin3. Simvastatin4. Fluvastatin

5. Pravastatin

Pre ?

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 pitavastatinlevels

3. Gemfibrozil has no effect on fluvastatinlevels

4. There were no cases of rhabdomyolysisreported in the FIELD Trial with statin/fenofibrate combinations

Pre ?

When measured by AUC, which of the following statins has the least drug interaction with cyclosporine?

1. Pravastatin2. Rosuvastatin3. Atorvastatin4. Fluvastatin

Pre ?

Statin Drug Interactionsand Special PopulationsAmit Khera, MD, MSc, FACCAssociate ProfessorDirector, Preventive Cardiology ProgramUT Southwestern Medical Center

2

Disclosures

• No relevant financial relationships to disclose

Statin Basic Pharmacological Principles

• 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.

Relationship between drug dose and clinical utility, and adverse drug event (ADE) is governed by 2 concepts:

PK Mechanisms of Statin-drug Interactions (SDI)

• METABOLISM: Induction &/or inhibition of:– PHASE I ENZYMES (Redox reactions) FMO, MAO

Cytochrome P (CYP)450 3A4, 2D6, 1A2, 2C9

– PHASE II ENZYMES (Conjugation) Sulfation: sulfotransferase (SULT)

Acetylation: N-acetyltransferase (NAT)

Glutathione conjugation (GST)

Methylation: methyltransferases (MT)

Glucuronidation: UDP-glucuronosyltransferase (UGT)

Shitara Y, et al. Annu Rev Pharmacol Toxicol. 2005;45:689-723.

Predominance of CYP450 System in Drug Metabolism

• 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

~75% of Drugs Metabolized Involve CYP450

Routes of Drug Metabolism

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.

~50% of CYP450 Metabolism Involves 3A4

Isoforms of CYP450 System Involved in Drug Metabolism

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.

Routes of Drug Metabolism Most Utilized CYP450 Isoforms

Most Statins Use CYP 3A4 or CYP 2C9 Isoforms

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.

Routes of Drug Metabolism Most Utilized CYP450 Isoforms

Isoforms of CYP450 System Involved in Statin Metabolism

SimvastatinLovastatinAtorvastatin

FluvastatinRosuvastatin (some)

Pitavastatin (minimal)

3

Select Inhibitors of CYP450 3A4

STRONG/MODERATE

• Protease Inhibitors

– Ritonavir, indinavir, nelfinavir

• Macrolide antibiotics

– Erythromycin, telithromycin, clarithromycin

• Azole antifungals

– Ketoconazole, fluconazole, itraconazole

• Chloramphenicol

• CCBs

– Verapamil, diltiazem

• Antidepressant- Nefazodone

• Antiemetic - aprepitant

• Bergamottin - constituent of grapefruit juice

WEAK/UNSPECIFIED

• H2 antagonist - cimetidine

• Antiarrhythmic - amiodarone

• CCBs amlodipine, felodipine

• Cyclosporine

• Analgesic - buprenorphine

• Antibiotics - norfloxacin, ciprofloxacin

• NNRTIs

– Nevirapine, efavirenz, delavirdine

• PIs - saquinavir

• Antineoplastics - imatinib

• SSRIs

– Fluoxetine, norfluoxetine, fluvoxamine

• Echinacea, Star Fruit, Milk Thistle

Budzinski, JW, et al. Phytomedicine. 2000;7(4):273-82 Lee SS, et al. Phytother Res. 2007;21(11):1096-9Kajbaf M, et al. Drug Metab Lett. 2011;5(1):30-9 http://medicine.iupui.edu/clinpharm/ddis/table.aspxChoi I, et al. Eur J Med Chem. 2009;44(6):2354-60 Yang J, et al. Current Drug Metabolism. 2008;9(5):384-393

Select Inhibitors of CYP450 2C9

STRONG/MODERATE

• Uricosuric

– Benzbromarone

• Antifungal

– Fluconazole

• Anticonvulsant

– Valproic acid

• ARBs

– Losartan, irbesartan

• Antibacterial

– Sulfaphenazole

• Amentoflavone

– Component of Ginkgo Biloba& St. John’s Wort

WEAK/UNSPECIFIED

• H2 antagonist - cimetidine

• Antiarrhythmic - amiodarone

• Antibiotics: Chloramphenicol, sulfamethoxazole

• Fluvastatin

• Fenofibrate

• Lovastatin

• Probenecid

• Sertraline

• Antifungal - voriconazole

• ChemoRx - teniposide

• Leukotriene antagonist - Zafirlukast

• Flavones

Kajbaf M, et al. Drug Metab Lett. 2011;5(1):30-9. Lee CR, et al. Pharmacogenetics. 2002; 12:251-26http://medicine.iupui.edu/clinpharm/ddis/table.aspxGleeson MP, et al. J Comput Aided Mol Des. 2007;21(10-11):559-73

PK Mechanisms of Statin-Drug Interactions

• 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)

Shitara Y, et al. Annu Rev Pharmacol Toxicol. 2005;45:689-723.

Competitive Glucuronidation: Gemfibrozil & Fenofibrate vs. Statins

Prueksaritanont T, et al. Drug Metab Dispos. 2002;30:1280-1287.

Glu

curo

nide

For

mat

ion,

pmol

/min

/mg

3000

2000

1000

50

Most Statins Utilize UGT 1A1 and 1A3 for Metabolism

Gemfibrozil competitively competes with statins for UGT 1A1 and 1A3 and is potent inhibitor of CYP 2C9 and 2C8 and OA1B1.

Fenofibrate Primarily Utilizes UGT 1A9 and 2B7 for Metabolism

Gemfibrozil Fenofibrate

+ Gemfibrozil

+ Placebo

Gemfibrozil Increased Cerivastatin Plasma Concentrations

Backman JT, et al. Clin Pharmacol Ther. 2002;72:685-691.

Time, h

Cer

ivas

tatin

Aci

d, n

g/m

L

Doses:Cerivastatin: 0.3 mgGemfibrozil: 600 mg BID

0 2 4 6 8 10 12 24

10

8

6

4

2

0

* Cerivastatinwithdrawn in 2001

Statin-fibrate Combination Therapy:Pharmacokinetic Interactions

Gemfibrozil Fenofibrate

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

4

Rhabdomyolysis in Fibrate Combination Therapy With Statins*

0.58

8.6

0

1

2

3

4

5

6

7

8

9

10

Fenofibrate Gemfibrozil

No

. C

ases

Rep

ort

ed

per

Mill

ion

Pre

scri

pti

on

s

15-Fold Increase

*Excludes cases involving cerivastatinJones PH, et al. Am J Cardiol. 2005;95:120-122

Other Mechanisms of Statin-Drug Interactions

• METABOLISM: Induction &/or inhibition of:– HEPATIC UPTAKE: Organic anion transporters (OAT)

Organic anion transporter polypeptides (OATP)

Na-dependent taurocholate cotransporter (NTCP)

– ELIMINATION: ACTIVE BILIARY SECRETION:

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

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.

*SNPs in gene SCLO1B1 affect statin plasma levels; Strong inhibitors include: gemfibrozil, rifampicin, cyclosporine, erythromycin, clarithromycin, telithromycin, atazanavir, indinavir, ritonavir, saquinavir

**All statins except rosuvastatin/fluvastatin are substrates; Inhibitors include: cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, elacridar: Inducers: rifampicin, St. John’s Wort

***SNPs in gene for ABCG2 increase response to rosuvastatin.

Statin Membrane Transporters

Statin Uptake (Influx)

Statin (metabolite) Exit (Efflux)

Blood

Bile

BiotransformationOf Statin

OATP1B1*

OATP1B3 Hepatocyte

NTCP OATP2B1

BCRP***MDR1(P-gp)**

MRP2**

Selected Drug/Food Interactions Increasing Statin Levels

Fold ↑ Statin AUC by CYP3A4 Inhibitors

Fold ↑ Statin AUC by other agents

ItraconazoleErythromycin

ClarithromycinVerapamilDiltiazem

Cyclosporine GemfibrozilGrapefruit

Juice

Atorvastatin 2-4 1.5-5 ? 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

Rosuvastatin () 5-10 2 ()

Simvastatin 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.

Select Statin Pk Properties

BioavailabiliyHalf-life

(hr)Active

MetabolitesFood Effect

Lovastatin 5% 2-4 YES 50% inc

Simvastatin 5% 2-3 YES NS

Pravastatin 18% 1-3 NO 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

Corsini A, et al. Curr Med Res Opin. 2011;27(8):1551-62.

Selected Statin-Drug Interactions Dosing Adjustments

Max. RecommendedStatinDose With Concomitant* Use

Other Max. Statin Dose or Adjustment Recommendations

Itraconazole;Clarithromycin

Amlodipine;Amiodarone

VerapamilDiltiazem

Cyclosporine Gemfibrozil OTHER

Atorvastatin 20 NR NR(?) AVOID AVOID Adj. Digoxin

Fluvastatin NR 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***

Rosuvastatin NR NR NR 5 AVOID(10) Adj.Warfarin

Simvastatin AVOID 20 10 AVOID AVOID Ranolazine-20*

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

Adapted from Neuvonen PJ, et al. Clin Pharmacol Ther. 2006;80:565-581.

5

Coadministration of Statins with Protease Inhibitors

Statins Protease Inhibitors Drug-Drug Interaction Dosing Recommendation

Rosuvastatin Darunavir; Saquinavir,Fosamprenavir,Lopinavir,TipranavirAtazanavirAtazanavir + RitonavirLopinavir + Ritonavir

Possible increase in rosuvastatin concentration

Inc. Rosuv. AUC 213% & Cmax by 6-fold Inc. Rosuv. AUC 3-fold & Cmax 7-foldInc. Rosuv. AUC 2-fold & Cmax 5-fold

Start 5 mg; Use lowest possible dose

Limit dose to 10 mgLimit dose to 10 mgLimit dose to 10 mg

Atorvastatin All Protease InhibitorsNelfinavirFosamprenavir+/-RitonavirDarunavir or Saquinqvir +Tipranavir+ RitonavirTelaprevir

Increase atorvastatin concentration Use lowest possible doseLimit dose to 40 mgLimit dose to 20mg Limit dose to 20 mgAVOIDAVOID

Pravastatin DarunavirLopinavir+/-RitonavirSaquinavirDarunavir/Ritonavir

Increases prava-concentrationIncreases pravastatin -concentrationMay decrease prava-concentration (~50%)Inc. Pravastatin AUC 81% & Cmax 63%

Use lowest possible dose No dose adjustment (FDA)

No dose adjustment (FDA)

Pitavastatin AtazanavirAtazanavir+ RitonavirDarunavir+RitanavirLopinavir+Ritonavir

31%increase in pitavastatin AUC

20-26% decrease in pitavastatin AUC.20-26% decrease 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

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.

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

Statin Intolerance and Side EffectsAmit Khera, MD, MSc, FACCAssociate ProfessorDirector, Preventive Cardiology ProgramUT Southwestern Medical Center

Disclosures

No relevant financial relationships to disclose

Statin Safety

• Hepatic toxicity

• Muscle toxicity

• 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)

Drug Interactions Increasing Statin Levels

Fold ↑Statin AUC by CYP3A4 Inhibitors

Fold ↑ Statin AUC by other agents

Itraconazole ErythromycinClarithromycin

VerapamilDiltiazem

Cyclosporine Gemfibrozil Grapefruit Juice

Atorvastatin 2-4 1.5-5 ? 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

Rosuvastatin () 5-10 2 ()

Simvastatin 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.

6

Statins and Rhabdomyolysis

TreatmentIncidence of Rhabdomyolysisper 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

3.70 (0.76-10.82)

0 (0-14.58)

Graham DJ, et al. JAMA. 2004;292:2585-2590

• Relative risk of cancer per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol

Cancer incidence

CTT Collaborators. Lancet. 2010; 376:1670-1681.

All Statin Clinical Outcome Trials: Effects on Cancer

Comparison Treatment arm Control armRelative risk

(95% CI)

More vs less statin5 trials (n=39,612) 1466 1472 1.02 (0.89-1.18)

Statin vs Control21 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)

Statins and the Liver

• LFT elevations > 3 times the ULN occur with all statins

• Incidence at lower doses is < 1% and 2-3% at 80 mg/day doses

• Almost always reversible with removalof therapy

• Liver failure reports are extremely rare, similar in frequency to that of general population, and causality from statins not established

McKenney JM, et al. Am J Card. 2006; 97(8A):89c-94c

Withdrawal of Statins Because of Elevated Liver Function Tests

• Withdrawal is recommended if LFTs are three times the upper limit of normal

• Physicians often stop statins for mildLFT elevation

• Role of fatty liver

Statin Advisory: Definitions of Muscle Toxicity

• 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 creatinekinase (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.

Statin Advisory: Risk Factors for Statin-associated Myopathy

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

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

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:568-573.Pasternak RC, et al. Circulation. 2002;106:1024-1028.

7

Aggravating Factors in Statin Myopathy

• Vitamin D deficiency and statin-induced 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

Ahmed W, et al. Transl Res. 2009;153(1):11-16.

Statin Myopathy (continued)

• Link between hypothyroidism and statin myopathy

• Additive risk has been reported in case reports

• Potential for misdiagnosis with occult hypothyroidism

Coenzyme Q10 and Statin Therapy

• More heat than light – 1 quality review published1

• 8 RCTs and 8 observational studies concluded that 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

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.

CoEnzyme Q10(Ubiquinone)

• Benefit for statin myalgia controversial• Issue of reduction in coenzyme Q10

levels in patients on statins

• If patient feels better, no need to proscribe

• CoQ10 carried on LDL particles

Marcoff L, et al. JACC. 2007;49:2231-2237; Palomaki A, et al. J Lipid Res. 1998;84:99-104

Treatment Options

• Change to a different statin

• If the patient is high risk, try all statin options

• Lower statin dose or consider twice weekly therapy (e.g., once or twice weekly rosuvastatin)

• Ezetemibe

• Bile acid sequestrants

• Niacin

• Add water soluble fiber and/or plant stanols

• Role of red yeast rice

Backes JM. The Annals of Pharmacotherapy. 2008;42(3):341-346.

Statin FibrateCombination Therapy

• Cerivastatin/gemfibrozil combination had >4000 times the rhabdo rate compared to statin alone

• Other statins with gemfibrozil rates are 1 to 1.5 per thousand pts treated

• Rhabdo rates with statin/fenofibrate combination are much lower with none reported in FIELD

• Rate of rhabdo is 33 times more for statin/gemfibrozil combination compared to statin/fenofibrate combination

Davidson MH, et al. Am J Card. 2007;99(6A):3C-18C

8

Incident Diabetes in Statin Trials

Sattar N, et al. Lancet. 2010;375:735-742.

13 trials, N = 91,140

nStatin Placebo or

control Or(95% Cl)

Weight(%)

Events Rate Events Rate

ASCOT-LLA7 7773 154 11.9 134 10.5 1.14 (0.89-14.6) 7.07%

HPS8 14573 335 9.2 293 8.0 1.15 (0.98-1.35) 13.91%

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) 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%

AFCAPS/TEXCAPS18 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%

GISSI PREV16 3460 96 27.5 105 30.6 0.89 (0.67-1.20) 4.94%

Overall (P=11.2% [95%Cl0-0-50.2%]) 1.09 (1.02-4.17) 100%

0.5 1.0 2.0

Association Between Incident Diabetes and Baseline Age or BMI in Statin Trials

1.61.41.2

0.8

0.60.0

Odd

s R

atio

(95%

Cl)

60 65 70 7555Mean age at baseline (years)

1.0MEGA

AFCAPS/TexCAPS

WOSCOPS

ASCOT-LLA

LIPID

GISSI PREVENZONE

HPS ALLHAT-LLT CORONA

PROSPER

4SGISSI HF

JUPITER

1.61.41.2

1.0

0.8

0.60.0

Odd

s R

atio

(95%

Cl)

35 27 28 29Mean body mass index at baseline (kg/m2)

24 26

MEGA

WOSCOPS

4S

PROSPERCORONA

HPSJUPITER ALLHAT-LLT

GISSI HF ASCOT-LLA

GISSI PREVENZONE

AFCAPS/TexCAPS

Sattar N, et al. Lancet. 2010;375:735-742.

13 trials, N = 91,140

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: 115 mg/dL• HDL-C: 26 mg/dL• Triglycerides: 177 mg/dL• TC: 176 mg/dL• Non-HDL-C: 150 mg/dL

• 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)

What is your LDL-C goal for this patient?

1. < 70 mg/dL2. < 100 mg/dL3. < 130 mg/dL4. Unsure

?

9

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)

What lipid lowering therapy would you add/institute?

1. Change simvastatin to rosuvastatin 20 mg od2. Change simvastatin to atorvastatin 40 mg od3. Change simvastatin to pitavastatin 4 mg od4. Add ezetimibe 10 mg od5. Change simvastatin to fluvastatin XL 80 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:

• 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

What lipid lowering therapy would you add/institute?

1. Pitavastatin 2 mg OD2. Fluvastatin XL 80 mg OD3. Fenofibrate/Ezetimibe4. Red Yeast Rice5. Rosuvastatin 20 mg once weekly6. Rosuvastatin 20 mg OW plus colesevelam daily

?

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

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

• HbA1C: 6.2%• eGFR: 40 mL/min• Urine microalbumin/creatinine

ratio: 55 mg/mmol(elevated)

What is your LDL-C goal for this patient?

1. < 70 mg/dL2. < 100 mg/dL3. < 130 mg/dL4. Unsure

?

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 lipid lowering therapy would you add/institute?

1. Pitavastatin 1 mg OD2. Fluvastatin XL 80 mg OD3. Rosuvastatin 10 mg OD4. Atorvastatin 10 mg OD5. Simvastatin 40 mg OD6. Pravastatin 40 mg OD

?

10

Statins in CKDCarl E. Orringer, MDHarrington Chair in Preventive Cardiovascular MedicineUniversity Hospitals Case Medical Center Harrington Heart and Vascular InstituteAssociate Professor of MedicineCase Western Reserve University School of MedicneCleveland, OH

Disclosures

• No relevant financial relationships to disclose

Population

Numberof

patientsDefinition of

CKD CV endpoints

UnadjustedCV hazard

ratio (95% CI)

Adjusted CVhazard ratio

(95% CI)*

ARIC 15,350eGFR: 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 4893eGFR: 15-59

ml/min/1.73m2

Cardiac death, MI, PCTA, CABG, angina,

CHF, peripheralvascular disease, stroke, and TIA

2.29(1.93-2.72)

1.31(1.06-1.62)

FHS/FOSmen

2837

serum creatinine: 136-

265μmol/l

CHD CHF,and ischemic

stroke

1.17(0.88-1.57)

1.06(0.79-1.43)

FHS/FOSwomen 3386

serum creatinine: 120-

265μmol/l

CHD CHF,and ischemic

stroke

2.19(1.70-2.83)

1.04(0.79-1.37)

Association of CKD and CV Events in Community-Based Studies

Adapted from: van der Zee S, et al. Nat Rev Cardiol. 2009;6:580-589.

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.

Analysis of CV Outcomes According to the Presence of Chronic Kidney Disease

No CKD eGFR 60-150 mi/min/1.73m2

eGFR 15-60 mi/min/1.73m2

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.

0.0

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

Yalew T, et al. Clin J Am Soc Nephrol. 2011;Mar 10. [Epub ahead of print]; doi:10.2215/CJN.10271110.

11

Factors Affecting Serum Creatinine Concentration

Frequently Asked Questions about GFR: Available at www.kidney.org/professionals/kls/pdf/KBA_FAQs_AboutGFR.pdf Accessed August 23, 2011.

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.pdfAccessed August 23, 2011.

When is Assessment of GFR Important?

Frequently Asked Questions about GFR: Available at www.kidney.org/professionals/kls/pdf/KBA_FAQs_AboutGFR.pdfAccessed August 23, 2011.

ATP III Update 2004: Pharmacologic Treatment

Risk Category LDL-C Goal Initiate TLCConsider

Drug Therapy

Very high risk: ACS, or CHD w/ DM, multiple CRF ? CKD

<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

Lower risk: 0-1 risk factor

<160 mg/dL 160 mg/dL ≥190 mg/dL

CRF=Cardiac Risk Factors. TLC=Therapeutic Lifestyle ChangesAdapted from: Grundy SM, et al. Circulation. 2004;110:227-239.

*optional goal:<100 mg/dL.

**100-129 mg/dLconsider drug option

Mechanisms of Dyslipidemia in CKD

Mechanism Change Effects

Lipoprotein Lipase DecreasedIncreased TG and increased lipid-poor LDL and HDL

ApoCII/ApoCIII Ratio Decreased Increased TG and LPL activity

VLDL Receptor Decreased Increased TG

CETP Increased Decreased HDL

ApoA-I Decreased Decreased HDL

LCAT Decreased Decreased HDL

LPL: lipoprotein lipase; CETP: cholesterol ester transfer protein; LCAT: lecithin cholesterol acyltransferase; VLDL: very low-density lipoproteinHarper CR, et al. J Am Coll Cardiol. 2008;51:2375-2384.Adapted from: Vaziri ND. Am J Physiol Ren Physiol. 2005;290:F262–F272.

Percentage of Lipid Abnormalities by Target Population

CKD StageTC

>240 mg/dLLDL-C

>130 mg/dLHDL-C

<35 mg/dLTGs

>200 mg/dL

General Population

20 40 15 15

CKD Stages1-4 With NS

90 85 50 60

CKD Stages 1-4 NO NS

30 10 35 40

CKD Stage 5Hemodialysis

20 30 50 45

CKD Stage 5Peritoneal Dialysis

25 45 20 50

NS, nephrotic syndromeWeiner DE, et al. J Gen Intern Med. 2004;19:1045-1052.

12

Study Population CKD Level Intervention + Follow-up Period

Primary End Point Results Summary

PravastatinPooling Project

N = 19768CKD = 4491 (22.8%)

eGFR 30-60(Stage 3)

40 mg pravastatinvs. placebo5.2-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 mgatorvastatin5-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 mgatorvastatin5-year follow-up

Cardiovascular events (death, nonfatal MI, fatal or nonfatal stroke)

4D N = 1255 eGFR < 15(Stage 5)

Atorvastatin 20 mg vs placebo4-year follow-up

Cardiovascular death (non-fatal MI, stroke)

Non-significant 8% events risk reduction (RR: 0.92; 95% CI: 0.77-1.1; p=0.37

AURORA N = 2766 eGFR < 15(Stage 5)

Rosuvastatin 10 mg vs. placebo3.2-year follow-up

Cardiovascular event (death, non-fatal MI, non-fatal stroke)

Non-significant 9.9% events risk reduction (HR: 0.96; 95% CI: 0.84-1.11; p=0.59

SHARP N = 9270 6247 stage 2-43023 stage 5

Simvastatin 20 mg + ezetimibe 10 mg vsplacebo4.9 year follow-up

Major atherosclerotic event (death, non-fatal MI, non-hemorrhagic stroke, revascularization procedure)

Total population 17% end point risk reduction (RR: 0.83; 95% CI 0.74-0.94; p=0.0021

ALERT N = 2102 Renaltransplant recipients

40-80 mg fluvastatinvs. placebo6-year follow-upextended to 8 years

Major cardiac event (cardiacdeath, non-fatal MI, coronary intervention)

Non-significant primary end point reduction p=0.139 at 6-year follow-up. After 2-year extension: RR: 0.79; 95% CI: 0.55-0.93; p=0.036

Summary of Trials with Lipid Lowering Rx in CKD

Clin Lipidol. 2011; 6(6) CKD: Chronic kidney disease; eGFR: estimated glomular filtration rate; HR: hazard ratio; RR: relative risk

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.

0 1 2 3 4 5

Years of follow-up

0

5

10

15

20

25

Pro

po

rtio

n s

uff

erin

g e

ven

t (%

)

Risk ratio 0.83 (0.74 – 0.94)

Logrank 2P=0.0022

Placebo

Eze/simv

Presented at American Society of Nephrology Meeting, November 20, 2010. Accessed at http://www.ctsu.ox.ac.uk/~sharp/SHARP_slides.

SHARP: MajorAtherosclerotic Events

Drug Dose Modification in CKD

• Statins: GFR 15-59 no dose reductions needed with 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

NLA, National Lipid AssociationHarper CR, et al. J Am Coll Cardiol.2008;51:2375-2384.

Proposed Treatment Algorithm for Lipid Management in Patients With CKD

Stage 3 to 5Moderate-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.

Management of Dyslipidemias in Adults With Chronic Kidney Disease

Dyslipidemia Goal Initiate Increase Alternative

TG ≥500 mg/dL TG <500 mg/dL TLCTLC + fibrate or niacin

Fibrate or niacin

LDL 100-129 mg/dL

LDL <100 mg/dL TLCTLC + low- dose statin

Bile acid sequestrant or niacin

LDL >130 mg/dL LDL <100 mg/dLTLC + low- dose statin

TLC + max-dose 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 + max-dose 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.

13

NKF Summary Recommendations

• 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

• 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

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.

Nephrology Referral

• eGFR <30ml/min, early referral improves dialysis survival and allows earlier transplantation

• Heavy proteinuria with albumin/creatinine ratio>1000 mg/g

• 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)

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.

Statin/Fibrate Combination Therapy: Pharmacokinetic Interactions

Gemfibrozil Fenofibrate

Atorvastatin ↑ in Cmax by 2.7-fold No effect

Simvastatin ↑ in Cmax by 2-fold No effect

Pravastatin ↑ in Cmax by 1.8-fold No effect

Rosuvastatin ↑ in Cmax by 2-fold No effect

Fluvastatin No effect No effect

Lovastatin ↑ in Cmax by 2.8-fold No effect

Cerivastatin ↑ in Cmax by 2-3-fold No effect

Pitavastatin ↑ in Cmax 31% No effect

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.

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.

Statins Dose Adjustmentsin CKD

GFR (ml/min/1.73m²)

Kassimatis TI, et al. Pharmacol Ther. 2009;122(3):312-23

Statin 60–90 15–59 <15 Notes

Atorvastatin No No No

Fluvastatin No ? ? Reduce by 50% in patients with GFR <30 ml/min/1.73m²

Pravastatin No No No Start at 10 mg/day for GFR <60 ml/min/1.73m²

Rosuvastatin No 5–10 mg 5–10 mg Start at 5 mg/day for GFR<30 ml/min/1.73m², do not exceed 10 mg/day

Simvastatin No Reduce by 50% in patients with GFR <30 ml/min/1.73m²

Start at 5 mg/day

Lovastatin No ↓ to 50% ↓ to 50% Reduce to 50% in patients with GFR <30 ml/min/1.73m²)

Pitavastatin

Adapted from K/DOQJ clinical practice guidelines K/DOQJ clinical practice guidelines for management of dyslipidemias in patients with kidney disease (2003).

↓ = decrease; ? = not defined; CKD = chronic kidney disease; GFR = glomerular filtration rate

Summary

• CKD is associated with an increased risk of CVD and a worse prognosis

• CKD is a CHD risk equivalent state

• 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

Which of the following statins is notmetabolized by cytochrome P-450 3A4 or 2C9?

1. Atorvastatin2. Rosuvastatin3. Simvastatin4. Fluvastatin

5. Pravastatin

Post ?

14

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 pitavastatinlevels

3. Gemfibrozil has no effect on fluvastatinlevels

4. There were no cases of rhabdomyolysisreported in the FIELD Trial with statin/fenofibrate combinations

Post ?When measured by AUC, which of the following statins has the least drug interaction with cyclosporine?

1. Pravastatin2. Rosuvastatin3. Atorvastatin4. Fluvastatin

Post ?

Questions & Answers

?