lipid lowering strategies - @mycme · ldl-c • primary target after tlc • ldl-c

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Lipid Lowering Strategies

www.cardiowellness.blogspot.com

Becky K. Captain, RN, MSN, CLS, BC, FNPBecky K. Captain, RN, MSN, CLS, BC, FNP--CCClinical Lipid SpecialistClinical Lipid Specialist

Conflict of Interest Disclosure & Resolution

•• Consultant for Good Things HealthConsultant for Good Things Health

•• Speaker for Abbott and Forest PharmaceuticalsSpeaker for Abbott and Forest Pharmaceuticals

Objectives

•• Know NCEP ATP III guidelinesKnow NCEP ATP III guidelines

•• Know how to lower LDL through diet and Know how to lower LDL through diet and medicationsmedications

•• Know how to lower nonKnow how to lower non--HDL cholesterol HDL cholesterol adntadnttriglycerides through diet and medicationtriglycerides through diet and medication

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“A Whole New World”

Cath Lab Sensation 16 MS CT

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How Much of the Patient Are We Treating?

0.0002 m2

1,000 m2

70 KG Male

= 1 / 5,000,000

Primary & Secondary Goals of Lipid ManagementAccording to NCEP

LDLLDL--CC•• Primary target after TLCPrimary target after TLC•• LDLLDL--C <100 mg/C <100 mg/dLdL

identified as optimal for identified as optimal for pts. w/ CHD or CHD risk pts. w/ CHD or CHD risk equivalent equivalent

•• NCEP recommends NCEP recommends optional LDLoptional LDL--C goal of C goal of <70 mg/<70 mg/dLdL for high risk for high risk pts.pts.

NonNon--HDLHDL--CC•• Secondary target if TG are Secondary target if TG are

200200--499 mg/499 mg/dLdL and LDLand LDL--C C goal is metgoal is met

•• NonNon--HDLHDL--C = Total C = Total Cholesterol minus HDLCholesterol minus HDL--CC

•• NonNon--HDLHDL--C represents all C represents all atherogenicatherogenic particlesparticles

•• NonNon--HDLHDL--C goal is 30mg/dL C goal is 30mg/dL higher than LDLhigher than LDL--C goalC goal

•• Increasing HDLIncreasing HDL--C will lower C will lower NonNon--HDLHDL--CC

NCEP ATP III Final Report, Circulation 2002; 106 3143-3421

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Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals

LDL-C Goal(mg/dL)Risk Category

Non-HDL-C Goal (mg/dL)

<100(optional <70)

CHD and CHD Risk Equivalent(10-year risk for CHD >20%)

<130(optional <100)

<130(optional <100)

Multiple (2+) Risk Factors and10-year risk <20%

<160(optional <130)

<1600–1 Risk Factor <190


CHD Risk Equivalents

•• >20% 10>20% 10--year risk of CHD year risk of CHD (Framingham projections)(Framingham projections)

•• DiabetesDiabetes

•• Other forms of clinical atherosclerotic Other forms of clinical atherosclerotic disease:disease:

–– Peripheral arterial diseasePeripheral arterial disease

–– Abdominal aortic aneurysmAbdominal aortic aneurysm

–– Carotid artery diseaseCarotid artery disease

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Peripheral Arterial Disease (PAD)

•• Studies of pts w/ PAD support the concept that Studies of pts w/ PAD support the concept that

PAD, regardless of diagnosis PAD, regardless of diagnosis (ABI, lower limb (ABI, lower limb

blood flow studies, or clinical symptoms) blood flow studies, or clinical symptoms) is a CHD is a CHD

risk equivalentrisk equivalent


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Abdominal Aortic Aneurysm (AAA)

•• Study population:Study population: 300 men and 43 women (aged 45300 men and 43 women (aged 45 89) 89) operated on for AAA, separated into 4 groups based on operated on for AAA, separated into 4 groups based on preoperative CHD history and ECGpreoperative CHD history and ECG

•• FollowFollow--up:up: 66 11 years11 years

•• Results:Results: annual CHD mortalityannual CHD mortality

1.9% in persons with no symptoms, no prior history of CHD, and 1.9% in persons with no symptoms, no prior history of CHD, and normal ECG (31%)normal ECG (31%)

2.0% in persons with no symptoms, but previous MI by ECG 2.0% in persons with no symptoms, but previous MI by ECG (33%)(33%)

3.9% in persons with angina/prior MI (30%)3.9% in persons with angina/prior MI (30%)

•• Because the rate of CHD events is at least twice that of CHD Because the rate of CHD events is at least twice that of CHD mortality, patients with no previous history of CHD events wouldmortality, patients with no previous history of CHD events wouldfall into the CHD risk equivalent categoryfall into the CHD risk equivalent category

Hertzer NR. Ann Surg 1980;192:667-673.

•• Mayo Asymptomatic Carotid Atherosclerosis StudyMayo Asymptomatic Carotid Atherosclerosis StudySubjectsSubjects

158 patients, 40% with history of CAD, 15% diabetic158 patients, 40% with history of CAD, 15% diabeticDisease severityDisease severity

Asymptomatic Asymptomatic stenosisstenosis ≥≥ 50%50%Trial stopped because of high MI and TIA event rate Trial stopped because of high MI and TIA event rate in surgical arm secondary to cessation of medical in surgical arm secondary to cessation of medical therapy (aspirin)therapy (aspirin)

CHD eventsCHD eventsAfter 2.5After 2.5--year followyear follow--up: 12 CHD eventsup: 12 CHD eventsEstimated 10Estimated 10--year CHD event rate = 30%year CHD event rate = 30%

Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273:1421-1428.

Carotid Artery Disease: Asymptomatic

0

10

20

30

40

50

Haffner SM et al. N Engl J Med 1998;339:229-234.

Incidence of MI during a 7-Year Follow-up in a Finnish Population

Fata

l o

r N

on

fata

l M

I (

%)

Prior MI

18.8

3.5

45.0

20.2P<0.001

P<0.001

Prior MINo prior MI No prior MINondiabetic subjects Diabetic subjects

(n=1373) (n=1059)

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Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals

LDL-C Goal(mg/dL)Risk Category

Non-HDL-C Goal (mg/dL)

<100(optional <70)

CHD and CHD Risk Equivalent(10-year risk for CHD >20%)

<130(optional <100)

<130(optional <100)

Multiple (2+) Risk Factors and10-year risk <20%

<160(optional <130)

<1600–1 Risk Factor <190


Major Risk Factors (exclusive of LDL)

•• Cigarette SmokingCigarette Smoking•• Hypertension Hypertension •• HDL < 40 mg/HDL < 40 mg/dLdL•• Family history of premature CHD Family history of premature CHD

–– First degree relative (male <55 yrs; female < 65 yrs)First degree relative (male <55 yrs; female < 65 yrs)

•• AgeAge–– Men > 45 yrsMen > 45 yrs–– Females > 55 yrsFemales > 55 yrs


LDL-C levels of all adults (United States)

More than 3 in 4 American adults have LDL-C levels of 100 mg/dLor higher

•• Dyslipidemia is a leading risk factor for CHDDyslipidemia is a leading risk factor for CHD——the most the most prevalent form of CVDprevalent form of CVD

Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES III), CDC 1994; data from 1991-1994. Summary report, March 2000.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285:2486-2497.

29%Near or above optimal

(100-129 mg/dL)

24%Optimal

(<100 mg/dL)

6%Very high

(≥190 mg/dL)

13%High

(160-189 mg/dL)

28%Borderline high

(130-159 mg/dL)

76%≥100 mg/dL

18

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Pygmy Pygmy ≈≈100100

San San ≈≈ 120120

HazdaHazda ≈≈110110

50 70 90 110 130 150

San

Pygmy

Ikung

Inuit

HazdaHunter-Gatherer Humans

Mean Total Cholesterol (mg/Mean Total Cholesterol (mg/dLdL))

!Kung ≈120

Inuit Inuit ≈≈140140

Baboon Baboon ≈≈ 110110

Howler Monkey Howler Monkey ≈≈ 110110Night Monkey Night Monkey ≈≈ 140140

50 70 90 110 130 150

Night Monkey

Howler Monkey

BaboonWild Primates


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Horse Horse ≈≈ 140140

Pig Pig ≈≈ 100100Rhino Rhino ≈≈ 9090

Elephant Elephant ≈≈ 110110

Boar Boar ≈≈ 7070

50 70 90 110 130 150 170 190 210

African Elephant

Black Rhinoceros

Pig

Boar

Horse

Mammals


Horse Horse ≈≈ 140140Rhino Rhino ≈≈ 9090

Elephant Elephant ≈≈ 110110

Boar Boar ≈≈ 7070

50 70 90 110 130 150 170 190 210

Adult American

African Elephant

Black Rhinoceros

Pig

Boar

Horse

Mammals


Adult American ~ 209Adult American ~ 209

How To Lower LDL Cholesterol

•• DietDiet–– Decrease Saturated and Trans FatsDecrease Saturated and Trans Fats

•• ExerciseExercise•• Prescription MedsPrescription Meds

•• SupplementsSupplements

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How To Lower LDL - Prescriptions

•• StatinStatin MedicationsMedications•• Cholesterol Absorption Cholesterol Absorption

InhibitorInhibitor•• Bile acid Bile acid

sequestrantsequestrant

CHD Risk Reduction with Statin Therapy

La Rosa JC et al. JAMA 1999;282:2340-2346. | Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.

EndpointsEndpoints +20 –35–30–250 –5 –10–15–20

Relative Risk Reduction (%)Relative Risk Reduction (%)

–40–45–50

Major coronary events

Coronary deaths

Cardiovascular deaths

Noncardiovascular events

Total mortality

Strokes

Intermittent claudication

Angina

% R

ed

uct

ion

in

LD

L-C

1927 28

35 3712

10 1212

18

0

10

20

30

40

50

60

Lovastatin20/80 mg

Fluvastatin20/80 mg

Simvastatin20/80 mg

Pravastatin20/80 mg

Atorvastatin10/80 mg

Response to Minimum/Maximum Statin Dose

3137

4047

55

Reprinted from Illingworth DR. Med Clin North Am. 2000;84:23–42, with permission from Elsevier

Limited.

Pharmacologic Therapy:Pharmacologic Therapy:Dose Response of Different Dose Response of Different StatinsStatins

LDL-C = low-density lipoprotein cholesterol

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Jones PH, et al. Am J Cardiol. 2003;92:152–160.

*P < 0.001 vs. atorvastatin 10 mg and simvastatin 20 mg and 40 mg†P = 0.026 vs. atorvastatin 20 mg

-60%

-50%

-40%

-30%

-20%

-10%

0%

Mean

% C

han

ge i

n

LD

L-C

fro

mU

ntr

eate

dB

ase

lin

e

Valu

e

Atorvastatin Rosuvastatin Simvastatin

14% with14% with3 titrations3 titrations



10 mg 20 mg 30 mg 40 mg

−28

−7−4−7

−46†

−6*−3*

−37

−6−5−3

LDL–C=low-density lipoprotein cholesterol

Pharmacologic Therapy:Pharmacologic Therapy:Dose Response of Different Dose Response of Different StatinsStatins

•• Assess Assess renal functionrenal function before initiating before initiating statinstatin therapytherapy

•• StatinStatin therapy may be used in patients therapy may be used in patients with with chronic kidney diseasechronic kidney disease (some (some statinsstatinsmay need dose adjustments)may need dose adjustments)

•• No need to routinely No need to routinely monitor serum monitor serum creatininecreatinine or or proteinuriaproteinuria

StatinsStatins: : Kidney IssuesKidney Issues

Reprinted from McKenney JM, et al. Am J Cardiol 2006;97:89C–94C, with permission from Elsevier.

30

NKF Recommendations for Statin Dose Adjustment in CKD

Use doses >20 mg/day cautiously in patients with GFR <30

No adjustmentLovastatin

No dose adjustments needed for mild to moderate kidney disease; use caution in patients with severe

kidney disease; fluvastatin not studied at doses >40 mg in these patients

No adjustmentFluvastatin

No adjustmentNo adjustmentNo adjustmentPravastatinStarting dose 5 mg daily in patients with

severe kidney diseaseNo adjustmentSimvastatin

Starting dose 5 mg and NOT to exceed 10 mg in patients with GFR <30No adjustmentRosuvastatin

No adjustment30–90

No adjustment

Adjust for reduced GFR (mL/min/1.73 m2)

No adjustmentAtorvastatin<15<30

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S180.

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Drug–Drug Interaction Comparison

* Sasiela W, et al. Poster presented at: 52nd ACC Scientific Session. March 30, 2003-April 2, 2003; Chicago, Ill; Crestor® (rosuvastatin) [package insert]. Wilmington, Del: AstraZeneca Pharmaceuticals LP; 2005; Lipitor® (atorvastatin) [package insert]. New York, NY: Pfizer, Inc; 2003; Zocor® (simvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co; 2003; Vytorin® (simvastatin/ezetimibe) [package insert]. North Wales, PA: MERCK/Schering-Plough Pharmaceuticals; 2006

RosuvastatinRosuvastatin SimvastatinSimvastatin simvastatinsimvastatin//ezetimibeezetimibe AtorvastatinAtorvastatin PravastatinPravastatin & &

FluvastatinFluvastatinAzole Fungal Agents, Macrolides, Protease Inhibitors, Nefazadone, Grapefruit Juice (>1 Qt/Day)

No Dose Limitations(Evaluate Risk-benefit) Avoid Avoid No Dose Limitations

(Evaluate Risk-benefit)No Dose Limitations

(Evaluate Risk-benefit)

Fibrates Dose Limitations (Max 10 mg)

Dose Limitations(Max 10 mg) Avoid No Dose Limitations



Niacin >1 G/D No Dose Limitations(Evaluate Risk-benefit)

No Dose Limitations(Evaluate Risk-benefit)




Cyclosporine Dose Limitations (Max 5 mg)

Dose Limitations (Max 10 mg)

Dose Limitations (Max 10/10)



Amiodarone/Verapamil Not Mentioned Dose Limitations(Max 10 mg)

Dose Limitations(Max 10/10) No Effect Not Mentioned

Warfarin Baseline INR 2–3 ↑ To >4

Baseline INR 1.7–1.8↑ To 2.6–3.4

Baseline INR 1.7–1.8↑ To 2.6-3.4 No Effect No Effect

The risk of The risk of myopathymyopathy increases with respect to:increases with respect to:

•• Age (>80 years; especially in women)Age (>80 years; especially in women)

•• Multisystem diseases Multisystem diseases (chronic renal failure, especially due to (chronic renal failure, especially due to diabetes)diabetes)

•• Multiple medicationsMultiple medications

•• Perioperative periodsPerioperative periods

•• Grapefruit juice >1 quart/dayGrapefruit juice >1 quart/day

StatinsStatins: : Muscle Issues (Continued)Muscle Issues (Continued)

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.

When When rhabdomyolysisrhabdomyolysis occurs:occurs:

•• Stop Stop statinstatin therapytherapy

•• Provide intravenous hydrationProvide intravenous hydration

•• After recovery, weigh the risks and After recovery, weigh the risks and benefits of restarting benefits of restarting statinstatin therapytherapy

StatinsStatins: : Muscle Issues (Continued)Muscle Issues (Continued)

Reprinted from McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C, with permission from Elsevier.

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Musculoskeletal AEs for Atorvastatin 80 mg

StudyStudyAtorvastatinAtorvastatin

DoseDose ComparatorComparator DurationDurationPatient Patient

PopulationPopulation

Patients on Patients on AtorvastatinAtorvastatin

80 mg80 mgCases of Cases of

RhabdomyolysisRhabdomyolysisMIRACLMIRACL 80 mg80 mg PlaceboPlacebo 16 weeks16 weeks ACSACS 15381538 00

PROVEPROVE--ITIT 80 mg80 mg PravastatinPravastatin 40 mg40 mg 2 years2 years ACSACS 20992099 00

REVERSALREVERSAL 80 mg80 mg PravastatinPravastatin 40 mg40 mg 18 months18 months Established CHDEstablished CHD 328328 00

ASAPASAP 80 mg80 mg SimvastatinSimvastatin 40 mg40 mg 2 years2 years Heterozygous FHHeterozygous FH 162162 00

ARBITERARBITER 80 mg80 mg PravastatinPravastatin 40 mg40 mg 12 months12 months ±± CHDCHD 6868 00

ALLIANCEALLIANCE 80 mg80 mg Usual CareUsual Care ~4 years~4 years Established CHDEstablished CHD 545545 00

AVERTAVERT 80 mg80 mg Angioplasty plus Angioplasty plus Usual CareUsual Care 18 months18 months Established CHDEstablished CHD 163163 00

TNTTNT 80 mg80 mg AtorvastatinAtorvastatin 10 mg10 mg 4.9 years4.9 years Established CHDEstablished CHD 49954995 2*2*

IDEALIDEAL 80 mg80 mg SimvastatinSimvastatin 20/40 mg20/40 mg 4.8 years4.8 years Established CHDEstablished CHD 44394439 00

StudyStudySimvastatiSimvastati

nn DoseDose ComparatorComparator DurationDurationPatient Patient

PopulationPopulation

Patients on Patients on SimvastatinSimvastatin40/80 mg40/80 mg

Cases ofCases ofRhabdomyolysisRhabdomyolysis

AA--toto--ZZ SimvastatinSimvastatin40/80 mg40/80 mg

Placebo/Placebo/SimvastatinSimvastatin 20 mg20 mg 2 years2 years ACSACS 22652265 33††

Musculoskeletal AEs Simvastatin 40/80 mg

* Not treatment-related.

14,33814,338

† 9 cases of myopathy.

Muscle Safety: Simvastatin

0.02%0.08%

0.53%

0.0%

0.1%

0.2%

0.3%

0.4%

0.5%

0.6%

20 mg 40 mg 80 mg

% o

f Pat

ient

s w

ith

Myo

path

y/rh

abdo

myo

lysi

s

Vytorin® (simvastatin/ezetimibe) [package insert]. North Wales, PA: MERCK/Schering-Plough Pharmaceuticals; 2006.

•• StatinsStatins are well tolerated by most peopleare well tolerated by most people

•• Some people experience problems with liver function. Some people experience problems with liver function. Elevations in liver Elevations in liver transaminasestransaminases::

–– Occur in 0.5% to 2.0% of Occur in 0.5% to 2.0% of statinstatin users users

–– Are doseAre dose--dependentdependent

–– Are usually reversed with a Are usually reversed with a lowered lowered statinstatin dosedose

–– Usually do not recur with Usually do not recur with rechallengerechallenge or use of another or use of another statinstatin

–– Rarely progress to liver failureRarely progress to liver failure

StatinsStatins: : Liver IssuesLiver Issues

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.

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•• Initiate Initiate statinsstatins

•• Continue Continue statinsstatins

•• Increase the dose of Increase the dose of statinsstatins

StatinsStatins: : Liver Issues (Continued)Liver Issues (Continued)

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. |McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C.

Modest increases* in liver transaminasesare not a contraindication to:

*Increases <3 × the upper limits of normal.

•• Repeat liver function testsRepeat liver function tests–– If values are still high, rule out other causesIf values are still high, rule out other causes

•• Based on clinical judgment, consider:Based on clinical judgment, consider:–– Continuing the Continuing the statinstatin

–– Reducing the dose of the Reducing the dose of the statinstatin

–– Discontinuing Discontinuing statinstatin therapytherapy


*Increased <3 × the upper limits of normal.

Reprinted from McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C, with permission from Elsevier.

When an elevation* in liver transaminases is isolated and asymptomatic:

Liver Effects: Ezetimibe Added to Simvastatin Increases LFTs

0.4%

1.3%1.0%

1.8%2.1%

3.6%

0%

1%

2%

3%

4%

% o

f Pat

ient

s w

ith L

FT

% o

f Pat

ient

s w

ith L

FT

Abn

orm

aliti

esA

bnor

mal

ities

StatinAlone

Statin+ Eze

SimvaOverall

Simva/EzeOverall

Simva80

Simva/Eze10/80

Zetia (ezetimibe) [prescribing information]: North Wales, PA Merck/Schering-Plough Pharmaceuticals North Wales, PA; 2006. Vytorin®

(simvastatin/ezetimibe) [package insert]. North Wales, PA: MERCK/Schering-Plough Pharmaceuticals; 2006; Zocor® (simvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co; 2003;

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0.3%

0.1% 0.1%

0.4%

0.9%

0.0%

0.4%

0.8%

1.2%

Placebo(n=1789)

10 mg(n=6093)

20 mg(n=2542)

40 mg(n=1983)

80 mg(n=3131)

Liver Effects: Atorvastatin

•• Based on a patient population that experienced ALT/AST >3 x ULNBased on a patient population that experienced ALT/AST >3 x ULNon 2 consecutive occasions more than 14 days apart, or other defon 2 consecutive occasions more than 14 days apart, or other defined criteriained criteria

•• Across all doses, 0.5% of Across all doses, 0.5% of atorvastatinatorvastatin patients experienced elevated ALT/ASTpatients experienced elevated ALT/AST

Newman CB, et al. Am J Cardiol. 2003;92:670-676.

Atorvastatin

Patie

nts

(%)

Patie

nts

(%)

Clinically Relevant Clinically Relevant TransaminaseTransaminase ElevationsElevations


Reprinted from McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C, with permission from Elsevier. | Pasternak RC, et al.

J Am Coll Cardiol. 2002;40:567–572.

Patients with these conditions may receive statins:

Chronic liver disease

Nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis

StatinsStatins: : Monitoring (Continued)Monitoring (Continued)

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. | McKenneyJM, et al. Am J Cardiol. 2006;97:89C–94C.

Lipid Panel

Baseline 6 weeks 3 months Every 6 months

Liver Function Tests

Baseline12 weeks after

starting/increasing therapy

Annually, as needed (when the patient reports

liver symptoms)

Creatine Kinase Test

BaselineAs needed (when patient reports muscle

soreness, tenderness, or pain)

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Bile Acid Bile Acid SequestrantsSequestrants

Bile Acid Sequestrants

•• ColesevelamColesevelam–– Indicated to lower LDL Indicated to lower LDL –– Improve glycemic control in adults w/ Type II Improve glycemic control in adults w/ Type II

DM DM » Colesevelam package insert

•• ColestipolColestipol•• CholestyramineCholestyramine

Bile Acid Sequestrants: Colesevelam and Statins

ColesevelamColesevelamHClHCl StatinStatin

TC*TC*(%)(%)

LDLLDL--C*C*(%)(%)

HDLHDL--C*C*(%)(%)

TG*TG*(%)(%)

2300 mg(~4 tablets)

Lovastatin10 mg

–7 –12 to –10 –3 to –1 –8 to +4

2300 mg(~4 tablets)

Simvastatin20 mg

–6 –8 –3 0

3750 mg(6 tablets)

Simvastatin10 mg

–9 –16 +7 +5

3750 mg(6 tablets)

Atorvastatin10 mg

–4 –10 +3 +23

* Change versus statin alone.

Bays H et al. Expert Opin Pharmacother 2003;4:779-790.Davidson MH et al. Expert Opin Investig Drugs 2000;9:2663-2671.

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Bile Acid Sequestrants•• Contraindications:Contraindications:

–– Bowel Obstruction, Bowel Obstruction, hxhx of TG > 500 mg/of TG > 500 mg/dLdL, , hxhx of of hypertriglyceridemiahypertriglyceridemia induced pancreatitisinduced pancreatitis

•• Side Effects:Side Effects:–– GI: constipation, flatulence, bloating, nauseaGI: constipation, flatulence, bloating, nausea

•• Careful:Careful:–– Reduces GI absorption of some drugs & Reduces GI absorption of some drugs &

vitamins. Recommended to be administered at vitamins. Recommended to be administered at least 4 hrs apartleast 4 hrs apart

EzetimibeEzetimibe: Efficacy: Efficacy““Added OnAdded On”” to Ongoing to Ongoing StatinStatin TherapyTherapy

Gagné C et. al. Am J Cardiol 2002;90:1084-1091.

*40% on *40% on atorvastatinatorvastatin (weighted mean baseline dose 34 mg); (weighted mean baseline dose 34 mg); 31% 31% simvastatinsimvastatin (37 mg), and 29% others combined (37 mg), and 29% others combined

((pravastatinpravastatin 29 mg, 29 mg, fluvastatinfluvastatin 35 mg, 35 mg, lovastatinlovastatin 26 mg, and 26 mg, and cerivastatincerivastatin 0.4 mg)0.4 mg)

Patients on ongoing Patients on ongoing stable stable statinstatin therapy* therapy*

not reaching NCEP not reaching NCEP ATPII LDLATPII LDL--C goalC goal

Week <–6

OpenOpen--label label statinstatin + placebo+ placebo(n=390, mean LDL(n=390, mean LDL--C = 139 mg/dl)C = 139 mg/dl)

OpenOpen--label label statinstatin + + ezetimibeezetimibe(n=379, mean LDL(n=379, mean LDL--C = 138 mg/dl)C = 138 mg/dl)

0 8

RANDOMIZATION

-30

-25

-20

-15

-10

-5

0

5LDLLDL--CC

Red

uct

i on

fr o

m b

ase

lin

e

at

week 8

(%

)

Ezetimibe: Efficacy: "Add On" Study

Reprinted from Gagné C et al. Am J Cardiol 2002;90:1084-1091, with permission from Elsevier.

*p<0.001*p<0.001††p<0.05p<0.05‡‡p<0.01p<0.01

––25.1 *25.1 *

1.01.0

––2.92.9

––14.0 14.0 ‡‡

HDLHDL--CC TGTG

––3.73.7

2.7 2.7 ††

StatinStatin + placebo (n=390)+ placebo (n=390)

StatinStatin + + ezetimibeezetimibe 10 mg (n=379)10 mg (n=379)

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Plant Sterols/Stanols: Efficacy in Lowering LDL-C

•• Maximum dose: 2 Maximum dose: 2 g/dg/d•• MetaMeta--analysis results:analysis results:

−− LDLLDL--C lowering about 9C lowering about 9––13%13%

•• Lowering greater in elderly:Lowering greater in elderly:−− Additive to Additive to statinstatin therapytherapy−− Used in various population groupsUsed in various population groups

•• WellWell--toleratedtolerated

Law M et al. BMJ 2000;320:861-864.Lichtenstein AH et al. Circulation 201;103:1177-1179

Case Study

Patient Profile:Patient Profile: White Female, 44 White Female, 44 y.oy.o..

Occupation:Occupation: Real Estate AgentReal Estate Agent

Social Habits:Social Habits: Never SmokedNever Smoked

rare ETOHrare ETOH

Exercise:Exercise: Runs 20 miles weeklyRuns 20 miles weekly

ConcomitantConcomitantMed. Cond.:Med. Cond.: Dyslipidemia, Dyslipidemia,

No Known History of CADNo Known History of CAD

Case Study cont’d

Current Meds:Current Meds: Omega 3 Fish Oils 1500 mg QD, MTV, Omega 3 Fish Oils 1500 mg QD, MTV, Calcium Supplement w/ Vitamin DCalcium Supplement w/ Vitamin D

Allergies:Allergies: NKDANKDA

Family History: Family History: Father died of MI age 50Father died of MI age 50Mother w/ CAD age 60Mother w/ CAD age 60

Exam:Exam: BMI 22.0, BP 110/70 BMI 22.0, BP 110/70 mmHGmmHGHR 58. Pt. denies HR 58. Pt. denies myalgiasmyalgias..

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Case Study cont’d

Lab Values:Lab Values:

TC 225; HDL 52; LDL 160; Trigs 65; Ratio 4.3; FBS 82 TC 225; HDL 52; LDL 160; Trigs 65; Ratio 4.3; FBS 82 CPK 180 CPK 180 CR 1.0CR 1.0ALT 15; AST 12ALT 15; AST 12

What would you do?What would you do?

Case Study cont’d

Would you recommend:Would you recommend:StatinStatinNicotinic AcidNicotinic AcidBile Acid ResinBile Acid ResinFibrateFibrateLifestyle modificationsLifestyle modificationsCalcium ScoreCalcium ScorehsCRPhsCRPOther SupplementsOther Supplements

??

Case Study cont’d

CardioScanCardioScan::

(+) CAD ((+) CAD (AgatstonAgatston Score 225 with normal nuclear study)Score 225 with normal nuclear study)

Recommendations?

hshs CRP:CRP:2.1

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Case Study cont’d

•• Added Added RosuvastatinRosuvastatin 20 mg, ASA 81 mg20 mg, ASA 81 mg•• 8 weeks later: 8 weeks later:

TC 140 HDL 54 LDL 75 Trigs 54 Ratio 2.8TC 140 HDL 54 LDL 75 Trigs 54 Ratio 2.8

hshs CRP 0.5CRP 0.5

•• Initial Labs:Initial Labs:TC 225 HDL 52 LDL 160 Trigs 65 Ratio 4.3TC 225 HDL 52 LDL 160 Trigs 65 Ratio 4.3hsCRPhsCRP 2.12.1

Limitations of Statin Monotherapy on CHD Events

Events,* nEvents,* n

2,7802,780

100100292292898898

1,4901,490

StatinStatinGroupGroup

3,7643,764

154154356356

1,2121,212

2,0422,042

ControlControlGroupGroup

67,46267,462

10,30510,3055,8045,804

20,58620,586

30,81730,817NN

74742626SimvastatinSimvastatinHPSHPS

81811919PravastatinPravastatinPROSPERPROSPER

2727

3636

2626

Risk Risk Reduction, Reduction,

%%††

7373TotalTotal

6464AtorvastatinAtorvastatinASCOTASCOT--LLALLA

7474SimvastatinSimvastatinPravastatinPravastatinPravastatinPravastatinLovastatinLovastatinPravastatinPravastatin

4S4SWOSCOPSWOSCOPSCARECAREAFCAPSAFCAPSLIPIDLIPID

Events Events notnotAvoided,Avoided, %%DrugDrugTrialTrial

Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105.

* Nonfatal MI and CHD death; AFCAPS also included unstable angina† Weighted average

Treatment of Mixed Hyperlipidemia


High LDLHigh LDL--C and C and TGsTGs

Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Drug TherapyDrug Therapy

Achieve the LDLAchieve the LDL--C goalC goal11STEPSTEP

Achieve the nonAchieve the non--HDLHDL--C goalC goalIncrease LDLIncrease LDL--C lowering orC lowering or

Add a niacin, Add a niacin, fibratefibrate or fish oilsor fish oils22STEPSTEP

N3-173 Global Risk29/10/2013 15:20:48

Cui Y et al. Arch Intern Med 2001;161:1413-1419.

LRC Follow-up Study: CVD Mortality by Non-HDL-C and LDL-C in Men

LRC = Lipid Research Clinics; RR = Relative risk; CI = confidence interval.

0 0.25 0.50 0.75 1.00 1.25 1.50 1.752.00 2.252.50 2.75 3.00

RR with 95% CI

Non-HDL-C(mg/dL)ii

Rate/10,000

<160 38.0

160 to <190 43.0

190 to <220 53.9

≥220 80.6

LDL-C (mg/dL)

<130 40.2

130 to <160 48.2

160 to <190 54.9

≥190 71.3

Cui Y et al. Arch Intern Med 2001;161:1413-1419.

LRC Follow-up Study: CVD Mortality by Non-HDL-C and LDL-C in Women

LRC = Lipid Research Clinics; RR = Relative risk; CI = confidence interval.

0 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00

RR with 95% CI

Non-HDL-C(mg/dL)

Rate/10,000

<160 17.6

160 to <190 26.5

190 to <220 29.2

≥220 51.3

LDL-C (mg/dL)

<130 25.4

130 to <160 22.8

160 to <190 27.7

≥190 40.1

The Tricks with Trigs

N3-173 Global Risk29/10/2013 15:20:48

Triglyceride Reduction

•• Counsel on Diet (Limit or cut out simple Counsel on Diet (Limit or cut out simple carbscarbs/simple sugars on a daily basis)/simple sugars on a daily basis)

•• Start or Increase Exercise 30Start or Increase Exercise 30--45 min of 45 min of aerobic activity 4 x weekaerobic activity 4 x week

•• Omega 3 Fish Oil 2Omega 3 Fish Oil 2--4 grams daily4 grams daily•• Return visit 6Return visit 6--8 weeks8 weeks•• StatinStatin / Fish Oil/ Fish Oil•• NiaspanNiaspan/IR Niacin/IR Niacin•• FibratesFibrates

AHA Recommendations for Omega-3 FA Intake

Kris-Etherton PM et al. Circulation 2002;106:2747-2757.

Population Recommendation

Patients without documented CHD

Eat a variety of (preferably oily) fish at least twice a week. Include oils and foods rich in α-linolenic acid (flaxseed, canola, and soybean oils; flaxseeds; and walnuts)

Patients with documented CHD

Consume ~1 g of EPA+DHA per day, preferably from oily fish. EPA+DHA supplements could be considered in consultation with the physician

Patients needing triglyceride lowering

2–4 grams of EPA+DHA per day provided as capsules under a physician’s care

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Fish Oils and Statins

•• Marine fish oils rich in omegaMarine fish oils rich in omega--3 fatty acids 3 fatty acids ↓↓ triglyceride triglyceride levels & may be effective in combination w/ levels & may be effective in combination w/ statinsstatins to treat to treat pts w/ combined pts w/ combined hyperlipidemiahyperlipidemia

•• Fish oils plus Fish oils plus statinstatin may often be an alternative to may often be an alternative to fibratefibrateplus plus statinstatin

•• Fish oils may have other CV effects complementary to those Fish oils may have other CV effects complementary to those of of statinsstatins, such as:, such as:

–– Reduction in malignant ventricular Reduction in malignant ventricular dysrhythmiasdysrhythmias–– Increased heart rate variabilityIncreased heart rate variability–– Antithrombotic effectsAntithrombotic effects–– Improved endothelial reactivity/relaxationImproved endothelial reactivity/relaxation–– AntiAnti--inflammatory effectsinflammatory effects–– Slight lowering of blood pressureSlight lowering of blood pressure

Bays HE et al. Expert Opin Pharmacother 2003;4:1901-1938.Kris-Etherton PM et al. Circulation 2002;106:2747-2757.

VA-HIT: Treating Dyslipidemia Beyond LDL-C Improves Clinical Outcomes

VA-HIT = Veterans Affairs High-Density Lipoprotein Intervention Trial.*p≤0.05. †p = 0.07. ‡Investigator-designated.2531 men with CHD, HDL ≤40 mg/dL, and LDL ≤140 mg/dL were randomized to gemfibrozil (1200 mg/d)or placebo, and followed for a median of 5.1 years.

% C

hang

e(G

emfib

rozi

lvs

Plac

ebo)

Rubins HB et al. N Engl J Med. 1999;341:410-418.

06*

-31*

-22* -22

-29*

-40

-30

-20

-10

0

10

20

LDL-C HDL-C TG Nonfatal CHD Stroke‡

MI or DeathCHD Death

†

Da Col PG et al. Curr Ther Res Clin Exp 1973;53:473-482. | Ellen RL et al. Am J Cardiol 1998;81:60B-65B.

Statin + Fibrate

-60-50-40-30-20-10

0102030

SimvaSimva ++GemfibrozilGemfibrozil

––50%50%

––39%39%

16%16%22%22%

––41%41%

––28%28%

Prava/SimvaPrava/Simva ++FenofibrateFenofibrate

230230 332332

3838

191191166166

LDL-CTG

HDL-C

LDL-CTG

HDL-C

Perc

en

t C

han

ge

Perc

en

t C

han

ge

3434

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ACCORD Study Design

• Overall ACCORD Glycemia Trial: 10,251 participants

• Lipid Trial: 5,518 in Lipid Trial • 2765 randomized to fenofibrate• 2753 randomized to placebo

• Primary Outcome: First occurrence of a major cardiovascular event (nonfatal MI, nonfatal stroke, cardiovascular death)

• 87% power to detect a 20% reduction in event rate, assuming placebo rate of 2.4%/yr and 5.6 yrs follow-up in participants without events.

Conclusion

• The combination of fenofibrate & simvastatin did not reduce the rate of fatal CV events, nonfatal

MI, or nonfatal stroke, as compared w/ simvastatin alone.

• These results do not support the routine use of combination therapy w/ fenofibrate & simvastatinto reduce CV risk in the majority of high-risk pts

w/ type 2 diabetes.

Drug–Drug Interaction Comparison

* Sasiela W, et al. Poster presented at: 52nd ACC Scientific Session. March 30, 2003-April 2, 2003; Chicago, Ill; Crestor® (rosuvastatin) [package insert]. Wilmington, Del: AstraZeneca Pharmaceuticals LP; 2005; Lipitor® (atorvastatin) [package insert]. New York, NY: Pfizer, Inc; 2003; Zocor® (simvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co; 2003; Vytorin® (simvastatin/ezetimibe) [package insert]. North Wales, PA: MERCK/Schering-Plough Pharmaceuticals; 2006

RosuvastatinRosuvastatin SimvastatinSimvastatin simvastatinsimvastatin//ezetimibeezetimibe AtorvastatinAtorvastatin PravastatinPravastatin & &

FluvastatinFluvastatinAzole Fungal Agents, Macrolides, Protease Inhibitors, Nefazadone, Grapefruit Juice (>1 Qt/Day)

No Dose Limitations(Evaluate Risk-benefit) Avoid Avoid No Dose Limitations



Fibrates Dose Limitations (Max 10 mg)

Dose Limitations(Max 10 mg) Avoid No Dose Limitations



Niacin >1 G/D No Dose Limitations(Evaluate Risk-benefit)





Cyclosporine Dose Limitations (Max 5 mg)

Dose Limitations (Max 10 mg)

Dose Limitations (Max 10/10)



Amiodarone/Verapamil Not Mentioned Dose Limitations(Max 10 mg)

Dose Limitations(Max 10/10) No Effect Not Mentioned

Warfarin Baseline INR 2–3 ↑ To >4

Baseline INR 1.7–1.8↑ To 2.6–3.4

Baseline INR 1.7–1.8↑ To 2.6-3.4 No Effect No Effect

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HDL Cholesterol

Classification of Serum HDL-C Levels

HDL-C Category

ATP II LevelsATP III Levels

Low HDL-C <35 mg/dL <40 mg/dL

High HDL-C ≥60 mg/dL ≥60 mg/dL

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269:3015-3023. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in

Adults. JAMA 2001;285:2486-2497.

Coronary Drug Project: MacrovascularOutcomes*

CDP Research Group. JAMA. 1975;231:360-381.

0

5

10

15

20

25

30

35 Placebo (n = 2789)Niacin (n = 1119)

Nonfatal MICHD Death/Nonfatal MI

Even

t Rat

e, %

15% ReductionP<.05

26% ReductionP<.05

Stroke/TIA CV Surgery†

*Total follow-up experience (mean, 6.2 yrs)†5-year incidenceTIA, transient ischemic attack

24% ReductionP<.05

47% ReductionP<.05

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Placebo S + N + AVS + N

0

5

10

15

20

25

Com

pos i

te E

ven

t R

ate

, %

Com

pos i

te E

ven

t R

ate

, %

HDL-Atherosclerosis Treatment Study (HATS)Niacin and Statin Outcome Trial

Brown BG et al. N Engl J Med 2001;345:1583-1592.

AV

Coronary Death, MI, Stroke, or RevascularizationCoronary Death, MI, Stroke, or Revascularization

89%89%ReductionReduction

21.4

2.6*

14.3

*P<.05vs

Placebo

23.7

0

5

10

15

20

2519.8 18.8

CV EventsEven

t R

ate

(%

)

Brown BG et al. Circulation 1998;98:I-635.

Familial Atherosclerosis Treatment Study (FATS): 10-Year Follow-up Results

Usual Care (n=101)

DeathsLDL-C 188→166 mg/dL; HDL-C 38→40 mg/dL ; TG 208→220 mg/dLLDL-C 202→106 mg/dL; HDL-C 43→53 mg/dL; TG 210→134 mg/dL

Triple Therapy (n=75)

1.3*

* p<0.05

5.3*

AIM HIGHAtherothrombosis Intervention in Metabolic Syndrome w/Low HDL-c/High Triglyceride & Impact on Global Health Outcomes

•• Randomized trial of niacin vs. placebo in the Randomized trial of niacin vs. placebo in the background of background of SimvastatinSimvastatin therapy in ~3,300 people therapy in ~3,300 people w/ CVD, low HDL, and high triglyceridesw/ CVD, low HDL, and high triglycerides

•• Stopped early due to lack of Stopped early due to lack of ““futilityfutility”” w/ about 2/3 of w/ about 2/3 of the events having occurred. the events having occurred. HDLHDL’’ss were higher and were higher and TG levels lower in the niacin group with LDL levels TG levels lower in the niacin group with LDL levels very low and equal in the two groupsvery low and equal in the two groups

•• There were more ischemic strokes in the niacin There were more ischemic strokes in the niacin group.group.

N3-173 Global Risk29/10/2013 15:20:48

Ch

an

ge f

rom

Base

lin

e in

M

ean

Pro

xim

al

% S

ten

osi

s(Δ

%S

)

0

Angiographic Effects of Lipid Drug Classes Meta-Analysis, 12 Trials

755025% Change in LDL% Change in LDL--CC in Rx(%Δ) Placebo-Adjusted

Placebo (6)Fibrates (1)Statins (6)Statin+Resin (1)Niacin Combos (4)

Progression

Regression

Brown BG, Curr Opin Lipidol. 2006;17:631-636.

-2

-1

0

1

2

3

4

Objectives

•• Know NCEP ATP III guidelinesKnow NCEP ATP III guidelines

•• Know how to lower LDL through diet and Know how to lower LDL through diet and medicationsmedications

•• Know how to lower nonKnow how to lower non--HDL cholesterol HDL cholesterol adntadnttriglycerides through diet and medicationtriglycerides through diet and medication

N3-173 Global Risk29/10/2013 15:20:48

QuestionsQuestions

Thank YouThank You

lipid lowering strategies - @mycme · ldl-c • primary target after tlc • ldl-c

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