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N3-173 Global Risk29/10/2013 15:20:48
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
N3-173 Global Risk29/10/2013 15:20:48
“A Whole New World”
Cath Lab Sensation 16 MS CT
N3-173 Global Risk29/10/2013 15:20:48
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
NCEP ATP III Final Report, Circulation 2002; 106 3143-3421
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
N3-173 Global Risk29/10/2013 15:20:48
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)
N3-173 Global Risk29/10/2013 15:20:48
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
NCEP ATP III Final Report, Circulation 2002; 106 3143-3421
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
NCEP ATP III Final Report, Circulation 2002; 106 3143-3421
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
Mean Total Cholesterol (mg/Mean Total Cholesterol (mg/dLdL))
N3-173 Global Risk29/10/2013 15:20:48
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
Mean Total Cholesterol (mg/Mean Total Cholesterol (mg/dLdL))
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
Mean Total Cholesterol (mg/Mean Total Cholesterol (mg/dLdL))
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
N3-173 Global Risk29/10/2013 15:20:48
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
N3-173 Global Risk29/10/2013 15:20:48
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
9% with9% with2 titrations2 titrations
18% with18% 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.
N3-173 Global Risk29/10/2013 15:20:48
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
(Evaluate Risk-benefit)No Dose Limitations
(Evaluate Risk-benefit)
Niacin >1 G/D No Dose Limitations(Evaluate Risk-benefit)
No Dose Limitations(Evaluate Risk-benefit)
No Dose Limitations(Evaluate Risk-benefit)
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)
No Dose Limitations(Evaluate Risk-benefit)
No Dose Limitations(Evaluate Risk-benefit)
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.
N3-173 Global Risk29/10/2013 15:20:48
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.
N3-173 Global Risk29/10/2013 15:20:48
•• 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
StatinsStatins: : Liver Issues (Continued)Liver Issues (Continued)
*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;
N3-173 Global Risk29/10/2013 15:20:48
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
StatinsStatins: : Liver Issues (Continued)Liver Issues (Continued)
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)
N3-173 Global Risk29/10/2013 15:20:48
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.
N3-173 Global Risk29/10/2013 15:20:48
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..
N3-173 Global Risk29/10/2013 15:20:48
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
N3-173 Global Risk29/10/2013 15:20:48
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
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
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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
(Evaluate Risk-benefit)No Dose Limitations
(Evaluate Risk-benefit)
Fibrates Dose Limitations (Max 10 mg)
Dose Limitations(Max 10 mg) Avoid No Dose Limitations
(Evaluate Risk-benefit)No Dose Limitations
(Evaluate Risk-benefit)
Niacin >1 G/D No Dose Limitations(Evaluate Risk-benefit)
No Dose Limitations(Evaluate Risk-benefit)
No Dose Limitations(Evaluate Risk-benefit)
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)
No Dose Limitations(Evaluate Risk-benefit)
No Dose Limitations(Evaluate Risk-benefit)
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.
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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
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