Lipid DisordersThe Science and Art of Treatment in 2004

Alan Jansujwicz, M.D.DHMC Cardiology Update Symposium

2004

Session Outline

• Background

• Review of Data to Support Current Lipid Treatment Paradigms

• Current Recommendations for Treatment

• Time for Questions (Hopefully)

Introduction

• CHD remains the no. 1 killer in the U.S.– Eradicate CAD – life expectancy up to 84– Eradicate Cancer – life expectancy up to 80

• Dyslipidemia plays a major role in CHD

• Safe and effective treatments available

• Less than ½ of eligible patients treated

• Many who are initially treated, stop Rx

Lipid Lowering Drugs and the Data

• HMG Co-A Reductase Inhibitors

• Niacin

• Fibrates

• Ezetimibe

• Others

HMG Co-A Reductase Inhibitors“Statins”

• Drugs structurally similar to HMG-CoA– precursor of cholesterol

• Competitive inhibitors of HMG-CoA reductase– last step in cholesterol synthesis

• Lower serum LDL concentrations by:– Upregulating LDL receptor activity– Reducing LDL entry into the circulation

• Most effective agents for lowering LDL• Impressive body of evidence for CHD treatment

LDL Reduction by Individual Statins

5 mg 10 mg 20 mg 40 mg 80 mg

Atorvastatin 39% 43% 50% 60%

Fluvastatin 21% 24%

Lovastatin 21% 24% 30% 40%

Pravastatin 22% 32% 34%

Rosuvastatin 45% 52% 58% 69%

Simvastatin 22% 30% 35% 41% 47%

In general, doubling dose = additional 6% reduction in LDL

Source: Gau G, Mayo Clinic Cardiovascular Review

Chronic Statin TherapyInitial Major Secondary Prevention Studies

• Scandinavian Simvastatin Survival Study (4S) – Lancet ‘94

– 4444 patients with remote MI or Angina

– Total Cholesterol 213-309 mg/dL

– Simvastatin 20/40 mg vs placebo for 5.4 years

• Cholesterol and Recurrent Events Trial (CARE) – NEJM ‘96

– 4159 patients with remote MI

– Total Cholesterol < 240 mg/dL, LDL 115-174 mg/dL

– Pravachol 40 mg vs placebo for 5 years

• Long-Term Intervention with Pravastatin (LIPID) – NEJM ‘98

– 9014 patients with remote MI or Angina

– Total Cholesterol 155 to 271 mg/dL

– Pravachol 40 mg vs placebo for 6.1 years

LDL Lowering in 4S, CARE, and LIPID

188

122

139

98

150

112

0

2040

6080

100

120140

160180

200

LD

L in

mg/

dL

4S CARE LIPID

BaselineTreatment

-35%-29%

-25%

Risk Reduction in 4S, CARE, and LIPID

30

42

37

9

20

27

2224

20

0

5

10

15

20

25

30

35

40

45

% R

isk

Red

ucti

on

4S CARE LIPID

Total MortalityCHD MortalityRevasc

LIPID Trial – Risk of CHD Death

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, N Engl J Med 1998;339:1349-1357

Time Delay to Benefit…

CARE Trial – CHD Events

Sacks, F. M. et al. N Engl J Med 1996;335:1001-1009

Investigators postulated that there might be a “benefit floor”

Possible Lower Limit to Benefit…

Chronic Statin TherapyThe Heart Protection Study

• 20K patients ages 40-80 years in the UK

• Inclusion criteria of– Known CAD

– Known PVD

– Diabetes

– Males > 65 with HTN (also a high risk group, but only 1%)

• No upper or lower limit of serum cholesterol

• Assigned to simvastatin 40 mg vs placebo

• Direct LDL measured from nonfasting samples

• Followed for average of 5 years

HPS Collaborative Group. Lancet 2002;360: 7-22.

The Heart Protection StudyLipid Levels

• Baseline Lipid Panel– Total Chol 228 mg/dL– dLDL 131 mg/dL (15% less than calculated LDL)

– HDL 41 mg/dL

– Trig 81 mg/dL

• Average dLDL levels during 5 years of follow-up– Simvastatin 89 mg/dL (85% avg compliance)

– Placebo 128 mg/dL (17% avg crossover)

HPS Collaborative Group. Lancet 2002;360: 7-22.

**Below previously suggested floor to benefit**

The Heart Protection StudyMajor Outcomes

12.914.7

5.7 6.9

4.3

5.7

9.1

11.7

0

2

4

6

8

10

12

14

16

Eve

nt R

ate

(%)

TotalMortality

CoronaryMortality

Stroke Revasc

SimvastatinPlacebo

RRR = 13% RRR = 18% RRR = 25% RRR = 24%

All risk reductions statistically significant

The Heart Protection StudySafety Measures

0.42

0.31

0.11

0.06 0.050.01

0.05 0.03

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

Eve

nt R

ate

(%)

Elev LFTs(4x)

Elev CK(10x)

Myopathy(10x + sx)

Rhabdo(40x)

SimvastatinPlacebo

p = ns p = ns p = ns p = ns

Chronic Statin TherapyPrimary Prevention

• WOSCOPS – NEJM ’95– 6595 men, age 45 to 64, with no documented CAD– Total cholesterol at least 252 mg/dL– Pravachol 40 mg vs placebo for 4.9 years– Primary Endpoint – Nonfatal MI or Death from CHD

• AFCAPS/TexCAPS – JAMA ’98– 997 women (age 55-73) and 5608 men (age 45-73)– No documented CAD or PVD– Total cholesterol 180 to 264 mg/dL– Lovastatin 20/40 mg vs placebo for 5.2 years– Primary Endpoint – MI, USA, or Sudden Cardiac Death

Primary Prevention TrialsLipid Lowering Results

192

142150

113

020406080

100120140160180200

LD

L (

mg/

dL

)

WOS AFCAP

Baseline

Treatment

7.9

5.5

10.9

6.8

0

2

4

6

8

10

12

Eve

nt

Rat

e (%

)

WOS AFCAP

Placebo

Drug

WOS – RRR 31%, due to reduction in nonfatal MI and CHD death

AFCAPS – RRR 37%, due to difference in nonfatal events

26%

25%

Acute Statin Therapy

• MIRACL – JAMA 2001

– 3086 patients undergoing noninvasive ACS treatment

– Total cholesterol less than 270 mg/dL; no lower limit

– Atorvastatin 80 mg vs placebo for 16 weeks

• PROVE-IT – NEJM 2004

– 4162 patients undergoing mostly invasive ACS treatment

– Total cholesterol less than 240 mg/dL (naïve), 200 mg/dL (Rx)

– Atorvastatin 80 mg vs Pravastatin 40 mg for 2 years

• A to Z – JAMA 2004

– 4497 patients with acute NSTEMI or STEMI (complicated trial)

– Total cholesterol less than 250 mg/dL; no lower limit

– Simva 40(1mo)/80 mg vs Placebo(4mo)/Simva 20 mg for 2 years

MIRACL Trial Results

124135

72

0

20

40

60

80

100

120

140

LD

L (

mg/

dL

)

Patients

BASEPLRX

17.4

14.8

13.5

14

14.5

15

15.5

16

16.5

17

17.5

Eve

nt

Rat

e (%

)Patients

PLRX

RRR = 16% in Treatment Group at 16 weeks (p=0.048)

Higher baseline LDL not predictive of increased event rate

No significant association between % change in LDL and event rate

PROVE-IT and AtoZ Results

26

22.4

16.714.4

0

5

10

15

20

25

30

Eve

nt

Rat

e (%

)

PROVEIT AtoZ

MOD

INT

106

95

62

112

81

66

0

20

40

60

80

100

120

LD

L (

mg/

dL

)

PROVEIT

BASE

MOD

INT

Similar Reductions in LDL achieved in both trials

RRR = 16% in PROVE-IT met significance

RRR = 11% in A to Z did not meet significance

Limitations in A to Z design likely responsible for lack of significant outcome

LDL Levels and CHD RiskLower is Better!

0

5

10

15

20

25

30

50 100 150 200

LDL (mg/dL)

Eve

nt

Rat

e (%

)

SecondaryPrimaryACS

4S-PL

4S-Rx

LIPID-PL

CARE-PLLIPID-Rx

CARE-RxHPS-PL

HPS-Rx WOS-PLAF-PL

WOS-RxAF-Rx

PROV-Rx PROV-PL

AtoZ-PLAtoZ-Rx

Niacin

• Cholesterol-lowering effect 1st reported in 1955• Reduces LDL (5-25%) by decreasing peripheral

mobilization of FFAs from adipose tissue• Most effective drug available clinically for raising

HDL (15-35%)• Also effective for reducing triglycerides (25-50%)• Reduces Lp(a) by 30%• Converts small, dense LDL to large, buoyant LDL

Niacin

• Pitfalls with niacin therapy– Cutaneous flushing, pruritis, nausea, abd pain– Hepatotoxicity– Glucose intolerance– Increase risk of myositis if used with statin– Minimal hard endpoint outcome data

Niacin Outcome Data Trials

• Coronary Drug Project – JACC 1986– 8,000+ men, post-MI, Rx with 1 of 5 drugs or placebo– Patients treated for 6 years (some arms stopped early)– Patients subsequently followed for 9+ years post-Rx

• HDL Atherosclerosis Treatment Study – NEJM 2001– 160 patients with established CAD– Low HDL (31 mg/dL), “normal” LDL (125 mg/dL)– Four Rx regimens: Placebo, N+S, AV, N+S+AV– Followed for 3 years for clinical or angiographic events– All but 14 patients underwent an end of trial angiogram

Niacin

Placebo

P = 0.0012

100908070605040302010

0 2 4 6 8 10 12 14 16

Years of follow-up

Surv

ival (%

)

Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

Coronary Drug ProjectLong-Term Mortality Benefit of Niacin

source = www.lipidsonline.org

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

23.7

2.6

21.4

14.3

0

5

10

15

20

25

30

Com

posi

te E

vent

Rat

e (%

)

Placebo S+N AV S+N+AV

RRR = 89% p < 0.05

LDL 116

HDL 34

LDL 75

HDL 40

LDL 112

HDL 33

LDL 79

HDL 36

Fibrates

• Class of drugs which resemble short chain fatty acids• Increase oxidation of fatty acids in muscle and liver• Most effective class of drugs for lowering triglycerides• Increase size of LDL particles and enhance removal• May increase HDL-mediated reverse cholesterol transport• Reduce levels of plasminogen activator inhibitor type I• Currently available drugs in U.S.

– Gemfibrozil– Fenofibrate (less risk of myopathy when used with a statin)

• ADRs: GI, ED, myopathy (CRF)

Major Fibrate Therapy Trials

• Helsinki Heart Study – NEJM 1987– Primary prevention trial– 4,081 dyslipidemic (non-HDL > 200 mg/dL) men, age 40 to 55– Gemfibrozil 600 mg bid vs Placebo for 5 years– Primary endpoint – CHD death or nonfatal MI

• VA-HIT – NEJM 1999– Secondary prevention trial– 2,531 men with documented CAD in the VA system– HDL < 40 mg/dL and LDL < 140 mg/dL– Gemfibrozil 600 mg bid vs Placebo for 5.1 years– Primary endpoint – CHD death or nonfatal MI

Major Fibrate TrialsOutcome Data

2.74.1

2.7

8

17.3

21.7

0

5

10

15

20

25

% C

HD

Dea

th o

r M

I

HHS HHS-PostHoc VA-HIT

TreatmentPlacebo

RRR = 34% RRR = 66% RRR = 22%

* HHS-Post Hoc: Subgroup with TG > 200 mg/dL and HDL < 42 mg/dL

** All results met statistical significance

Ezetimibe

• 1st in new class of cholesterol absorption inhibitors

• Likely works by binding to and blocking the sterol transporter on the intestinal brush border

• Results in increased LDL-R activity and LDL clearance

• Drug and its metabolites circulate enterohepatically with little systemic penetration

• Potential toxicities essentially limited to liver

• Does not induce or inhibit cytochrome P450 system

• Single dosing option of 10 mg once daily

Lipid Lowering with Ezetimibe

20

50 51

0

10

20

30

40

50

60

% L

DL

Low

erin

g

Zetia Zetia+Atorv10 Atorv80

ZetiaZetia+Atorv10Atorv80

Ballantyne CM. Circulation 2003; 107: 2409-2415.

Lipid Risk AssessmentNCEP ATP III + Recent Update

• Obtain a fasting lipoprotein profile on all adults aged 20 years or older (repeat every 5 years)

• Assess for CHD, CHD risk equivalents, and risk factors for developing CHD

• Framingham Risk Assessment for intermediate risk patients

• Assess for the metabolic syndrome• Consider emerging risk factors (i.e. hs-CRP)

NCEP. JAMA 2001; 285(19): 2486-97.

Lipoprotein Profile Classification

• LDL Cholesterol– < 70 Optimal in HRP– < 100 Optimal– 100-129 Near Optimal– 130-159 Borderline High– 160-189 High– 190+ Very High

• HDL Cholesterol– < 40 Low– 60+ High

• Total Cholesterol– < 200 Desirable– 200-239 Borderline High– 240+ High

• Triglycerides– < 150 normal– 150-199 Borderline High– 200-499 High– 500+ Very High

CHD and CHD Risk Equivalents

• CHD

• CHD Risk Equivalents– Peripheral Vascular Disease– Abdominal Aortic Aneurysm– Symptomatic Carotid Arterial Disease– Diabetes– Framingham 10-year risk 20+%

Major Risk FactorsATP III

• Cigarette Smoking• Hypertension (140+/90+ or on meds)• Low HDL Cholesterol (< 40 mg/dL)• FH of Premature CAD

– Male 1st degree relative < 55– Female 1st degree relative < 65

• Personal Age– Male 45+– Female 55+

Framingham Risk AssessmentFor Intermediate Risk Patients

• Gender Specific• Calculates risk based on

– Age– Total Cholesterol (age stratified)– Current Smoking Status (age stratified)– HDL Cholesterol– Systolic Blood Pressure (Rx or no Rx)

• Overall point score allows for calculation of 10 year risk of a CHD event

• Framingham Risk stratifies patients into– CHD equivalent 10-year risk > 20%– Moderately high risk 10-year risk 10-20%– Intermediate Risk 10-year risk < 10%

The Metabolic SyndromeAny 3 of the following

• Abdominal Obesity (waist circumference)– Men > 40 inches– Women > 35 inches

• Triglycerides 150+ mg/dL

• HDL– Men < 40 mg/dL– Women < 50 mg/dL

• Blood Pressure 130+/85+ mm Hg

• Fasting Glucose 110+ mg/dL

Risk StratificationUpdate to ATP III

• Very High Risk– CHD + multiple risk factors (diabetes)– CHD + poorly controlled risk factor (smoking)– CHD + metabolic syndrome– CHD + ACS

• High Risk– CHD– CHD Equivalents

• Moderately High Risk– 2+ Risk Factors + Framingham Risk of 10-20%

• Intermediate Risk– 2+ Risk Factors + Framingham Risk of < 10%

• Low Risk– 0-1 Risk Factor

LDL Treatment Based on Risk Stratification

• Very High Risk Patient– Optional LDL goal of < 70 mg/dL– Standard LDL goal of < 100 mg/dL– For LDL ≥ 100 mg/dL, initiate both lifestyle

changes and drug treatment– For LDL < 100 mg/dL, lifestyle changes are

indicated, drug Rx is therapeutic option

• High Risk Patient (CHD / CHD Equivalent)– LDL goal of < 100 mg/dL– For LDL ≥ 100 mg/dL, initiate both lifestyle

changes and drug treatment– For high TG / low HDL, consider adding niacin

or fibrate to statin

LDL Treatment Based on Risk Stratification

• Moderately High Risk Patients– 2+ RFs and 10-year risk 10-20%– Optional LDL goal of < 100 mg/dL– Standard LDL goal of < 130 mg/dL– For LDL ≥ 130 mg/dL, initiate both lifestyle

changes and drug treatment– For LDL 100 to 129 mg/dL, lifestyle changes

are indicated, drug Rx is therapeutic option

LDL Treatment Based on Risk Stratification

• Intermediate Risk Patients– 2+ RFs and 10-year risk < 10%– LDL goal < 130 mg/dL– For LDL ≥ 130 mg/dL, initiate lifestyle changes– For LDL ≥ 160 mg/dL, initiate both lifestyle

changes and drug Rx

LDL Treatment Based on Risk Stratification

• Low Risk Patients– 0 to 1 risk factor– LDL goal < 160 mg/dL– For LDL ≥ 160 mg/dL, initiate lifestyle

changes, drug Rx optional– For LDL ≥ 190 mg/dL, initiate both lifestyle

changes and drug Rx

LDL Treatment Based on Risk Stratification

Secondary Goal – Non HDL Cholesterol

• Elevated triglycerides are an independent risk factor for CHD (meta-analyses)

• Non HDL cholesterol captures risk of both LDL and triglycerides

• Non HDL goals are set 30 mg/dL higher than LDL goals– High risk non HDL goal < 130 mg/dL– Int risk non HDL goal < 160 mg/dL– Low risk non HDL goal < 190 mg/dL

hs-CRP

• Large body of evidence now supports CRP as in independent predictor of CHD risk

• However, the data all comes from post hoc analysis of lipid-lowering trials and observational trials

• Probably most useful in identifying moderately high risk patients who may be at greater risk than predicted by traditional risk assessment

hs-CRP

• hs-CRP measurement is now a Class IIa recommendation in two subgroups of patients– Moderately high risk Framingham patients (10-

20% risk)– Patients with known CAD for risk assessment

of future events

Measuring and Using hs-CRP

• Measure twice, two weeks apart, in metabolically stable patients

• Tertiles of risk– Low risk < 1 mg/dL– Intermediate risk 1-3 mg/dL– High risk > 3 mg/dL

• High risk CRP results in moderately high risk patients and in those with CHD should result in intensification of treatment

• hs-CRP values > 10 mg/dL indicate an ongoing inflammatory or infectious process and should not be used

When to Stop Treatment

• Statins and Ezetimibe– Myopathy - Muscle aches with CK > 10x ULN– Abnormal LFTs – 3x ULN– Pregnancy and Breast Feeding

• Niacin– Abnormal LFTs (3x ULN) or chronic liver disease– Gout– Poorly controlled diabetes– Pregnancy

• Fibrates– Chronic liver dysfunction or renal failure– Abnormal LFTs or myopathy– Pregnancy

Summary• Recent clinical trials have confirmed the log-linear

relationship between CHD risk and LDL cholesterol at lower levels

• This relationship means that risk reduction is independent of initial cholesterol levels and is dependent only on absolute reduction in levels

• This has led to more aggressive lipid lowering benchmarks, especially in certain high risk groups

• Additionally, novel risk factors such as hs-CRP have become available which allow us to further stratify certain risk populations

• The charge remains to identify and effectively treat our dyslipidemic patients over the long-term