The Moving LDL Target: Getting Your Patients to Goal

The Moving LDL Target: Getting Your Patients

to Goal

Tampa, Florida December 4, 2008

Education Partner:

Session 4: The Moving LDL Target: Getting Your Patients to Goal Learning Objectives

• Describe at least 2 challenges in treating dyslipidemia to NCEP-ATP III goals and getting patients to goal. • Define the patients at increased risk for cardiovascular events and identify at least 2 lipid-lowering strategies

that will help these patients reach goal taking into consideration current lifestyle and pharmacologic treatment options available for lipid management.

Faculty Emma A. Meagher, MD Associate Professor, Medicine and Pharmacology Executive Chair Associate Director, Cardiac Risk Program University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Dr Meagher received the MB (MD) degree from the Royal College of Surgeons in Dublin, Ireland. Since 1995, she has been associate professor of medicine, Division of Experimental Therapeutics at the University of Pennsylvania School of Medicine. Dr Meagher’s area of research interest includes mechanisms of vascular dysfunction in cardiovascular disease and alcohol-induced vascular disease. Her clinical practice is in the area of cardiovascular risk modification. She is associate director of the Center for Assessment and Treatment of Complex Hypertension and associate director of the Cardiovascular Risk Intervention Program at the University of Pennsylvania School of Medicine. Dr Meagher is program director of the Patient Oriented Research Training Program at the University of Pennsylvania. This training program in research methodology includes a course for medical students, residents, fellows, and junior faculty. In addition, she is the director of a master’s degree program in experimental medicine and translational research, and she is the course director for pharmacology education in the school of medicine. Dr Meagher is a member of the American Heart Association’s Council on Atherosclerosis, Thrombosis, and Vascular Biology, the American Society of Hypertension, the American Federation for Medical Research, and the American Gastroenterological Association. She has written extensively on lipid lowering drug therapy in primary prevention, antioxidant therapy and atherosclerosis, the safety and effectiveness of niacin in combination with lovastatin, lipid peroxidation, and balancing cardioprotection and gastroprotection with selective cox-2 inhibitors. Barry L. Hainer, MD Professor, Department of Family Medicine Medical University of South Carolina Charleston, South Carolina

Dr Barry Hainer writes for and speaks to primary care physician audiences on a variety of clinical topics. He is a reviewer for American Family Physician and is a member of the Society of Teachers of Family Medicine, among other professional societies. He is a Diplomate of the National Board of Medical Examiners and the American Board of Family Medicine and was awarded the Certificate of Added Qualifications in Geriatrics by the American Board of Family Practice and American Board of Internal Medicine. Dr Hainer is included in the 2007-2008 edition of Guide to America’s Top Physicians.

Dr Hainer received his MD degree from Georgetown University, Washington, DC. He completed a residency in the Department of Family Medicine at the Medical University of South Carolina, Charleston. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Meagher is a consultant for Abbott Laboratories. Dr Hainer is on the speakers bureau of Merck & Co, Inc. and Sanofi Pasteur Inc. Education Partner Financial Disclosure Statements The content collaborators at Turnkey Solutions, LLC have reported the following: Emily A. Bakerman, RN, MS, APN-C, executive vice president, has nothing to disclose. Drug List Generic Trade atorvastatin Lipitor

Generic Trade colesevelam Welchol

Session 4

Session 4

Generic Trade ezetimibe Zetia ezetimibe/simvastatin Vytorin fenofibrate Tricor gemfibrozil Lopid glipizide Glucotrol losartan Cozaar lovastatin Altoprev, Mevacor metformin Glucophage

Generic Trade niacin (nicotinic acid) Niacor, Niaspan omega-3 fatty acids Lovaza (formerly Omacor) pravastatin Pravachol rosuvastatin Crestor simvastatin Zocor stanol esters Benecol margarine sterol esters Take Control margarine valsartan/HCTZ Diovan HCT

Acronym List Acronym Definition ACS acute coronary syndrome ALT alanine aminotransferase CAD coronary artery disease CAI cholesterol absorption inhibitors CHD coronary heart disease CPK creatine phosphokinase HbA1c hemoglobin A1c HDL-C high-density lipoprotein cholesterol HTN hypertension IDL intermediate-density lipoprotein IGT impaired glucose tolerance

Acronym Definition IMT intima media thickness LDL-C low-density lipoprotein cholesterol MI myocardial infarction Non–HDL-C total cholesterol minus HDL-C NSTEMI non–ST-elevation myocardial infarction TC total cholesterol TG triglyceride TFT thyroid function test TLC therapeutic lifestyle changes VLDL very low-density lipoprotein

Suggested Reading List Armani A, Toth PP. Colesevelam hydrochloride in the management of dyslipidemia. Expert Rev Cardiovasc Ther. 2006;4(3):283-291. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278. Bertoni AG, Bonds DE, Steffes S, et al. Quality of cholesterol screening and management with respect to the National Cholesterol Education's Third Adult Treatment Panel guideline in primary care practices in North Carolina. Am Heart J. 2006;152(4):785-792. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592. Catapano AL, Davidson MH, Ballantyne CM, et al. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin. 2006;22:2041-2053. Davidson M. Striated muscle safety of ezetimibe/simvastatin. Am J Cardiol. 2006;97:223-228. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. Jones PH, Davidson MH, Stein EA, et al; for the STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol 2003;92:152-160. McKenney JM, Jones PH, Adamczyk MA, et al; for the STELLAR Study Group. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial. Curr Med Res Opin. 2003;19(8):689-698. Smith S. AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2006 Update: Endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-2372. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512-3517. Wiviott SD, Cannon CP, Morrow DA, et al; PROVE IT-TIMI 22 investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46:1411-1416.

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1

The Moving LDL Target: The Moving LDL Target: Getting Your Patients Getting Your Patients

to Goalto Goal

EMMA A. MEAGHER, MDAssociate Professor, Medicine and Pharmacology

Executive ChairAssociate Director, Cardiac Risk Program

University of Pennsylvania School of MedicinePhiladelphia, Pennsylvania

EndpointTreatmentEvents (%)

ControlEvents (%) Relative Risk (CI)

Non-fatal MI 2001 (4·4) 2769 (6·2) 0·74 (0·70 – 0·79)

CHD death 1548 (3·4) 1960 (4·4) 0·81 (0·75 – 0·87)

Any major coronary event 3337 (7·4) 4420 (9·8) 0·77 (0·74 – 0·80)

Any coronary revascularisation 2620 (5·8) 3434 (7·6) 0·76 (0·73 – 0·80)

Haemorrhagic stroke 105 (0·2) 99 (0·2) 1·05 (0·78 – 1·41)Presumed ischemic stroke 1235 (2·8) 1518 (3·4) 0·81 (0·74 – 0·89)

Any stroke 1340 (3·0) 1617 (3·7) 0·83 (0·78 – 0·88)

Any major vascular event 6354 (14·1) 7994 (17·8) 0·79 (0·77 – 0·81)

0·5 1·5Control

1·0Treatment

better betterp < 0·00001

Baigent C et al. Lancet. 2005;366:1267-1278.

Key Lessons From Lipid Trials (>90,000 pts)

LOWERING LDL REDUCES CV EVENTS

Risk Category LDL-C Goal Initiate TLCConsider

Drug TherapyVery High risk:

ACS, CHD w/DM, mult CRF<70 mg/dL ≥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 Rx)

Moderately high risk:2+ risk factors (10-year risk 10% to 20%)

<100 mg/dL ≥130 mg/dL > 130 mg/dL(100-129 mg/dL:

consider Rx )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

ATP III Update 2004:LDL-C Goals and Cutpoints for Therapy

in Different Risk Categories

Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

KEY CHANGESLower LDL< 70 goal in very high-risk groups:

Diabetes Other clinical forms of atherosclerotic disease (with multiple risk factors, recent ACS,CAD, PAD, Carotid disease)

Multiple risk factors and increased 10-y CHD riskIntensified therapeutic lifestyle changes (TLC)

for metabolic syndromeMore aggressive targets (LDL, non-HDL)

.Grundy SM, et al. Circulation 2004;110:227-239.

ATP III ATP III –– 2004 Update: Report on the Detection, 2004 Update: Report on the Detection, Evaluation,Evaluation, and Rx of High Cholesterol in Adults and Rx of High Cholesterol in Adults

Recent Data Since ATP III: Recent Data Since ATP III: Lower LDL GoalsLower LDL Goals

20032002

HPS

PROSPER

2004

ASCOT-LLA

CARDS

REVERSAL

PROVE IT

A to Z

2005

IDEAL

TNT

METEOR

ASTEROID

CORONA

Recent Trials of Intensive LDL Lowering Recent Trials of Intensive LDL Lowering in Patients with ACS or Stable CADin Patients with ACS or Stable CAD

StudyStudyPopulation

LDL Cholesterol (mg/dL)

High Dose Standard Dose

PROVE IT ACS 62 95

A to Z ACS 63 77

TNT Stable CAD 77 101

IDEAL Stable CAD 81 104

Cannon CP, et al. JACC 2006; 48:438-445.

2

MetaMeta--analysis of Intensive analysis of Intensive StatinStatinTherapy: Coronary Death or MITherapy: Coronary Death or MI

High-dose better High-dose worse

Odds Reduction

Event Rates

No./Total (%)High Dose Std Dose

-17% 147/2099 (7.0)

172/2063 (8.3)

-15% 205/2265 (9.1)

235/2232 (10.5)

-21% 334/4995 (6.7)

418/5006 (8.3)

-12% 411/4439 (9.3)

463/4449 (10.4)

-16% 1097/13798 (8.0)

1288/13750 (9.4)

PROVE IT-TIMI 22

A-to-Z

TNT

IDEAL

Total

0.66 1 1.5

OR, 0.8495% CI, 0.77-0.91p=0.00003

Odds Ratio (95% CI)

Cannon CP, et al. JACC 2006; 48:438-445.

Safety of Lower LDL Goals: Safety of Lower LDL Goals: PROVE ITPROVE IT

% w

ith A

dver

se E

vent

p=0.75

p=0.18

p=0.98

p=0.48p=0.12

Wiviott SD et al. JACC. 2005;46:1411-1416.

How Low Should LDLHow Low Should LDL--C Go?C Go?

Wiviott SD, et al. J Am Coll Cardiol. 2005;46:1411-1416.

>40-60

≤ 40

>60-80

>80-100

0.61

0.67

0.80

Referent

Ach

ieve

d LD

L (m

g/dL

)

00 11 22Lower LDL-C

BetterHigher LDL-C

Better

Hazard Ratio for Primary Endpoint

Current LDL Treatment Rates: Current LDL Treatment Rates: NEPTUNE IINEPTUNE II

% A

chie

ving

LD

L G

oal

Davidson MH et al. Am J Cardio 2005;96:556-563.

Why ArenWhy Aren’’t Patients Getting to Goal?t Patients Getting to Goal?

Patient non-compliance

Lipid lowering therapies not initiated

Low doses started with lack of further titration

Lack of comfort in prescribing higher doses or combinations of medications

Concerns about safety of low LDL-C levels

ATP III 2004 Update: ATP III 2004 Update: Stepwise ApproachStepwise Approach

1.Measure fasting lipid profile

2.Determine Risk:

–CHD or CHD equivalents

–Total # non-LDL risks

–Framingham risk score

3.Determine target LDL

4.Assessment beyond LDL

Adult Treatment Panel III of the National Cholesterol Education Program. JAMA. 2001;285:2486-2497.Grundy SM, et al. Circulation 2004;110:227-239.

3

NCEP: Additional StepsNCEP: Additional Steps

Target LDL-C and stay with it until it is at goal

Use statin doses that reduce LDL-C by 30%-40%

– Potential combinations include bile acid sequestrants, ezetimibe, nicotinic acid, plant stanols/sterols

Identify the metabolic syndrome and treat with more aggressive lifestyle interventions

Consider adding fibrate or niacin to statin if non-HDL cholesterol (TC – HDL) is >30 mg/dLabove LDL-C goal

Adult Treatment Panel III of the National Cholesterol Education Program. JAMA. 2001;285:2486-2497.Grundy SM, et al. Circulation 2004;110:227-239.

NonNon--HDL Cholesterol Represents HDL Cholesterol Represents All All AtherogenicAtherogenic Lipid ParticlesLipid Particles

VLDL VLDLR IDL LDL HDL

TG-rich lipoproteins

Non–HDL-C = Total Cholesterol minus HDL-C

Grundy SM, et al. Circulation 2004;110:227-239.Grundy SM, et al. Am J Cardiol. 2005;95:462-468.

TotalCholesterol =

Non-HDL-C

+

NonNon--HDL Cholesterol as the Second HDL Cholesterol as the Second Goal of Therapy: NCEP ATP IIIGoal of Therapy: NCEP ATP III

LDL-C lowering is the primary goal of lipid lowering therapy

When Triglycerides are ≥ 200 mg/dL, non-HDL-C is a secondary target of therapy, with a goal 30 mg/dL higher than the identified LDL-C goal

Adult Treatment Panel III of the National Cholesterol Education Program. JAMA. 2001;285:2486-2497.Grundy, S. et al., Circulation 2004;110:227-39

Interventions to Lower LDLInterventions to Lower LDL--CC

Dietary Interventions– Saturated fat <7% of calories

– <200mg/d of dietary cholesterol

– Plant stanol esters

Statin Therapy at appropriate doses

Combination Therapies

Net Cholesterol Balance in HumansNet Cholesterol Balance in Humans

Slide source: Lipids Online Slide Library. Available at: http://lipidsonline.org/slides/cme_pdf/talk029.pdf Accessed Jan 10, 2008.

Lipid Modifying DrugsLipid Modifying DrugsLDL-C HDL-C TG Evidence

Statins 18-55% 5-15% 7-30% ++++++

Bile acid resins 15-30% 3-5% 0 -15% ++

Absorption inhibitors (CAI) 18-20% 3% 8% ++

Nicotinic acid 5-25% 15-35% 20-50% ++

Stanol Esters 5-14% No change No change ++

Fibrates 5-20% 10-20% 25-50% +++

Omega-3 fatty acids 2-5% No change 30-40% +Adult Treatment Panel III of the National Cholesterol Education Program. JAMA. 2001;285:2486-2497.

Katan MB, et al. Mayo Clin Proc. 2003; 78:965-978.

4

Change in LDL Values Change in LDL Values with Different Statin Doseswith Different Statin Doses

‐20

‐28

‐37

‐46

‐24

‐35

‐43

‐52

‐30

‐39

‐48

‐55

‐46

‐51

-60

-50

-40

-30

-20

-10

0

Pravastatin10 20 40 (mg)

Simvastatin10 20 40 80 (mg)

Atorvastatin10 20 40 80 (mg)

Rosuvastatin10 20 40 (mg)

% C

hang

e in

LD

L-C

Jones PH, Am J Cardio. 2003;92:152-160.

If If StatinsStatins Are So Effective, Why Is Are So Effective, Why Is Combination Therapy Often Necessary?Combination Therapy Often Necessary?

• Despite overwhelming success of the statins, coronary event rates remain unacceptably high

• The majority of patients do not reach LDL-C goals

• If LDL is not managed on an appropriate dose of statin monotherapy then combination therapy may be warranted and more efficacious and tolerable than high-dose monotherapy

• There’s more to the story than LDL-C!

Therapeutic CombinationsTherapeutic Combinations

Statins + niacin

Statins + fibrates

Statins + bile acid sequestrants

Statins + ezetimibe

Ezetimibe + fibrate

Statins + omega-3 fatty acids

Modified from Bays H, et al. Expert Opin Pharmacother. 2003;4:779-790.

Niacin ER 1000 mg/Lovastatin 40 mg: Comparison With Atorvastatin 10 mg and 20 mg

in an Open-Label Trial

Results reflect mean LDL-C and HDL-C responses and median TG response. Lovastatin/NiacinER 1000 mg/40 mg dose was administered as two 500 mg/20 mg tablets. This open-label trial did not compare the highest available doses of atorvastatin and simvastatin, and such a comparison could produce different results from those presented above.

-60

-40

-20

0

20

LDL-C HDL-C TG

-38 -38

+20

+3

-30

-20

p≤0.05

p≤0.05

Lovastatin 40mg /NiacinER 1000 mgAtorvastatin 10 mg

p=NS

Week 8

-42 -45

+19

+4

-36-30

p≤0.05

p≤0.05p=NS

Lovastatin 40 mg/ NiacinER 1000 mg Atorvastatin 20 mg

Week 12

-60

-40

-20

0

20

LDL-C HDL-C TG

% C

hang

e Fr

om B

asel

ine

% C

hang

e Fr

om B

asel

ine

Bays HE et al. Am J Cardiol. 2003;91:667-672.

0.87

Statin + Placebo Statin + ER Niacin

Bas

elin

e C

IMT

0.89

Baseline Carotid IMT

Cha

nge

in C

IMT,

mm

0.014 (p=0.23*)

Statin + Placebo

0.044(p<0.001*)

* Within-group comparisons.

Δ Carotid IMT After 1 Year

ARBITER 2: ARBITER 2: HDLHDL--C C ↑↑ 18% (p=0.002); TG 18% (p=0.002); TG ↓↓ 10% (p=0.03); No change in LDL10% (p=0.03); No change in LDL--CC

Taylor AJ et al. Circulation. 2004;110:3512-3517.

Statin + ER Niacin

ARBITER 3: ER Niacin for 12ARBITER 3: ER Niacin for 12--24 24 mthsmths88% (n=130) of pts in ARBITER 2 cont’d in the open-label ARBITER 3 studyAll pts rec’d ER Niacin from months 12 -> 24

Δ CIMT (mm)

Statin + placebo(12m)

Statin + ERN(12m)

Statin + ERN(24m)

ΔH

DL

(mg/

d L)

+0.100

+0.075

+0.050

+0.025

0.000

-0.025

-0.050

ΔHDL< 5 mg/dL -> progression

ΔHDL> 12 mg/dL -> regression

Taylor AJ et al. Curr Med Res and Opin. 2006;22:2243-2250. P<0.0001

5

StatinStatin Plus Plus FibrateFibrate Combination TherapyCombination TherapyTargets both LDL-C (statin) and TGs (fibrate)When fibrates are added to statins;– Decrease TG and VLDL levels by 20-50% – Decrease LDL-C by 5-20% (fenofibrate)– Increases HDL-C by 10-29%– Reduces small dense LDL levels

Safety/efficacy data come from small clinical trialsNo outcomes data yet Increased risk of myopathyOnly approved with low-dose statins

ACC/AHA/NHLBI Clinical Advisory on Statins. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/statins.pdf. Accessed Jan 10, 2008.

SAFARI: Combination Therapy in Patients SAFARI: Combination Therapy in Patients With Combined HyperlipidemiaWith Combined Hyperlipidemia

Grundy SM, et al. Am J Cardiol. 2005;95:462-468.*P<0.001 versus simvastatin

**

*

*

N=618; 18-weeks

-20.1-24.1 -25.8

9.7

-43-49.1

-31.2

18.6

-60

-50

-40

-30

-20

-10

0

10

20

30

TG VLDL-C LDL-C HDL-C

Cha

nge

from

Bas

elin

e, %

Simvastatin 20 mg

Simvastatin 20 mg + Fenofibrate 160 mg

Stanol Esters: The EvidenceStanol Esters: The Evidence• Over 20 published studies support efficacy

• Cholesterol absorption is nearly halved

• Cholesterol-lowering effect of plant stanols– TC is lowered by up to 10%– LDL-C is lowered by up to 14%– HDL-C and TG are unaffected

• Must take 2-3 grams/day (OJ, chocolate, granola chews, yogurt drinks etc)

• Now incorporated as part of TLC diet

Katan MB, et al. Mayo Clin Proc. 2003; 78:965-978.

Bile Acid SequestrantsBile Acid SequestrantsMajor actions– Reduce LDL-C 15%-30%– Reduces LDL-C by additional 10-16% when added to

statin therapy– May increase TG– Colesevelam added to sulfonylurea, metformin or

insulin improves glycemic control in type 2 diabeticsSide effects– GI distress/constipation– Decreased absorption of other drugs

Contraindications– Elevated TG (especially >400 mg/dL)

Adult Treatment Panel III of the National Cholesterol Education Program. JAMA. 2001;285:2486-2497.Bays, H., Goldberg r.b. et al. AHA Scientific Sessions 2006; November 12-15, poster 1561.

Clinical Studies of Ezetimibe: MonotherapyClinical Studies of Ezetimibe: Monotherapy

Knopp RH, et al. Eur Heart J. 2003;24:729-741.Dujovne CA, et al. Am J Cardiol. 2002;90:1092-1097.

Pooled Results From 2 Phase III Multicenter, Double-Blind, Placebo-Controlled, 12-Wk Studies in 1719 Patients With Primary Hypercholesterolemia

Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ezetimibe.

1% 0%

– 2%

– 18%*

– 8%*

1%*

–20%

–15%

–10%

–5%

0%

5%LDL-C TG (median) HDL-C

Mean %

change

from

untreated

baseline

Placebo (N = 431)

Ezetimibe 10 mg (N = 1288)

*P ≤ 0.01 vs placebo

Combination Therapy: Combination Therapy: EzetimibeEzetimibe Plus Plus SimvastatinSimvastatin vs. vs. RosuvastatinRosuvastatin

P<0.05 for EZE + simvastatin vs. rosuvastatin for each comparison

Eze+Simva80 mg

(n=474)

Eze+Simva40 mg

(n=477)

Rosuva10 mg

(n=475)

Eze+Simva20 mg

(n=476)

Mean %Change in LDL-C

FromUntreatedBaseline

rosuvastatin ezetimibe + simvastatin

Rosuva20 mg

(n=478)

Rosuva40 mg

(n=475)

Low Dose Medium Dose High Dose

Catapano AL, Curr Med Res Opin. 2006;22:2041-2053.

6

LongLong--Term Term EzetimibeEzetimibe + + FibrateFibrate

P<0.001

*P<0.001

P=0.02

P=0.002

TGLDL-C

HDL-C

TC

McKenney. J Am Coll Cardiol. 2006;47:1584-1587.

% pts

63%*

32%

Change in Lipids From Baseline to 48 Weeks Early Discontinuation

Clinical Uses and Safety of Clinical Uses and Safety of EzetimibeEzetimibe

1Physicians' Desk Reference, 58th ed. Montvale, NJ: Thomson PDR; 2004.2 Davidson M, Am J Cardiol. 2006;97:223-228.

Potential Clinical UsesMonotherapy– Patients with mild to moderate LDL-C elevation in whom

statin therapy fails or is contraindicatedCombination therapy– Patients who do not reach goal with starting statin dose– Patients who do not reach goal with maximal statin dose

SafetySlight increase in LFTs when coadministered with statins1

Postmarketing reports of hypersensitivity reactions, including angioedema, rash, and cholelithiasisNo increase in muscle side-effects when added to statin2

• Randomized double blind comparator trial of 720 patients with heterozygous familial hypercholesterolemia (rare condition affecting 0.2% of population)

• Baseline LDL of 320 mg/dL• 80% of patients previously treated with statins

• Surrogate endpoint • Primary endpoint – mean change in carotid intima

media thickness (IMT)• Study duration – 24 months

ENHANCE TRIAL: Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia

ENHANCE Trial

Kastelein J et al . New Engl J Med. 2008;358:1431-1443.

ENHANCE TrialEzetemibe/ Simvastatin Simvastatin p value

Mean IMT Δ 0.0111 0.0058 0. 29 (NS)

LDL Δ - 58% - 41% < 0.01

CV Death 2/357 1/363 NS

Non Fatal MI 3/357 2/363 NS

Non Fatal CVA 1/357 1/363 NS

ALT Δ 2.8% 2.2 % NS

Elevated CPK 1.1% 2.2% NS

Kastelein J et al. New Engl J Med 2008 358:1431-1443.

ConclusionsConclusionsATP III increased the population eligible for lifestyle and pharmacologic management of lipids

Expanded use of statins as first-line drug therapy for hypercholesterolemia

For those who do not tolerate statins, other agents alone or in combination with intestinally active agents offer novel therapeutic approaches

Expanded use of multiple drug therapy targeting the whole lipid profile when indicated

Choice of therapy depends on achievement of therapeutic goals, outcomes based data, and patient safety --especially in high-risk patients

CASE PRESENTATIONSCASE PRESENTATIONS

BARRY L HAINER, MDProfessor, Department of Family Medicine

Medical University of South CarolinaCharleston, South Carolina

7

Case 1Case 157-year-old overweight man with a sedentary lifestyle who has smoked one pack per day since his teens. He has medication-controlled hypertension. The patient and his father have type 2 diabetes. History of MI 4 years ago

Medication: Physical exam:

Losartan/HCTZ 100/25 mg/d Wt = 220 lb; Ht = 5’11” (BMI = 30)

Glipizide 10 mg OD Waist = 42”

Metformin 500 mg BID BP = 138/94 mm Hg

Aspirin, 81 mg/d No carotid bruits; good distal pulses

Case 1: 57M, HTN, Type 2 DiabetesCase 1: 57M, HTN, Type 2 DiabetesFasting lab results:

– FBS 108 mg/dL– TFTs – WNL – Blood chemistries – WNL – Urine with no evidence of proteinuria– TC 225 mg/dL– TG 195 mg/dL– LDL-C 152 mg/dL– HDL-C 34 mg/dL– HbA1C 6.2

1. <130 mg/dL

2. <100 mg/dL3. < 100 mg/dL with an option to go to <70 mg/dL4. <70 mg/dL

Case 1: 57M , HTN, Type 2 DiabetesAccording to the NCEP, what is the LDL-C goal?

TEST YOUR KNOWLEDGE ? The Continuum of CV Risk in Type 2 DiabetesThe Continuum of CV Risk in Type 2 Diabetes

Adapted from American Diabetes Association. Diabetes Care. 2003;26:3160-3167.Tsao PS et al. Arterioscler Thromb Vasc Biol. 1998;18:947-953.

Hsueth WA et al. Am J Med. 1998;105(1A);4S-14S.Adapted from American Diabetes Association. Diabetes Care. 1998;21:310-314.

Relationship Between Obesity and Relationship Between Obesity and Insulin Resistance and Insulin Resistance and DyslipidemiaDyslipidemia

HDLTG Small, Dense LDL

Central Obesity

FFA Insulin Resistance

Apolipoprotein BHepatic Lipase

Adapted from Brunzell JD et al. Diabetes Care. 1999;22(suppl 3):C10-C13.

HDLHDL--C and Coronary Artery Disease C and Coronary Artery Disease (CAD) Risk(CAD) Risk

Kwiterovich PO Jr. Am J Cardiol. 1998;82:13Q-21Q.

Data from Framingham Heart Study-Men

8

TEST YOUR KNOWLEDGE

1. Rosuvastatin 10 mg

2. Simvastatin 40 mg

3. Atorvastatin 10 mg

4. Simvastatin 40mg/ Ezetimibe 10 mg

5. Lovastatin 40 mg/ Niacin ER 1000 mg

6. Simvastatin 40 mg + Fenofibrate

?Case 1: 57M , HTN, Type 2 Diabetes In addition to TLC, what medication would you use to get this patient to his LDL-C Goal:

Current LDL-C: 152 mg/dL. Desired LDL-C: 70 mg/dL. = 54% reduction

Comparison of Statins for Surrogate Marker Reduction (Stellar Trial)

2431 Patients

LDL-C Triglycerides HDL-C non HDL-C

Rosuvastatin(10-40 mg)

-(46-55) -(20-26) +(7.7-9.6) -(40-52)

Atorvastatin(10-80 mg)

-(37-51) -(20-28) +(5.7-2.1) -(34-46)

Simvastatin(10-80 mg)

-(28-46) -(12-18) +(5.3-6.8) -(25-42)

Pravastatin(10-40 mg)

-(20-30) -(8-13) +(3.2-5.6) -(19-27)

Jones PH et al. Am J Cardiol 2003;92:152-60. McKenney JM et al. Curr Med Res Opin. 2003;19:689-698.

Follow Up Data at 6 Weeks on Rosuvastatin 10 mg

TC 155 mg/dL

HDL-C 37 mg/dL

TG 155 mg/dL

LDL-C 82 mg/dL

Non-HDL-C 118 mg/dL

FBS 108

NCEP Guidelines for Diabetics

• Get to LDL-C goal first

• When LDL-C goal is achieved, second target is non HDL-C (address low HDL-C and elevated triglycerides)

Grundy, S. Circulation 2004;110:227-239.

1. Add Niacin ER 500 mg

2. Add Ezetimibe 10 mg

3. Add Fenofibrate

4. Add Gemfibrozil

5. Increase Rosuvastatin to 20 mg

6. Do nothing as patient is at goal

6 week follow up, patient is on Rosuvastatin 10 mg: What change would you make to achieve the multiple lipid goals for this diabetic patient?

TEST YOUR KNOWLEDGE ? Case 1: TakeCase 1: Take--Home MessageHome Message

Recognize and aggressively treat all patients with CHD or CHD risk equivalents to LDL-C goal <100 mg/dL, with the option to go as low as <70 mg/dL

Focus on % reduction needed to get to goal

Consider combination lipid-lowering therapies that include a statin to achieve targets safely and efficiently

9

Case 2Case 2

– No known history of coronary heart disease– On cholesterol-lowering supplement, prefers

“natural” lipid lowering remedies– Sedentary lifestyle– Tobacco use 1 pack/day for 25 years– Medication: Valsartan/HCTZ 80/12.5

A 61-year-old female with hypertension and elevated cholesterol. Father died of a myocardial infarction at age 53.

Case 2: 61F, HTN, Elevated CholesterolClinical and Laboratory Data

BMI 30Waist circumference 38 inchesBP 143/89TC 257 mg/dLHDL-C 31 mg/dLTG 343 mg/dLLDL-C 187 mg/dLNon-HDL-C 226 mg/dLFBS 101

Case 2: 61F, HTN, Elevated Cholesterol Does this patient have the Metabolic Syndrome?

1. Yes2. No3. Need more data

TEST YOUR KNOWLEDGE ? ATP III: The Metabolic SyndromeATP III: The Metabolic SyndromeDiagnosis is established when Diagnosis is established when ≥≥3 of these risk factors are present3 of these risk factors are present

Risk factor Defining levelAbdominal obesity (Waist circumference*)

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

TG† ≥150 mg/dLHDL-C †

MenWomen

<40 mg/dL<50 mg/dL

BP † ≥130/≥85 mm HgFasting glucose >100 mg/dL‡

*†Some men develop metabolic risk factors when circumference is only marginally increased. Lower waist circumference cut point (eg, 90 cm [35 inches] in men and 80 cm [31 inches] in women) appears to be appropriate for Asian Americans.†Or drug treatment for BP, TGs or HDL-C.‡Revised American Diabetes Association Guidelines

Adult Treatment Panel III of the National Cholesterol Education Program. JAMA. 2001;285:2486-2497.Grundy SM et al. Circulation. 2004;109:551-556 ‡; Grundy SM et al. Circulation. 2005;112:2735-2752.

Metabolic Syndrome as a Predictor of Metabolic Syndrome as a Predictor of CHD and Diabetes in WOSCOPSCHD and Diabetes in WOSCOPS

Sattar N, et al. Circulation. 2003;108:414-419.

14

12

10

6

01

% with event

0 32 64Years

1 32 65

12

6

4

2

00

Years

4

2

5 4

% with event

CHD death/nonfatal MI Onset of new DM

8

10

RR RR

24.40

7.26

4.502.36

1.00

3.65

3.19

2.25

1.79

1.00

4/5 factors3 factors2 factors1 factor0 factors

4/5 factors3 factors2 factors1 factor0 factors

Count Traditional CHD Risk FactorsCount Traditional CHD Risk Factors

- No history of CHD or CHD equivalents + Age (> 45 in men, > 55 in women)+ Medication-treated hypertension+ Smoker

--------------------------------------------------------

Since ≥ 2 risk factors:– Calculate 10-y risk of CHD event to

determine LDL-C level at which to start meds

ATP III. Available at: www.nhlbi.nih.gov/guidelines/cholesterol . Accessed January 28, 2008.

10

Assessing CHD Risk in WomenAssessing CHD Risk in WomenATP III Framingham Risk Scoring

Step 1: AgeYears Points20-34 -735-39 -340-44 045-49 350-54 655-59 860-64 1065-69 1270-74 1475-79 16

Step 2: Total Cholesterol

TC (mg/dL) Points at Age 20-39

Points at Age 40-49

Points at Age 50-59

Points at Age 60-69

Points at Age 70-79

<160 0 0 0 0 0

160-199 4 3 2 1 1

200-239 8 5 4 2 1

240-279 11 8 5 3 2

≥280 13 10 7 4 2

Step 3: HDL-C-Cholesterol

HDL-C(mg/dL) Points

≥60 -150-59 040-49 1<40 2

Step 4: Systolic Blood PressureSystolic BP

(mm Hg)Points

(if untreated)Points

(if treated)<120 0 0

120-129 0 3130-139 2 4140-159 3 5≥160 4 6

Step 5: Smoking Status

TC (mg/dL) Points at Age 20-39

Points at Age 40-49

Points at Age 50-59

Points at Age 60-69

Points at Age 70-79

Nonsmoker 0 0 0 0 0Smoker 9 7 4 2 1


Step 6: Adding Up the PointsStep 6: Adding Up the Points(Sum from Steps 1(Sum from Steps 1––5)5)

Risk Factor Points

Age = 61 10

TC = 257 3

HDL-C = 31 2

SBP = 143 5

Smoker 2

TOTAL = 22

ATP III Framingham Risk Scoring


Step 7: CHD Risk for WomenStep 7: CHD Risk for Women

Note: Determine the 10-y absolute risk for hard CHD (MI and coronary death) from point total.

ATP III Framingham Risk Scoring

Point Total 10-Year Risk Point Total 10-Year Risk

9 <1% 18 6%

10 1% 19 8%

11 1% 20 11%

12 1% 21 14%

13 2% 22 17%

14 2% 23 22%

15 3% 24 27%

16 4% ≥25 30%

17 5%


Risk Category LDL-C Goal Initiate TLCConsider

Drug TherapyVery High risk:

ACS, CHD w/DM, mult CRF<70 mg/dL ≥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 Rx)

Moderately high risk:2+ risk factors (10-year risk 10% to 20%)

<100 mg/dL ≥130 mg/dL > 130 mg/dL (100-129 mg/dL:

consider Rx )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

ATP III Update 2004: PharmacologicTreatment

Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

Case 2: 61F, HTN, Elevated Cholesterol Initial Pharmacologic Management:What LDL goal would you choose?

1. <130 mg/dL (30% reduction needed)



TEST YOUR KNOWLEDGE ? Case 2: 61F, HTN, Elevated Cholesterol In addition to TLC, which medication would you choose?

1. Rosuvastatin 10 mg

2. Atorvastatin 20 mg

3. Simvastatin 40 mg

4. Simvastatin 20 mg/ Ezetimibe 10 mg

5. Lovastatin 40 mg/ Niacin ER 1000 mg

TEST YOUR KNOWLEDGE ?

11

1-STEP COADMINISTRATION

3-STEP TITRATION

Statin and Complementary GIStatin and Complementary GI--Acting Acting Drugs vs Statin TitrationDrugs vs Statin Titration

Statin at starting dose 1st1st 2nd2nd 3rd3rd

Statin at starting dose

18%

Doubling

+ GI+ GI--acting acting drugdrug

% Reduction in LDL-C

6% 6% 6%

Bays H, et al. Expert Opin Pharmacother. 2003;4:779-790.

Follow Up Visit After Six More WeeksPatient is on Simvastatin 20 mg and Ezetimibe 10 mg

LDL-C 94 mg/dL

HDL-C 34 mg/dL

TG 280 mg/dL

TC 164 mg/dL

Non-HDL-C 130 mg/dL

61F, HTN, Elevated Cholesterol At this point, which further therapeutic option would you select?

1. Add Niacin

2. Add Fenofibrate

3. Add fish oils

4. Increase Simvastatin/Ezetimibe to 40/10 mg

5. No further therapy

TEST YOUR KNOWLEDGE ? Omega-3 AEE Improve the Lipid Profile in Patients With High TG on Simvastatin

Simvastatin 10-40 mg/day (average 32 mg/day)

Durrington PN et al. Heart. 2001;85:544-548.

*after 48 weeks (NS after 24 weeks)AEE=Acid Ethyl Esthers

P <0.0005

P <0.005

P <0.025P <0.025*

NS

Case 2 TakeCase 2 Take--Home MessageHome MessageBecome familiar with calculating absolute risk (Framingham). This will allow for better risk stratification

Think about your NCEP targets in terms of % reduction needed to get your patient to goal; in general target at least 30% reduction*

Then choose agents based on evidence, efficacy, and patient safety

Don’t forget to counsel on lifestyle changes

*Grundy SM, et al. Circulation 2004;110:227-239.

The Moving LDL Target: The Moving LDL Target: Getting Your Patients Getting Your Patients

to Goalto Goal

EMMA A. MEAGHER, MDBARRY L HAINER, MD

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The Moving LDL Target: Getting Your Patients to Goal