The Moving LDL Target: Getting Your Patients to Goal
Transcript of 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
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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.
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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
ATP III. Available at: www.nhlbi.nih.gov/guidelines/cholesterol . Accessed January 28, 2008.
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
ATP III. Available at: www.nhlbi.nih.gov/guidelines/cholesterol . Accessed January 28, 2008.
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%
ATP III. Available at: www.nhlbi.nih.gov/guidelines/cholesterol . Accessed January 28, 2008.
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)
2. <100 mg/dL (47% reduction needed)
3. <70 mg/dL (64% 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 ?
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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