Transcript The management of hyperlipidemia

Duke Internal Medicine Residency Curriculum
The Management of Hyperlipidemia
Author: Laura Leigh Fitzpatrick MD, MPH
Editor: Amy Shaheen, MD, Assistant Professor
of Clinical Medicine
Duke University Medical Center
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The NCEP/ ATP III guidelines
• Assigns levels of risk based on the Framingham score.
• Sets goals for LDL-c lowering based on level of risk.
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Classification of hyperlipidemia
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Identify the patient’s risk
• Identify history of CHD, or “CHD equivalent”
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Diabetes mellitus
Peripheral arterial disease
Abdominal aortic aneurysm
Symptomatic carotid artery disease
Multiple RF’s conferring > 20% Framingham risk over 10 years.
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Identify other risk factors than CHD
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Cigarette smoking
FH premature CAD
Age >45 in men, >55 in women
Hypertension
Low HDL (<40)
HDL > 60 counts as a “negative” RF
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Determine LDL-c goal and therapy
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More simply…
• If CHD or equivalent, LDL-c goal <=100, lifestyle changes
for 100-130, drugs for >130.
• If 2 or more RF’s, LDL-c goal is 130, lifestyle changes for
130-160, unless 10-yr. risk is >10%, then start drugs.
• If 0-1 RF’s, LDL-c goal is 160, lifestyle changes 160-190,
drugs for >190.
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Other measures of cholesterol
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One study compared 4 different measures and their correlation with risk
of coronary disease and coronary death:
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Total cholesterol
LDL
Total/ HDL ratio
LDL/HDL ratio
– The study found that total/ HDL ratio identified larger at-risk groups than did
LDL alone.
– Although the total/ HDL ratio may be better at predicting coronary risk, no
lipid-lowering studies are based upon that ratio. Therefore, we target LDL.
(Ann Intern Med 1994 Nov 1;121(9):641-7 )
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Drug therapy for hyperlipidemia: statins
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Drug therapy for hyperlipidemia
• Statins – (HMG CoA reductase inhibitors)
– These reduce intracellular cholesterol; and cause
upregulation of the LDL-receptor, increasing LDL-c removal
from blood.
– Potency with respect to LDL lowering:
• Pravastatin (pravachol), fluvastatin (lescol) – least potent
• Simvastatin (zocor), lovastatin (mevacor) – intermediate
• Rosuvastatin (crestor), atorvastatin (lipitor) – most potent
– On average, statins lower TG’s by 20% and raise HDL by
5%. They lower LDL by 30-60%.
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Primary prevention
• WOSCOPS (1995) – among middle-aged men with LDL-c >155,
pravastatin reduced coronary events and coronary mortality.
• AFCAPS/TexCAPS (1998) – among low-risk men and women
with average cholesterol, lovastatin reduced USA, fatal/ nonfatal
MI and sudden cardiac death.
• ASCOT (2003) – men and women with normal cholesterol, but
with HTN and >=3 RF’s, atorvastatin 10 mg reduced MI, CV
events/ procedures and CVA.
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Secondary prevention
• 4S trial (1994) – pts with elevated total cholesterol given simvastatin
for 5 yrs, had significant reductions in mortality, major coronary events,
cerebrovascular events, CHD deaths, coronary procedures.
(Lancet 1994 Nov 19;344(8934):1383-9)
• CARE (1996) – pts with average cholesterol treated with pravastatin,
at 5 yrs, had reduced coronary death, nonfatal MI, frequency CVA/
TIA’s, and decrease in CABG/PTCA.
(Sacks et al. N Engl J Med 1996 Oct 3;335(14):1001-9)
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Secondary prevention
• Heart Protection Study (2002)
– 20,000 pts with coronary disease, occlusive arterial disease
or diabetes randomized to simvastatin 40 mg vs placebo.
– Followed for 5 years
– Outcomes:
• reduced all-cause mortality (p=.0003)
• reduced MI, CVA, revascularization by about 25%
(Lancet 2002 Jul 6;360(9326):7-22)
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Heart Protection Study
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Heart Protection Study
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CARE
Sacks et al. N Engl J Med 1996;335:1001-9
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Secondary prevention
• PROVE IT trial (2004)
– Randomized 4000 pts with ACS in the prior 10 days to
pravastatin 40mg or atorvastatin 80mg.
– LDL: 95- (pravastatin);
62- (atorvastatin)
– Primary endpoints of death, MI, revascularization, USA were
significantly reduced with atorvastatin at 2 years.
(Cannon et al. N Engl J Med 2004 Apr 8;350(15):1495-504)
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PROVE IT (2004)
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Secondary Prevention
• REVERSAL trial (2004)
– RCT of 654 patients with coronary disease randomized to
atorvastatin 80 mg vs. pravastatin 40 mg.
– Mean LDL -150, was reduced to 110 in pravastatin group, 79
in atorvastatin group.
– Progression of atherosclerosis by IVUS far less in the
atorvastatin group. (p=.02)
(JAMA 2004 Mar 3;291(9):1071-80)
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Benefits of Statins
• Lipid lowering
– Decreased plaque cholesterol content  increased plaque
stability decreased CV events
• Anti-inflammatory effects
• Anti-thrombotic effects
• Endothelial effects
• ? Can they lower risk of diabetes and lower BP ?
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Anti-inflammatory effects
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Anti-thrombotic effects
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Endothelial effects
• After plaque rupture, loss of endothelial cell monolayer
predisposes to constriction.
• Coronary reendothelialization important for myocardial
perfusion and endothelial fxn.
• Statins observed to accelerate this process in rats,
following balloon-mediated vascular injury.
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Adverse effects of statins
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Muscle – uncommon with statin therapy alone: 2-11%
myalgias, 0.5% myositis, <0.1% rhabdomyolysis.
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? Less risk with pravastatin, fluvastatin
Hepatic – statins are associated with a 0.5-3% incidence in
transaminase elevations.
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Occur early, usually in the 1st 3 months
Dose-dependent
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Adverse effects of statins
• High potential for drug interactions, particularly with
other drugs metabolized via the CYP3A4 system.
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Antifungals (azoles)
HIV protease inhibitors
SSRI’s/ benzos
CV meds: CCB’s, amiodarone, dig
• Can avoid this with pravastatin, rosuvastatin, fluvastatin
as they are not metabolized by CYP3A4.
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Other therapies:
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Ezetimibe
Fibrates
Bile acid sequestrants
Niacin
Fish oil
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Comparison of lipid lowering effects
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Lipid-lowering therapies
• Ezetimibe (Zetia®)
– cholesterol absorption inhibitor
– works at the brush border of the small intestine
– no clinical outcomes data
– provides a small amount of LDL lowering alone, but best
used in conjunction with a statin. Avoids high doses of
statins.
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Fibrates
• gemfibrozil, fenofibrate
• lower triglycerides (- 35 to 50%)
• raise HDL (+15 to 25%)
• ? Decreased cardiac risk
• Side effects:
– Muscle toxicity (particularly w/ statin)
– Interferes with warfarin ( ↑ levels )
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Bile acid sequestrants
• Cholestyramine, cholestipol, colesevelem
• Bind bile acids in the intestine
• Side effects: GI effects, nausea, flatulence, elevation in
TG
• No clinical outcomes data
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Nicotinic acid
• Raises HDL, lowers LDL and TG
• Inhibits hepatic production of VLDL
• Adverse effects: flushing, nausea, pruritis, liver toxicity,
insulin resistance, hyperuricemia, hypotension.
• No good outcomes
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Fish oil
• Reduce triglycerides
• Need high doses, many tabs/ day
• The GISSI prevention study looked at fish oil vs. vitamin
E, or both in patients just having an MI.
– Found reduced incidence of sudden death, cardiac and
coronary deaths.
(Lancet 1999 Aug 7;354(9177):447-55)
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Hypertriglyceridemia
• Less data to support treatment
• ATP III recommends:
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Treat LDL first
For TG 150-199: weight loss and exercise
For 200-499: can consider fibrate or niacin
For >500: start TG-lowering meds to prevent pancreatitis.
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Case 1
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A 54 y.o. WM with PMH of CAD s/p MI 3 years ago presents to
your office to establish a new PCP. His bp is 156/92, fasting
lipid panel: LDL- 167, HDL- 34, TG- 245.
(1) What is his goal LDL-c, given the above data?
(2) What are his other CV risk factors?
(3) What is your first step in management of his
hyperlipidemia?
(4) Would you treat his triglycerides?
(5) By how much would you expect his lipids to change, if you
decide to start a statin?
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Answers
(1)
(2)
(3)
(4)
(5)
What is his goal LDL-c, given the above data? Goal LDL-c is 100,
given his past history of CAD.
What are his other CV risk factors? age>45, hypertension, low
HDL (<40).
What is your first step in management of his hyperlipidemia?
Start a statin.
Would you treat his triglycerides? Treat his LDL first, recommend
diet and exercise changes. This alone may correct his high TG;s.
If they remain high, could consider niacin or a fibrate.
By how much would you expect his lipids to change, if you decide
to start a statin? On average, statins lower TG’s by 20% and
raise HDL by 5%. They lower LDL by 30-60%
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Cases
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A 62 y.o. AAF presents with hyperlipidemia but no other past medical
history. She has never smoked, reports no FH of premature CAD, BP=
124/78. Her fasting lipid panel: LDL-c: 178, HDL: 55, TG- 180.
(1) What is her goal LDL-c?
(2) What is the first step in managing her lipids?
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Answers
(1)
(2)
What is her goal LDL-c? She has 1 known additional risk factor,
her age. Her goal is therefore 160.
What is the first step in managing her lipids? You can suggest
lifestyle modifications, but if these fail, starting a statin is
appropriate.
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Cases
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You have a 52 y.o. WM with type 2 DM, previous MI, HTN and a
fasting lipid panel: LDL-c: 99, HDL: 39, TG- 280. He is a smoker. He
asks you if his cholesterol is “good”. What do you tell him?
(1) “Your cholesterol is fine.”
(2) “Your cholesterol is almost at goal, you need to try diet and
exercise.”
(3) “Let’s talk about starting a new medication.”
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Answers
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The patient’s official LDL-c goal is <100, given his history of CAD or even given his
diabetes alone. However, this patient is at extremely high risk for another CV
event. The Heart Protection Study and PROVE IT suggested benefit to lowering
LDL-c to levels even when already around or less than 100. Other studies are
underway to determine if lowering LDL to very low levels has additional benefit.
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In this particular patient, starting a statin is reasonable. Some recent publications
are suggesting an LDL goal of <70 in such high-risk patients. (Grundy et al.
Circulation. 2004; 110: 227-239)
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