Transcript LDL

Approach to
Dyslipidemia
Dr Zuhair M Shawagfeh
FRCPI
Covered Topics
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Physiology of Lipid Metabolism
Role of lipoproteins in atherosclerosis
Hypolipidemic Agents ,indications, and side
effects
Screening and Risk Assessment
Treatment Paradigms
Treatment of Special Population
Exogenous Pathway of Lipid
Metabolism
Cholest
AA
FA
P,
glycerol
Vessel wall
Endogenous Pathway of Lipid
Metabolism
Key Enzymes and Cofactors in Lipid
Metabolism
HMG-CoA reductase-reduces HMG-CoA to
mevalonic acid in the rate-limiting step of
cholesterol biosynthesis (mainly liver and
intestine)
 Lipoprotein Lipase- digests TG core of
CMC and VLDL
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LDL Oxidation and Atherosclerosis
Increased Atherogenicity of Small
Dense LDL
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Direct Association
– Longer residence time in
plasma than normal sized LDL
due to decreased recognition
by receptors in liver
– Enhanced interaction with
scavenger receptor promoting
foam cell formation
– More susceptible to oxidation
due to decreased antioxidants
in the core
– Enter and attach more easily
to arterial wall
– Endothelial cell dysfunction
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Indirect Association
– Inverse relationship with HDL
– Marker for atherogenic TG
remnant accumulation
– Insulin resistance
High Density Lipoprotein and
Atherosclerosis
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Reverse cholesterol transport
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Maintenance of endothelial function
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Protection against thrombosis
– With Apo A-I inhibits generation of calcium-induced
procoagulant activity on erythrocytes by stabilizing
cell membrane
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Low blood viscosity via permitting red cell deformability
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Anti-oxidant properties-may be related to enzymes called
paraoxonase
Lipoprotein (a)
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Specialized form of LDL
(apolipoprotein (a) covalently bound to
apo B by disulfide bridge)
Structural similarity to plasminogen,
thus interfering with fibrinolysis
Macrophage binding and cholesterol
deposition
Measured by ELISA
Cross-sectional and retrospective
epidemiologic studies have shown
association between excess Lp (a) and
CHD while prospective results are
conflicting
Associated with unstable angina and
presence of complex coronary lesions
Commonly detected in premature CHD
Possible role in target organ damage
in presence of HTN
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Indications for screening:
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CHD and no other identifiable
dyslipidemia
– Strong CHD family history and no
other dyslipidemia
– HTN and early premature target
organ damage
– Hypercholesterolemia refractory to
statins and bile acid sequestrants
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Treatment guidelines
– Primary goal is to lower LDL to
target and lowering to <80 may
reduce risk
– If LDL cannot become optimized,
then Lpa loweing with nicotinic
acid (38%) shoud be tried
– Goal <20 in whites
Primary Disorders of
LDL-Cholesterol Metabolism
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Familial hypercholesterolemia- defect in gene coding for apo B/E LDL receptor thus reduced
clearance of LDL from circulation
– Homozygotes with higher LDL-C levels
– Excess LDL deposited in arteries as atheroma and in tendons and skin as xanthomata and
xanthelasma
– Hypercholesterolemia, normal TG, genetic or cellular confirmation of LDL receptor defect
– Usually serum cholesterol levels AND premature CHD in first-degree or 2 second-degree
relatives
– Usually requires multiple drugs for treatment
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Familial combined hyperlipidemia
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Usually associated with metabolic syndrome
1-2% general population
1/3-1/2 familial causes of CHD and 10% of premature cases
Overproduction of hepatically derived apo-B 100 associated with VLDL +/- decreased LDL
receptor activity
LDL phenotype B, increased TG, decreased HDL (atherogenic dyslipidemia)
Phenotypic heterogeneity depends on problems with VLDL or LDL metabolism
 Elevated TG and cholesterol
 Elevated LDL
 Isolated hypertriglyderidemia (rise in VLDL)
Statins
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Competitive inhibitors of HMG CoA reductase, rate-limiting step in
cholesterol biosynthesis
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Reduction in intrahepatic cholesterol leading to increased LDL
receptor turnover
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Most powerful for lowering LDL cholesterol
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Modest effect on raising HDL
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Reduction in TG due to decreased VLDL synthesis and clearance of
VLDL remnants by apo B/E (LDL) receptors
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Reduction in oxidized and small dense LDL subfractions and
reduce remnant lipoprotein cholesterol levels (reduction of CE
transfer from LDL to VLDL)
Comparable Efficacy of
Statins
Special considerations:
No renal dosing: Atorvastatin and Fluvastatin
Use in chronic liver disease: pravastatin or rosuvastatin
Less drug interactions: pravastatin, fluvastatin,
rosuvastatin (not metabolized via CYP3A4)
Less muscle toxicity: Pravastatin and Fluvastatin
Cost-effectiveness: Rosuvastatin, atorvastatin, fluvastatin
Evidence in Primary Prevention
Name of Study
Design
Outcome
West of Scotland
Coronary Prevention
Study (WOSCOPS)
6595 men
Mean TC 272; LDL>155
diet + placebo
Diet + pravastatin
31 % risk reduction in
coronary deaths and
nonfatal MI
Benefit >treating mild
HTN but 3 x less than
that in 4S study
Air Force/Texas Coronary 5614 Men; 991 women
Atherosclerosis
45-73 y.o.
Prevention Study
mean TC 221; LDL 150
(130-190)
Diet + placebo
Diet + lovastatin
37 % risk reduction in
coronary events
Evidence in Secondary Prevention
Name of Study
Design
Outcome
Scandinavian Simvastatin
Survival Study (4S)
4444 patients (angina or h/o
MI)
TC 212-309; 5 year f/u
Placebo v. simvastatin 20-40 qd
Goal TC <200
Total mortality (8 v.12%)
Major events (19 v. 28%)
CHD deaths 42% lower
Revascularization 37%
CVA (2.7 vs 4.3)
1% LDL decrease=1.7% RR
CARE
4159 h/o MI 2 yrs prior
Borderline Average TC 209;
LDL 139; HDL 39
Pravastatin 40 qhs x 5 yrs
Coronary death/MI 10.2 v. 13.2
Revascularization 14.1 v. 18.8
Stroke frequency 2.6 v. 3.8
% LDL reduction unrelated
to events
LIPID
9014 men and women with
recent MI or unstable angina
TC 155-270
Pravastatin or placebo
CHD deaths 6.4 v. 8.3
Total mortality 11 v. 14
Stroke 20% decrease
Bypass 8.9 v. 11.3
Heart Protection Study
20,536; simvastatin 40 qd; 33%
LDL<116;25% 116-135; 42%
LDL>135 h/o CVD, DM, or
treated HTN; 5.5 yrs
All cause mortality RRR 13%
CHD death RRR 17%
Major events RRR 24%
Similar in 3 tertiles of LDL
and in those with LDL<100
Mechanism of Benefit of Statins in
Secondary Prevention
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Regression of atherosclerosis
Plaque stabilization
Reduced inflammation
Decreased thrombogenicity
Reversal of endothelial dysfunction
Others
– Reduced monocyte adhesion to endothelium
– Reduced oxidative modification of LDL
– Increased mobilization and differentiation of
endothelial progenitor cells leading to new vessel
formation
Adverse Effects of Statins
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In general, less than with other agents. Fairly tolerable and safe
Myopathy
– Ranges from myalgias (2-11%), myositis(0.5%) to rhabdomyolysis (<0.1%)
(possibly ARF)
– Few weeks-4 months onset
– Symptoms and CK should normalize over days to one month after d/c
– Pravastatin and Fluvastatin less risk
– Increased risk in
 ARF/CRF
 Obstructive liver disease
 Hypothyroidism
 Concomittant use of drugs interfering with CYP3A4??
 Gemfibrozil combined therapy
Hepatic
– 0.5 to 3% persistent elevations in amino-transferases in first 3 months and dosedependent
– Several randomized trials have found no difference compared with placebo
– FDA recommends LFTs before and 12 weeks after starting and with any dose
elevation and periodically
CNS
– Case reports of memory loss associated with statins (mainly lipophilic)
– If memory loss and recent initiation of statin, then d/c and use a hydrophilic
statin such as pravastatin or rosuvastatin
– No significant difference with placebo in trials
Fibric Acid Derivatives
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Decrease Triglycerides (35-50%)
– Reduced hepatic secretion of VLDL through activation of PPAR-alpha receptors in liver
– Stimulate lipoprotein lipase and thus clearance of TG-rich lipoproteins
Raise HDL (15-25%)
– Direct stimulation of HDL apolipoprotein synthesis A-I,II
– Increased transfer of apo A-I with diminished cholesterol transfer from HDL to VLDL
Increases LDL buoyancy
May also improve endothelial function and favorable effect on macrophage responses (possible
reduction in CHD risk independent of effect on lipoproteins)
Agents
– Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little effect in
combined hyperlipidemia. Can increase LDL in pure hypertriglyderidemia
– Fenofibrate 200 mg capsules or iii caps 67 mg qd (renal dosing and can decrease
Cyclosporin levels). Better for LDL lowering
Side effects
– Gallstone formation
– Dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and myalgias
Adverse drug interaction
– Gemfibrozil- inhibits glucuronidation of lipophilic statins and increases levels thus increasde
risk of myopathy. Also decreases warfarin by 30%
Bile Acid Sequestrants
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Lower LDL (10-15%)
 BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE IN HEPATIC CHOLESTEROL
POOL; THUS SYNTHESIS OF apo B/E (LDL) RECEPTORS
 Max doses cause 30% reduction
– Raise HDL
 Intestinal formation of nascent HDL
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Available agents
– Cholestyramine 8 grams/day. 24-30 grams/day can lower LDL up to 24%
– Colestipol 10 grams/day
– Colesevelam 1.5-4.5 grams/d
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Adverse effects
– Usually limit use
– Mainly GI (nausea, bloating, cramping)- least problematic with colesevelam
– Increased liver enzymes
– Also drug interactions (impair absorption)
 Digoxin, warfarin, and fat soluble vitamins (give one hour before or 4 hours after bile
acid sequestrant)
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Contraindications: pts with elevated TG
Nicotinic Acid
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Mechanism of Action
– Inhibits hepatic VLDL production and its metabolite LDL
– Raises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL
clearance
– Increase in LDL size
– Reduction in plasma fibrinogen levels
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Formulations and dosing
– Immediate release (crystalline): 100 TID and titrated to tolerance
– Sustained release
 Niacor
 Niaspan: 500 mg qhs x one month and then titrated to 1000 mg usually given daily
after evenng meal
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1-1.5 grams/day for HDL raising
3 grams/day for VLDL and LDL lowering and possibly lowering lipoprotein a levels
OTC IR preps are cheaper and effective
OTC preps labeles “NO FLUSH” usually not efficacious
Side effects
– Flushing (less common with controlled release) minimized with ASA 30 minutes before and
limited in 7-10 days
– Nausea, paresthesias, pruritis (20% each)
– Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant
hepatitis (generally less common with Niaspan and crystalline niacin)
– Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan)
– Hyperuricemia (AVOID IF H/O GOUT)
– Hypotension in combination with other vasodialtors (can increase unstable angina)
Ezetimibe
(Zettia)
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Mechanism:
– impairs dietary and biliary cholesterol absorption at the brush border of the
intestines without affecting TG or fat-soluble vitamins
– possible Niemann-Pick C1 like protein involved in cholesterol transport
– LDL decrease 15-20%
– Trivial effects on HDL and TG
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Also adjunctive therapy to statins but same effect with higher dose of statin as in one
study 10 zettia and 10 atorvastatin same effect as 80 atorvastatin
Indications
– Avoiding high doses of statins
– Very high LDL (FCH) not sufficiently controlled on statins
Adverse effects
– Only 20% absorption so lower side-effect profile
– Higher incidence of myopathy and elevated transaminases when coadministered
with a statin
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Should not be used as the first-line agent in lowering LDL
Check LFTs prior to starting in combo with statins
No definite clinical outcome studies available
Effect of Lifestyle Modification
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Diet
– Decreased saturated fat (decrease LDL)
– Replacing saturated and trans unsaturated fats with unhydrogenated
monounsaturated or polyunsaturated fats
– Recommended diet
 Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7%
 CHO (whole grains, fruits,veggies) 50-60% total calories
 Dietary fiber 20-30 g/d
 Protein 10-25 g/day
 Plant stanols/sterols 2 grams/day
– Effect of LDL lowering should be evident in 6-12 months
– Elevated BMI associated with decreased dietary response
– Referral to dietitian helpful
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Exercise
– In a prospective study of 111 sedentary men and women with dyslipidemia
randomized to different levels of exercise, decrease in VLDL TG and increase in
LDL size observed. Increase in HDL and size and largest effect on LDL seen with
high amount high intensity exercise
– Mechanisms of benefit: reduction in CETP, elevation in LCAT, reduced hepatic
lipase and elevated LPL activity
– Possible effect on LDL particle size
– Moderate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the week
Diet Supplements
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Fish Oil (source of omega-3 polyunsaturated fatty acids)
– Salmon, flaxseed, canola oil, soybean oil and nuts
– At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and
apolipoprotein B
– Possibly decreases small LDL (by inhibiting CETP)
– Several studies have shown lower risk of coronary events
– 2 servings of fish/week recommended??
– Pharmacologic use restricted to refractory hypertriglyceridemia
– Number of undesirable side effects (mainly GI)
Soy
– Source of phytoestrogens inhibiting LDL oxidation
– 25-50 grams/day reduce LDL by 4-8%
– Effectiveness in postmenopausal women is questionable
Garlic
– Mixed results of clinical trials
– In combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observed
Cholesterol-lowering Margarines
– Benecol and Take Control containing plant sterols and stanols
– Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis
– 10-20% reduction in LDL and TC however no outcome studies
– AHA recommends use only in hypercholesterolemia pts or those with a cardiac event
requiring LDL treatment
Other agents include soluble fiber, nuts (esp. walnuts), green tea
Overall a combination diet with multiple cholesterol-lowering agents causes much more significant
LDL reductions
Measurement of Lipoproteins
Lipoprotein analysis 12-14 hours fasting
 TC and HDL-C can be measured fasting or non-fasting
 LDL-Cholesterol = Total cholesterol –VLDL (1/5 TG)-HDL
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– Validity depends on TG <400 mg/dL
– Measured directly if patients have profound hypertrig
– Errors in TC, HDL, and TG can affect values
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Non-HDL cholesterol= TC – HDL-C
– All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL, VLDL
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Acute phase response (i.e. MI, surgical trauma or infection)
– Can reduce levels of TC, HDL, LDL, apo A+B through impairment of hepatic
lipoprotein production and metabolism
– Raise Lpa and TG
– Lipoprotein analysis should be done as outpatient one month after event
Risk Assessment
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CHD equivalents:
– Symptomatic carotid artery disease
– Peripheral arterial disease
– AAA
– DM
– Multiple risk factors that confer a 10-year risk of CHD > 20%
Identify major risk factors other than LDL:
– Smoking
– HTN BP >140/90 or on anti-hypertensive medication
– Low HDL <40 mg/dL
– Family history premature CHD (CHD in men 1st degree relative <55;
women <65 y.o.)
– Age (men > or =45; women >or =55)
Other potential risk factors
– Chronic renal insufficiency (Cr > 1.5 mg/dL OR GFR <60 cc/min) per
Up-To-Date
– Obesity, physical inactivity, impaired fasting glucose, markers for
inflammation
HDL > 60 mg/dL is a negative risk factor
If patient without CHD or equivalent has 2 or more major risk factors, then
calculate the Framingham risk (age,TC,HDL,smoking,SBP)
Validation study
found Framingham
CHD predictor
worked well in
white and black
population but
overestimated risk
in Japanese
American,
Hispanic men and
native American
women and other
studies have
shown possible
overestimation in
European and
Asian populations
New Guidelines for LDL Goal
Risk category
Goal LDL (mg/Dl)
CHD (CHD risk equivalent)
<100
<70 optional
2 or more major risk factors + 10
yr >20%
<100
<70 optional
2 or more major risk factors +10
yr 10-20%
<130
<100 optional
2 or more major risk factors +10
yr risk <10%
<130
0-1 major risk
<160
Elevated LDL
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Statins are first choice and selection is based on extent of LDL
reduction, cost and reduction in clinical CHD events as well as
presence of renal impairment
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30-35% decrease in LDL-C with equivalent doses
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Titrate statin dose at 3-4 week intervals
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Doubling statin dose reduced LDL an additional 6%
Consider adding second agent instead of dose increase
Variable drug response depending on endogenous v. exogenous
hypercholesterolemia
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Second agents may include bile acid resins (15%), ezetimibe
(20%), or plant stenol/sterol margarine (10%)
Niacin may be added as a third agent if needed
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Mixed (Combined Hyperlipidemia)
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Elevated LDL and/ or triglycerides
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Objective is to achieve LDL goals
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With very high TG> 400, start with fibrate or niacin
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Then treat LDL with statin
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If LDL-C goal achieved, but TG>200, non-HDL-C should be
targeted
Non-HDL goal 30 above LDL goal
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Statin titration dose OR Statin-fibrate OR Statin-Niacin
combinations more effective in this type of dyslipidemia but
adverse reactions more common with combined treatment
so benefit/risk ratio considered
– Titration for mild TG elevations
– Combination TX for moderate to severe TG elevations
Isolated Low HDL
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Treatment Indications of Isolated
low HDL
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CHD OR CHD equivalent
– if first-degree relative early onset
CHD and similar lipid profile
Weight management, exercise, and
smoking cessation
Niacin +/- gemfibrozil
CETP inhibitors (NEW and
investigational)
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Treatment Guidelines
Always Consider secondary causes of dyslipidemia (DM, hypothyroidism,
obstructive liver disease, CRF or nephrotic syndrome or drugs)
All patients with LDL above goal start with adequate trial of lifestyle
modification only but concomitant drug therapy may be appropriate if:
– LDL >220 or > 190 if >= 2 risk factors
– Pre-existing CHD or CHD equivalent
If CHD or risk equivalent and? significantly above goal, then start
pharmacotherapy (preferably statin) immediately
If CHD or equivalent and LDL goal <100 not achieved on maximal statin
(atorvastatin 80 or rosuvastatin 40), then additional agent should be
added based on abnormalities in other lipoproteins
In no CHD or CHD equivalent, consider drug therapy with statin if after
adequate lifestyle trial:
– LDL >190 if 0 or 1 risk factor
– LDL >160 if 2 or more risk factors if 10 yr risk <10%; 130 if risk 1020%
If persistent elevation in LDL purely, then add bile acid sequestrant or
zettia
In patients with ACS, atorvastatin 80 mg/day should be started soon after
hospitalization
– PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial
When LDL goal reached but TG >200, then consider non-HDL cholesterol
and treat to goal 30 above LDL
In patients with ACS, atorvastatin 80 mg/day should be started soon after
hospitalization (event reduction and LDL lowering effect)
– PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial
Elderly
Should be individualized based on chronologic and physiologic age
 Secondary prevention studies support treatment
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– CARE :50% patients >60 derived similar benefits as in younger patients
– HPS :% reduction in events similar in < or > 65 y.o.
Cardiovascular Health Study showed benefit in primary prevention in >65
y.o.
 All major statin trials and VA-HIT trial have shown reduction of
atherothrombotic stroke with lipid-lowering
 ATP III recommends diet as first line of primary intervention but drugs can
be considered if multiple risk factors possibly with LDL >160
 Underutilization of lipid-lowering drugs in elderly due to
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– Concern for safety (hapatic/renal impairment)
– Time course to benefit
Adults With DM
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Both primary and secondary intervention trials have shown benefit and
reduction of CVD in diabetic subgroups treated with lipid-lowering agents
(HPS and CARE trial showed significant outcome improvement with statins
even at LDL <116)
Despite their often elevated TG and low HDL due to insulin resistance, etc.
LDL should be primary goal
Niacin-Statin combination can be particularly effective
LDL goal <100 and threshold for drug tx is 130 and optional 100-129 if diet
effective
ADA 2004 guidelines: adults >40 y.o. and TC >135, statin to lower LDL by
30%
Based on HPS, drug therapy should not be postponed if LDL goal unlikely
achieved by nonpharmacologic means
TZDs are insulin sensitizers and affect adipose tissue distribution by
decrease in intraabdominal fat; shown to increase HDL and peak LDL
buoyancy; rosiglitazone/atorvastatin led to reduction in TG/LDL and
elevation in HDL (Promising but more studies required)
Hyperlipidemia in Nephrotic
Syndrome
Marked hypercholesterolemia
– Increased apo B lipoprotein synthesis by liver due to decreased oncotic
pressure
– Decreased catabolism
 Hypertriglyceridemia
– Slow conversion of VLDL to IDL then LDL
– Decreased LDL-receptor clearance of LDL and IDL
 Associated Risks
– Small study showed RR 5.5 for MI and 2.8 for coronary death
– Possible progression of glomerular disease
 Treatment rationale
– Tx of underlying disease (i.e. steroids in minimal change disease)
– Little benefit in diet therapy (vegetable soy diet rich in MUFA/PUFA) and
low protein with 20-30 % reduction in lipids
– Best drug tx is statins
– ACE-Inhibitor or ARB by decreasing protein excretion cause 10-20%
reduction in TC and LDL
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Thank you