2. Covered Topics
Physiology of Lipid Metabolism
Role of lipoproteins in atherosclerosis
Hypolipidemic Agents ,indications, and side
effects
Screening and Risk Assessment
Treatment Paradigms
Treatment of Special Populations
Emerging issues in Dyslipidemia
6. 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
Hepatic Lipase-conversion of IDL to LDL
CETP-transfers cholesteryl esters from HDL to other lipoproteins in
exchange for TG
LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol
to cholesterol esters
Apolipoprotein A-major protein of HDL activating many reactions
Apo-B-major protein of VLDL, IDL, and LDL
Apo-CII and Apo E obtained from HDL by CMC and VLDL for
activation of LPL and receptor recognition respectively
8. Mechanism of Atherogenic
Dyslipidemia
Insulin resistance
increased NEFA and
glucose flux to liver
Insulin resistance
and decreased
apo-B
degradation
Insulin
resistance
and
decreased
LPL
IR impairs
LDLR
Increased
VLDL
FCHL
DM II
Metabolic
syndrome
9. Increased Atherogenicity of Small
Dense LDL
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
Indirect Association
– Inverse relationship with HDL
– Marker for atherogenic TG
remnant accumulation
– Insulin resistance
10. High Density Lipoprotein and
Atherosclerosis
Reverse cholesterol transport
Maintenance of endothelial function
Protection against thrombosis
– With Apo A-I inhibits generation of calcium-induced
procoagulant activity on erythrocytes by stabilizing
cell membrane
Low blood viscosity via permitting red cell deformability
Anti-oxidant properties-may be related to enzymes called
paraoxonase
11. Lipoprotein (a)
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
Indications for screening:
– 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
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
12. Primary Disorders of
LDL-Cholesterol Metabolism
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
Familial defective apolipoprotein B-100
– Mutation in apo-B 100 ligand and impaired binding to LDL receptor with decreased clearance
of LDL and 2-3 fold increase
– Similar clinical manifestation as FH and only distinguished by molecular biology techniques
Familial combined hyperlipidemia
– 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)
13. Statins
Competitive inhibitors of HMG CoA reductase, rate-limiting step in
cholesterol biosynthesis
Reduction in intrahepatic cholesterol leading to increased LDL
receptor turnover
Most powerful for lowering LDL cholesterol
Modest effect on raising HDL
Reduction in TG due to decreased VLDL synthesis and clearance of
VLDL remnants by apo B/E (LDL) receptors
Reduction in oxidized and small dense LDL subfractions and
reduce remnant lipoprotein cholesterol levels (reduction of CE
transfer from LDL to VLDL)
14. 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
15. 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
Atherosclerosis
Prevention Study
5614 Men; 991 women
45-73 y.o.
mean TC 221; LDL 150
(130-190)
Diet + placebo
Diet + lovastatin
37 % risk reduction in
coronary events
16. 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
17. Mechanism of Benefit of Statins in
Secondary Prevention
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
18. Adverse Effects of Statins
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 dose-
dependent
– 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
19. Fibric Acid Derivatives
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%
20. Bile Acid Sequestrants
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
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
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)
Contraindications: pts with elevated TG
21. Nicotinic Acid
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
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
– 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)
22. Ezetimibe
(Zettia)
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
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
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
23. Effect of Lifestyle Modification
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
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
24. Diet Supplements
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
25. 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
– Validity depends on TG <400 mg/dL
– Measured directly if patients have profound hypertrig
– Errors in TC, HDL, and TG can affect values
Non-HDL cholesterol= TC – HDL-C
– All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL, VLDL
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
26. Screening Recommendations
Adult Treatment Panel III (NCEP)
Fasting lipid profile at least once q 5 years for all
persons 20 y.o. or older
– If non-fasting obtained and TC >200 or HDL <40, f/u
panel recommended
– If no known CHD and serum LDL <160 (0-1 risk
factors) or LDL <130 (2 or more risk factors) then re-
screen in 5 years
– Borderline high cholesterol and <2 risk factors, re-
screen in 1-2 years
27. Risk Assessment
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)
28. 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
29. 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%
0-1 major risk
<130
<160
30. Basis of New Guidelines in July
2004
REVERSAL (secondary prevention)
– Moderate tx (40 qd pravastatin)
– Intensive tx (80 qd atorvastatin)
– Coronary intravascular US after 18 months
Mod tx (: increase in atheroma volume 2.7%, mean LDL 110 mg/dL
Intensive tx: decrease in atheroma volume 0.4%, mean LDL 79
No clinical outcomes
PROVE-IT: 4162 patients with ACS measuring clinical outcomes
– Moderate tx (40 qd pravastatin): median LDL-C 96
– Intensive tx (80 qd atorvastatin): median LDL 62 AND 16% reduction of CV events (all
cause death, MI, UA, revasc, stroke)
– Benefit of pushing LDL below 70
HPS: >20,000 patients with established CAD or CHD-equivalent
– Simvastatin 40 qd
– Placebo
– 27% reduction in nonfatal MI and coronary death in Tx group
– Patients w/o CHD but with CHD equivalents benefited from treatment
– Benefit was present regardless of pretreatment LDL <100
Application of New guidelines for LDL <70
– Very high risk (established CHD plus multiple major risk factors)
– CHD + smoking
– CHD +metabolic syndrome
– ACS
2004 ACC/AHA: for STEMI, LDL “substantially <100 mg/Dl”
31. Elevated LDL
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
30-35% decrease in LDL-C with equivalent doses
Titrate statin dose at 3-4 week intervals
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
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
32. Mixed (Combined Hyperlipidemia)
Elevated LDL and/ or triglycerides
Objective is to achieve LDL goals
With very high TG> 400, start with fibrate or niacin
Then treat LDL with statin
If LDL-C goal achieved, but TG>200, non-HDL-C should be
targeted
Non-HDL goal 30 above LDL goal
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
33. Hypertriglyceridemia
Normal <150 mg/dL; very high
>500 mg/dL
Evidence-Based Data
– Evidence-Based studies
include Helsinki Heart Study
and VA-HIT trial assessing
efficacy of gemfibrozil and CV
risk reduction from lowering
TG
– In many large studies,
elevated TG were determined
to be independent risk factor
for CHD
Identify those with
hyperchylomicronemia: TG >1000
mg/dL, eruptive xanthomas,
pancreatitis
Familial hypertrig (200-500) or
combined hyperlipidemia
Treatment Recommendations:
– After achievement of LDL goal
– (150-199): emphasize weight
reduction and physical
activity
– (200-499): non-HDL second
target and pharmacologic tx
for those with h/o MI or at
high risk
– >500: prevention of
pancreatitis with non-
pharmacologic and
pharmacologic therapy
– Isolated hypertrig tx
indications
Overt CHD
Strong FH of CHD
Multiple cardiac risk
factors
– Statins (atorvastatin or
rosuvastatin) if LDL elevated
– Fibrates or nicotinic acid
– Add fish oil for refractory
Rule out secondary causes and eliminate
Obesity
DM
Nephrotic syndrome
Hypothyroidism
Estrogen replacement
Beta blockers
Glucocorticoids, cyclosporin
34. Isolated Low HDL
Framingham Heart Study: MI risk
increases by 25% per 5 mg/Dl
decrease below mean HDL for men
and women
LIPID and CARE trials: 10 increase in
HDL, 29% decrease in event rate in
LDL <125 vs 10% decrease in
LDL>125
Familial h/o premature CHD
helpful in differentiating high from low
risk pts with low HDL
Causes:
– Familial forms
– Elevated CETP
– LPL deficiency
– Elevated hepatic TG lipase
– LCAT deficiency
– Insulin deficiency
– Drugs
Beta blockers
BDZ
Anabolic steroids
Evidence in Treatment
– VA-HIT trial: strong correlation
of reduction in MI and CHD death
with serum HDL achieved with
gemfibrozil
– Simvastatin plus Niacin:
higher reduction in events
achieved than statin-only trial
HPS: vascular event rate in baseline
HDL <35 was 29.9% vs 20.9% for
HDL >42
HDL < 40 mg/Dl; if metabolic
syndrome <40 men and <50 women
Treatment Indications of Isolated
low HDL
– 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)
35. 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 10-
20%
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
36. Elderly
Should be individualized based on chronologic and physiologic age
Secondary prevention studies support treatment
– 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
– Concern for safety (hapatic/renal impairment)
– Time course to benefit
37. Adults With DM
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)
38. Metabolic Syndrome
ATP III criteria: (3 or more)
– Abdominal obesity (waist circumference >40 inches in men or >35 in
women)
– Hypertriglyceridemia (TG>150 mg/dL)
– Low HDL <40 men; <50 women
– SBP >130 or DBP >85
– Fasting glucose >110 mg/dL
Increased risk of DM and cardiovascular disease although there has been
some controversy in the literature
– Kuopio Ischemic Heart Disease Risk Factor Study: 1209 Finnish men
(42-60 y.o.) without CVD, cancer or DM at baseline followed for 11.4
years. Results showed that CVD and all-cause mortality are increased
in men with MS even in absence of CVD or DM at baseline
Dyslipidemia is atherogenic with low HDL, elevated TG, and small dense
LDL
Treatment Recommendations:
– Weight reduction and exercise
– LDL goal is same as in patient w/o MS
– If LDL goal reached, then focus on TG if >200?
– Calculate non-HDL and goal is 30 above LDL goal
– Fibrates and nicotinic acid are good choices for elevated TG
39. 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
40. CRF and Dialysis
Hypertriglyceridemia
– Diminished clearance due to apo C-III and reduction in lipoprotein
lipase and hepatic triglyceride lipase
– Usually not enough elevation to increase coronary risk
– Diet modification preferable over drug therapy because of risk of
rhabdomyolysis
– Isolated marked hypertrig with cardiac risk factors may warrant drug
therapy
Modest decline in HDL raising LDL/HDL ratio
Elevated Lipoprotein a
Increase in oxidative modification of LDL
Statins should be used to lower LDL <100 or better yet <80 as CKD
considered CHD risk equivalent. Atorvastatin and fluvastatin better choices.
Hydrophilic statins safer and dose adjustment needed with CrCl <30
EPO appears to have modest hypolipidemia effect though unknown
mechanisms
41. Evolving Methods of Risk
Assessment
Total/HDL cholesterol ratio
– Ratio <4.0 advocated by the Canadian guidelines
– Aggressive lowering LDL vs raising HDL
– Better epidemiologic predictor of CV events than LDL (Lipid Research Clinics and Framingham
Heart Study) however no trials based on this ratio
Non-HDL cholesterol (Total-HDL)
– Includes all atherogenic cholesterol (LDL, lipoprotein a, IDL, VLDL)
– Lipid Research clinics program showed slightly stronger predictor of CVD than LDL
– Secondary target in pts with high triglycerides >200 mg/Dl (ATP III)
– Goal 30 above LDL goal
Apolipoprotein measurement
– Apo B/ Apo A-I found to be a better predictor of events than LDL and total/HDL in AMORIS
study; best predictor of events on statins in AFCAPS/TexCAPS study
– <0.7 considered target in Canadian guidelines
– Most useful in the hypertriglyceridemic patient (elevated apoB levels)
– Not universally available and much more expensive
– Needs more cost-benefit analysis before routine use
– May be useful for determining the efficacy of novel therapies
Hs-CRP
– Intensity of atherosclerotic process
– Recommendation of AHA, should be measured in the patient with intermediate Framingham
risk (10-20%) with LDL below the cutoff point for tx
– Would not add much to those already at high risk
43. Investigational Issues
To what extent should plasma levels of LDL-C be lowered by therapy to
afford optimal risk reduction?
Can risk assessment be improved by using novel risk measures (such as hs-
CRP) to indicate patients at higher risk who may benefit from more
aggressive intervention?
Should the metabolic syndrome be considered a high risk state warranting
aggressive intervention irrespective of risk categorization using current
scoring methods?
Awaiting prospective trials investigating the preventive benefits of lipid-
altering treatment in metabolic syndrome (COMETS trial)
44. References
Management of atherogenic dyslipidemia of the metabolic syndrome: evolving rationale for
combined drug therapy. Endocrinology and Metabolism Clinics of North America 33 (2004) 525-
544
Obesity and dyslipidemia. Endocrinology and Metabolism Clinics of North America 32 (2003) 855-
867
Management of Metabolic Sydrome: statins. Endocrinology and Metabolism Clinics of North
America 33 (2004) 509-523
Emerging therapeutic strategies for the management of dyslipidemia in patients with the
metabolic syndrome. The American Journal of Cardiology June 3, 2004
Past, Present and Future Standards for Management of Dyslipidemia. The American Journal of
Medicine March 22, 2004
Cardiovascular Endocrinology: Special Features. Medical Management of
Hyperlipidemia/Dyslipidemia. Journal of Clinical Endocrinology and Metabolism, June 2003
Effects of Lipid-Altering Treatment in DM and the Metabolic Syndrome. American Journal of
Cardiology June 3, 2004
Statins as the cornerstone of drug therapy for dyslipidemia: Monotherapy and combination
therapy options
Use of combination Therapy for Dyslipidemia: A Lipid Clinic Approach
Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density
lipoprotein heterogenity. The American Journal of Cardiology October 2002
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