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Transcript
Hyperlipidemia/Dyslipidemia
J.B. Handler, M.D.
Physician Assistant Program
University of New England
1
Abbreviations













LDL- low density lipoprotein
HDL- high density lipoprotein
IDL- intermediate density lipprotein
VLDL- very low density lipoprotein
Lp(a)- lipoprotein a
CAD- coronary artery disease
CHD=CAD= coronary heart disease
CVD- cerebrovascular disease
LFT- liver function test
GI- gastrointestinal
ETOH- alcohol
D.M.- diabetes mellitus
CK- creatine kinase












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NNT- number needed to treat
ARR- absolute risk reduction
IVUS- intravascular ultrasound
RRR- relative risk reduction
PAD- peripheral arterial disease
PVD- peripheral vascular disease
CVD- cerebrovascular disease
ACS- acute coronary syndrome
HTN- hypertension
TLC- therapeutic lifestyle changes
UAP- unstable angina pectoris
PE- physical exam
ACC- American College of
Cardiology
2
Lipids and Atherosclerosis


Thickened and hardened lesions of the medium and large
muscular and elastic arteries; lipid rich. Lesions occur in
the innermost layer of the artery (intima) and are largely
confined to this region of the vessel.
Deposition of lipid within the artery is dependent on 2
major factors:
– LDL: carries lipid to the arteries (LDL must be oxidized)
– HDL: removes lipid from the arteries

The role triglycerides play is not as well understood, but
considered a risk factor. See below.
3
Lipoproteins


Lipoproteins carry lipids - Cholesterol, Triglyceride,
Phospholipids.
Lipoproteins of importance: VLDL, (IDL), LDL,
chylomicrons.
– Apolipoproteins- Protein constituents of lipoproteins that add
structural stability; may help mediate catabolism.
Apolipoprotein B (LDL) increases coronary risk.

Lipid catabolism - 70% LDL removed in liver by LDL
receptors.
4
Cholesterol Biosynthesis




Liver and intestines - major sources of
endogenously derived cholesterol.
Diet - exogenously derived cholesterol.
In liver- rate limiting step is converting HMG
CoA to mevalonic acid by HMG CoA
Reductase (role of “STATINS”).
Increase intake in dietary cholesterol - down
regulation of LDL receptors  subsequent
elevation of serum LDL cholesterol.
5
Hypercholesterolemia
Diet and drug induced reductions of total and
LDL Cholesterol can significantly reduce
mortality and morbidity from Coronary Heart
Disease.
 Cholesterol reduction can slow progression of
atherosclerosis, and in some cases, halt or reverse
(isolated cases) its course.

6
Lipids and Atherogenesis
Vascular injury from any source (smoking,
HTN, DM) can lead to uptake of
lipoproteins.
 Elevation of LDL (oxidized) can lead to
vascular injury resulting in premature
atherosclerosis.

7
Lipids and Atherogenesis




LDL oxidation necessary for endothelial damage.
HDL- Inverse correlation between serum HDL
and atherosclerosis; reverse cholesterol transport
and prevents oxidation of LDL- cardioprotective.
A low HDL level (dyslipidemia) is a strong risk
factor for CHD even when LDL and total
cholesterol are normal.
Next major advance: safe drugs that substantially
increase HDL levels, while reducing cardiac
events (MI, Death).
8
Hyperlipidemia- Clinical Findings
Often asymptomatic.
 Atherosclerosis and disease- CHD, PVD, etc.
 Eruptive xanthomas- red papules on buttocks seen
with extremely high levels of chylomicrons or
VLDL (triglycerides).
 Tendinous xanthomas- Very high LDL- nodules
on tendons (achilles, back of hand, patella).
 Xanthelasma- yellow placques in skin around the
eyes.

9
Xanthelasma
Images.google.com
Dyslipidemias in Adults
Most cases are multifactorial
 Influenced by diet, lifestyle and genes
 Often detected in asymptomatic adults during
routine blood screening
 In patients with atherosclerosis involving the
coronary arteries, carotids, aorta or periperal
vessels, a high percentage will be found to have a
dyslipidemia.

11
Secondary Dyslipidemia
Diabetes Mellitus (discussed in Endocrine
section)
 Nephrotic Syndrome (Renal system)
 Chronic Renal Failure
 Hypothyroidism - high TG, low HDL

12
Familial Dyslipidemia




At least six documented disorders all with accelerated
atherosclerosis.
Example: Familial hypercholesterolemia
LDL receptor defect; heterozygous -total cholesterol at
birth> 350 mg/dl;
Homozygous - total cholesterol > 700mg/dl
PE: Tendon xanthomas, xanthelasma, cutaneous
xanthomas
Most patients with lipid disorders carry genes that can
predispose them to develop dyslipidemia when additional
factors (diet, obesity, etc.) are present. Likely multiple
13
genes involved.
Rationale for Treatment


Primary prevention- Lowering cholesterol/LDL
will prevent new onset CHD. Every 1% drop in
cholesterol produces a 2-3% decrease in CHD
risk.
Secondary prevention - Lowering cholesterol/LDL
will prevent recurrent coronary events and
decrease coronary and total mortality in the
presence of existing CHD or equivalent(s).
– Angiographic/IVUS trials retarded progression of of
coronary lesions; regression in some.
14
Primary Prevention


ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial)
10,305 patients with HTN but without heart disease
randomized to Placebo vs. Atorvastatin 10 mg/daily
– Baseline LDL-133 mg/dL, treated LDL- 103mg/dL

Primary endpoints: Nonfatal MI and fatal CHD
– Study ended prematurely at 3.3 years

Results: 36%  in primary endpoint (100 vs 154 events)
15
Secondary Prevention
High risk prevention
 Patients with known CHD have a 5-7x risk of
recurrent MI.
 Patients with known PAD, Carotid or Aortic
disease have a 4-6x incidence of developing CHD
and it’s consequences.
 Other high risk subsets: DM, others (see below)
 Goal: lower LDL to <100 mg/dl or less (below).

16
Heart Protection Study



Patients with documented CHD or equivalent (DM,
PAD).
>20,000 patients; placebo vs 40mg Simvastatin daily.
Baseline LDL 131-155 mg/dL. Rx with simvastatin
resulted in:
–
–
–
–
–
–
 all cause mortality by 13%
 coronary death by 18%
 non fatal MI + coronary death by 27%
 coronary revascularization procedures by 24%.
 stroke by 25% .
 major vascular events by 24%
17
Risk Stratification (NCEP)

Determine number of major risk factors besides elevated
lipids. Excludes patients with documented
CHD/PAD/CVD or diabetes (coronary risk equivalent).
– Age/gender: men>45, women >55
– FH of premature CHD MI or SD in 1st degree relative:
male<55, female < 65
– Hypertension whether treated or not
– Current cigarette smoker
– Low HDL: < 40 mg/dL

2 or more risk factors calculate statistical risk for
subsequent MI/death in next 10 years.
18
Risk Stratification (NCEP)
For patients with 2 or more risk factors and no
evidence yet of CHD: Determine 10 year CHD
risk (for “hard CHD outcomes”- MI or coronary
death) assessment using Framingham risk
assessment tool.
 Newest guidelines and options: NCEP ATP III,
7/04; amended in 2007.

19
Risk Assessment Tool




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
Estimates 10 yr risk (%) of developing “hard” CHD (MI
or coronary death) outcomes in patients without CHD.
Gender and age
Total or LDL cholesterol
HDL cholesterol
Smoker
Systolic blood pressure; on meds for HTN?
Tables based on Framingham Heart Study
20
High Risk





Presence of CHD, PAD, CVD or DM (coronary risk
equivalent even if no CHD yet documented).
Absence of clinical atherosclerosis with 2 or more risk
factors (such as smoking or HTN) that give a greater than
20% chance of having an MI or coronary death within 10
years (risk factor tool). Remember IS case: Lenny L.
Goal: LDL< 100 mg/dL; initiate meds if > 100mg/dL.
Initiate TLC simultaneously.
Some High Risk patients will fall into the “Very High
Risk subset (see below).
21
Very High Risk





Established CHD with: DM, multiple and poorly
controlled risk factors (such as smoking), metabolic
syndrome, or recent ACS (MI or UAP).
Goal: LDL < 70mg/dL is a “therapeutic option”- a
reasonable therapeutic strategy, on the basis of available
clinical trial evidence.
This will require drug therapy, possibly 2 drugs (see
below).
Initiate TLC if not already done.
Evidence: PROVE-IT trial (see below).
22
Metabolic Syndrome (3 of 5 Factors)




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
Central obesity: waist circumference>88cm in women,
>102 cm in men.
Hyperglycemia: FBS 110 mg/dL.
Hypertension: BP  135/85.
trig:  150 mg/dL.
HDL: 40 for men, 50 for women (any 3 of 5 meets
criterion).
3x risk of atherosclerosis.
Metabolic syndrome often associated with insulin
resistance- to be discussed in Endocrine system.
23
Is Greater Lowering Better?




PROVE IT-TIMI 22: Atorvastatin 80 mgs/d vs
Pravastatin 40 mgs/d in patients with ACS (AMI or
UAP). Prospective, randomized, double blind study of
4162 patients; 2 yr follow-up.
End-points: All cause mortality, MI, UAP, coronary
revascularization, stroke.
Pravastatin group: mean LDL- 95mg/dL, 26.3% had
primary end-point.
Atorvastatin group: mean LDL- 62mg/dL, 22.4% had
primary end point.
– ARR with Atorvastatin= 3.9%, NNT= 25
– RRR 16%
24
Moderately High Risk
Absence of clinical atherosclerosis
 2 or more risk factors for CHD and a 10-20% risk
of MI/Coronary Death within 10 years (risk factor
tool).
 Goal: LDL<130mg/dL

– Therapeutic option: LDL<100mg/dL
Initiate TLC if not already started.
 Initiate drug therapy for LDL>130 mg/dL.

25
Moderate Risk
Absence of clinical atherosclerosis
 2 or more risk factors for CHD and a < 10% risk
for MI/coronary death within 10 years (risk factor
tool).
 Goal: LDL<130mg/dL
 Initiate TLC
 Initiate drug therapy if LDL160 mg/dL

26
Lower Risk
0-1 risk factors
 Do not need to calculate risk score as will be
<10%.
 Goal: LDL< 160 mg/dL
 TLC
 Initiate drug therapy if: LDL190mg/dL
 Option: Initiate drug therapy if LDL
160mg/dL

27
Other Goals
Total Cholesterol < 200mg/dL
 HDL  40 (45) mg/dL in men;  50 (55) mg/dL in
pre-menopausal women.
 Bloodwork: Fasting Lipoprotein Analysis
Total chol, Triglycerides, HDL, LDL
LDL = TC - HDL - (Trig /5).
 Can now measure “direct LDL”- does not require
fasting; values usually lower (10%) than
calculated LDL levels.

28
Treatment Considerations
Age, weight and sex of patient
 Presence or absence of CAD risk factors
 Socioeconomic factors
 Patient compliance
 Availability of support personnel: dietary,
educational, administrative

29
Hypertryglyceridemia





Risk for developing CAD/CHD from elevated
triglycerides alone is controversial; likely
contributes when LDL-C is  or HDL-C is .
Pure hypertriglyceridemia associated with VLDL
elevations is often accompanied by mild
elevations of total and LDL-C (small dense LDL).
Inverse relationship between VLDL (triglycerides)
and HDL.
Tryglycerides (>500 mg/dL) s risk of
pancreatitis
Consensus: treat hypertriglyceridemia but
lowering LDL-C much more important.
30
Hypertriglyceridemia




Often associated with obesity, type 2 diabetes &
metabolic syndrome; mildly  with some drugs:
estrogen, corticosteroids, ß-Blockers (Nonselective) and thiazides. Increased by alcohol.
Very sensitive to diet, weight reduction and
exercise.
Triglycerides > 200mg/dL may warrant additional
Rx. Important to consider Rx if HDL is very low.
Rx with fibric acid agents or niacin.
31
HDL




Cardioprotective; facilitates removal of
cholesterol in tissues; also has direct protective
effects.
Reduced in presence of obesity, smoking,
inactivity.
Modest increase with weight reduction, regular
exercise, smoking cessation, estrogen therapy in
post menopausal women (avoid where
possiblerisks), alcohol in low quantities.
Increased with some meds: fibric acid
derivatives and niacin. Off label indication in
patients with CHD and very low HDL levels
32
Therapeutic Lifestyle Changes (TLC)
Smoking cessation
 Decrease intake of saturated fats (details below)
 Decrease total calories if overweight
 Increase physical activity
 Decrease sodium intake
 Treat other risk factors if applicable

33
Treatment of Dyslipidemia: Diet






The “typical” American diet is a major contributor
to lipoproten disorders.
Dietary Cholesterol - Raises LDL - Egg yolks,
animal fat, red meat, etc.
Dietary Fat- Saturated fat, saturated fatty acids and
animal fat.
Ideal Diet: < 30% fat, <7% saturated fat, <200
mgs/day cholesterol. Fat replaced with
carbohydrates.
Obesity - Minimum 10% weight reduction.
Result: 10% lowering of LDL, but varies.
34
Drug Therapy - Hyperlipidemia
HMG CoA reductase inhibitors (statins)
 Bile Acid sequestrants (resins)
 Nicotinic Acid (niacin)
 Fibric Acid derivatives (fibrates)
 Cholesterol absorption inhibitor- Ezetimibe

35
HMG CoA Reductase Inhibitors

Atorvastatin (Lipitor) 10-80 mg/D
Simvastatin (Zocor/generic) 10-80 mg/D
Rousuvastatin (Crestor) 5-40 mg/D
Lovastatin (Mevacor/generic) 10-80 mg/D
Pravastatin (Pravachol/generic) 10-80 mg/D

Fluvastatin (Lescol) 20-40 mg/D

Inhibit rate limiting step in cholesterol synthesis in
liver; up regulate synthesis of LDL receptors further reduction LDL cholesterol; LDL and TC
lowered by 30-55%.
Some statins triglycerides and HDL but mildly.




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36
Statins - Side Effects

Increase in serum transaminase levels- must be
monitored closely initial year.
GI disturbance infrequent

Myopathy – Dose related skeletal muscle complaints

are most commonly reported adverse effects.
– Myalgia is most common (1-5%) and benign.
– Myositis with rhabdomyolysis is rare but can be life
threatening; CK confirmation is essential to decision
making; >10 ULN with myositis or rhabdo
37
“Statin” Induced Myopathy


Mechanism unknown but dose related. Evaluate
patients with muscle Sx ASAP hold drug and
obtain CK. It may be as simple as lowering the dose.
Signs and symptoms: myalgia, muscle weakness, CK,
rarely progressing to rhabdomyolysis, myoglobinemia,
renal failure and death.
– Cerivistatin (Baycol) was taken off market because of 31
reported deaths from rhabdomyolysis.

Risk of myopathy increased with a variety of drugs
that inhibit statin metabolism: niacin, fibrates, bile acid
sequestrants, ketoconazole, erythromycin,
clarithromycin, cyclosporin and others.
38
Statins: Pleiotropic Effects

Statins have beneficial effects independent of
lipid lowering:
–
–
–
–
Placque stabilization
Anti-inflammatory effects
Reduce C-reactive protein levels
Protection of vessels subject to invasive coronary
interventions
39
Ezetimibe
Relatively new- released in 2003; inhibits
intestinal absorption of dietary and biliary
cholesterol
 As monotherapy (randomized double blind study
of 893 patients), 10 mg daily lowered LDL by up
to 17%, triglycerides by 6% and increased HDL
by 1.3 (minimal) %.
 Very well tolerated but avoid in patients with
hepatic insufficiency.

40
Ezetimibe
When added to a statin there was additional LDL
cholesterol lowering of up to 25% likely a
synergistic effect.
 Ezetimibe plus low/moderate dose statin is more
effective in lowering LDL cholesterol than
doubling the dose of the statin. But…see
controversies below.
 Ezetimibe very low incidence of myopathy

41
Ezetimibe- Recent Concerns




1/14/08- Enhance Trial (Merck/Schering Plough),
simvastatin vs simvastatin + ezetimibe.
Patients with familial hyperlipidemia: marked  in LDLC. Simvastatin  LDL-C by 41% (2 yrs), simvastatin +
ezetimibe  LDL-C by 58%. No difference in outcomes
(MI or stroke), but study not powered for outcomes.
But: Carotid intima media wall thickness (IMT*)
increased faster in group treated with combined therapy
compared with simvastatin alone. ?Significance.
More trials needed. Opinion (ACC): Continue to use if
LDL goal not reached with statin (hi dose) alone.
*IMT- surrogate end point for clinical coronary events
42
Bile Acid Sequestrants (Resins)




Bind bile in the intestine and stimulate conversion of
cholesterol to bile acids in the liver; up regulate LDL
receptors- result is decrease in LDL cholesterol.
Cholestyramine and Cholestipol- up to 12 scoops of
powder in water daily. Colesevelam (Welchol) tablet
form. Expensive.
Side effects - Constipation, GI Distress (flatulence,
constipation, dyspepsia); less common with colesevelam
These drugs can also cause myopathy.
43
Nicotinic Acid




Mechanism of action unclear (hepatic).
Lowers Triglycerides and to a lesser degree LDL
cholesterol.
Modest (20-30% increase) elevation HDL.
Side effects: GI distress; flushing/itching, small
elevations of LFT’s.
– Pre-treat with ASA for itching/flushing
– Caution: use in uncontrolled diabetes blood sugar.
– Start with very low doses and work upwards

Increases the likelihood of myopathy when added to
statins or bile acid sequestrants.
44
Fibric Acid Derivatives




Gemfibrozil 600 mgs. 2x/day
Primary effect - lower triglycerides
Fenofibrate: Once daily, may be more effective than
gemfibrozil in lowering LDL and triglycerides.
Rx of low HDL (off label indication). HDL by 15-20%
Consider fibrates in patients with CHD and very low
(<30 mg/dL) HDL levels. Variable reduction in LDL.
Side effects: GI, myopathy, gallstones.
45
Guidelines for Drug Therapy


Elevations of total and LDL cholesterol:
Statin (TC and LDL decreased up to 50%) Goal
based on degree of risk; statin dose increased to
maximum as necessary (see below).
If goal not achieved, the addition of other agents
(cholestyramine, niacin, ezetimibe, etc) will need
to be determined on a case by case basis as
supported by clinical trials, weighing the
pros/cons, cost, side-effects, compliance and
more.
– Most experts recommend adding additional drugs to
max dose statins to lower LDL to goals if necessary.
46
Guidelines for Drug Therapy



 Triglycerides + mild hypercholesterolemia:
Gemfribrozil, Fenofibrate or Niacin. Must control
Diabetes, reduce smoking, reduce ETOH and lose
weight if indicated. Add statin if LDL remains
above goal.
Combination drugs (Advicor- extended release
niacin plus lovastatin in fixed combination;
Vytorin- simvastatin + ezetimibe) may play a role
for some patients.
Very low HDL with CHD: consider fibric acid
agent or niacin.
47
References
Grundy, SM, et. Al., Implications of Recent Trials
for National Cholesterol Education Program
Adult Treatment Panel III Guidelines.
Circulation, 2004; 110: 227-239
 Canon, CP, et. al., PROVE IT TIMI trial; NEJM,
2004; 350:1495-1504

48