Dyslipidemia(Hyper

lipidemia)
 Patient Case

• MI is a 55 year-old man with hypertension and type 2

diabetes. He has a strong family history of premature
coronary disease, and has a past medical history of
hypertension, diabetes mellitus, and peripheral arterial
disease. He smokes and is overweight (his BMI is 32). He
is on enalapril 10 mg daily and HCTZ 25 mg daily. Testing
today shows a total cholesterol = 250 mg/dL, HDL = 35
mg/dL, LDL = 160 mg/dL, and BP = 136/88 mm Hg.
 Introduction

• Atherosclerotic Vascular Disease( AVD): is a disease of the

large arteries characterized by the development of complex
lesions that result from the accumulation of cholesterol in
the vessel wall.
• Of the deaths resulting from cardiovascular disease,
approximately 75% can be attributed to atherosclerotic
vascular disease (AVD).
• Extensive data clearly demonstrate a relationship
between heart attack and the dysregulation of lipid
metabolism.
Association of AVD with Dyslipidemia
 Methods to Protect Heart Problems
• Blood Pressure Control
• Cholesterol Control
• Blood Glucose Control
• Life Style Modifications/Smoking Cessation
• Medications
 Hyperlipidemia
• Defined as elevated blood levels of lipoproteins
(cholesterol, triglycerides, phospholipids)
• Lipoprotein abnormalities: > 1 of the following
– elevated total cholesterol (TC)
– elevated low-density lipoprotein (LDL)
– elevated triglycerides (TG)
– reduced high-density lipoprotein (HDL)

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 Hyperlipidemia…
• Hypercholesterolemia is additive to nonlipid CHD risk
factors: cigarette smoking, HTN, DM, low HDL,
electrocardiographic abnormalities
• LDL level: significant predictor of morbidity/mortality
• ~50% of MIs and > 70% of CHD deaths occur in patients
with known CHD risk factors.
• Lipid lowering drug therapy reduces risk of
cardiovascular/cerebrovascular events, death
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 Background & Pathophysiology
• Cholesterol: essential for cell membrane formation &
hormone synthesis
• Lipids not present in free form in plasma; circulate as
lipoproteins
• 3 major plasma lipoproteins:
– VLDL carries ~10 to 15 % of total serum cholesterol; carried
in circulation as TG; VLDL = TG/5
– LDL carries 60 to 70% of total serum cholesterol; LDL
transports fat from liver to body
– HDL carries 20 to 30% of total serum cholesterol; reverse
transportation of cholesterol
 transports cholesterol from lipid-laden foam cells to the
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liver
 Background & Pathophysiology…

• Oxidized LDL in artery walls provokes inflammatory

response
• Monocytes recruited & transformed into
macrophages
– results in cholesterol laden foam cell accumulation

• Foam cells: beginning of arterial fatty streak

• If processes continue: angina, stroke, MI, peripheral

artery disease, arrhythmias, death 9
Pathophysiology
 Etiology

• Many genetic abnormalities & environmental

factors lead to lipoprotein abnormalities

• 2˚ hyperlipidemia should be initially managed by

correcting underlying abnormality when possible

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Lipoprotein Abnormalities: 2˚ Causes
• Hypercholesterolemia

– hypothyroidism
– obstructive liver disease (diminished hepatic
export of FFA- TGs accumulation )

– anorexia nervosa

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Lipoprotein Abnormalities: 2˚ Causes
Hypercholesterolemia from medications

– progestins
– thiazide diuretics
– glucocorticoids
– β-blockers
– Isotretinoin
– Protease inhibitors

13
Lipoprotein Abnormalities: 2˚ Causes
• Hypertriglyceridemia

– obesity
– DM
– glycogen storage
– sepsis
– Pregnancy

– lymphoma

– acute hepatitis 14
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Lipoprotein Abnormalities: 2˚ Causes
Hypertriglyceridemia from medications
– alcohol
– estrogens
– isotretinoin
– β-blockers
– glucocorticoids
– bile acid resins
– Thiazides
– azole antifungals
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Lipoprotein Abnormalities: 2˚ Causes
• Hypocholesterolemia
– malnutrition

– Malabsorption

– chronic infectious diseases

• acquired immune deficiency syndrome

• tuberculosis

– chronic liver disease 16

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 Lipoprotein Abnormalities: 2˚ Causes
Low HDL-C

• Low HDL: strong independent CHD risk predictor

• Low HDL-C < 40 mg/dL
• No specific goal for HDL-C raising
• Causes of low HDL
– insulin resistance
– physical inactivity
– type 2 diabetes mellitus
– cigarette smoking
– very high carbohydrate intake
– certain drugs
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Lipoprotein Abnormalities: 2˚ Causes
Low high-density lipoprotein……………
malnutrition
obesity
medications

– non-selective β-blockers • isotretinoin

– anabolic steroids • progestins

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 Clinical Presentation
• Most patients asymptomatic for years before
disease is clinically evident
• Metabolic syndrome: > 3 of the following
– abdominal obesity
– atherogenic dyslipidemia
– increased BP
– insulin resistance
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 Clinical Presentation
• Symptoms:
– none
– severe chest pain, palpitations
– sweating
– anxiety
– SOB
– loss of consciousness
– speech or movement difficulty
– abdominal pain
– sudden death

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 Clinical Presentation….
• Signs
– none
– severe abdominal pain
– pancreatitis
– peripheral neuropathy
– HTN
– BMI > 30 kg/m2
– waist size > 40 in (men), > 35 in
(women) 21
 Clinical Presentation…..
• Lab Tests:
–↑ TC
–↑ LDL
–↑ TG
–↓ HDL
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 Patient Evaluation
• Fasting lipid panel every 5 yrs adults > 20 years
– if patient not fasting only TC & HDL are reliable

– TC > 200 or HDL < 40: obtain follow-up fasting lipid

panel

• Once lipoprotein abnormality confirmed;

assess health & CV risk factors
• Initiate individualized LDL goals & treatment
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Total cholesterol
Classification
<200 mg/dL Desirable
200–239 mg/dL Borderline high
240 mg/dL High
LDL cholesterol
<100 mg/dL Optimal
100–129 mg/dL Near or above optimal
130–159 mg/dL Borderline high
160–189 mg/dL High
190 mg/dL Very high
HDL cholesterol
<40 mg/dL Low
60 mg/dL High
Triglycerides
<150 mg/dL Normal
150–199 mg/dL Borderline high
200–499 mg/dL High
500 mg/dL Very high

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 Risk Factors
Age
Men: 45 years
Women: 55 years or premature menopause without estrogen
replacement therapy
Family history of premature CHD (definite myocardial infarction
or sudden death before age 55 years in father or other male first-
degree relative, or before age 65 years in mother or other female
first-degree relative)
Cigarette smoking
Hypertension (140/90 mm Hg or taking antihypertensive
medication)
Low HDL cholesterol (<40 mg/dL)

Diabetes regarded as coronary heart disease (CHD) risk

equivalent. 25
Management of
Dyslipidemia

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 Lifestyle Modification
• Initial treatment for any lipoprotein disorder is TLC (Therapeutic
Lifestyle Changes)
– restricted total fats, saturated fats, cholesterol intake
– modest increase in polyunsaturated fat
– increased soluble fiber intake
– exercise: moderate intensity 30 min/day most days
• caution in high risk patients or those with CAD
– weight reduction (initial goal of 10%) if needed
– smoking cessation
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– treat HTN
 Non-Pharmacologic Therapy
• TLC
– Dietary Recommendations
• Decrease intake of total fat, saturated fat, and
cholesterol
• Increase fiber intake
 Treatment
• Most patients should receive 3 month TLC trial before
initiating pharmacologic therapy unless very high risk
• If patient unable to reach goals with TLC alone choose
lipid-lowering drugs based on lipoprotein disorder
• Combination therapy may be necessary
– monitor closely: increased risk of drug interactions,
adverse effects

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 HMG-CoA Reductase Inhibitors
• Lovastatin, pravastatin, simvastatin, fluvastatin,
atorvastatin, rosuvastatin

• Inhibit HMG-CoA conversion to mevalonate

– rate limiting step in cholesterol bio-synthesis

• Most potent TC/LDL lowering agents

• Dose dependent decrease in TC/LDL

– averages > 30% reduction of TC/LDL when used with

dietary therapy 30
 HMG-CoA Reductase Inhibitors
• Dosed once daily in evening
– hepatic cholesterol production peaks at night

– exceptions: atorvastatin, rosuvastatin

• Rosuvastatin requires dosage adjustment in severe renal

impairment & hepatic disease
• Good compliance rate, low incidence of adverse effects

• Adverse effects:
– elevated serum transaminases, myalgia, myopathy,
rhabdomyolysis, flu-like symptoms, mild GI disturbance 31
 Bile Acid Resins
• Colestipol, cholestyramine, colesevelam
– stimulate bile acid synthesis from cholesterol
– Bind intestinal bile acid
– increase fecal bile excretion
– upregulate LDL receptors
– ↓ LDL by 15-30%, ↑ HDL by 3-5%, no therapeutic effect
in TG
• Normally 2nd-line agents when statins not sufficient or not
tolerated
• May aggravate hypertriglyceridemia
– caution if TG > 200 mg/dL
– contraindicated if TG > 400 mg/dL 32
 Bile Acid Resins…
• Adverse effects:
– GI distress, constipation
• titrate slowly, increase fluid intake, increase dietary bulk,
add stool softeners
– hypernatremia, hyperchloremia
– impair fat soluble vitamin absorption
• A, D, E, K
– reduce bioavailability of other medications
• warfarin, levothyroxine, digoxin
• dose 6 hrs from other medications to avoid interactions
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 Fibric Acids
• Gemfibrozil, fenofibrate, clofibrate

• First line for severe TG (↓ 20-50%)

• TC remains fairly unchanged

• May increase HDL > 10 to 15%

• Efficacy depends on lipoprotein type, baseline

TG
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 Fibric Acids…

• Gemfibrozil dosed BID 30 min before meals

• Fenofibrate can be taken without regards to

food
• CI in renal failure

• Combination therapy with niacin or statins

increases risk of muscle toxicity

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 Fibric Acids…
• Adverse effects:
– GI complaints, rash, myalgia, headache, fatigue
– transient increase in transaminase & alkaline
phosphatase
– gallstones (clofibrate)
– enhanced hypoglycemic effects in patients on
sulfonylureas
– may potentiate effects of oral anticoagulants
• monitor PT/INR closely in patients on anticoagulants 36
 Nicotinic Acid/Niacin
• Inhibits the syntheisis of very low density lipoprotein
Decreases LDL & TG
• Add on to statin therapy
• Best agent for raising HDL
• May exacerbate gout & DM
– monitor closely
– slow dose titration
• Contraindications: active liver disease, severe gout
• Combination with statin or gemfibrozil therapy
increases myopathy risk 37
 Nicotinic Acid/Niacin

• Adverse effects:
– cutaneous flushing, itching
• ASA 325mg 30 min prior
• titrate dose slowly, avoid spicy foods/hot beverages

– GI intolerance
– acanthosis nigricans (marker for insulin resistance)
– elevated LFTs, hyperuricemia, hyperglycemia
– niacin associated hepatitis
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• more common with SR
Drug Mechanism of Effects on Lipids Effects on Comment
Action Lipoproteins

Cholestyramine, ↑ LDL catabolism ↓Cholesterol ↓ LDL Problem with compliance; binds many
colestipol, ↓ Cholesterol ↓ VLDL coadministered acidic drugs
colesevelam absorption

Niacin ↓ LDL and VLDL ↓ Triglyceride ↓ VLDL Problems with patient acceptance; good in
synthesis ↓Cholesterol ↓ LDL combination with bile acid resins; ER niacin
↑ HDL causes less flushing and is less hepatotoxic
than SR form

Gemfibrozil, ↑ VLDL clearance ↓ Triglyceride ↓ VLDL Clofibrate causes cholesterol gallstones;

fenofibrate, ↓ VLDL synthesis ↓Cholesterol ↓ LDL modest LDL lowering; raises HDL;
clofibrate ↑ HDL gemfibrozil inhibits glucuronidation of
simvastatin, lovastatin, atorvastatin
Lovastatin, ↑ LDL catabolism; ↓Cholesterol ↓ LDL Highly effective in heterozygous familial
pravastatin, inhibit LDL hypercholesterolemia and in combination
simvastatin, synthesis with other agents
fluvastatin,
atorvastatin,
rosuvastatin
Ezetimibe Blocks cholesterol ↓Cholesterol ↓ LDL Few adverse effects; effects additive to
absorption across other drugs; ENHANCE trial – no change in
the intestinal carotid intima media thickness (CIMT)
border compared to simvastatin monotherapy in
patients with familial hypercholesterolemia

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 Omega 3 Fatty Acids
• Diets rich in omega 3 fatty acids from oily fish decrease
TC, TG, LDL, increase HDL & decrease CV events
• Rx fish oil: Lovaza®
– lowers TG 14 to 30%
– raises HDL ~10%
• FDA approved as dietary adjunct for very high TG levels
(> 500 mg/dL)
• Thrombocytopenia, bleeding disorders: potential
complication of high doses
• < 3 g/day generally recognized as safe
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 Diabetic Dyslipidemia
• Characterized by hypertriglyceridemia, low HDL, &
minimally elevated LDL
• CHD risk equivalent

• 1˚target: LDL

• Goal of treatment: LDL-C < 100 mg/dL

• LDL > 130 mg/dL: TLC + drug therapy often required

• Statins often considered initial drugs of choice

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 Elderly Patients
• More susceptible to adverse effects of lipid-
lowering drug therapy
• Start with lower doses, titrate slowly to
minimize adverse effects
• Risks or benefits from cholesterol reduction not
well defined
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 Hyperlipidemia in Pregnancy
• TC & TG levels increase throughout pregnancy
– average cholesterol increase: 30 to 40 mg/dL around
weeks 36 to 39
– TGs may increase as much as 150 mg/dL
• Drug therapy typically not initiated/continued
during pregnancy
• TLC is the mainstay but BARs & absorption
inhibitors may be considered in high risk patients
– ezetimibe: category C
• Statins: category X 43
 Children

• Drug therapy not recommended age < 8 yrs

• Bile acid sequestrants 1st-line in the past

– GI adverse effects limit use

• New evidence shows statins are safe & effective

in children
– greater lipid lowering than BAR

– severe forms may require more aggressive treatment

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 Concurrent Disease States

o Nephrotic syndrome, end-stage renal disease, HTN

– compound dyslipidemia risks

– may be difficult-to-treat

• Nephrotic syndrome lipoprotein metabolism

abnormalities
– elevated TC, LDL-C, VLDL, TGs

• Statins reduce TC & LDL-C in nephrotic syndrome

– levels do not usually return to normal

– may slow declining renal function 45

 Concurrent Disease States…

• Renal insufficiency without proteinuria:

hypertriglyceridemia, slightly elevated TC &
LDL-, low HDL
• Polyunsaturated fatty acids may slow
pregression of renal disease & CV complications
• Bile acid sequestrants do not correct lipid
abnormalities seen in renal insufficiency
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 Concurrent Disease States…
• Lovastatin or its active metabolite may
accumulate in renal insufficiency, use lower
doses to avoid adverse effects
• Treat CKD patients to LDL goal < 100 mg/dL
– lowering LDL to < 70 in high risk patients not
supported by clinical trials

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 Concurrent Disease States…
• Combination of statins & fibric acid
derivatives increases risk of severe
myopathy
– monitor for myositis

• Niacin may be useful in nondiabetic

patients with renal insufficiency
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 Concurrent Disease States…
• Hypertensive patients: greater-than-expected
prevalence of hypercholesterolemia
• Patients with hypercholesterolemia have a higher
than expected prevalence of HTN
– caused by metabolic syndrome
• HTN management
– avoid drugs that elevate cholesterol
• diuretics
• α-blockers
– niacin may magnify vasodilator hypotensive effects 49
Thank YOU!

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