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1. HYPERLIPIDEMIA
Gobezie T.
1

2. Introduction
 Hyperlipidemia refers to elevated blood levels of
lipoproteins (cholesterol, triglycerides, phospholipids)
 Dyslipidemia refers to any abnormality in circulating
lipid levels.
 Lipoprotein abnormalities: > 1 of the following
 elevated total cholesterol (TC)
 elevated low-density lipoprotein (LDL)
 elevated triglycerides (TG)
 reduced high-density lipoprotein (HDL)
2

3. Introduction… Dyslipidemia vs CHD
risk
 CHD risk directly correlates with TC & LDL levels in
graded, continuous fashion
 More than half of individuals at borderline high risk
remain unaware that they have hypercholesterolemia
and
 fewer than half of highest-risk persons (those with
symptomatic CHD) are receiving lipid-lowering
treatment.
 Lipid lowering drug therapy reduces risk of
cardiovascular/cerebrovascular events, death
3

4. Introduction… Dyslipidemia vs CHD
risk…
 Hypercholesterolemia is additive to the other nonlipid
risk factors for CHD, including
 cigarette smoking, HTN, DM, low HDL levels, and
electrocardiographic abnormalities.
 Presence of CHD, prior MI ↑s MI risk 5 to 7 times
 LDL level: significant predictor of morbidity/mortality
4

5. Pathophysiology
 Malfunctions in lipoprotein generation & transport
system.
 Lipid transport is divided into exogenous and
endogenous pathways, which are regulated by
 specific apolipoproteins, lipoprotein receptors,
lipolytic enzymes, and transfer proteins.
• Each of these components plays a vital role in
maintaining the balance of cholesterol and TGs in
tissues and plasma.
5

6. Pathophysiology…defected
clearance/metabolism
 Plasma LDL taken up by receptors on liver, adrenal, &
peripheral cells and then degraded.
 Ingestion of cholesterol and saturated fatty acids is
associated with reduction in LDL-R activity, ↑ed LDL
production rate, and elevation in LDL plasma
concentration.
 Increased intracellular cholesterol levels inhibits HMG-CoA
reductase & decreases LDL receptor synthesis
 LDL cholesterol may also be excreted into bile and
become part of the enterohepatic pool or may be lost
in the stool.
6

7. Pathophysiology…
 Oxidized LDL in artery walls provokes inflammatory
response
 Monocytes recruited & transformed into macrophages
 results in cholesterol laden foam cell
accumulation… atherosclerosis
 Foam cells: beginning of arterial fatty streak
 If processes continue: angina, stroke, MI, peripheral
artery disease, arrhythmias, death
7

8. Secondary Causes of Lipoprotein
Abnormalities
8

9. Clinical Presentation
 Most patients asymptomatic for years before
disease is clinically evident
 Metabolic syndrome: > 3 of the following
 large waistline: apple shape
 High blood pressure
 High blood sugar levels
 High blood triglycerides
 Low HDL cholesterol
9

10. Clinical Presentation
Symptoms:
 none
 severe chest pain,
palpitations
 sweating
 anxiety
 SOB
 loss of consciousness
 speech or movement
difficulty
 abdominal pain
 sudden death
10
 Signs
 none
 severe abdominal pain
 pancreatitis
 eruptive xanthomas
 peripheral
polyneuropathy
 HTN
 BMI > 30 kg/m2
 waist size > 40 in (men),
> 35 in (women)

11.  Lab Tests:
 ↑ TC
 ↑ LDL
 ↑ TG
 ↑ apolipoprotein B
 ↑ C-reactive protein
 ↓ HDL
11
Clinical Presentation

12. DIAGNOSIS
 A fasting lipoprotein profile including total
cholesterol(TC), LDL-C, HDL-C, and triglycerides
should be measured in all adults 20 years and older at
least once Q 5 years
 If the profile is obtained in the nonfasted state, only
TC & HDL-C will be usable because LDL-C usually is
a calculated value. If total cholesterol is 200 mg/dL or
HDL-C is <40 mg/dL, a follow up fasting lipoprotein
profile should be obtained.
 VLDL= triglycerides ÷ 5;
 LDL=total cholesterol–(VLDL+HDL) 12

13. Classification of Total, LDL, and HDL
Cholesterol, and Triglycerides
Total cholesterol
<200 ………………………… Desirable
200–239 …………………….. Borderline high
≥240 ………………………High
LDL cholesterol
<100………………………………Optimal
100–129…………………………..Near or above optimal
130–159 ………………………….Borderline high
160–189 ………………………….High
≥190 ………………………………Very high
HDL cholesterol
<40 ………………………………….Low
≥60 mg/dL …………………………..High
Triglycerides
<150 ………………………………..Normal
150–199 ……………………………Borderline high
200–499……………………………. High
≥500 ………………………………...Very high
13

14. Treatment Goals
 Lower total & LDL-C to reduce the risk of first or
recurrent events such as MI, angina, HF, ischemic
stroke, or peripheral arterial disease.
 LDL: predicts morbidity, mortality
 1˚ treatment target
 More CHD risk factors: more stringent LDL goal
14

15. Risk Factors (Exclusive of LDL
Cholesterol) That Modify LDL Goals
 Age
Men: 45 years
Women: >55 years or premature menopause without estrogen
replacement therapy
 Family history of premature CHD (definite MI 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
 HTN (130/80 mm Hg or taking antihypertensive medication)
 Low HDL cholesterol (<40 mg/dL)b
15
HDL cholesterol (=60 mg/dL [=1.55 mmol/L]) counts as a “negative” risk factor;
its presence removes one risk factor from the total count.

16. Goals & cutpoints
Risk Category LDL Goal
(mg/dL)
LDL Level at
Which to
Initiate TLC
(mg/dL)
LDL Level at Which
to Consider Drug
Therapy (mg/dL)
High risk:
CHD or CHD risk
equivalents (10-year
risk >20%)
<100
(optional goal:
<70)
100 100
(<100 mg/dL;
consider drug
options)a
Moderately high risk:
2+ risk factors (10-year
risk >10%–20%)
<130 130 130
(100–129: consider
drug options)
Moderate risk:
2+ risk factors (10-year
risk <10%)
<130 130 160
Lower risk:
0–1 risk factorb
<160 160 190
(160–189: LDL-
lowering drug
optional)
16

17. Non pharmacologic therapy
 Lifestyle Modification: Initial treatment for any lipoprotein
disorder is TLC (Therapeutic Lifestyle Changes) Including:
 Dietary therapy
 restricted total fats, saturated fats, cholesterol intake
 modest ↑ in polyunsaturated fat, ↑ed soluble fiber
intake
 exercise:
 moderate intensity 30 min/day for most days of the
week
• caution in high risk patients or those with CAD
 weight reduction: 17

18. 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
 For every 1% reduction in LDL, there is a 1% reduction in
CHD event rates
 Elevations of HDL of 1% result in approximately a 2%
reduction in CHD events
 Combination therapy may be necessary
 monitor closely: ↑ed risk of drug interactions, adverse
effects
18

19. Treatment…
 Although many efficacious lipid-lowering drugs exist,
none is effective in all lipoprotein disorders
 Lipid-lowering drugs can be broadly divided into:
1-agents that ↓ synthesis of VLDL (Fibrates, niacin) & LDL
(statins),
2-agents that enhance VLDL clearance (Fibrates),
3-agents that enhance LDL catabolism (statins, BARs),
4-agents that ↓ cholesterol absorption (Ezetimibe, BARs),
5-agents that elevate HDL (niacin), or
6- some combination of these characteristics
19

20. Pharmacotherapy for Hyperlipidemia
A.HMG CoA reductase inhibitors (statins):
E.g.: Atorvastatin, Fluvastatin, Lovastatin, Pravastatin,
Rosuvastatin, Simvastatin.
B. Bile acid binding sequestrants (resins):
E.g.: Colesevelam, Colestipol, Cholestyramine
C. Niacin, nicotinic acids
D. Fibric acid derivatives (Fibrates):
E.g.: Fenofibrate, Gemfibrozil, Clofibrate
E. Intestinal cholesterol absorption inhibitors (ICAIs)
E.g.: Ezetimibe.
F. Omega-3-acid ethyl esters 20

21. Drug Mechanism of
Action
Effects on
Lipids
Effects on
Lipoproteins
Comment
Cholestyramine,
colestipol,
colesevelam
↑ LDL catabolism
↓ Cholesterol
absorption
↓Cholesterol ↓ LDL
↓ VLDL
Problem with compliance; binds many
coadministered acidic drugs
Niacin ↓ LDL and VLDL
synthesis
↓ Triglyceride
↓Cholesterol
↓ VLDL
↓ LDL
↑ HDL
Problems with patient acceptance; good in
combination with bile acid resins; ER
niacin causes less flushing and is less
hepatotoxic than SR form
Gemfibrozil,
fenofibrate,
clofibrate
↑ VLDL clearance
↓ VLDL synthesis
↓ Triglyceride
↓Cholesterol
↓ VLDL
↓ LDL
↑ HDL
Clofibrate causes cholesterol gallstones;
modest LDL lowering; raises HDL;
gemfibrozil inhibits glucuronidation of
simvastatin, lovastatin, atorvastatin
Lovastatin,
pravastatin,
simvastatin,
fluvastatin,
atorvastatin,
rosuvastatin
↑ LDL catabolism;
inhibit LDL
synthesis
↓Cholesterol ↓ LDL Highly effective in heterozygous familial
hypercholesterolemia and in combination
with other agents
Ezetimibe Blocks cholesterol
absorption across
the intestinal
border
↓Cholesterol ↓ LDL Few adverse effects; effects additive to
other drugs; ENHANCE trial – no change
in carotid intima media thickness (CIMT)
compared to simvastatin monotherapy in
patients with familial
hypercholesterolemia
21
Effects of Drug Therapy on Lipids and Lipoproteins

22. HMG –COA reductase inhibitors (statins)
 Inhibit the first enzymatic step in cholesterol
synthesis. i.e Inhibit HMG-CoA conversion to
mevalonate which is the rate limiting step in
cholesterol synthesis
 Production of this enzyme and of LDL receptors is
transcriptionally regulated by the content of
cholesterol in the cell.
 Simvastatin, lovastatin (prodrugs), Atorvastatin &
Rosuvastatin are the most potent
22

23. Statins …
• Most potent TC/LDL lowering agents
 Dose dependent decrease in TC/LDL
 averages > 30%↓ when used with dietary therapy
 Short t½ except atorvastatin, rosuvastatin
 may account for higher atorvastatin & rosuvastatin
potency
 Statins are best combined with BARs or
ezetimibe
23

24. Statins …
 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:
 Liver: elevated serum transaminases,
 Muscle: myalgia, myopathy, rhabdomyolysis (rare),
 flu-like symptoms,
24

25. Bile Acid Resins
 BARs (cholestyramine, colestipol, colesevelam)
 The primary action of BAR is binding bile acids in the
intestinal lumen, with concurrent interruption of
enterohepatic circulation of bile acids and markedly
↑ed excretion of acidic steroids in the feces
 Decrease T-C & LDL-C concentrations by interfering
with hepatic microsomal cholesterol content; however,
this effect is not as great as with statins
 The ↑ in hepatic cholesterol biosynthesis may be
paralleled by ↑ hepatic VLDL production;
consequently, BARs may aggravate
hypertriglyceridemia in patients with combined
25

26. BARs Adverse effects
 GI complaints: of constipation, bloating, epigastric
fullness, nausea, and flatulence are common
 At least 40% of patients discontinue therapy within 1 year
 Adherence rates can be improved with pharmacist
interventions
 Manage by ↑ing fluid intake, ↑bulk in diet, & use stool
softeners
 Other major limiting complaint is their gritty texture &
bulk-
 minimized by mixing the powder with orange drink or juice.
 Tablet forms of BARs should help to improve compliance
with this form of therapy
26

27. BARs Adverse effects….
 Other potential adverse effects include
 impaired absorption of fat-soluble vitamins A, D, E,
& K;
 hypernatremia and hyperchloremia;
 gastrointestinal obstruction; and
 reduced bioavailability of acidic drugs such as
• coumarin anticoagulants, digitoxin, hydrochlorothiazide,
• thyroxine, hydrocortisone,
• acetaminophen, loperamide,
• Vit B 3 (nicotinic acid), and possibly iron
27

28. BARs….
 Colestipol has better palatability=cse odorless &
tasteless
 Colesevelam is the newest BAR, and total and LDL-
C reduction are dose related.
 Adverse effects are common at higher doses
 BARs are used in combination with other drugs since low
doses are better tolerated well
28

29. Niacin (also known as nicotinic acid or
Vit B3)
 MOA:
 Reduces hepatic synthesis of VLDL, thus reduced
synthesis of LDL
 Niacin also ↑ HDL by reducing its catabolism
 Use:
 Used primarily for tx of mixed hyperlipemia (IIb and V)
 Tx. of primary hypercholesterolemia (IIa) alone or in
combination with bile acid sequestrants
 First-line agent or alternative for tx. of hypertriglyceridemia
(IV) and diabetic dyslipidemia
29

30. NIACIN SE
 Cutaneous flushing & itching….Prostaglandin
mediated &
 reduced by aspirin 325 mg given shortly before niacin
ingestion
 Take dose with meals & slowly upward titration may
minimize these effects
 Concomitant alcohol and hot drinks may magnify flushing
and pruritus with niacin and should be avoided at the time of
ingestion.
 Laropiprant is a selective antagonist of the prostaglandin D2
receptor –vasodilation???? No more used
 GI- intolerance and flushing are common problems
 Acanthosis nigricans, a darkening of skin in skinfold
areas & external marker of insulin resistance, may be
30

31. NIACIN SE
 Potentially important laboratory abnormalities
occurring with niacin therapy include
 elevated liver function tests, hyperuricemia, and
hyperglycemia
• Preexisting gout and diabetes may be exacerbated by niacin;
• Niacin is contraindicated in patients with active liver disease.
 Dry eyes & other ophthalmologic complaints are
occasionally noted.
 Niaspan is reported to have fewer dermatologic
reactions and a low risk for hepatoxicity
 Niaspan need dose titration to decrease side effects
31

32. Fibrates
 Three fibric acid derivatives (clofibrate, gemfibrozil, &
fenofibrate)
 Gemfibrozil and fenofibrate
 used much more commonly than clofibrate
 MOA:
 Fibrates monotherapy is effective in reducing VLDL, but a
reciprocal rise in LDL may occur, and total cholesterol values may
remain relatively unchanged
 Gemfibrozil reduces synthesis of VLDL and, to a lesser extent,
apolipoprotein B, with a concurrent ↑ in rate of removal of
triglyceride-rich lipoproteins from plasma
 All reduce LDL-C by 20% to 25% in patients with heterozygous
familial hypercholesterolemia
 Plasma HDL concentrations may rise 10% to 15% or more with
32

33. Fibrates Adverse effect
 GI complaints occur in 3% to 5% of patients,
 rash in 2%,
 dizziness in 2.4%, and
 Transient elevations in transaminase levels and
alkaline phosphatase in 4.5% and 1.3%, respectively
 May enhance formation of gallstones however, the
rate is low (0.5%–7%) and similar to that seen with
placebo in the Helsinki Heart Study
33

34. Fibrates Adverse effect…
 A myositis syndrome of myalgia, weakness,
stiffness, malaise, and elevations in creatinine
phosphokinase and aspartate aminotransaminase is
seen with the fibric acid derivatives and seems to be
more common in patients with renal insufficiency
 potentiate the effects of oral anticoagulants,
 prothrombin time & INR should be monitored very closely
when this combination is used.
34

35. Fish Oil Supplementation
 Diets high in omega-3 polyunsaturated fatty acids
(from fish oil), most commonly eicosapentaenoic acid
(EPA), reduce cholesterol, triglycerides, LDL, & VLDL
& may ↑ HDL-C.
 Fish oil supplementation may be most useful in
patients with hypertriglyceridemia, but its role in
treatment is not well defined.
 Available products in the market
 Eicosapentaenoic acid (EPA)
 Docosahexaenoic acid (DHA) 35

36. 36

37. 37