Dyslipidemia

Hisham Aljadhey, PharmD, PhD

 Etiology
• Primary hyperlipidemia
– Familial hypercholesterolemia
• Secondary hyperlipidemia
– Disease states: hypothyroidism, nephrotic
syndrome, obesity, DM, alcoholism
– Drugs: thiazides, B-blockers, isotretinoin,
prednisone, progestins, estrogens, protease
inhibitors, anabolic steroids, cyclosporine
 Diagnosis
• Check fasting lipoprotein profile (9-12 hours of
fasting)
• Screening:
– Every 5 yrs. in patients > 20yo

• Other method
– Non-fasting total cholesterol and HDL
Benefits of Treating Hyperlipidemia

• Lowering LDL & TG, Raising HDL will

reduce:
– Mortality,
– Coronary events including MI,
– Stroke
National Cholesterol Education
Program (NCEP) Reports

• Adult Treatment Panel (ATP) I: 1988

• Adult Treatment Panel (ATP) II: 1993
• Adult Treatment Panel III (ATP) III: 2001
• Update to the ATP III (2004)
• [Link]
terol/[Link]
Step 1: Determine lipoprotein
levels
 ATP III Lipid and
Lipoprotein Classification
Total Cholesterol (mg/dL)

<200 Desirable
200–239 Borderline high
240 High
 ATP III Lipid and
Lipoprotein Classification

LDL Cholesterol (mg/dL)

<100 Optimal
100–129 Near optimal/above
optimal
130–159 Borderline high
160–189 High
190 Very high
 ATP III Lipid and
Lipoprotein Classification (continued)
HDL Cholesterol
(mg/dL)

<40 Low
60 High
 ATP III Lipid and
Lipoprotein Classification (continued)
Triglycerides (mg/dL)

• <150 Normal
• 150–199 Borderline high
• 200–499 High
• 500 Very high
 Assessment
• If total cholesterol <200mg/dL and HDL
>40mg/dL. No follow-up for patients without
CHD and <2 risk factors.
Step 2: Identify presence of CHD
or CHD risk equivalents
CHD and CHD Risk Equivalents

• Established CHD
• Other clinical forms of atherosclerotic
disease (peripheral arterial disease,
abdominal aortic aneurysm, and
symptomatic carotid artery disease)
• Diabetes
• Multiple risk factors that confer a 10-year
risk for CHD >20%
Step 3: Determine presence of
major risk factors (other than
LDL)
 Major Risk Factors
• Cigarette smoking
• Hypertension (BP 140/90 mmHg or on
antihypertensive medication)
• Low HDL cholesterol (<40 mg/dL)†
• Family history of premature CHD
– CHD in male first degree relative <55yrs
– CHD in female first degree relative <65yrs
• Age (men 45 years; women 55 years)
† HDL cholesterol 60 mg/dL counts as a “negative” risk
factor; its presence removes one risk factor from the total
count.
Step 4: Assess 10-year CHD risk if
2+ risk factors
• For patients with multiple (2+) risk factors
– Use Framingham risk tables to perform 10-
year risk assessment

• For patients with 0–1 risk factor

– 10 year risk assessment not required
– Most patients have 10-year risk <10%
Framingham Risk Tables
 Step 5: Determine risk category:
LDL Cholesterol Goals
Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy
High risk: < 100mg/dL > 100mg/dL > 100mg/dL
CHD or CHD Risk (optional < 70mg/dL) (<100mg/dL: consider drug
Equivalents options)
(10-year risk >20%)

Moderately high < 130mg/dL > 130mg/dL > 130mg/dL

risk: (optional < (100-129mg/dL: consider drug
2+ Risk Factors 100mg/dL) options)
(10-year risk 10-20%)

Moderate risk: < 130mg/dL > 130mg/dL > 160mg/dL

2+ Risk Factors
(10-year risk <10%)

Lower risk: < 160mg/dL > 160mg/dL > 190mg/dL

0–1 Risk Factor (160-189mg/dL: LDL-lowering
drug optional)
Step 6: Initiate therapeutic
lifestyle changes (TLC)
Therapeutic Lifestyle Changes (TLC) in
LDL-Lowering Therapy
Major Features
• TLC Diet
– Reduced intake of cholesterol-raising nutrients:
• Saturated fats <7% of total calories
• Dietary cholesterol <200 mg per day
– LDL-lowering therapeutic options
• Plant stanols/sterols (2 g per day)
• Viscous (soluble) fiber (10–25 g per day)
• Weight reduction
• Increased physical activity
Step 7: Consider adding drug
therapy if LDL is above goal
 Drug Therapy
• Drug therapy should decrease LDL levels
by 30-40% in high-risk and moderately
high-risk pts.
• For patients hospitalized for coronary
events or procedures
• Measure LDL within 24 hours
• Discharge on LDL-lowering drug if LDL-C 70
• Start lifestyle therapies simultaneously with drug
 Therapeutic Options
• Statins
• Bile acid sequestrants
• Cholesterol absorption inhibitors
• Nicotinic acid
• Fibric acids
 Drug Effects on the Lipid Profile
Drug LDL HDL TG

Statins - 18-55% + 5-15% - 7-30%

Bile acid - 15-30% + 3-5% + 3-10%
sequestrants
Ezetimibe - 17% + 1.3% - 6%
Nicotinic acid - 5-25% + 15-35% - 20-50%

Fibric acids - 5-20% (nl TG) + 10-20% - 20-50%

+10% (high TG)
 HMG CoA Reductase
Inhibitors (Statins)
Statin Dose Range
Lovastatin (MevacorR) 20–80 mg
Pravastatin (PravacholR) 20–40 mg
Simvastatin (ZocorR) 20–80 mg
Fluvastatin (LescolR) 20–80 mg
Atorvastatin (LipitorR) 10–80 mg
Rosuvastatin (CrestorR) 5–40 mg
 HMG CoA Reductase
Inhibitors (Statins) (continued)

Demonstrated Therapeutic Benefits

• Reduce major coronary events

• Reduce CHD mortality
• Reduce coronary procedures
(PTCA/CABG)
• Reduce stroke
• Reduce total mortality
 Comparison of Statins
Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin
(MevacorR) (PravacholR) (ZocorR) (LescolR) (LipitorR) (CrestorR)

Dose- 20mg: 29% 10mg: 19% 10mg: 28% 20mg: 17% 10mg: 38% 5mg: 41%
response 40mg: 31% 20mg: 24% 20mg: 35% 40mg: 25% 20mg: 46% 10mg: 48%
LDL
Reduction 80mg: 48% 40mg: 34% 40mg: 40% 80mg: 35% 40mg: 51% 20mg: 55%
80mg: 48% 80mg: 54% 40mg: 62%

Metabolism CYP3A4 Sulfation CYP3A4 CYP2C9 CYP3A4 Not signif.

 HMG CoA Reductase
Inhibitors (Statins) (continued)
• Major side effects
– Myopathy, Rhabdomyolysis
– Increased liver enzymes

• Cautions:
– Liver disease
– Drug interactions: Amiodarone, verapamil, diltiazem, itraconazole,
fluconazole, erythromycin, clarithromycin,, nefazodone,
fluvoxamine,, grapefruit juice: significantly increase levels of
lovastatin and simvastatin and slightly increase levels of
atorvastatin
– Cyclosporine and gemfibrozil increase level of all statins
 HMG CoA Reductase
Inhibitors (Statins) (continued)
• Monitoring
– Myalgia- baseline, 6-12 weeks after initiation, and
at each follow-up visit
– CK- baseline and prn muscle symptoms
– LFTs- baseline and 6-12 weeks after initiation or
dosage increase, then periodically and/or prn
symptoms
 Bile Acid Sequestrants
Drug Dose
Range
Cholestyramine 4–16 g
Colestipol 5–20 g
Colesevelam 2.6–3.8
g
 Bile Acid Sequestrants (continued)
• Side effects
– GI distress/constipation
• Contraindications
– Elevated TG (especially >400 mg/dL)
• Drug interactions
– Colesevelam does not decrease absorption of other
drugs
– Cholestyramine and colestipol decrease absorption of
other drugs
Cholesterol Absorption Inhibitors
• Ezetimibe: 10mg QD
• Reduces LDL-C and TG
• Increases HDL-C
• Synergistic with statin
– Combination more effective than increasing
statin dose
 Cholesterol Absorption
Inhibitors (continued)
• Side effects
– Abdominal pain, diarrhea, arthralgia, back pain
– Inc. LFTs when administered with a statin
• Contraindications
– Moderate to severe hepatic impairment
 Nicotinic Acid
Drug Form Dose
Range

Immediate release 1.5–3 g

(crystalline)
Extended release 1–2 g
Sustained release 1–2 g
 Nicotinic Acid (continued)
• Side effects
– flushing, hyperglycemia, hyperuricemia,
upper GI distress, hepatotoxicity,
myositis/rhabdomyolysis
• Contraindications/cautions
– liver disease, severe gout, peptic ulcer
• Monitoring
– LFTs (baseline and q 6-12 wks x 1 yr, then
periodically and/or prn symptoms) uric acid,
glucose, GI adverse effects, flushing, CPK prn
symptoms
 Fibric Acids
Drug Dose

• Gemfibrozil 600 mg BID

• Fenofibrate 200 mg QD
 Fibric Acids (continued)
• Side effects
– dyspepsia, gallstones, myopathy
• Contraindications
– Severe renal or hepatic disease
• Drug interactions
– Fenofibrate does not inhibit statin metabolism
and is less likely to increase risk of
rhabdomyolysis
• Monitoring
– LFTs periodically, CPK prn symptoms
 Omega-3 fatty acids (Fish oil)
Drug Dose Range

Omacor 4gm QD

• Decreases TG by 20-50%
• Reduce MI, stroke, and total mortality
Step 8: Identify metabolic
syndrome and treat after 3
month of TLC
 Clinical Identification
• Diagnosis requires 3 or more of the following
risk factors:
– Abdominal obesity: M waist >40 in., F waist >35
in.
– Triglycerides >150mg/dL
– Low HDL: M <40mg/dL, F <50mg/dL
– Blood pressure: >130/>85 mmHg
– Fasting glucose: >110mg/dL
Treatment of Metabolic Syndrome
• Treat underlying causes
– Overweight and obesity
– Physical inactivity
 Treatment of Metabolic Syndrome
• Treat associated lipid and non-lipid risk factors
– Hypertension
– Prothrombotic state- use low-dose ASA for CHD
patients
– Atherogenic dyslipidemia (lipid triad)- treat
elevated TG and/or low HDL
• TLC x 3mo.
• Consider drug therapy if lipid control still suboptimal
Step 9: Treat elevated
triglycerides
Classification of Serum Triglycerides

• Normal <150 mg/dL

• Borderline high 150–199 mg/dL
• High 200–499 mg/dL
• Very high 500 mg/dL
 Causes of Elevated Triglycerides
• Obesity and overweight
• Physical inactivity
• Smoking, excess alcohol intake
• High carbohydrate diets (>60% of energy
intake)
• Diseases (type 2 diabetes, chronic renal failure)
• Various genetic dyslipidemias
 Treatment
• Primary target is LDL
• Intensify weight management
• Increase physical activity
• If a high risk pt has high TG or low HDL-C, may
consider adding a fibrate or nicotinic acid to
LDL-lowering drug
• If TG are >200mg/dL after LDL goal is reached,
determine non-HDL goal
 Non-HDL Cholesterol

• Non-HDL cholesterol = VLDL + LDL

cholesterol
= (Total Cholesterol – HDL cholesterol)

• VLDL cholesterol: denotes atherogenic

remnant lipoproteins
• Non-HDL cholesterol: secondary target
of therapy when serum triglycerides are
200 mg/dL (esp. 200–499 mg/dL)
• Non-HDL cholesterol goal:
Comparison of LDL & Non-HDL Cholesterol Goals

Risk Category LDL-C Goal Non-HDL-C Goal

High risk: < 100mg/dL < 130mg/dL

CHD or CHD Risk Equivalents (optional < 70mg/dL) (optional < 100mg/dL)
(10-year risk >20%)

Moderately high risk: < 130mg/dL < 160mg/dL

2+ Risk Factors (optional < 100mg/dL) (optional < 130mg/dL)
(10-year risk 10-20%)

Moderate risk: < 130mg/dL < 160mg/dL

2+ Risk Factors
(10-year risk <10%)

Lower risk: < 160mg/dL < 190mg/dL

0–1 Risk Factor
 Treatment (continued)

Management of High Triglycerides (200-499 mg/dL)

• If TG remain elevated after LDL goal is reached:

– Intensify therapy with lipid-lowering drug
– Add nicotinic acid or fibrate to lower VLDL
 Treatment (continued)

Management of Very High Triglycerides (500 mg/dL)

• Reduce triglycerides before LDL lowering

• Goal of therapy: prevent acute pancreatitis
• Very low fat diets (15% of caloric intake)
• Triglyceride-lowering drug usually required (fibrate or
nicotinic acid)
 Causes of Low HDL Cholesterol

• Elevated triglycerides
• Overweight and obesity
• Physical inactivity
• Type 2 diabetes
• Cigarette smoking
• Very high carbohydrate intakes (>60% energy)
• Certain drugs (beta-blockers, anabolic steroids,
progestational agents)
Treatment of Low HDL Cholesterol
• Reach LDL goal first
• Implement weight reduction and increased
physical activity (if the metabolic syndrome is
present)
• If TG are 200 mg/dL, achieve non-HDL goal
• If TG are <200 mg/dL (isolated low HDL), consider
nicotinic acid or fibrates for patients with CHD or
CHD risk equivalents
– Increase physical activity
– Smoking cessation
 Place in Therapy
• Statins: high LDL
• Bile acid sequestrants: young, not high TG
• Ezetimibe: high LDL, combined with statin
• Nicotinic acid: high TG and/or high LDL
• Fibric acids: high TG
• Combination therapy: statin and ezetimibe,
statin and bile acid sequestrant, statin and
nicotinic acid, statin and fibric acid
 Monitoring and Follow-up
• Recheck fasting lipid profile in 4-6 weeks after
starting drug therapy