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) http://www.nhlbi.nih.gov/guidelines/choles terol/index.htm

Step 1: Determine lipoprotein levels

ATP III Lipid and Lipoprotein Classification

Total Cholesterol (mg/dL)
<200 Desirable 200239 Borderline high 240 High

ATP III Lipid and Lipoprotein Classification

LDL Cholesterol (mg/dL)

<100 100129 optimal 130159 160189 190

Optimal Near optimal/above

Borderline high High Very high

ATP III Lipid and Lipoprotein Classification (continued)

HDL Cholesterol (mg/dL) <40 60 Low High

ATP III Lipid and Lipoprotein Classification (continued)

Triglycerides (mg/dL)
<150 150199 200499 500 Normal Borderline high High 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 10year risk assessment

For patients with 01 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:
CHD or CHD Risk Equivalents (10-year risk >20%)

< 100mg/dL
(optional < 70mg/dL)

> 100mg/dL > 100mg/dL

(<100mg/dL: consider drug options)

Moderately high < 130mg/dL risk: (optional <

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

> 130mg/dL > 130mg/dL

(100-129mg/dL: consider drug options)

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

< 130mg/dL < 160mg/dL

> 130mg/dL > 160mg/dL > 160mg/dL > 190mg/dL

(160-189mg/dL: LDL-lowering drug optional)

Lower risk:
01 Risk Factor

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 (1025 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
Statins

LDL
- 18-55%

HDL
+ 5-15%

TG
- 7-30%

Bile acid sequestrants

Ezetimibe

- 15-30%
- 17%

+ 3-5%
+ 1.3%

+ 3-10%
- 6%

Nicotinic acid
Fibric acids

- 5-25%
- 5-20% (nl TG) +10% (high TG)

+ 15-35%
+ 10-20%

- 20-50%
- 20-50%

HMG CoA Reductase Inhibitors (Statins)

Statin Lovastatin (MevacorR) Pravastatin (PravacholR) Simvastatin (ZocorR) Fluvastatin (LescolR) Atorvastatin (LipitorR) Rosuvastatin (CrestorR) Dose Range 2080 mg 2040 mg 2080 mg 2080 mg 1080 mg 540 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 (MevacorR) Doseresponse LDL Reduction 20mg: 29% Pravastatin Simvastatin Fluvastatin (LescolR) Atorvastatin Rosuvastatin (LipitorR) 10mg: 38% (CrestorR) 5mg: 41% (PravacholR) (ZocorR) 10mg: 19%

10mg: 28% 20mg: 17%

40mg: 31%
80mg: 48%

20mg: 24%
40mg: 34%

20mg: 35% 40mg: 25%

40mg: 40% 80mg: 35% 80mg: 48%

20mg: 46%
40mg: 51% 80mg: 54%

10mg: 48%
20mg: 55% 40mg: 62% Not signif.

Metabolism

CYP3A4

Sulfation

CYP3A4

CYP2C9

CYP3A4

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 Range Cholestyramine Colestipol Colesevelam g Dose 416 g 520 g 2.63.8

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 Range Immediate release (crystalline) Extended release Sustained release Dose 1.53 g 12 g 12 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
Gemfibrozil Fenofibrate

Dose
600 mg BID 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 Borderline high High Very high <150 mg/dL 150199 mg/dL 200499 mg/dL 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. 200499 mg/dL) Non-HDL cholesterol goal:

Comparison of LDL & Non-HDL Cholesterol Goals

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

High risk:
CHD or CHD Risk Equivalents (10-year risk >20%)

< 100mg/dL
(optional < 70mg/dL)

< 130mg/dL
(optional < 100mg/dL)

Moderately high risk:

2+ Risk Factors (10-year risk 10-20%)

< 130mg/dL
(optional < 100mg/dL)

< 160mg/dL
(optional < 130mg/dL)

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

< 130mg/dL
< 160mg/dL

< 160mg/dL
< 190mg/dL

Lower risk:
01 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