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 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) <150 150 199 200 499 500 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 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: CHD or CHD Risk Equivalents (10-year risk >20%) Moderately high risk: 2+ Risk Factors (10-year risk 10-20%) Moderate risk: 2+ Risk Factors (10-year risk <10%) Lower risk: 0 1 Risk Factor < 100mg/dL (optional < 70mg/dL) < 130mg/dL (optional < 100mg/dL) > 100mg/dL > 100mg/dL (<100mg/dL: consider drug options) > 130mg/dL > 130mg/dL (100-129mg/dL: consider drug options) < 130mg/dL > 130mg/dL > 160mg/dL < 160mg/dL > 160mg/dL > 190mg/dL (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 sequestrants - 15-30% + 3-5% + 3-10% Ezetimibe - 17% + 1.3% - 6% Nicotinic acid - 5-25% + 15-35% - 20-50% Fibric acids - 5-20% (nl TG) +10% (high TG) + 10-20% - 20-50%
HMG CoA Reductase Inhibitors (Statins) Statin Lovastatin (Mevacor R ) Pravastatin (Pravachol R ) Simvastatin (Zocor R ) Fluvastatin (Lescol R ) Atorvastatin (Lipitor R ) Rosuvastatin (Crestor R ) Dose Range 20 80 mg 20 40 mg 20 80 mg 20 80 mg 10 80 mg 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 (Mevacor R ) (Pravachol R ) (Zocor R ) (Lescol R ) (Lipitor R ) (Crestor R ) Doseresponse LDL Reduction 20mg: 29% 40mg: 31% 80mg: 48% 10mg: 19% 20mg: 24% 40mg: 34% 10mg: 28% 20mg: 35% 40mg: 40% 80mg: 48% 20mg: 17% 40mg: 25% 80mg: 35% 10mg: 38% 20mg: 46% 40mg: 51% 80mg: 54% 5mg: 41% 10mg: 48% 20mg: 55% 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
Monitoring HMG CoA Reductase Inhibitors (Statins) (continued) 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 Dose 4 16 g 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
Side effects Cholesterol Absorption Inhibitors (continued) 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 1.5 3 g 1 2 g 1 2 g
Side effects Nicotinic Acid (continued) 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 150 199 mg/dl 200 499 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. 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: 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%) Moderate risk: 2+ Risk Factors (10-year risk <10%) Lower risk: 0 1 Risk Factor < 130mg/dL < 160mg/dL (optional < 100mg/dL) (optional < 130mg/dL) < 130mg/dL < 160mg/dL < 160mg/dL < 190mg/dL
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