Cholesterol: The Expanded Lipid Profile Ben Brown MD December 19, 2011 Thanks also to Wendy K and Fasih H Outline What is the expanded lipid panel? Why order it? How to order it? What to do with results? Cases Questions Cases 1. 54 y/o woman with no risk factors and an LDL of 189. She does not want meds. 2. 35 y/o Latino male with new onset DM and a “perfect” lipid panel. 3. 40 y/o male who comes in and tells you that his Dad and brother both had their first MI at 45y/o. His lipids look more or less normal. 4. Bonus Case from Wendy 5. A 72 y/o woman obese, HTN, IGT, depression. What is my risk of heart disease or stroke? Why bother with more? 1. 2. Not all lipids are the same risk: impact of LDL size & number HDL subtypes In selected patients: Other Risk Factors missed with typical lipid panel Lp(a) hsCRP FHx early CADz and close to normal lipids Metabolic Syndrome and need more info to change High Lipids and wants to avoid statins or difficulty tolerating Question? In addition to the standard lipid profile, What is included in the expanded lipid panel? A. LDL subtypes (apoB) B. HDL subtypes (2 and 3) C. LPa D. hsCRP E. Homocysteine F. All of the above G. It depends What is there and How to Order? Expanded Lipid Profiles Quest: expanded lipid panel (or lipid- or homocyt- with homocysteine) Lipoprotein Particle Analysis (LPP) Spectracell Berkeley HeartLab (BHL) NMR: Liposcience VAP: Atherotec Hunter: Cardiovascular Risk/Metabolic Syndrome LDL: particle size and number Bigger is Better Small LDL is the bad guy why? it goes across the endothelium more readily absorbed by macrophages more readily = foam cells…bad Less is more (better) ApoB ( one per particle) scientifically accepted measurement for LDL particle number. Can be used to Monitor statin therapy. Apo B (LDL pattern) Nl <60 Small LDL= pattern B Case 1 According to ATP 3 Guidelines what would you recommend for our 54 y/o woman with no risk factors and an LDL of 189? A. Life style with a goal of LDL 160 B. Life style with a goal of LDL 130 C. Start a Statin D. Start Bile Acid Binder or Niacin Case 1 According to ATP 3 Guidelines what would you recommend for our 54 y/o woman with no risk factors and an LDL of 189? A. Life style with a goal of LDL 160 B. Life style with a goal of LDL 130 C. Start a Statin D. Start Bile Acid Binder or Niacin ATP 3 Guidelines-surprisingly generous Google: ATP 3 Guidelines at a glance ATP3 Guidelines Step 3:risk factors Her expanded panel results LDL=189, TG=102, HDL =63 apoB 20 (low) hsCRP 0.5 (normal) HDL2 (normal) HDL3 (normal) What if her Apo B or hsCRP or AIC was high? Lp(a) low Later an AIC was 5.0 Treatment of small dense LDL Treat LDL cholesterol and think Metabolic or Inflammation Insulin Resistance (glycocylation) Check AIC and treat accordingly Note: I start metformin early in someone who does not make LS changes easily (provider choice). Inflammation (oxidation) Check hsCRP Think of antioxidants Will cover with hsCRP HDL HDL 2 (a and b) HDL 3 Again bigger is better Smaller less protective Reverse cholesterol (signal of inefficient transport) transport Antioxidant effect Increases with exercise, fish oil, niacin, fibric acid, statin and niacin combo’s, moderate alcohol consumption. Case 2 35 y/o Latino male with new onset DM and a “perfect” lipid panel. Expanded Panel TC 168 HDL 2 low/3 normal HDL 41 Hs CRP 1.7 TG 115 Lp(a) normal LDL 104 What would you do? Apo B high Treatment of Low HDL 2 Exercise Niacin Moderate alcohol consumption (both 2 and 3) Stop smoking ?Fish oil ?statin, Fibric Acids, Bile acid binder might start for high apoB Mediterranean Diet, fish oils, consider probiotic for his high CRP LipoProtein (a) • Lp(a) is an inherited abnormal protein attached to LDL. • Normal level < 30 mg/dL • Lp(a) increases coagulation and triples CVD risk. Treatment options: Niacin NAC 600 mg twice daily Case 3 40 y/o male who comes in and tells you that his Dad and brother both had their first MI at 45y/o. His lipids look more or less normal. Expanded panel results Lp(a) high (104) Others normal What would you do? Lp(a) Bonus case: Wendy’s patient 58 yo woman, slender, healthy eater with h/o ischemic stroke age 58. Year later, ischemic bowel. Inflammation Hs-CRP Inflammatory marker Better then ESR and leucocytes for predicting vascular events Low Risk level < 1.0 mg/L Lp-PLA2 Slightly more specific for vascular inflammation Low risk <200 mg/ml hsCRP Treatment of increased hsCRP Look for cause: inflammation, infection, trauma. Consider checking Lp-PLA2 (endothelial inflammation) Anti-inflammatory regimen Diet (Mediterranean anti-inflammatory or mod elim) Exercise (any is better) Fish oils (dose by EPA/DHA 2-6g a day) Probiotics (10 billion org a day) Vit D (check level and treat to 50) Decrease Stress and support good sleep (cortisol) 4th Patient • 72 y/o woman obese, HTN, IGT, depression. • “What is my risk of heart disease or stroke?” • How do you answer this question? • Very Concrete thinker • Can you do it in a way that furthers the patients motivation to change and is affordable? Thoughts after test Advanced Risk Markers Routine lipid panel • • • At Goal – HDL = 65 – VLDL = 18 – Chol/HDL ratio =3.2 – TG’s = 90 moderate risk – TC = 211 – LDL = 128 – Non-HDL chol = 146 • High Risk – hsCRP = 4.88 [<1] – sd-LDL = 36.2 [20] Moderate Risk – Apo B 113 [<60] – Homocysteine 11.2 (<10) At Goal – Lp-PLA2 185.4 (<200) How to treat • NCEP –ATC diet with goal of dropping 5-10% weight • Lower carbohydrate, higher fiber diet • Omega 3 fats; substitute olive oil • Screen for DM, hypothyroidism • Lower LDL* ECW tricks: 3 other tests you may want… Summary High apoB = Small dense LDL ~ metabolic syndrome check AIC, treat LDL earlier, LS changes, consider earlier metformin, check hsCRP Low HDL (especially low High HDL 2) Exercise, Niacin, moderate ETOH High Lp(a) bad Niacin, NAC High hsCRP (cardio CRP) > 1.0 r/o infection, inflammation, trauma. Repeat test/ck lp-PLA2 Anti-inflam regimen (diet, ex, stress, fish oil, probiotic, antioxidants) Homocysteine: a definite risk factor, interventions lower it, ?if that makes a difference unless they have the condition hyperhomocysteinuria (rare). Homocysteine Methylation (if high also check B12/folate/methylmalonic acid) Functions primarily to protect DNA How to help For most Mediterranean Diet adequate, if still a problem may need supplementation B6 25 micrograms/d B12 1000micrograms/d Folate 800micrograms/d (may need as methyl THF) Progression of Drug Therapy in Primary Prevention Initiate LDLlowering drug therapy • Start statin or bile acid sequestrant or nicotinic acid 6 wks If LDL goal not achieved, intensify LDL-lowering therapy • Consider higher dose of statin or add a bile acid sequestrant or nicotinic acid 6 wks If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist • If LDL goal achieved, treat other lipid risk factors Q 4-6 mo Monitor response and adherence to therapy Lipids Background Cholesterol Functions 1. Plasma Membranes 2. Myelinated structures in the CNS 3. Inner Mitochondrial Membranes 4. Bile Acids 5. Steroid Hormones and Sex Hormones 6. Ergosterol (UV skin) Vit D3 Lipids Background Lipids in Atherosclerosis Dys-Function 1. Endothelium and damage 2. LDL and Macrophages 3. Oxidized LDL and Foam Cells Also glycosylated and acetylated LDL 4. Plaque and rupture 5. HDL as scavenger Cholesterol General (TC/HDL) Total Cholesterol/HDL ratio Best Lipid predictor of CHD in Framingham Study TC/HDL ratio 1 unit = CHD risk by 60% Eg TC/HDL ratio of <4 is normal 6 = 120% increased risk 3 = 60% decreased risk JAMA: 2009 68 Studies: 300,000 patients Mean fu 6 years Risk for coronary disease was Risk for coronary disease was associated with higher values of associated with higher values of •non–HDL-C and LDL-C, •higher ratios of non–HDL-C/HDL-C •non–HDL-C and LDL-C, •higher ratios of non–HDL•apo B/A1 (LDL/HDL) C/HDL-C •lower values of HDL-C. •apo B/A1 •not associated with triglyceride •lower values of HDL-C. levels •not associated with •No difference in risk prediction was triglyceride levels •No difference in risk prediction observed between fasting and nonwas observed between fasting fasting measurements. and nonfasting measurements. Di Angelantonio E et al. for the Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009 Nov 11; 302:1993. IM4U Treatment Pyramid Environment Relationships Internal Environment Life Style Natural Therapies Drugs Surgery Rescue Resources IM4U Treatment Pyramid (expanded) Environment Relationships Belief-Attitude-Identity-Spirituality Food-Movement-RelaxationSleep-Habits Structural-MetabolicEnergetic Drugs Surgery Rescue Resources Drug Therapy 1) HMG CoA Reductase Inhibitors (Statins) Reduce LDL-C 18–55% & TG 7–30% Raise HDL-C 5–15% Major side effects Myopathy Increased liver enzymes Contraindications Absolute: liver disease Relative: use with certain drugs 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 Statins: Drug-Nutrient Side Effects Nutrients Depleted Coenzyme Q10: Statins inhibit the enzyme HMG CoA reductase that is required to make cholesterol and Coenzyme Q10. Could explain myalgia, exercise intolerance, myoglobuinuria Also, Selenium, Zinc, Copper Lower serum PUFA’s and alter the relative % of omega 6:3 fats Arch Neurol 2004;61(6):889 Nutr Metab Cardiovasc Dis 2005; 15(1): 36 Drug Therapy 2) Bile Acid Sequestrants Ex: cholestyramine, colestipol, colesevelam Major actions Reduce LDL-C 15–30% Raise HDL-C 3–5% May increase TG Contraindications Dysbetalipoproteinemia Raised TG (especially >400 mg/dL) Bile Acid Sequestrants (continued) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Side effects GI distress/constipation Decreased absorption of other drugs Decreases beta-carotene, calcium, folate, Fe, Mg, Vit B12, D, E, K & zinc (cholestyramine) Drug Therapy 3) Nicotinic Acid Major actions Lowers LDL-C 5–25% Lowers TG 20–50% Raises HDL-C 15–35% Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Contraindications: liver disease, severe gout, peptic ulcer Nicotinic Acid Drug Form Dose Range Immediate release (crystalline) 1.5–3 g Extended release 1–2 g Sustained release 1–2 g Nicotinic Acid (continued) Demonstrated Therapeutic Benefits Reduces major coronary events Possible reduction in total mortality Drug Therapy 4) Fibric Acids Example: gemfibrozil, fenofibrate, clofibrate Major actions Lower LDL-C 5–20% (with normal TG) May raise LDL-C (with high TG) Lower TG 20–50% Raise HDL-C 10–20% Contraindications: Severe renal or hepatic disease Fibric Acids (continued) Demonstrated Therapeutic Benefits Reduce progression of coronary lesions Reduce major coronary events Side effects: dyspepsia, gallstones, myopathy Drug-nutrient interactions: Decrease CoQ10 also, Vitamin E, (fenofibrate incr’s homocysteine)