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Lipid Management: Role of Foods, Lifestyle, & Drugs for M anagement

Lipid Management: Role of Foods, Lifestyle, & Drugs for M anagement. Steve Kopecky MD Preventive Cardiology Mayo Clinic Rochester MN. Disclosure : Conflict of Interest Stephen L Kopecky. Research Grants: NIH/NHLBI, Mayo Clinic, Genzyme, Sanofi , Genetech , Regeneron Consultant:

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Lipid Management: Role of Foods, Lifestyle, & Drugs for M anagement

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  1. Lipid Management: Role of Foods, Lifestyle, & Drugs for Management Steve Kopecky MD Preventive Cardiology Mayo Clinic Rochester MN

  2. Disclosure : Conflict of InterestStephen L Kopecky • Research Grants: • NIH/NHLBI, Mayo Clinic, Genzyme, Sanofi, • Genetech, Regeneron • Consultant: • AmerSoc for Prev Card- President (2012-2014) • Acad of Clin Research Professionals: • Chair, Global Certification Exam Committee • Applied Clinical Intelligence: • DSMB Chair • Prime Therapeutics – Formulary Committee

  3. Learning Objectives • Appreciate the different lipid biomarkers and their role in assessing risk from hyperlipidemia • 2. Understand lifestyle issues involved with hyperlipidemia • 3. Learn the beneficial effects and side effects of drug therapy for hyperlipidemia

  4. Secondary CV Prevention: US 2011 “Million Hearts Campaign” In patients with Hyperlipidemia: 1/3 have adequate treatment Frieden and Berwick N Engl J Med 2011; 365:e27 September 29, 2011

  5. Seven Countries Study: Relationship of Serum Cholesterol to Mortality 35 Northern Europe 30 25 United States 20 Death rate from CHD/1000 men 15 Southern Europe, inland 10 Serbia Southern Europe, Mediterranean 5 Japan 0 2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05 Serum total cholesterol (mmol/L) Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136

  6. What Diet Components Decrease Risk for MI ? INTERHEART Study: 55 countries All inhabited continents of the world Association w/ MI Increases Western Diet: Fried foods, salty snacks, and meat Oriental Diet: Tofu, pickled foods, soy and other sauces Neutral Prudent Diet: Dairy, fruits, vegetables, nuts Decreases Iqbal et al INTERHEART Study:Dietary patterns and risk of MI AHA EpiConf Orlando 2007

  7. CAD Associated with Daily Replacement (1 serving) of Protein Source Replacing 1 serving per day of red meat with 1 serving per day of fish was associated with a 24% (95% CI, 6% to 39%) lower risk Less Heart Disease More Heart Disease High Fat Dairy for Fish Poultry for Red Meat Fish for Red Meat Nuts for Red Meat Beans for Red Meat Nurse’s Health Study 27 Year Follow-up 0.4 0.6 0.8 1 1.2 1.4 1.6 Hazard Ratio RRs and 95% CIs Bernstein Circulation. 2010;122:876-883

  8. Low Carbohydrate Diets : Mortality Effect ? Health Professional’s Follow Up Study n=51,529 : 20 Yr follow-up All Cause Mortality (HR) Any Low Carb Diet 1.12 ( 95% CI 1.01-1.24) Vegetable Low Carb p<0.001 p<0.001 p=0.051 p=0.029 Animal Low Carb Low Carb Diet : Hi Animal – Increased Total/CV Mortality Hi Vegetable – Decreased Total/CV Mortality Fung Low Carbohydrate Diets and All-Cause and Cause-Specific Mortality Ann Int Med 2010;153:289-298

  9. Reducing Heart Disease Risk: Lowering Cholesterol Plant Sterols/Stanols 1.6 / 3.4 gm/day Oat b-glucan Viscous Fiber Psyllium Nuts Almonds 42 g Diet Drug Effect Block cholesterol Ezetimibe absorption Reduce hepatic Statin cholesterol synthesis Increase bile Cholestyramine acid losses Source of plant sterols monounsaturated fats, vegetable protein Soy 0.8 Oz Annals Int Med 2005;142:793-795

  10. Portfolio Diet : Per 1000 kcal of DietLower LDL ~15% over 6 months • Plant sterols- 0.94 g in margarine; • Viscous fibers- 9.8 g from oats, barley, and psyllium; • Soy protein-22.5 g as soy milk, tofu, and soy meat ; • Nuts - 22.5 g (including tree nuts and peanuts) • ¾ of an ounce • Consumption of peas, beans, and lentils encouraged. Jenkins et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum Lipids and C-reactive protein. JAMA. 2003;290(4):502–510 Jenkins et al JAMA.2011;306(8):831-839. doi: 10.1001/jama.2011.1202

  11. Supplements to Reduce LDL: Reduce Intestinal Cholesterol Absorption Product How much to take Plant stanols 800 - 4,000 mg/day divided and taken with meals (2 to 3 tsps Benecol Light™ Spreads or 2 to 4 Smart Chews) Plant sterols 800 mg to 6 gms/day, divided and taken with meals (= 2 tsps Promise activ™ Spread or -2 servings of SuperShots™) Plant stanol, 900 mg (usually found in 450 mg caplets) sterol supplements two times per day with a meal (sitostanol, such as Benecol Light™ Spreads, Smart Chews) (Promise activ™ Spreads, SuperShots™) (CholestOff™ and Centrum Cardio™)

  12. Supplements to Reduce LDL: Reduce Cholesterol Production in Liver Product How much to take Oat bran Up to 150 g of whole oat products per day (about equal to eating 1½ cups of cooked oatmeal) (oatmeal,oat bran products; look for oat bran or whole oats as ingredient on label) Do not use Red Yeast Rice – Contains lovastatin Not regulated adequately Dosage variable Instead-Use generic (low cost) statin

  13. Supplements to Reduce LDL:Increase Loss of Cholesterol via Bile Acid into Intestine Product How much to take Blonde psyllium 5 g seed husk twice per day, or 1 serving of product such as Metamucil™ (seed husks and products such as Metamucil™)

  14. Lipid Management Drugs and their Effects on Lipids/Lipoprotein % Fish Oil : EPA and DHA = 4-6 gms/day NCEP/ATP III 2001

  15. Effect of Different Anti-lipidemic Agents and Diets on Overall Mortality 95% UL Risk ratio RR (95% CI P I2 (%) Statins (n=35) 0.87 (0.81-0.94) 0.05 30 0-54 Fibrates (n=17) 1.00 (0.91-1.11) 0.01 33 0-63 Resins (n=8) 0.84 (0.66-1.08) 0.86 0 0-68 Niacin (n=2) 0.96 (0.86-1.08) 0.81 0 n-3 FA (n=14) 0.77 (0.63-0.94) 0.01 53 14-75 Diet (n=18) 0.97 (0.91-1.04) 0.19 23 0-56 0.5 0.8 1.0 1.25 2.0 AIM-HIGH : Niacin no benefit once LDL reduction acheived Favors Tx Favors ctrl Effect of Different Antilipidemic Agents and Diets on Mortality: A Systematic Review Studer et al Arch Intern Med. 2005;165:725-730.

  16. Normalization of Serum Triglycerides by Exercise • 7 Men – Sedentary then 4 days of exercise, • 3 to 4 miles in approximately 40 minutes. • Ask about : • “White” –bread, • rice, pasta • Soft drinks • Juices • Sports drinks • Alcohol Oscai et al AJC 1972; 30:775-780

  17. Statins : LDL Reduction From Starting to Max Dose Fluva Prava Lova Simva Atorva Rosuva 20-80 20-40 20-80 20-80 10-80 5-40 Dose Increase : 4x 2x 4x 4x 8x 8x Illingworth Medical Clinics of North America- Volume 84, Issue 1(January 2000);23-42

  18. Are Statins of Benefit in Primary Prevention ? Effects on major vascular events at 1 Yr per 1·0 mmol/L reduction in LDL C LDL cholesterol : 1.0 mmol/L reduction = 38 mg/dl reduction 99% CI 95% CI Statin/More Better Controls/Less Better RR= Rate ratios CHD=coronary heart disease Efficacy and safety of more intensive lowering of LDL cholesterol : meta-analysis of 170 000 participants in 26 randomised trials Lancet 2010; 376: 1670–81

  19. Statins for Primary Prevention of CV Disease Risk Ratio Study ACAPS 1994 Adult Japanese MEGA AFCAPS/TexCAPS 1998 ASPEN 2006 CARDS 2004 KAPS 1995 PREVEND IT 2004 WOSCOPS 1997 Total (95% CI) Total Mortality Does not include JUPITER, which also showed decrease in Total Mortality Total Statin Placebo n 14,058 14,103 0.84 [0.73,0.96] .2 .5 1 2 5 Favors Favors Statin Control Statins for the primary prevention of cardiovascular disease (Review) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

  20. Statins and All-Cause Mortality in High-Risk Primary Prevention: Benefit by Baseline Age Age explained ~70% of variation in events between groups 11 Trials p<.001 Would you send this patient to the cath lab if they had a STEMI tomorrow ? Arch Intern Med. 2010;170(12):1024-1031

  21. Proposed Definitions for Statin-Related Myopathy Joy Ann Intern Med 2009;150:858-868 ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am CollCardiol. 2002;40:567-72. NLA Am J Cardiol. 2006;97:89C-94C SewrightStatin myopathy: incidence, risk factors, and pathophysiology. CurrAtheroscler Rep. 2007;9:389-96

  22. Statin Intolerance: Definition Unable to take statin to get to goal due to symptoms of intolerance Most common symptom : muscle aches, weakness, cramps

  23. Statins: Side Effects in Clinical Trials – METEOR (Rosuva 40) Event (%) Rosuva Myalgia 12.7 Placebo 12.1 7.1 10.3 2.8 2.1 2.1 2.8 1.1 0.7 3.6 1.1 46% Age 57 Yrs; n=984 Arthralgia 10.1 Back Pain 8.4 MM Spasms 3.7 Tendinitis 3.3 Ext Pain 2.9 Shoulder Pain 2.0 Neck Pain 1.6 Arthritis 1.6 Stiffness 1.1 MM Weak 0.7 Total 48% Exclusion Criteria: Statin Intolerance Event (%) Rosuva Placebo Musculoskeletal Side Effect or Withdrew Consent 75% 72% MM=Muscle; Ext=Extremity Crouse et al METEOR Trial JAMA. 2007;297(12)1344-1353

  24. Heart Protection Study Simvastatin 40 mg vs Placebo n=20,536 patients randomized • At 25 months - no difference in myalgias. • 81% still on simvastatin or placebo • How was the study performed ? • 63,603 attended study screening clinics • 32,145 pre-randomization run-in phase • Run-in (10 weeks), if side-effects to treatment - then do not randomize • 32% of original patient pool randomized Heart Protection Study Collaborative Group European Heart Journal (1999) 20, 725–741

  25. Prevalence of Statin Use on Self Reported Musculoskeletal Pain: NHANES Any region 1.33 (1.06-1.67) 0.96 (0.81-1.15) Neck/upper back 0.88 (0.53-1.45) 0.81 (0.61-1.08) Upper extremities 0.82 (0.49-1.35) 0.84 (0.62-1.15) Lower back 1.47 (1.02-2.13) 1.05 (0.81-1.37) Lower extremities 1.59 (1.12-2.22) 0.96 (0.76-1.22) Body Region W/O Arthritis (n=5170) W/ Arthritis (n=3058) Statin use was associated with a higher prevalence of musculoskeletal pain in the lower extremities, among individuals without arthritis *Adjusted :age, sex, race, smoking, self-reported health, CHD, DM, cancer, Sys BP, BMI, TC,ABI Buettner et al American Journal of Medicine (2012) 125, 176-182

  26. Risk Factors for Statin Intolerance: Patient-related • Patient • Advanced age (>80) • Female sex • Low BMI • Multisystem disease (particularly liver, kidney, or both) • Hypothyroidism (untreated) • Excess Alcohol • Grapefruit or Cranberry juice consumption (_1 qt/d) • Vigorous activity • Major surgery or trauma • Intercurrent infections • History of myopathy on another lipid-lowering therapy • History of creatine kinase elevation • Unexplained cramps • Family history of myopathy on lipid-lowering therapy • Family history of myopathy • (polymorphisms of P450 isoenzymes or drug • transporters, inherited defects of muscle metabolism, traits • that affect oxidative metabolism of fatty acids)

  27. Risk Factors for Statin Intolerance: Treatment-Related • High-dose statin therapy • Interactions with concomitant drugs (esp P450 Pathway) • Amiodarone • Antifungals ( Azoles) • Cyclosporine • Fibrates • Macrolide antibiotics • Nefazodone • Nicotinic acids • Protease inhibitors • Thiazolidinediones • Verapamil • Warfarin

  28. Differential Diagnosis of Myopathy or CreatineKinase Elevations Not Due to Lipid-Lowering Therapy • Creatine kinase elevations • Physical exertion • Hypothyroidism • Metabolic or inflammatory myopathies • Alcoholism • Neuropathy or radiculopathy • Ethnicity (black Americans may have elevated • baseline creatine kinase levels) • Idiopathic hyperCKemia‡ • Seizure or severe chills • Trauma • Medications • Illicit drugs (cocaine or amphetamines) • Antipsychotics • Muscle symptoms • Physical exertion (deconditioned) • Viral illness • Vitamin D deficiency • Hypo- or hyperthyroidism • Cushing syndrome or adrenal insuffic • Hypoparathyroidism • Fibromyalgia • Polymyalgia rheumatica • Polymyositis • Systemic lupus erythematosus • Tendon or joint disorder • Trauma • Seizures or severe chills • Peripheral arterial disease† • Medications • Glucocorticoids • Antipsychotics • Antiretroviral drugs • Illicit drugs (cocaine or amphetamines) † For patients who present with cramping in their calves or thighs. ‡ Refers to elevated creatine kinase level without another cause identified

  29. FDA Advisory : Statins Feb 28, 2012 • Routine monitoring of liver enzymes in the blood is no longer needed • Cognitive impairment ( memory loss, forgetfulness and confusion) has been reported by some statin users • People being treated with statins may have an increased risk of raised blood sugar levels and the development of Type 2 diabetes • Some medications interact with lovastatin and can increase the risk of muscle damage.

  30. Blood-Brain Barrier Permeability of Major Statins Name Permeability Lovastatin Yes Pravastatin No Fluvastatin No Simvastatin Yes Atorvastatin Disputed Cerivastatin Disputed Rosuvastatin No Shepardson et al Arch Neurol. 2011 Nov;68(11):1385-92. Cholesterol level and statin use in Alzheimer disease

  31. Statin Use and Risk of DM in Postmenopausal Women in the Women's Health Initiative Culver et al Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women's Health Initiative Arch Intern Med. 2012;172(2):144-152.

  32. Are Statins Associated with Dementia ? Statin Ever User Statin Never User Dementia-free survival probability Beydoun et al J Epidemiol Community Health 2011;65:949-957 doi:10.1136/jech.2009.100826 Ageing Research report Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment

  33. Take Home Messages: • Integrating lifestyle and diet changes with • medical Rx key to lipid management • Dietary changes and exercise are best initial • steps to treating hypertriglyceridemia • Statins and fish oil are the only medical Rx • shown to consistently lower CV mortality • For primary prevention, elderly patients derive • most benefit from statin therapy. • Statin intolerance is more common than • previously thought and must be addressed

  34. Thank you for your attention !kopecky.stephen@mayo.edu

  35. www.aspconline.org

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