SESSION 5 2:15pm 3:45pm

Transcription

1 SESSION 5 2:15pm 3:45pm Current Perspectives and Emerging Approaches in Lipid Management SPEAKERS Michael Miller, MD, FACC, FAHA Michael Blaha, MD, MPH Presenter Disclosure Information The following relationships exist related to this presentation: Dr Miller has received consultant and/or honorarium fees from AstraZeneca and Amarin. Dr Blaha has received honorarium fees from Pfizer and Regeneron. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Drug List Drug List (cont d) Generic Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Pitavastatin Tirofiban Cholestyramine Colesevelam Colestipol Ezetimibe Trade Lipitor Lescol, Lescol XL Mevacor, Altoprev Pravachol Crestor Zocor Livalo Aggrastat Questran, Questran Light, Prevalite, Locholest, Locholest Light Welchol Colestid Zetia Generic Clarithromycin Nefazadone Verapamil Amiodarone Niacin/Nicotinic acid Gemfibrozil Bezafibrate Fenofibrate Omega-3-acid ethyl esters Icosapent ethyl Omega-3 free fatty acids Trade Biaxin, Biaxin XL Serzone Calan, Verelan, Verelan PM, Isoptin, Isoptin SR, Covera-HS Pacerone, Cordarone, Cordarone IV, Nexterone Niacor, Niaspan, Slo-Niacin Lopid Bezalip Tricor, Lipidil, Antara, Triglide, Trilipix Lovaza Vascepa Epanova Itraconazole Sporanox Ketoconazole Nizoral, Extina, Xolegel, Kuric Erythromycin E-mycin, Eryc, Ery-tab, PCE, Ilosone, Pediazole Educational Objectives Evaluate primary and secondary prevention evidence with statins. Explain the importance of lowering LDL-C for reducing cardiovascular risk, interpret statin safety data, assess benefit/risk with statins, and discuss current guideline recommendations. Explain the association of hypertriglyceridemia with increased risks and identify currently available therapies for reducing elevated triglycerides. Discuss similarities and differences between currently available and emerging omega-3 fatty acid agents, and indicate patient populations for potential incorporation of omega-3 fatty acids in clinical practice.

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8 Disclosures Hypertriglyceridemia & Omega-3 Fatty Acids: Exploring Current & Emerging Treatment Options Michael Miller, MD, FACC, FAHA Professor of Medicine, Epidemiology & Public Health Director, Center for Preventive Cardiology University of Maryland Medical System Baltimore, MD Amarin: Consultant and Member, Steering Committee- REDUCE-IT trial. AstraZeneca: Consultant Zydus: Consultant

9 Dietary Fat E B-100 C-III IDL Overview of TG Metabolism LPL, HGTL B-100 LPL Miller M, et al. Circulation. 2011;123: Adipose Tissue and Muscle CIII GPIHBP1 B-48 C-II E Chylomicron LDL CII E VLDL B-100 C-III LPL LRP LPL C-III LDL-R VLDL C-III FFAs CMR LRP B-100 E E B-48 Apo A-V B-100 IDL, VLDL-R Vascular Wall Macrophages Metabolic Consequences of Hypertriglyceridemia Insulin Resistance FFA DGAT Glycerol Liver TG TG TG TG TG CE Miller M, et al. Circulation. 2011;123: HDL TG/VLDL-C CETP TG Apo B-100 CETP LDL Apo A-I CE CE TG HTGL Atherogenic Dyslipidemia HDL-C small-dense VLDL LDL particles VLDL ( LDL-C) Apo B-100 HTGL TG HDL Small, dense HDL LDL Apo A-I Apo B-100 Small, dense LDL Mechanisms for Enhanced Atherogenesis of Small Dense LDL Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles Fewer Particles More Particles Apo B LDL= 130 mg/dl More Apo B Cholesterol Ester Correlates with: TC 198 mg/dl LDL-C 130 mg/dl TG 90 mg/dl HDL-C 50 mg/dl Non HDL-C 148 mg/dl Correlates with: TC 210 mg/dl LDL-C 130 mg/dl TG 250 mg/dl HDL-C 30 mg/dl Non HDL-C 180 mg/dl Mudd JO, et al. J Am Coll Cardiol. 2007;50(18): Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. Prevalence of Elevated TG ( ) Epidemiology of High TG and CVD Risk 20+ yrs Borderline High Very High >150 >200 > 500 Overall 31% 16% 1.1% Men 35% 20% 1.8% Women 27% 13% 0.5% Heritage Mexican 35% 20% 1.4% African 16% 8% 0.4% European 33% 18% 1.1% Miller M, et al. Circulation. 2011;123: Units: mg/dl

10 Secondary Causes of Hypertriglyceridemia Estrogen Tamoxifen Alcohol Hypothyroidism Diabetes Liver disease Nephrotic syndrome Pregnancy Obesity Lipodystrophy Medications Thiazides Beta blockers Corticosteroids Retinoids Protease inhibitors Long-term interferon Antipsychotic meds Residual CVD Risk in Patients Treated With Statins Miller M, et al. Circulation. 2011;123: Residual CVD Risk in Statin vs Placebo Trials CHD Events Occur in Patients Treated with Statins TG >150 mg/dl & CHD Events a In Patients With ACS on Statins b PROVE IT-TIMI 22 Trial N = 4162 Patients Experiencing Major CHD Events, % Placebo Statin CHD Event a Rate, % HR: 0.81 (0.68, 0.96) P=.015 LDL-C LDL-C 70 LDL-C <70 CHD Event a Rate, % HR: 0.73 (0.62, 0.87) P<.001 TG TG 150 TG <150 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/TexCAPS 6 N LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary 1 4S Group. Lancet. 1994;344: HPS Collaborative Group. Lancet. 2002;360: LIPID Study Group. N Engl J Med. 1998;339: Shepherd J et al. N Engl J Med. 1995;333: Sacks FM et al. N Engl J Med. 1996;335: Downs JR et al. JAMA. 1998;279: Days After Month 1 Visit ACS, acute coronary syndrome a Death, MI, and recurrent ACS b Atorvastatin 80 mg or pravastatin 40 mg Lipid values are in mg/dl 0.00 Reprinted with permission from Miller M, et al. J Am Coll Cardiol. 2008;51: Days After Month 1 Visit Each 10 mg/dl in TG = 1.8% in CHD risk (P<.001) TG < 150 mg/dl Associated With Lower Risk of CHD Events a Independent of LDL-C Level PROVE IT-TIMI 22 Trial b Achieving both low LDL-C and low TG (<150 mg/dl) may be important therapeutic strategies in patients after an ACS CHD Event a Rate After 30 Days c, % HR: 0.72 P=.017 HR: 0.85 P=.180 HR: 0.84 P=.192 Referent LDL-C 70 N = 4162 LDL-C <70 a Death, MI, and recurrent ACS TG <150 TG 150 b ACS patients on atorvastatin 80 mg or pravastatin 40 mg c Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment Lipid values are in mg/dl Reprinted with permission from Miller M, et al. J Am Coll Cardiol. 2008;51: Effects of Nutrition Practices on Triglyceride Lowering Nutrition Practice TG-Lowering Weight loss 20% (5% to 10% of body weight) Implement a Mediterranean-style diet 10 15% vs a low-fat diet Add marine-derived PUFA (EPA/DHA) (per gram) 5 10% Decrease carbohydrates 1% Energy replacement with MUFA/PUFA 1 2% Eliminate trans fats 1% Energy replacement with MUFA/PUFA 1% Miller M, et al. Circulation. 2011;123:

11 Effect of Lipid-lowering Therapies on TG Reduction (%) Fibrates 30-50% Niacin 20-50% Omega % Statins 10-30% Ezetimibe 5-10% Treating Beyond LDL-C: Fibrate Therapy Clinical Lipidology: A Companion to Braunwald s Heart Disease (Ballantyne CM, ed) 2009; Meta-Analysis: Randomized Trials of Fibrate Drugs Meta-analysis of Randomized Trials of Fibrate Drugs Treating Beyond LDL-C: Omega-3 Fatty Acid Therapy Dyslipidemia: TG 204 mg/dl, HDL-C 34 mg/dl Complementary subgroups: TG < 204 mg/dl, HDL-C > 34 mg/dl Odds ratio 35% in dyslipidemia Sacks FM, et al. N Engl J Med. 2010;363(7): What are EPA and DHA? (Essential fatty acids) Schema of Potential Dose Responses & Time Courses for Altering Clinical Events of Physiologic Effects of Fish or Fish Oil Intake Plant sources Limited conversion (few percent) Fatty fish Calder P, et al. J Nutr. 2012;142:592S-9S. Fatty fish Mozaffarian, D. et al. JAMA 2006;296:

12 Japan EPA Lipid Intervention Study (JELIS) 18,645 subjects, primary and secondary prevention Patient Subgroup TG >150 mg/dl and HDL <40 mg/dl: JELIS Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: Sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS) Major CV Events (%) Statin Statin +EPA (1.8g/day) Hazard ratio = 0.81 ( ) p = % Years Saito S, et al. Atherosclerosis. 2008;199: Adapted from Yokoyama M. Lancet. 2007;369: Available Forms of Omega-3 Fatty Acids for Supplement and Pharmaceutical use Available Forms of Omega-3 Fatty Acids for Supplement and Pharmaceutical use PL Om-3 Absorption Concentr. FFA Om-3 Absorption? (Good Conc.) EE Om-3 Absorption (Good Conc.) Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald s Heart Disease: Expert Consult (2 nd edition) Editor Christie M. Ballantyne (2014, in press) Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald s Heart Disease: Expert Consult (2 nd edition) Editor Christie M. Ballantyne (2014, in press) Dietary Supplements vs Drugs Demonstrated Efficacy and Safety FDA Approved Regulated Manufacturing Regulated Claims FDA Safety Monitoring Intended to Treat Disease Prescription drugs 1 OTC drugs 2 (No omega-3 Available) Dietary supplements * 3 Prescription Omega-3 Fatty Acids (EPA and DHA Ethyl Esters) Omega-3-acid ethyl esters (Lovaza ) is a combination of ethyl esters of omega-3-fatty acids containing 465 mg EPA and 375 mg DHA in 1 gram capsule Omega-3-acid ethyl esters is FDA approved for Very High TG (>500 mg/dl) The daily dose of omega-3-acid ethyl esters is 4 g per day taken as a single 4-gram dose (4 capsules) or as two 2- gram doses (2 capsules given twice daily). * Structure, function and qualifying health claims only

13 Prescription Omega-3 Fatty Acids (EPA Ethyl Esters Only) Prescription Omega-3 Fatty Acids (EPA and DHA Free Fatty Acids) Icosapent ethyl (Vascepa ) is a 96% pure ethyl ester of eicosapentaenoic acid (EPA) Icosapent ethyl is FDA approved for Very High TG (>500 mg/dl) The daily dose is 4 g per day taken as 2 capsules twice daily Omega-3-carboxylic acids (Epanova ) is a fish oil-derived mixture of free fatty acids, with at least 850 mg of polyunsaturated fatty acids, including multiple omega-3 fatty acids (EPA and DHA being the most abundant) Omega-3-carboxylic acids is FDA approved for Very High TG (>500 mg/dl) The daily dose of omega-3-carboxylic acids is 2 g (2 capsules) or 4 g (4 capsules) once daily New Research in Omega 3 Formulations ECLIPSE STUDY: Epanova Compared to Lovaza in a Pharmacokinetic Single-dose Evaluation Is there a difference in bioavailability between Omega 3 fatty acids taken orally as free fatty acids (Epanova) versus their ethyl ester form (Lovaza and Vascepa)? Would these differences in formulation be clinically significant in terms of triglyceride reduction or effectiveness on a low fat diet? Kataoka Y et al. Future Cardiol. 2013;9: Epanova 2g (N=215) Lipid Effects of Prescription Om-3 in TG >500 mg/dl EVOLVE (EPA+DHA FFA) LS Mean Change from Baseline (%) * * * * Epanova 4g (N=216) Olive Oil (N=216) MARINE (EPA EE) Median Change from Baseline (%) Vascepa 4g (N=76) Placebo Corrected (N=76) Placebo (N=75) Median Change from Baseline (%) Lovaza 4g (N=42) EPA+DHA EE Placebo Corrected LDL-C +19.4%* +19.2%* +3% -4.5% -7.5% +3% +45%* +49.8% -4.8% Kastelein JJP, et al. J Clin Lipidol. 2014;8: Bays HE, et al. Am J Cardiol. 2011;108: * * * * (N=42) * *P<0.05 Placebo (N=42) OM-3 FA combined with statin trials Lovaza Vascepa Epanova Study COMBO (n=256) ANCHOR (n=702) ESPRIT (n=647) Lipid inclusion 200 mg/dl TG < 500 mg/dl 200 mg/dl TG < 500 mg/dl Patients with high risk for CV events with 200 mg/dl TG < 500 mg/dl Duration 8 weeks 12 weeks 6 weeks Treatments 4 g/d plus Simva 40mg Placebo plus Simva 40mg 4 g/d plus statin Placebo plus statin 2 g/d plus ongoing statin 4 g/d plus ongoing statin Triglycerides -29.5* * LDL-C * Non-HDL-C -9* * TC -4.8* * HDL-C 3.4* * Apo B -4.2* * *Difference from placebo, p<0.05 Davidson MH et al. Clin Ther. 2007;29: Ballantyne CM et al. Am J Cardiol 2012;110: Maki KC et al. Clin Ther. 2013;35: %Δ LSGM, p<0.05 Olive oil plus ongoing statin

14 Omega-3 Fatty Acid Prescription Products Event-driven CV outcome trials with OM-3 FA Ethyl Esters EPA DHA Dose Bioavailability Omega-3-Acid- Ethyl Esters (Lovaza) Icosapent Ethyl Esters (Vascepa) Free Fatty Acids Omega-3- carboxylic acids (Epanova) Yes Yes Yes Yes No Yes 4 grams once daily or 2 grams twice daily 2 grams twice daily 2 or 4 grams once daily good good excellent Take with Meals clinical trials with meals clinical trials with meals not necessary Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) Enrolling 8000 men and women 45 years; prior CHD (70% patients) or T2DM + > 1RF; atherogenic dyslipidemia (Hx of increased TC (at LDL-C goal on statin), TG mg/dl Treatment: Vascepa 4 g/d or placebo Primary outcome measure: composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, and unstable angina determined to be caused by myocardial ischemia by non-invasive testing and requiring emergent hospitalization Follow-up: 4-6 years Estimated primary completion date: November 2016 Outcome Study to Assess Statin Residual Risk Reduction With Epanova in Hypertriglyceridemia (STRENGTH) Estimated enrollment: 28,890 high risk adults for CVD on statin therapy Treatment: Epanova 4 g/d or placebo Primary outcome measure: cardiovascular death, nonfatal MI, nonfatal stroke, emergent/elective coronary revascularization, or hospitalization for unstable angina Follow-up: 5 years Summary Hypertriglyceridemia is associated with increased CV risk Omega-3 fatty acids are a safe and effective therapy for TG lowering in hypertriglyceridemic subjects Ongoing clinical trial(s) will assess whether combination therapy is clinically superior to statin monotherapy in hypertg patients Rodale: Ebook: amazon.com Case Presentation Developed by Joanne Foody, MD and Terry A. Jacobson, MD Case 48-year-old man relocates to your town, and sees you for a physical F Hx + No history of cardiovascular disease Tobacco 20 pack years but quit 5 years ago Diet 6 servings of fruits and vegetables daily 5 servings of whole grains daily Fish thrice weekly Fats are nearly all PUFAs and MONOs Exercise Sporadic twice weekly

15 Drugs Lisinopril 10 mg (for HTN) Case Physical Exam Vital Signs Pulse: 64 BP: 146/86 Weight: 74.3 kg Waist circ: 99 cm BMI: 28.8 kg/m 2 No other abnormalities Metabolic Panel Total cholesterol: 232 mg/dl TG: 330 mg/dl HDL-C: 31 mg/dl LDL-C: 135 mg/dl ALT normal FPG 110 mg/dl; AIC 6.2 Case ACC/AHA Cholesterol Treatment Guidelines Clinical ASCVD LDL-C > 190 mg/dl Diabetes w age 40-75, LDL-C > yrs w >7.5% 10yr risk, LDL-C > 70 < 75 yrs, high intensity statin >75 yrs, moderate-intensity statin High Intensity Statin Moderate Intensity Statin Moderate to High Intensity Statin Stone NJ et al. Circulation Nov 12 (Epub ahead of print). Primary Prevention Global Risk Assessment To estimate 10-year ASCVD risk New Pooled Cohort Risk Equations White and Black men and women Heart Attack AND Stroke Risk included More accurately identifies higher risk individuals for statin therapy Focuses statin therapy on those most likely to benefit Avoid statin therapy in high-risk groups found not to benefit (heart failure, hemodialysis) Stone NJ et al. Circulation Nov 12 (Epub ahead of print) Pooled Cohort Equations ASCVD Risk Calculator - By Nathaniel Lee, MD Gender Age Race Total Cholesterol HDL Cholesterol Systolic BP Treatment for BP? Diabetes Smoking Scan code or visit or google: 2013 pooled cohort risk calculator app

16 Using the Risk Estimator Gender: Male Age: 48 Race: White Total Cholesterol: 232 mg/dl HDL-Cholesterol: 31 mg/dl SBP: 146 mm Hg Treatment for Hypertension: Yes Diabetes: No Smoker: No Using the Risk Estimator 10-Year ASCVD Risk: 8.8% calculated risk 1.7% with optimal risk factors Optimal risk factors include: Total cholesterol 170 mg/dl HDL-C 50 mg/dl SBP 110 mm Hg Not taking meds for hypertension Not diabetic Non smoker ACC/AHA Cholesterol Treatment Guidelines Case Clinical ASCVD LDL-C > 190 mg/dl < 75 yrs, high intensity statin >75 yrs, moderate-intensity statin High Intensity Statin Atorvastatin 10 mg initiated Diabetes w age 40-75, LDL-C > 70 Moderate Intensity Statin yrs w >7.5% 10yr risk, LDL-C > 70 Moderate to High Intensity Statin Stone NJ et al. Circulation Nov 12 (Epub ahead of print). Case Patient returns to the office 6 weeks later, complaining of muscle aches. You discontinue the statin and investigate. Statins:Myopathy Myopathy: Any disease of muscles Myalgias: pain in a muscle of group of muscles ~10% Myositis: muscle symptoms with CK ~2.5% Rhabdomyolysis: > 50 fold in CK + renal impairment <0.1% Bruckert E et al, Cardiov Drugs 19:403, 2005 Brown WV, Curr Opin Lipid 19:558, 2008 Onusko E, J Fam Pract 57:449, 2008

17 Case Patient labs: CPK 122 Creatinine Urinalysis negative for myoglobinuria What the Clinician Needs to Consider Hypothyroidism Other drugs Fibrates, azole anti-fungals, cyclosporine, macrolides, diltiazem, HIV protease inhibitors Genetic differences in drug-metabolizing enzymes, e.g. OATP1B1 SLCO1B1, CYP2D2, 3A4 Neuromuscular diseases Mitochondrial myopathy, McArdles disease, myotonic dystrophy, polymyositis Case You decide to add a low dose of a different statin (i.e.- 5 mg rosuvastatin). The patient tolerates this dose and does not report any muscle symptoms. Due to prior muscle symptoms, the patient is unwilling to have his dose titrated up. His lipids are shown on the next slide. Laboratory Assessment Measurement Baseline 6 weeks Statin Added TC (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) Non-HDL-C (mg/dl) What are the next steps? Final Laboratory Assessment--Prescription Omega 3 Added to Statin Therapy Measurement Baseline 6 weeks 12 weeks Statin Added TC (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) Non-HDL-C (mg/dl) Omega 3 Added