Achieving Effective Hypertriglyceridemia Treatment Peter P. Toth, MD, PhD Professor of Clinical Family and Community Medicine University of Illinois Director of Preventive Cardiology CGH Medical Center Sterling, Illinois Karol E. Watson, MD, PhD Professor of Medicine/Cardiology Codirector, UCLA Program in Preventive Cardiology Geffen School of Medicine at UCLA Los Angeles, CaliforniaLearning Objectives * Discuss the rationale for treating HTG and possible treatment options * Identify patient education strategies to relay the importance of lowering TGsPatient Case Presentation * A 58-year-old man with CHD (prior NSTEMI 2 y ago) and hypertension * Hospitalized for an episode of pancreatitis last year * Current complaint: — High TG levels — Prior episode of pancreatitisPatient Profile * Medical History — CHD = NSTEMI2 y ago — Hypertension — Pancreatitis * Physical Examination — HR 64/min, BP 148/88 mm Hg — Normal cardiac examination — Mild diffuse abdominal tenderness * Medications — Metoprolol XL 50 mg PO daily — Lisinopril 10 mg PO daily — Atorvastatin 40 mg PO daily — Aspirin 81 mg PO daily — OTC fish oil capsules * Laboratory Values — Total cholesterol 346 mg/dL LDL-C treated to target — HDL-C 37 mg/dL — TGs 745 mg/dL 8Fatty Acid Metabolism © e-<~ CETP ‘Small 16 ) dense HDL Increased FFA & Renal clearance | Chylomicron/VLDL —— Lipases KX 1s CETP © Cholesterol eA Oe Pur lils Small dense LDL — Lipases Fay ver °° Bays H, et al. Future Lipidol. 2006;1:389-420.Mechanism of HTG-Induced Pancreatitis AP develops when intracellular mechanisms to inhibit trypsin activation are overwhelmed by biochemical/structural injury. Pancreatitis induction depends on a cascade of events. ecg Saeco eg CCL to org Pi i er sea em NCE RRs Mull col E Wang GJ, et al. World J Gastroenterol. 2009;15:1427-1430; Felderbauer P, et al. Basic Clin Pharmacol Toxicol. 2005;97:342-350; Makhija R, et al. J Hepatobiliary Pancreat Surg. 2002;9:401-410.Patient Profile * Medical History — CHD = NSTEMI2 y ago — Hypertension — Pancreatitis * Physical Examination — HR 64/min, BP 148/88 mm Hg — Normal cardiac examination — Mild diffuse abdominal tenderness * Medications — Metoprolol XL 50 mg PO daily — Lisinopril 10 mg PO daily — Atorvastatin 40 mg PO daily — Aspirin 81 mg PO daily — OTC fish oil capsules * Laboratory Values — Total cholesterol 346 mg/dL LDL-C treated to target — HDL-C 37 mg/dL — TGs 745 mg/dL 8Omega-3 Fatty Acid Intake AHA Recommendations Population Patients without documented CHD Patients with documented CHD Patients who need to lower TG levels Recommendation Eat fish at least twice a week Include oils and foods rich in a-linolenic acid Consume approximately 1 g/d of EPA plus DHA (capsule form could be considered) Consume 2 to 4 g/d of prescription EPA plus DHA Kris-Etherton PM, et al. Circulation. 2002;106:2747-2757.Prescription-Only Omega-3s vs Dietary Supplement Omega-3s Omega-3 Acid Icosapent Ethyl Esters Ethyl FDA product classification pie Die FDA approval Yes Yes Ingredients DHA plus EPA EPA Quantity of omega-3 ‘i per capsule, g Capsules/d to achieve ce 4g omega-3 Tested in clinical trials Yes Yes Kris-Etherton PM, et al. Circulation. 2002;106:2747-2757. Dietary Supplements Food No Variable amounts of DHA plus EPA (may include other PUFAs) Typically 300 to 800 mg EPA plus DHA Typically 100 to 400 mg EPA Typically 5 to 13 for EPA plus DHA Typically 10 to 40 EPA Not requiredPatient Presentation Metabolic Syndrome * Patient has characteristic features of metabolic syndrome: — Elevated TG levels associated with some depression of HDL-C, hypertension, overweight * Physical examination characterized by: — Normal HR and high BP despite therapy with lisinopril — Normal cardiac examination — Some mild, diffuse tenderness in the abdomen characteristic of patients prone to recurrent pancreatitis; possible low-grade inflammatory changes of visceral adipose tissue or the omentum * FBG not measured, but based on the patient profile, it is highly likely he was dysglycemicOmega-3 Preparations Agent Trade Name Indication EPA Vascepal*! TGs = 500 mg/dL Lovazal®) TGs = 500 mg/dL EPA/DHA Omtryg!*) TGs 2 500 mg/dL Epanoval4! TGs > 500 mg/dL. 9 Omega-3 EPA'*); ge ee ee ee ee 5 double bonds . OH EPA (20:5 n-3) 9 Omega-3 DHA): ee HC ‘OH 6double bonds "2 DHA (22:6 n-3) a.Vascepa® PI 2012; b. Lovaza® Pl 2004; c. Omtryg® PI 2004; d. Epanova® PI 2014; e. Bays HE. Drugs of Today. 200! 105-246.Secondary Causes of HTG Positive-energy balanced diet with high saturated fat or high glycemic index content * Obesity Uncontrolled diabetes Hypothyroidism Nephrotic syndrome Various medications: antiretroviral regimens, some phenothiazines and second-generation antipsychotics, nonselective B-blockers, thiazide diuretics, oral estrogens, glucocorticosteroids, tamoxifen, isotretinoin Excessive alcohol consumption Bays HE. The Johns Hopkins Textbook on Dyslipidemia. 2010:245-257.Incidence of Pancreatitis by TG Level * Effect of TG Level on AP Incidence of AP Risk: w N a — Significant dose- response relationship between TG level and incident AP (adjusted hazard ratio 1.04 [95% CI 1.02 to 1.05]) a ° a — Risk of incident AP increased by 4% for every 100-mg/dL increase in TG level ° 149 mg/dL 150-499mg/dl > 500 mg/dL (n=31,740) (n=31,887) (n= 3642) TG Level Crude Incidence, cases per 1000 patient-y After adjustment for covariates and removal of patients hospitalized for gallstones, chronic pancreatitis, alcohol-related morbidities, renal failure, and other biliary disease. Murphy M, et al. JAMA Intern Med. 2013;173:162-164.Effects of Nutrition Practices on TG Lowering Weight loss (5%-10% of body weight) 20% Implement a Mediterranean-style diet 15% Add omega-3 fatty acids (per gram) 10% Decrease carbohydrate - 1% Energy replacement with omega fatty acids Eliminate trans fats - 1% Energy replacement with omega fatty acids 0 5 10 15 20 TG Lowering, % Miller M, et al. Circulation. 2011;123:2292-2333.Patient Empowerment in Managing HTG * Important to effectively communicate with patients about the need to treat HTG and making sure they understand: — Why they are taking omega-3 fatty acids — Why omega-3 formulations need to be pure — What impact omega-3s have on TG levels * Important for patient to follow through on a comprehensive approach to lifestyle modificationAbbreviations AHA = American Heart Association AP = acute pancreatitis DHA = docosahexaenoic acid EPA = eicosapentaenoic acid FDA = US Food and Drug Administration HDL = high-density lipoprotein HTG = hypertriglyceridemia LDL = low-density lipoprotein OTC = over-the-counter TG = triglyceride VLDL = very low-density lipoprotein