Using Evidence-Based Strategies to Manage Elevated Triglycerides

Transcription

1 Using Evidence-Based Strategies to Manage Elevated Triglycerides Louis Kuritzky, MD Family Medicine Gainesville, Florida Peter P. Toth, MD, PhD, FAAFP, FNLA, FAHA, FCCP, FACC CGH Medical Center Sterling, Illinois University of Illinois College of Medicine Peoria, Illinois Michael Miller, MD, FACC, FAHA University of Maryland School of Medicine Center for Preventive Cardiology University of Maryland Medical Center Baltimore, Maryland This event is not a part of the official AAFP Assembly. This CME activity is jointly provided by the University of New Mexico School of Medicine, Office of Continuing Medical Education and PVI, PeerView Institute for Medical Education. This activity is supported by an independent educational grant from AstraZeneca LP.

2 Faculty Disclosures Louis Kuritzky, MD, has no financial interests/relationships or affiliations in relation to this activity. Michael Miller, MD, FACC, FAHA, has a financial interest/relationship or affiliation in the form of: Consultant for Amarin Corporation and AstraZeneca. Advisory Board for Amarin Corporation and AstraZeneca. Other Financial or Material Support from Steering Committee for REDUCE-IT study. Peter P. Toth, MD, PhD, FAAFP, FNLA, FAHA, FCCP, FACC, has a financial interest/relationship or affiliation in the form of: Consultant for Amgen Inc.; AstraZeneca; Kowa Pharmaceuticals America, Inc. and Merck & Co., Inc. Speakers Bureau participant with Amarin Corporation; AstraZeneca; Genzyme Corporation, a Sanofi company; Kowa Pharmaceuticals America, Inc.; and Merck & Co., Inc. This event is not a part of the official AAFP Assembly. This CME activity is jointly provided by the University of New Mexico School of Medicine, Office of Continuing Medical Education and PVI, PeerView Institute for Medical Education. This activity is supported by an independent educational grant from AstraZeneca LP.

3 Visit us at Watch for the ondemand version in the coming weeks Download the slides and Practice Aids Apply for CME credit Need more information? Send an to

4 Exploring the Association Between Elevated Triglycerides and Cardiovascular Disease Photo Pending Michael Miller, MD, FACC, FAHA University of Maryland School of Medicine Center for Preventive Cardiology University of Maryland Medical Center Baltimore, Maryland

5 NHANES : Elevated Triglycerides Are Prevalent 1 NHANES: National Health and Nutrition Examination Survey; TG: triglyceride. 1. Miller M et al. Circulation. 2011;123:

6 Racial/Ethnic Differences in Dyslipidemia Prevalence 1,2 TG Cutoff Points, mg/dl a Demographic Overall (age 20 years) Men Women b Mexican American Non-Hispanic, black Non-Hispanic, white Use of triglyceridelowering medications c 18 About one-third of US adults have elevated TG ( 150 mg/dl) d a Percentage of participants. b Excludes pregnant women. c Includes fenofibrate, gemfibrozil, niacin, or statin. d US Census age 20 and older, July 1, 2010, was 226,113, Miller M et al. Circulation. 2011;123: Ford ES et al. Arch Intern Med. 2009;169:

7 Do Elevated Triglycerides Raise CV Risk? On the one hand Statin trial results have conflicted, showing either an association or a lack thereof between high TGs and CV risk 1,2 Univariate analyses of epidemiologic studies in the general population associate high TGs with CV risk This association is attenuated after correcting for other standard lipids, including plasma levels of high-density lipoprotein cholesterol 3 1. Miller M et al. J Am Coll Cardiol. 2008;51: Pedersen TR et al. Circulation. 1998;97: The Emerging Risk Factors Collaboration. JAMA. 2009;302:

8 Do Elevated Triglycerides Raise CV Risk? 1-3 (Cont d) On the other hand Mechanistic and genetic studies suggest an association between elevated coronary risk and high levels of TRLs High TGs are a marker for high TRLs TRL remnant cholesterol appears to contribute to plaque formation and progression in animal models TRL remnants are retained in the arterial intima and are found in atherosclerotic plaques TRLs: TG-rich lipoproteins. 1. Daugherty A et al. J Lipid Res. 1985;26: Nordestgaard BG et al. Arterioscler Thromb Vasc Biol. 1995;15: Proctor S et al. Eur J Clin Invest. 1998;28:

9 High Residual CV Risk Persists in Some Statin-Treated Patients 1 Residual CV risk: the risk of CV events that persists despite meeting treatment goals for LDL-C, BP, and blood glucose, according to current standards of care Residual risk may be reduced by targeting atherogenic dyslipidemia secondary to LDL-C reduction Lower elevated triglycerides Raise low HDL-C HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol. 1. Fruchart J-C et al. Cardiovascular Diabetology. 2014;13:26.

10 Overview of Triglyceride Metabolism 1 Apo A-V: apolipoprotein A-V; CMR: chylomicron remnant; FFA: free fatty acid; HTGL: hepatic triglyceride lipase; IDL: intermediate-density lipoprotein; LDL-R: LDL receptor; LPL: lipoprotein lipase; LRP:LDL receptor related protein; VLDL: very low-density lipoprotein; VLDL-R: VLDL receptor. 1. Miller M et al. Circulation. 2011;123:

11 Metabolic Consequences of Elevated Triglycerides 1 CETP: cholesteryl ester transfer protein. 1. Miller M et al. Circulation. 2011;123:

12 Do Triglycerides Directly Raise CV Risk or Simply Represent a Biomarker of CV Risk? 1 Direct TG-rich lipoproteins are atherogenic, especially cholesterol-rich remnants TG lipolysis by lipoprotein lipase creates inflammatory FFAs High TGs cause atherogenic changes in LDL-C and HDL-C TG levels of mg/dl are often associated with hyperapob Lowering TGs reduces CV events in patients with dyslipidemia Indirect The association of high TGs with CV risk is weaker than the association with LDL-C Partially dependent on HDL-C Severely elevated TGs associated with elevated chylomicrons is not related to high CV risk No TG accumulation in atherosclerotic plaques TG-lowering drugs are not clearly proven to lower CV risk hyperapob: hyperapobetalipoproteinemia. 1. Miller M et al. Circulation. 2011;123:

13 Positive Relationship Between CAD and Postprandial Plasma Triglycerides 1 TG levels in the course of postprandial lipemia in CAD patients and control subjects Postprandial TG levels corrected for fasting TGs in the same subjects CAD: coronary artery disease. 1. Patsch JR et al. Arterioscler Thromb. 1992;12:

14 Elevated Triglycerides Associated With Small-Diameter LDL Particles, HDL-C, and Non-HDL-C 1 Fasting Lipid Panel, mg/dl Total cholesterol 108 LDL-C 130 Triglycerides 90 HDL-C 50 Non-HDL-C 148 Fasting Lipid Panel, mg/dl Total cholesterol 210 LDL-C 130 Triglycerides 250 HDL-C 30 Non-HDL-C Otvos JD et al. Am J Cardiol. 2002;90:22i-29i.

15 NHANES : Association Between BMI and High Triglycerides 1 Percentage of participants within a triglyceride category as a function of BMI status BMI, kg/m 2 <150 (n = 3,250) Triglyceride Concentration, mg/dl <200 (n = 4,057) 150 (n = 1,744) 200 (n = 937) < times greater prevalence 1. Miller M et al. Circulation. 2011;123:

16 Enlarged Waist Combined With Elevated Triglycerides May Predict CVD as Well as MetS in Menopausal Women 1 Kaplan-Meier curves indicating CV event rates in women with (n = 88) or without (n = 469) EWET or with (n = 100) or without (n = 433) MetS, per 2001 NCEP (EWET: waist 88 cm and TG 128 mg/dl) CVD: cardiovascular disease; EWET: enlarged waist with elevated triglycerides; MetS: metabolic syndrome; NCEP: National Cholesterol Education Program. 1. Tankó LB et al. Circulation. 2005;111:

17 PROVE IT-TIMI 22: Lowering Triglycerides Lowers CHD Risk, Independent of LDL-C 1 Achieving both low LDL-C and low TG (<150 mg/dl) may be important therapeutic strategies in patients after ACS a Death, MI, and recurrent ACS. b ACS patients on atorvastatin 80 mg or pravastatin 40 mg. c Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, or prior statin therapy, prior ACS, peripheral vascular disease, and treatment. ACS: acute coronary syndrome; CHD: coronary heart disease; MI: myocardial infarction; PROVE-IT TIMI: Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction. 1. Miller M et al. J Am Coll Cardiol. 2008;51:

18 Low HDL-C and High Triglycerides Increase CVD Risk Even When LDL-C Levels Are Well Controlled 1 a On-treatment level (3-month statin therapy), N = b Mean LDL-C 58 mg/dl, mean TG 126 mg/dl. c P =.03 for differences among quintiles of HDL-C. TNT: Treating to New Targets. 1. Barter P et al. N Engl J Med. 2007;357:

19 PROCAM: Fasting Triglyceride is an Independent Risk Factor for CHD Events 1 N = 4,849 middle-aged men 8-year follow-up Outcome = CHD events according to the risk factors present at study entry LDL-C/HDL-C ratio > 5 carries a 19.2% chance of a CHD event over 8 years LDL-C/HDL-C ratio > 5 combined with high TGs carries a 26.9% risk PROCAM: Prospective Cardiovascular Münster study. 1. Assmann G et al. Eur Heart J. 1998;19(Suppl M):M8-14.

20 Consistent Significant Association Between Triglycerides and CHD Risk 1a a Available prospective studies of triglycerides and CHD in essentially general populations. b Includes three studies that were published before 1995 but were not included in the previous review. 1. Sarwar N et al. Circulation. 2007;115:

21 Association Between CHD Risk and Genotypes That Raise Triglyceride Levels 1 Disease risk for genetically raised triglycerides (20,842 patients with CHD, 35,206 control patients) was compared with that recorded for equivalent differences in circulating triglyceride levels in prospective studies (302,430 participants with no history of CVD; 12,785 incident cases of CHD during 2.79 million person-years at risk). 1. Sarwar N et al. Lancet. 2010;375:

22 Adjustment for Non-HDL-C, But Not HDL-C, Attenuates Risk 1 a Nonlipid risk factors include: systolic BP, smoking status, Hx of diabetes, and BMI. 1. Sarwar N et al. Lancet. 2010;375:

23 AHA Scientific Statement on Triglyceride Classification 1 Triglyceride Designation Triglyceride Revisions Between 1984 and NIH Consensus Panel, mg/dl 1993 NCEP ATP II, mg/dl 2001 NCEP ATP III, mg/dl Desirable <250 <200 <150 Borderline high High Very high >1,000 >1,000 >500 AHA: American Heart Association; ATP: Adult Treatment Panel; NIH: National Institutes of Health. 1. Miller M et al. Circulation. 2011;

24 Can Hepatic Triglycerides Cause Atherosclerosis? 1 Con HTG CVD weaker than LDL-C, partly HDL-C dependent Severe HTG from chylomicrons not related to CVD Triglyceride accumulation not seen in atherosclerotic plaque Triglyceride-lowering drugs not completely proven to CVD Pro TG-rich lipoproteins are atherogenic (especially cholesterol-rich remnants) TG lipolysis by lipoprotein lipase pro-inflammatory free fatty acids (uptake by CD36 and fatty acid binding proteins to nucleus) HTG causes atherogenic changes in LDL and HDL TG-lowering drugs CVD in HTG/low-HDL-C patients TG ~ mg/dl is often associated with hyper-apo B (ie, pro-atherogenic state) HTG: hepatic triglyceride. 1. Miller M et al. Circulation. 2011;123;

25 How Should We Use Lipid Measures to Assess CV Risk in Patients With Dyslipidemia?

26 Predicting a First Atherosclerotic Cardiovascular Event 1,2 Calculator uses the Pooled Cohort Equations to estimate the 10-year primary risk of ASCVD among patients without preexisting CVD who are between 40 and 79 years old Patients are considered to be at elevated risk if the Pooled Cohort Equations predicted risk 7.5% The Pooled Cohort Equations have been proposed to replace the Framingham 10-year CVD calculation ACC: American College of Cardiology; ASCVD: atherosclerotic cardiovascular disease. 1. ACC/AHA 2013 Prevention Guidelines CV Risk Calculator. Accessed September 10, Goff DC et al. JACC 2014;63:

27 2013 ACC/AHA Guideline: Hypertriglyceridemia 1 Although elevations in LDL-C often occur simultaneously with elevated triglyceride levels, the Panel did not conduct a systematic review on lifestyle and drug therapies for the treatment of elevated triglyceride levels. Marked exacerbations of triglycerides > 1,000 mg/dl may indicate those who may develop very marked triglyceride elevations that could trigger hyperlipidemic pancreatitis. Because of the increased risk for pancreatitis at these triglyceride levels, drug therapy specifically to lower triglycerides is advised. The fibrates fenofibrate and gemfibrozil are considered first-line agents for triglyceride-lowering. Marine omega-3 fatty acids (docohexanoic acid [DHA] and EPA) in doses of 3 to 4 g and niacin 2 g also have been shown to reduce triglycerides in individuals with severe hypertriglyceridemia. EPA: eicosapentanoic acid. 1. Stone NJ et al. Circulation. 2014;129(25 Suppl 2):S1-45.

28 Targets for Therapy After LDL-C Goals in Patients With Triglycerides 200 mg/dl 1 Patient Category LDL-C Target, mg/dl Non-HDL-C Target, mg/dl No CHD, <2 risk factors <160 <190 No CHD, 2 risk factors <130 <160 CHD or CHD risk equivalent <100 < Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:

29 Summary and Conclusions HTG and low HDL-C (with high apob, LDL-P, and SD LDL) are the atherogenic dyslipidemia common in insulin resistance/mets and type 2 diabetes Both HTG and low HDL-C strongly predict CVD risk, even with excellent LDL-C control on a statin

30 Summary and Conclusions (Cont d) 1-3 After assessing for ASCVD with risk calculator, guideline recommendations for statin treatment include: 1.Individuals with clinical ASCVD 2.Individuals with primary elevations of LDL 190 mg/dl 3.Individuals aged years with diabetes and an LDL of mg/dl without clinical ASCVD 4.Individuals without ASCVD or diabetes aged years with LDL of mg/dl and a 10-year ASCVD risk of 7.5% or higher 1. ACC/AHA 2013 Prevention Guidelines CV Risk Calculator. Accessed September 10, Goff DC et al. J Am Coll Cardiol 2014;63: Goff DC et al. JACC. 2014;63: Stone NJ et al. Circulation. 2014;129(25 Suppl 2):S1-45.

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32 Fine-Tuning Elevated Triglyceride Management: Assessing Conventional and Emerging Management Strategies Peter P. Toth, MD, PhD, FAAFP, FNLA, FAHA, FCCP, FACC CGH Medical Center Sterling, Illinois University of Illinois College of Medicine Peoria, Illinois

33 2013 ACC/AHA Guidelines for Initiating Treatment of Elevated Triglycerides 1 Clinical ASCVD and not currently on statin Evaluation before initiating statin Fasting lipid panel ALT CK (if indicated) Consider evaluation for other secondary causes or conditions that may influence statin therapy Evaluate and treat laboratory abnormalities Triglycerides 500 mg/dl LDL-C 190 mg/dl Secondary causes If primary, screen family for FH Unexplained ALT > 3X ULN If nonfasting TGs are >500 mg/dl A fasting lipid panel is required Lowering TGs should be the focus of therapy ALT: alanine aminotransferase; CK: creatine kinase; FH: familial hypercholesterolemia; ULN: upper limit of normal. 1. Stone NJ et al. Circulation. 2014;129:S1-S45.

34 ATP III Treatment Goals for Triglyceridemia 1 TG, mg/dl Classification Borderline high Primary Target of Therapy LDL-C goal High LDL-C goal 500 Very high Reduce TG to prevent acute pancreatitis Treatment Recommendations Weight reduction, increased physical activity Weight reduction, increased physical activity; consider drug therapy to achieve non-hdl-c goal (intensify LDL-C lowering with statin or lower VLDL-C by adding niacin or fibrate) Very low-fat diet (fat 15% of total calories), weight reduction, increased physical activity, and drug therapy with niacin or fibrate

35 Secondary Causes of Hypertriglyceridemia Estrogen Tamoxifen Alcohol Coffee Hypothyroidism Diabetes Liver disease Nephrotic syndrome Pregnancy Obesity Lipodystrophy Gaucher s disease Glycogen storage disease type I Medications Thiazides Beta blockers Corticosteroids Retinoid Protease inhibitors Long-term interferon Antipsychotic meds

36 Effects of Nutrition Practices on Triglyceride Lowering 1 Nutrition Practice TG Lowering, % Weight loss (5%-10% of body weight) 20 Implement a Mediterranean-style diet vs a low-fat diet Add marine-derived PUFA (EPA/DHA), per gram 5-10 Decrease carbohydrates 1% energy replacement with MUFA/PUFA Eliminate trans fats 1% energy replacement with MUFA/PUFA PUFA: polyunsaturated fatty acids. 1. Miller M et al. Circulation. 2011;123:

37 Effect of Lipid-Lowering Therapies on TG Reduction 1 Fibrates 30%-50% Niacin 20%-50% Omega-3 10%-40% Statins 10%-30% Ezetimibe 5%-10% 1. Ballantyne CM, ed. Clinical Lipidology: A Companion to Braunwald s Heart Disease. 2009;

38 Treating Hypertriglyceridemia: Niacin Therapy

39 Nicotinic Acid ER: A Broad Spectrum Lipid-Modulating Agent ER: extended release.

40 AIM HIGH: Baseline Lipids On Statin, mg/dl (n = 3,196) Off Statin, mg/dl (n = 218) LDL-C (mean) HDL-C (mean) Triglycerides (median) Non-HDL (mean) ApoB

41 AIM HIGH: Primary Outcome

42 Effect of High-Risk Groups on Primary Outcome No. Patients With Events (% of Category) TG 198 and HDL < 33 a ERN Better ERN Worse HR (95% CI) P b Int. Yes 48 (17.0) 54 (22.4) 0.74 ( ) No 234 (16.3) 220 (15.1) 1.09 ( ) TG 200 and HDL < 32 Yes 40 (16.7) 50 (25.0) 0.63 ( ) No 242 (16.2) 224 (15.0) 1.11 ( ) Log HR and 95% CI a Highest tertile of TG and lowest tertile of HDL-C. b Heterogeneity by treatment. ERN: extended-release niacin.

43 Treating Hypertriglyceridemia: Fibrate Therapy

44 Reduction in CV Events a : Fibrate Studies Study (Fibrate) ACCORD (fenofibrate/ simvastatin) FIELD (fenofibrate) Primary Endpoint (All Patients) 8% (P =.32) 11% (P =.16) BIP (bezafibrate) 7.3% (P =.24) HHS (gemfibrozil) 34% (P <.02) Lipid Criteria, mmol/l TG HDL-C 0.88 Primary Endpoint (Lipid Subgroup) 31% TG low HDL-C b 27% (P =.005) TG HDL-C 0.9 TG > LDL/HDL > % (P =.02) 71% (P <.005) a Comparator treatments: simvastatin in ACCORD Lipid and placebo in other studies. b < 1.03 in men and < 1.29 in women.

45 SAFARI: Combination Therapy in Patients With Combined Hyperlipidemia 1 N = 618 a P <.001 versus simvastatin. 1. Grundy SM et al. Am J Cardiol. 2005;95:

46 Treating Hypertriglyceridemia: Omega-3 Fatty Acid Therapy

47 Relative Risk of Sudden Cardiac Death and Blood Omega-3 Levels: Physicians Health Study 1 FA: fatty acid. 1. Albert CM et al. N Engl J Med. 2002;346:

48 GISSI-Prevenzione: Time Course of Clinical Events 1 >11,300 post-mi patients were given usual care with or without 850 mg EPA+DHA for 3.5 years Total mortality reduced by 28% (P =.027) Days Days Sudden death reduced by 47% (P =.0136) 1. Marchioli R et al. Circulation 2002;105: Days

49 Structure of Omega-3 and Omega-6 Fatty Acids 1 1. Din JN et al. BMJ. 2004;328:30-35.

50 AHA Recommendations for Omega-3 Fatty Acid Intake 1 Population Patients without documented CHD Patients with documented CHD Patients needing triglyceride lowering Recommendation Eat a variety of (preferably oily) fish at least twice a week; include oils and foods rich in alpha-linolenic acid (flaxseed, canola, and soybean oils; flaxseeds; and walnuts) Consume ~1 g of EPA+DHA per day, preferably from oily fish; EPA+DHA supplements could be considered in consultation with the physician 2-4 g of EPA+DHA per day provided as capsules under a physician s care 1. Kris-Etherton PM et al. Circulation 2002;106:

51 GISSI-Prevenzione: Effects of 850 mg/d of EPA+DHA on Serum Lipids 1 1. Marchioli R et al. Circulation 2002;105: n-3, PUFA

52 Effects of EPA on Major Coronary Events in Hypercholesterolemic Patients (JELIS) 1 Controls (n = 9,319) EPA Treatment (n = 9,326) Age (years) 61 (9) 61 (8) N > 18,000 (Japan) All administered statins 1 o and 2 o prevention 5-year follow-up 1,800 mg EPA/day Mean TG = 150 mg/dl Male 2,908 (31%) 2,951 (32%) BMI (kg/m 2 ) 24 (3) 24 (3) CV history MI Angina CABG or PTCA 502 (5%) 1,484 (16%) 433 (5%) 548 (6%) 1,419 (15%) 462 (5%) Risk factors Smoking Diabetes Hypertension 1,700 (18%) 1,524 (16%) 3,282 (35%) 1,830 (20%) 1,516 (16%) 3,329 (36%) Serum lipid values, mmol/l Total cholesterol LDL-C HDL-C 7.11 (0.68) 4.70 (0.75) 1.51 (0.44) 7.11 (0.67) 4.69 (0.76) 1.52 (0.46) TG 1.74 ( ) 1.73 ( ) BP, mmhg Systolic Diastolic 135 (21) 79 (13) 135 (21) 79 (13) CABG: coronary artery bypass grafting; HMG-CoA: 3-hydroxy-3-methylglutarylcoenzyme; PTCA: percutaneous transluminal coronary angioplasty. 1. Yokoyama M et al. Lancet. 2007;370:215. HMG CoA RI Pravastatin Simvastatin Other statin 5,553 (60%) 3,417 (37%) 128 (1%) 5,523 (60%) 3,272 (36%) 110 (1%)

53 JELIS Study: Ethyl-EPA Reduced CV Events 1 But minimal (5%) net triglyceride-lowering effect 1. Yokoyama M et al. Lancet. 2007;370:215.

54 Addition of EPA to Statin Therapy in Japanese Patients 1 a Sudden cardiac death, fatal and non-fatal MI, unstable angina, angioplasty, stenting, or CABG. TC: total cholesterol. 1. Yokoyama M et al. Lancet. 2007;369:

55 Patient Subgroup: TG > 150 mg/dl and HDL < 40 mg/dl (JELIS) 1 1. Saito S et al. Atherosclerosis. 2008;199:

56 Prescription Omega-3 Fatty Acids: EPA and DHA Ethyl Esters 1 Omega-3-acid ethyl esters is a combination of ethyl esters of omega-3-fatty acids containing 465 mg EPA and 375 mg DHA in 1-g capsules Omega-3-acid ethyl esters is FDA approved for very high triglycerides (>500 mg/dl) The daily dose of omega-3-acid ethyl esters is 4 g/d taken as a single 4-g dose (four capsules) or as two 2-g doses (two capsules given twice daily) 1. Lovaza (omega-3-acid ethyl esters) Prescribing Information. Accessed September 30, 2014.

57 Prescription Omega-3 Fatty Acids: EPA and DHA Free Fatty Acids 1 Omega-3-carboxylic acids 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-acid ethyl esters is FDA approved for very high triglycerides (>500 mg/dl) The daily dose of omega-3-carboxylic acids is 2 g (two capsules) or 4 g (four capsules) once daily 1. Espanova (omega-3-carboxylic acids) Prescribing Information. Accessed September 30, 2014.

58 Prescription Omega-3 Fatty Acids: EPA Ethyl Esters Only 1 Icosapent ethyl is a 96% pure ethyl ester of EPA Icosapent ethyl is FDA approved for very high triglycerides (>500 mg/dl) The daily dose is 4 g/d taken as two capsules twice daily 1. Vascepa (icosapent ethyl) Prescribing Information. Accessed September 30, 2014.

59 Statin + EPA (TG mg/dl): ANCHOR Lipid Endpoints 1 12-week trial in high-risk statin-treated patients (n = 702) with TG and LDL-C a P < b P <.001. c P <.01. d P <.05. Bottom line: EPA+DHA better for TG and HDL-C. EPA better for LDL-C, non-hdl-c, apob ( CVD?) 12-week trial in high-risk statin-treated patients (n = 702) with TG and LDL-C NS: not significant (P.05). Ballantyne CM et al. Am J Cardiol. 2012;110: Ballantyne CM et al. Am J Cardiol. 2012;110:

60 Statin + EPA/DHA (TG mg/dl): COMBOS Lipid Endpoints 1 TG baseline on statin a P < b P =.0522 between groups. c P =.0232 between groups. P: prescription. 1. Davidson MH et al. Clin Ther. 2007;29:

61 MARINE Trial: EPA Ethyl Ester 1 a P <.001. b P <.05. c P < d P <.01. ITT: intent-to-treat 1. Bays H et al. Am J Cardiol. 2011;108: P values reflect differences between AMR101 and placebo

62 Lipid Effects of Prescription Omega-3 in TG >500 mg/dl 1,2 a P < Kastelein JJP et al. J Clin Lipidol. 2014;8: Bays HE et al. Am J Cardiol. 2011;108:

63 EVOLVE: Omega-3 Free Fatty Acids Yield Significant TG Reduction Versus Olive Oil 1 1. Kastelein JJP et al. J Clin Lipidol. 2014;8:

64 ESPRIT: Significant TG Reduction Versus Olive Oil in Patients With Baseline TGs Between 200 and 500 mg/dl 1,2 1. Maki KC et al. JACC 2013;61(10_S):. doi: /s (13) Maki KC et al. Accessed August 5, 2014.

65 Event-Driven CV Outcome Trials With Omega-3 Fatty Acids 1,2 Reduction of Cardiovascular Events With EPA-Intervention Trial (REDUCE-IT) Enrolling 8,000 men and women 45 years; prior CHD (70% patients) or T2DM + 1 RF; 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 noninvasive 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: CV death, nonfatal MI, nonfatal stroke, emergent/elective coronary revascularization, or hospitalization for unstable angina Follow-up: 5 years Hx: hypophysectomized; RF: risk factor; TC: total cholesterol Accessed October 5, Accessed October 5, 2014.

66 Conclusions Hypertriglyceridemia is an important risk factor for atherosclerosis disease and continues to residual risk after statin therapy HTG is a marker for elevated serum levels of remnant lipoproteins, all components of non-hdl Niacin and fenofibrate have the capacity to reduce hepatic VLDL secretion; fenofibrate also promotes TG lipolysis by activating lipoprotein lipase Subgroup analyses from niacin and fibrate trials suggest they may impact CV risk in patients with HTG and low HDL

67 Conclusions (Cont d) Omega-3 fish oils are long-chain fatty acids that activate key pathways for TG disposal and reduce serum levels of TG Omega-3 fish oils are indicated for the treatment of severe HTG (>500 mg/dl) Outcomes trials (STRENGTH, REDUCE-IT) are underway to establish if these agents reduce risk for CV events in patients with moderate HTG

68 Triglycerides: Why You Should Think Twice About Pharmacotherapy Photo Pending Louis Kuritzky, MD Family Medicine Gainesville, Florida

69 Two Basic Clinical Questions and Answers Two Basic Clinical Questions 1. Has pharmacologic prescription of elevated triglycerides been proven to improve CV outcomes? 2. Has pharmacologic prescription of triglycerides been proven to reduce risk for pancreatitis? Two Basic Clinical Answers 1. CVD? No RCT has demonstrated this 2. pancreatitis? No RCT has demonstrated this RCT: randomized, controlled trial.

70 The Triglyceride Story: UpToDate Uncertainty Whether TGs Cause Atherosclerosis [I]t now seems clear that elevated TG levels are independently associated with CV risk It remains uncertain, however, whether this association is causal, such that hypertriglyceridemia causes atherosclerosis. CVD Risk Reduction With Treatment: Uncertain It is uncertain whether pharmacologic treatment targeted at reducing TG levels will reduce CV risk. 1. Rosenson RS. Accessed October 6, 2014.

71 The Triglyceride Story: UpToDate (Cont d) Preventing Pancreatitis: No High Quality Evidence Although high-quality evidence is lacking, for 1 0 prevention of pancreatitis, we and others suggest initiating pharmacologic treatment to TG when fasting concentration is >1000 mg/dl 1. Rosenson RS. Accessed October 6, 2014.

72 NICE UK Lipid Guidelines 2014 Do not routinely offer fibrates and do not offer nicotinic acid, a bile acid sequestrant, or omega-3 FA compounds for the prevention of CV disease to People who are being treated for 10 prevention People who are being treated for 20 prevention People with CKD People with type 1 or type 2 diabetes Tell people that there is no evidence that omega-3 fatty acid compounds help to prevent CV disease. 1. NICE Clinical Guideline Accessed October 6, 2014.

73 Lipid-Modifying Therapies and Risk of Pancreatitis: A Meta-Analysis 1 Hypertriglyceridemia has been reported to be the third most common cause of pancreatitis. This has led to major guidelines advice to commence TG-lowering treatment, usually fibrates, in persons with moderate and severe hypertriglyceridemia (above mg/dl). However, high quality evidence for this approach is lacking. no convincing trial data exist to support use of any agents for prevention of pancreatitis. 1. Preiss D et al. JAMA. 2012;308:

74 Fibrates to Treat Hypertriglyceridemia: Are Benefits Clinically Meaningful? When would we use fibrates? High triglycerides Very high triglycerides to prevent pancreatitis Add-on for elevated cholesterol Sometimes for other dyslipidemias

75 Fenofibric Acid Indications 1 In addition to an optimally dosed statin to TG and HDL in mixed dyslipidemia patients with CHD or CHD equivalent Monotreatment to TG in severe hypertriglyceridemia As monotreatment to LDL, total cholesterol, and Apo B, and HDL in 10 hypercholesterolemia or mixed dyslipidemia 1. Trilipix (fenofibric acid) Prescribing Information. Accessed October 6, 2014.

76 Fenofibrate: Does it Work? Quotes From the Prescribing Information 1 Indication: add to statin No incremental benefit on CV morbidity and mortality over and above that demonstrated for statin monotherapy has been established Indication: add to statin with CHD equivalent Fenofibrate at a dose equivalent to fenofibric acid 135 mg was not shown to reduce CHD morbidity and mortality in patients with type 2 diabetes mellitus 1. Trilipix (fenofibric acid) Prescribing Information. Accessed October 6, 2014.

77 Fenofibrate: Does it Work? Quotes From the Prescribing Information 1 (Cont d) Indication: to decrease TG in severe hypertriglyceridemia Markedly elevated levels of serum TG (eg. >2,000 mg/dl) may the risk of pancreatitis; the effect of fenofibric acid treatment on reducing this risk has not been adequately studied 1. Trilipix (fenofibric acid) Prescribing Information. Accessed October 6, 2014.

78 The Incomplete Story of Triglycerides and Pancreatitis You and I learned TG associated with pancreatitis TG >500 mg/dl must be lowered to prevent pancreatitis Fibrates, fish oil, diet, and nicotinic acid useful for this However TG IS associated with pancreatitis Unclear if is causal, consequential, or both No RCT has proven that TG in persons with TG reduces risk of pancreatitis Where did we get the TG >500 from?

79 The Incomplete Story of Triglycerides and Pancreatitis (Cont d) Pancreatitis has been reported in patients taking drugs of the fibrate class, including fenofibric acid. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge However formation with obstruction of the common bile duct. 1. Trilipix (fenofibric acid) Prescribing Information. Accessed October 6, 2014.

80 Triglycerides and CVD: Where Does This Leave Me? Triglycerides are associated with ASCVD Maybe causal, maybe not If causal, it remains to be determined whether modulation improves CV outcomes What s the risk:benefit ratio? However We know every medication has toxicity; a risk:benefit ratio, when benefits are indeterminate, cannot be measured

81 Triglycerides and Pancreatitis: Where Does This Leave Me? Triglycerides are associated with pancreatitis Maybe causal, maybe not If causal, it remains to be determined whether modulation improves CV outcomes What s the risk:benefit balance? However We know every medication has toxicity; a risk:benefit ratio, when benefits are indeterminate, cannot be measured

82 Case-Based Panel Discussion Photo Pending Photo Pending Louis Kuritzky, MD Family Medicine Gainesville, Florida Peter P. Toth, MD, PhD, FAAFP, FNLA, FAHA, FCCP, FACC CGH Medical Center Sterling, Illinois University of Illinois College of Medicine Peoria, Illinois Photo Pending Michael Miller, MD, FACC, FAHA University of Maryland School of Medicine Center for Preventive Cardiology University of Maryland Medical Center Baltimore, Maryland This event is not a part of the official AAFP Assembly. This CME activity is jointly provided by the University of New Mexico School of Medicine, Office of Continuing Medical Education and PVI, PeerView Institute for Medical Education. This activity is supported by an independent educational grant from AstraZeneca LP.

83 Case 1: K.B., a Woman With New-Onset Hypertriglyceridemia 55-year-old woman presents for yearly physical 3 years ago is post-menopausal and experiences hot flashes She is very active, exercises regularly, and drinks 1-2 glasses of wine with meals several times each week On exam: BP = 143/91; pulse 73; weight 130 lb; height 5 3 ; BMI = 30 Physical examination was unremarkable and without stigmata of hyperlipidemia Her fasting glucose is 103; A1c 5.3 Total cholesterol = 256; TG = 600; HDL = 40 A repeated lipid panel conducted in the fasting state confirmed very high triglycerides Asthma Hypertension GERD Medical History Medications Esomeprazole 40mg Montelukast 10mg once daily Lisinopril 20mg daily Metoprolol succinate 50mg

84 Deciding on the Treatment Plan Discuss treatment options Patient goals? Identify barriers to success in previous attempts Discuss intensities of various approaches and commitment required» Structured or less intensive lifestyle modification» Medications» Interventions to circumvent suboptimal adherence

85 K.B., Follow-Up Important to get TG levels down and reduce the risk of pancreatitis Intensive lifestyle modification Diet, exercise, weight loss Adequate dose of omega-3 fatty acids Start treatment with prescription omega-3 fatty acid therapy When TGs are very high, not necessary to start slow and titrate up

86 Case 2: R.D., a Hispanic Woman With Dyslipidemia R.D is a 64-year-old Hispanic woman with a history of type 2 diabetes, MI, and PCI 3 years ago who is being treated for dyslipidemia Laboratory Values Nonfasting lipid profile: LDL-C = 76 mg/dl HDL-C = 39 mg/dl Non-HDL-C = 140 mg/dl TG = 685 mg/dl A1c = 6.5% Medications ASA 81 mg once daily Atorvastatin 80 mg once daily Metformin 500 mg twice daily Saxagliptin 5 mg Examination: BMI = 28 kg/m 2, BP = 128/84 mmhg

87 Practical Algorithm for Screening and Management of Elevated Triglycerides 1

88 R.D., Follow-Up Assess risk factor profile to determine treatment goals In the setting of elevated TGs, LDL-C may be misleadingly low Non-HDL-C goal is a good lipid target to use, especially in patients with TG >200 mg/dl Compliance is always an important treatment issue

89 Ask the Faculty Q&A and Conclusions Photo Pending Photo Pending Louis Kuritzky, MD Family Medicine Gainesville, Florida Peter P. Toth, MD, PhD, FAAFP, FNLA, FAHA, FCCP, FACC CGH Medical Center Sterling, Illinois University of Illinois College of Medicine Peoria, Illinois Photo Pending Michael Miller, MD, FACC, FAHA University of Maryland School of Medicine Center for Preventive Cardiology University of Maryland Medical Center Baltimore, Maryland This event is not a part of the official AAFP Assembly. This CME activity is jointly provided by the University of New Mexico School of Medicine, Office of Continuing Medical Education and PVI, PeerView Institute for Medical Education. This activity is supported by an independent educational grant from AstraZeneca LP.

90 Thank You and Good Evening! Please remember to complete and submit your Post-Test and Evaluation for CME credit. Missed anything? Visit us at Download slides and Practice Aids Watch for the ondemand version of this symposium PVI, PeerView Institute for Medical Education, and the University of New Mexico School of Medicine are responsible for the selection of this report s topics, the preparation of editorial content, and the distribution of this report. The preparation of PeerView reports is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and the University of New Mexico School of Medicine. Our reports may contain references to unapproved products or uses of these products in certain jurisdictions. For approved prescribing information, please consult the manufacturer's product labeling. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports. Copyright , PeerView Press