September 19, 2013

Boston, MA

Faculty Eliot A. Brinton, MD, FAHA, FNLA

William C. Cromwell, MD, FAHA, FNLA

Session 2

Session 2: Tackling the Toughest Issues and Cases of Hypertriglyceridemia Learning Objectives

1. Discuss the role of elevated triglyceride (TG) levels in the assessment and diagnosis of dyslipidemia, including cardiovascular risk factors.

2. Apply best practices in the attainment of TG levels, including the role of fasting and nonfasting states in accurate evaluation.

3. Evaluate the management of hypertriglyceridemia through greater adherence to evidence-based practices and accepted guidelines.

4. Select potential new and emerging therapeutic approaches to manage TG-based dyslipidemia, mixed dyslipidemia, and associated cardiovascular risk.

Faculty

Eliot A. Brinton, MD, FAHA, FNLA President, American Board of Clinical Lipidology President, Utah Lipid Center Director, Atherometabolic Research Utah Foundation for Biomedical Research Salt Lake City, Utah

Dr Brinton obtained his MD from the University of Utah, trained in internal medicine at Duke University, and in endocrinology at the University of Washington. He has been on the faculty of Rockefeller University, Wake Forest University, the University of Arizona, and the University of Utah. He served as a founding board member of both the National Lipid Association and the American Board of Clinical Lipidology (ABCL). In 2012 he shared, with Jan L. Breslow, MD, of the Rockefeller University, the Robert I. Levy Award for excellence in lipoprotein metabolism research from the Kinetics and Metabolism Society. Currently, he serves as an editor of Lipids Online, assistant editor of the Journal of Obesity and on the editorial boards of the Journal of Clinical Lipidology, Lipids Online, the Journal of Managed Care Pharmacy, and Clinical Lipidology. He is currently president of the ABCL, president of the Utah Atherosclerosis Society, president of the Utah Lipid Center, and director of atherometabolic research at the Utah Foundation for Biomedical Research in Salt Lake City, Utah.

William C. Cromwell, MD, FAHA, FNLA Chief, Lipoprotein and Metabolic Disorders Institute Raleigh, North Carolina Adjunct Associate Professor Hypertension and Vascular Disease Center Wake Forest University School of Medicine Winston-Salem, North Carolina

Dr Cromwell is chief of the Lipoprotein and Metabolic Disorders Institute in Raleigh, North Carolina. He also serves as adjunct associate professor in the Hypertension and Vascular Disease Center at Wake Forest University School of Medicine in Winston-Salem, North Carolina. Dr Cromwell received his doctoral degree in medicine from the Louisiana State University School of Medicine. He completed residency training at the Trover Clinic Foundation, where he received one of twenty national Meade Johnson Graduate Fellowships. Subsequently, he completed postgraduate work in lipid disorders at the Washington University School of Medicine Lipid Research Center. Since 1990, Dr Cromwell's practice has specialized in the management of lipid and lipoprotein disorders affecting patients of all ages, as well as the evaluation of early vascular disease. Faculty Financial Disclosure Statements The presenting faculty reports the following: Dr Brinton receives grants from Abbott Laboratories, Amarin Corporation plc, Health Diagnostic Laboratory, Inc., and Roche; and honoraria from Abbott Laboratories, Aegerion Pharmaceuticals, Inc., Amarin Corporation plc, Atherotech, Daiichi Sankyo Co., Ltd., Essentialis, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., and Takeda Pharmaceutical Company Limited. Dr Cromwell receives consulting fees from Genzyme, Health Diagnostic Laboratory, Isis, and LabCorp, and fees for non-CME/CE services from Abbott, Kowa, Merck, and LipoScience.

Session 2

Education Partner Financial Disclosure Statement The content collaborators at Medtelligence, LLC have reported the following: Ben Caref, PhD, Managing Partner and Chief Medical Officer, develops content and has no financial relationships to report. Pamela J. Clark, Director of Editorial Services, provides editorial assistance and has no financial relationship to report. Acronym List Acronym Definition Apo apolipoprotein CVD cardiovascular disease HDL-C high density lipoprotein cholesterol HTG hypertriglyceridemia

Acronym Definition LDL-C low density lipoprotein cholesterol TG triglyceride(s) T2DM type 2 Diabetes Mellitus VLDL-C very low density lipoprotein cholesterol

Suggested Reading List American Diabetes Association. Standards of medical care in diabetes–2012. Diabetes Care. 2012;35(suppl 1):S11-S63. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7): 984-992. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108(5):682-690. Brinton EA, Ballantyne CM, Bays HE, et al. Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study. Cardiovasc Diabetol. 2013;12:100-109. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512-1524. Jellinger PS, Smith DA, Mehta AE, et al; for the AACE Task Force for Management of Dyslipidemia and Prevention of Atherosclerosis. American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1-78. Miller M, Stone NJ, Ballantyne C, et al; for the American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;30:115(4):450-458. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4(3):337-345. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375(9726):1634-1639.

1

Tackling the Toughest Issues and Cases of Hypertriglyceridemia

SPEAKERSEliot A. Brinton, MD, FAHA, FNLAWilliam C. Cromwell, MD, FAHA, FNLA

SESSION 29:45–11am

Presenter Disclosure Information

►Dr Brinton receives grants from Abbott Laboratories, AmarinCorporation plc, Health Diagnostic Laboratory, Inc., and Roche; and honoraria from Abbott Laboratories, AegerionPharmaceuticals, Inc., Amarin Corporation plc, Atherotech, Daiichi Sankyo Co., Ltd., Essentialis, Inc., KowaPharmaceuticals America, Inc., Merck & Co., Inc., and Takeda Pharmaceutical Company Limited.

►Dr Cromwell receives consulting fees from Genzyme, Health Diagnostic Laboratory, Isis, and LabCorp, and fees for non-CME/CE services from Abbott, Kowa, Merck, and LipoScience.

The following relationships exist related to this presentation:

Presenter Disclosure Information

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.

Tackling the Toughest Issues and Cases of Hypertriglyceridemia

September 19, 2013

Drug Names

Generic name Brand name(s)

Atorvastatin Lipitor (combination with amlodipine: Caduet)

Bezafibrate none

Estrogen Premarin, Estrace, Activella, Climara, etc.

Ezetimibe Zetia (and in statin combination: Vytorin, Liptruzet)

Fenofibrate Antara, Fenoglide, Lipofen, Tricor, Triglide, Trilipix

Fluvastatin Lescol, Lescol XL

Gemfibrozil Lopid

Icosapent Ethyl Vascepa

Isotretinoin various

Lovastatin Mevacor, Altoprev (combinationwith ER niacin: Advicor)

Generic name Brand name(s)

Metformin Glucophage, Glumetza, etc.

Niacin (extended,sustained & im-mediate release

Niaspan, Nicobid, Nicolar, Slo-Niacin, Niacor, etc.

Omega-3-acidethyl esters

Lovaza, Omacor

Pravastatin Pravachol, Pravigard PAC

Rosuvastatin Crestor

Simvastatin Zocor (ezetimibe combo Vytorin), niacin combo: Simcor)

Tamoxifen Nolvadex, Soltamox

Thiazide diuretic various

Learning Objectives

• Discuss the role of elevated triglyceride (TG) levels in the assessment and diagnosis of dyslipidemia, including cardiovascular risk factors

• Apply best practices in the attainment of TG levels, including the role of fasting and nonfasting states in accurate evaluation

• Evaluate the management of hypertriglyceridemia (HTG) through greater adherence to evidence based practices and accepted guidelines

• Select potential new and emerging therapeutic approaches to manage TG-based dyslipidemia, mixed dyslipidemia, and associated cardiovascular risk

2

What Is the Relationship of Hypertriglyceridemia and Low HDL-C to the Increased CVD Risk in T2DM?

William C. Cromwell, MD, FAHA, FNLAChief, Lipoprotein and Metabolic Disorders InstituteRaleigh, NCAdjunct Associate ProfessorHypertension and Vascular Disease CenterWake Forest University School of MedicineWinston-Salem, NC

Prevalence (%) of HTG by Age, Sex, and Ethnicity in NHANES 1999–2008

TG Cut Points, mg/dLa

Demographic ≥150 ≥200 ≥500

Overall (age ≥20 yrs) 31 16 1.1

Men 35 20 1.8

Womenb 27 13 0.5

Mexican American 35 20 1.4

Non-Hispanic, black 16 8 0.4

Non-Hispanic, white 33 18 1.1

Use of TG-lowering medicationsc 18

a Percentage of participants. bExcludes pregnant women. Miller M et al. Circulation. 2011;123:2292-333.c Includes fenofibrate, gemfibrozil, niacin, or statin. Ford ES et al. Arch Intern Med. 2009;169:572-8. dUS Census Age 20 and above, July 1, 2010, was 226,113,653. HTG=hypertriglyceridemia; NHANES=National Health and Nutrition Examination Survey; TG=triglyceride; yrs=years.

70 million persons, or ~1/3 of US adults, have elevated TG (≥150 md/dL)d

Fattyliver

Three Atherogenic Consequences of HTG

TG

CE

CETP HDL

Hepatic Lipase

Kidney

Rapid Lossof Apo A-I

HDL-C, HDL-P, & Apo A-I

SDHDL

3CE

TG

CETP

SDLDL

Apo B & LDL-P

LDL size Hepatic Lipase

LDL

2

VLDL

FFA / TGand

Fructose(glucose)

CentralAdiposity

FFA / TG

↑VLDL Synthesis

Apo=apolipoprotein; CE=cholesterol ester; CETP=CE transfer protein; FFA=free fatty acid; HDL=high-density lipoprotein; HDL-C=HDL cholesterol; LDL=low-density lipoprotein; LDL-P=LDL particle; SD=small dense; VLDL=very-low-density lipoprotein; VLDL-C=VLDL cholesterol; VLDL-P=VLDL particle.

Fatty liver & ↑VLDL synthesis are key to ↑TG and consequences

Fattyliver

TGVLDL-CVLDL-P

1

“Atherogenic Dyslipidemia”

1.↑TG, VLDL-C, VLDL-P2.↑LDL-P, Small LDL-P3.↓HDL-C & Apo A-I

123

Elevated TG Associated with ↑LDL-P, ↓HDL-C, and ↑Non-HDL-C

Apo B

LDL=130 mg/dL

Fewer Particles More Particles

CE

More Apo B

LDL-C=LDL cholesterol; TC=total cholesterol. Otvos JD et al. Am J Cardiol. 2002;90:22i-29i.

Fasting Lipid Panel:TC 198 mg/dLLDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dLNon-HDL-C 148 mg/dL

Fasting Lipid Panel:TC 210 mg/dLLDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dLNon-HDL-C 180 mg/dL

Postprandial TG (Remnants) Increased in CAD Patients

CAD=coronary artery disease. Patsch JR et al. Arterioscler Thromb. 1992;12:1336-45.

Pla

sma

TG

(m

g/d

L)

Hours after meal

*P=0.025; †P0.001.

*

†

†

CAD (n=61)

0

100

200

300

400

0 2 4 6 8

No CAD (n=40)

Can HTG Cause Atherosclerosis?

Con• HTG → CVD weaker than LDL-C, partly HDL-C dependent

• Severe HTG from ↑chylomicrons not related to ↑CVD

• TG accumulation not seen in atherosclerotic plaque

• TG-lowering drugs not completely proven to ↓CVD

Pro• TG-rich lipoproteins are atherogenic (esp. cholesterol-rich remnants)

• TG lipolysis by lipoprotein lipase (LPL) → pro-inflammatory FFA (uptake by CD36 & FA binding proteins to nucleus)

• HTG causes atherogenic changes in LDL and HDL

• TG-lowering drugs ↓CVD in HTG / low HDL-C patients

• TG ~100–800 mg/dL is OFTEN associated with hyper-Apo B (ie, pro-atherogenic state)

CVD=cardiovascular disease; FA=fatty acid. Miller M et al. Circulation. 2011;123:2292-333.

3

CV=cardiovascular; MetS=metabolic syndrome; NCEP=National Cholesterol Education Program. Tankó LB et al. Circulation. 2005;111:1883-90.

MetS-NCEP +

EWET –

CV P<0.001

-2 0 2 4 6 8 10

0.7

0.8

0.9

1.0

1.1

Follow-up Time (yrs)

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

0.7

0.8

0.9

1.0

1.1

-2 0 2 4 6 8 10

P<0.001

MetS-NCEP –

EWET +

CV

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 as per 2001 NCEP. EWET=Waist ≥88 cm and TG ≥128 mg/dL.

Follow-up Time (yrs)

Enlarged Waist Combined with Elevated TG(EWET) May Predict CVD as Well as MetS in Menopausal Women

PROVE IT-TIMI 22 Trialb

Miller M, et al. J Am Coll Cardiol. 2008;51:724-730.

TG <150 mg/dL Associated with Lower Risk of CHD Eventsa Independent of LDL-C Level

Achieving both low LDL-C and low TG (<150 mg/dL) may be important therapeutic strategies in patients after acute coronary syndrome (ACS)

CH

D E

ven

taR

ate

a

fte

r 3

0 D

ays

c(%

)

aDeath, myocardial infarction (MI), and recurrent ACS. bACS patients on atorvastatin 80 mg or pravastatin 40 mg. cAdjusted for age, gender, low HDL-C, smoking, hypertension (HTN), obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment. CHD=coronary heart disease; HR=hazard ratio; PROVE IT=Pravastatin or Atorvastatin Evaluation and Infection Therapy; TIMI=Thrombolysis In Myocardial Infarction. Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

N=4162

TG <150 TG ≥150

LDL-C ≥70

LDL-C <70

HR: 0.72P=0.017

HR: 0.85P=0.180

HR: 0.84P=0.192

Referent

Lipid values in mg/dL

Low HDL-C and High TGs Increase CVD Risk Even when LDL-C Levels Are Well-Controlled

0

2

4

6

8

10

<38 38 to <43 43 to <48 48 to <55 >=55HDL-C Quintilesa

(mg/dL)

5-yr

Ris

k of

Maj

or

CV

D E

vent

s (%

)

Patients with LDL-C ≤70 mg/dL on statina,b

aOn-treatment level (3 months statin therapy), n=2661.bMean LDL-C 58 mg/dL, mean TG 126 mg/dL. *P=0.03 for differences among quintiles of HDL-C.

Q237 to <42

Q342 to <47

Q5≥55

Q447 to <55

HR vs Q1* 0.85 0.57 0.55 0.61

39% Lower Risk

TG=186 TG=168 TG=150 TG=142 TG=124

TNT=Treating to New Targets.Barter P et al. N Engl J Med. 2007;357:1301-10.

Q1<37

TG values in mg/dL

TNT Study

TG Levels and CHD Risk: Meta-analysis of 29 Studies (N=262,525)

*Individuals in top vs bottom third of usual log-TG values, adjusted for at least age, sex, smoking status, lipid concentrations, and (in most studies) blood pressure (BP).

CI=confidence interval. Sarwar N et al. Circulation. 2007;115:450-8.

Groups CHD CasesDuration of Follow-up≥10 yrs 5902<10 yrs 4256

SexMale 7728Female 1994

Fasting StatusFasting 7484Nonfasting 2674

Adjusted for HDL-CYes 4469No 5689

Overall CHD Risk Ratio*Decreased

Risk

CHD Risk Ratio* (95% CI)

1.72 (95% CI, 1.56–1.90)

21Increased

Risk

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

Key Points in NCEP / ATP III Guidelines Regarding TG

Practice Standards

• Do a fasting lipoprotein profile in all adults

• Patients with TG ≥200 mg/dL should have non-HDL-C calculated and treated to goal (=LDL-C goal + 30)

• If TG ≥500 mg/dL, lowering TG is 1st priority

• Consider Rx with fibrates or niacin if TG >200 mg/dL (or HDL-C <40 mg/dL) after statin Rx to LDL-C / non-HDL-C goals

National Cholesterol Education Program, National Heart, Lung and Blood Institute, National Institutes of Health (NIH). Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III). Executive Summary;2001:NIH publication 01-3670. ATP=Adult Treatment Panel; Rx=prescription. Grundy SM et al. Circulation. 2004;110:227-39.

4

Rationale for Non-HDL-C Assessment

• In the presence of HTG (>200 mg/dL), non-HDL-C better assesses atherogenic particles than does LDL-C1

• Unlike calculated LDL-C, non-HDL-C can be accurately measured in nonfasting patients2,3

• Non-HDL-C is highly correlated with total Apo B1

– Serum total Apo B has been shown to have a strong predictive power for severity of coronary atherosclerosis and CHD events1

• Non-HDL-C is the difference between 2 values in the standard lipid panel (ie, TC – HDL-C) and therefore incurs no additional cost1,4

1. NCEP ATP III. Circulation. 2002;106:3143-421. 3. Brunzell JD et al. J Am Coll Cardiol. 2008;51:1512-24. 2. Miller M et al. Circulation. 2011;123:2292-333. 4. Mora S. Circulation. 2009; 119:2396-404.

Non-HDL-C Predicts CHD Better than LDL-C

• In HTG, at a given non-HDL-C level, little / no association between LDL-C and CHD

• In contrast, non-HDL-C predicts CHD at all LDL-C levels

• Non-HDL-C is a much stronger CHD risk predictor than LDL-C

Framingham Cohort and Offspring Data.Liu J et al. Am J Card. 2006;98:1363-8.

0

0.5

1

1.5

2

2.5

LDL-Cmg/dL

Non-HDL-C mg/dL

Re

lati

ve

CH

D R

isk

<130 130-159 ≥160

≥190

160-189<160

Note also that non-HDL-C is:• Included (free) in lipid panel• Accurate non-fasting• Accurate in HTG pts

N=5794

Referencegroup

Adapted from Sniderman AD et al. Am J Cardiol. 2003;91:1173-7.

Apo B vs LDL-C

Quintile Concordant (%) Discordant (%)

1st Quintile 66 34

Middle 3 Quintiles 38 62

5th Quintile 64 36

Overall 49 51

Apo B vs Non-HDL-C

Quintile Concordant (%) Discordant (%)

1st Quintile 76 24

Middle 3 Quintiles 47 53

5th Quintile 73 27

Overall 63 37

Discordance Between Alternate LDL MeasuresQuebec Cardiovascular Study (n=2103)

1. Contois JH et al. Clin Chem. 2009;55:407-19.2. Otvos JD et al. J Clin Lipidol. 2011;5:105-13.3. Brunzell JD et al. J Am Coll Cardiol. 2008;51:1512-24.4. Jellinger PS et al. Endocr Pract. 2012;18(Suppl 1):1-78.5. Davidson MH et al. J Clin Lipidol. 2011;5:338-67.

Biomarker PopulationPercentile Equivalent Concentration

<5th 20th 50th 80th

LDL-C (mg/dL)Framingham [1]

<75 100 130 160

Apo B (mg/dL) <60 80 100 120

NMR LDL-P (nmol/L)Framingham [1] <850 1100 1400 1800

MESA [2] <800 1000 1300 1600

OrganizationProposed Targets of Therapy

Very High Risk High Risk Moderate Risk

American Diabetes Association / American College of Cardiology Foundation Consensus Statement [3]

Apo B <80 Apo B <90 NA

American Association for Clinical Chemistry Lipoproteins & Vascular Diseases Working Group Recommendations [1]

<20th Percentile (see above) <50th Percentile

American Association of Clinical Endocrinologists Guidelines for Management of Dyslipidemia [4]

Apo B <80 Apo B<90 NA

National Lipid Association Expert Recommendations [5] Option Apo B <70 Apo B <80 or LDL-P <1000

Apo B <100 or LDL-P <1300

Canadian Cardiovascular Society Guidelines [6] NA Apo B <80

ESC/EAS Guidelines for the Management of Dyslipidaemias [7] Apo B <80 Apo B <100 NA

6. Genest J et al. Can J Cardiol. 2009;25:567-79.7. Reiner Z et al. Eur Heart J. 2011;32:1769-1818.EAS= European Atherosclerosis Society; ESC= European Society of Cardiology; MESA= Multi-Ethnic Study of Atherosclerosis; NMR= Nuclear Magnetic Resonance.

Courtesy of William C. Cromwell, MD.

Recommendations for Using LDL Particle Number Measures as Targets of Therapy

Summary and Conclusions

HTG (and low HDL-C)

• HTG and low HDL-C (with high Apo B, LDL-P, and SD LDL) is the “atherogenic dyslipidemia” common in insulin resistance / MetS and T2DM

• Both HTG and low HDL-C strongly predict CVD risk even with excellent LDL-C control on a statin

Non-HDL-C

• ↑Non-HDL-C (and ↑Apo B / ↑LDL-P) strongly predicts CVD risk

• Non-HDL-C has ATP III Rx goals (=LDL-C goal + 30)

• Several expert panels and guidelines advocate managing to Apo B / LDL-P goals in addition to Non-HDL-C

T2DM=type 2 diabetes mellitus.

How Should HTG be Managed in MetS / T2DM?

Eliot A. Brinton, MD, FAHA, FNLAPresident, American Board of Clinical LipidologyPresident, Utah Lipid CenterDirector, Atherometabolic Research,Utah Foundation for Biomedical Research

5

Basic Principles of CVD Risk Management

1. Systematically quantify CVD risk

2. CVD risk category determines LDL-C / non-HDL-C goals

3. Look for 2o causes of dyslipidemia and high BP

4. Treat 2o factors/contributory metabolic disorders

5. Encourage diet and lifestyle change in everyone

6. Statins & statin adjuncts to achieve LDL-C / non-HDL-C goals

7. Consider TG / HDL-C medications (fibrates, niacin, and Om-3) if HTG / low HDL-C persists

Based on NCEP ATP III. Om=omega.NCEP ATP III. Circulation. 2002;106:3143-421.

*All measurements in mg/dL. AHA=American Heart Association.Miller M et al. Circulation. 2011;123:2292-33.

TG Revisions between 1984 and 2001

AHA Scientific Statement on TG Classification

TG Designation 1984 NIH Consensus Panel

1993 NCEPATP II

2001 NCEPATP III

Desirable* <250 <200 <150

Borderline High* 250–499 200–399 150–199

High* 500–999 400–999 200–499

Very High* >1000 >1000 >500

AHA Statement in 2011 classified TG <100 mg/dL as “optimal”(SD LDL becomes much more prevalent with TG >100 mg/dL)

ATP III Treatment Recommendations for Elevated TG

TG (mg/dL)

ATP III Classification

Primary Target of Therapy Treatment Recommendations

150–199 Borderline high LDL-C goal Weight and Physical activity

200–499 High LDL-C goal

Weight and Physical activity

Consider non-HDL-C goal:LDL-C with statin or VLDL-C with niacin

or fibrateSugar and carbs*

≥500 Very high

TGto prevent

acute pancreatitis

Very low fat diet (fat ≤15% total calories)Weight and Physical activityAdd niacin or fibrates(+Om-3 as per FDA indication*)

*Not in ATP III statement.carbs=carbohydrates; FDA=US Food and Drug Administration; Om=omega.NCEP ATP III. Circulation 2002;106:3143-421.

Primary Causes of HTG

Relatively common• Familial combined hyperlipidemia (FCHL)

– Variable phenotype (↑TG alone, or ↑TC alone, or both increased)– Associated with ↑↑CVD and ↑central obesity– Multiple genetic associations of unclear causal significance– “Hyper-Apo B”

• Familial HTG (FHTG)– ↑TG alone (not TC)– Associated with ↑CVD if ↑central obesity / MetS– Largely due to ↑hepatic VLDL production– Apo B is usually normal

Rare• LPL deficiency

• Apo C-II deficiency

• Familial dysbetalipoproteinemia (Type III)

• GPIHBP1 deficiency

GPIHBPI=glycophosphatidylinositol-anchored HDL-binding protein.Bays HE. In: Kwiterovich PO Jr, ed. The Johns Hopkins Textbook of Dyslipidemia. 1st ed. Lippincott Williams & Wilkins;2010:245-57.

Note: FCHL and FHTG may NOT be distinct entities

Secondary Causes of HTG

Note: Common causes are in bold type

HIV=human immunodeficiency virus. Bays HE. In: Kwiterovich PO Jr, ed. The Johns Hopkins Textbook of Dyslipidemia. 1st ed. Lippincott Williams & Wilkins;2010:245-57.

Cause Clinically useful details

Positive energy balance Calories, Saturated fat intake and/or Glycemic index

Carbohydrate intake Fructose (& other sugars?) especially if with Dietary fiber

Adiposopathy, fatty liver,visceral fat, insulin resistance

Adipose tissue dysfunction, waist girth, transaminase levels, plasma fatty acids, impaired adipogenesis, adipocyte hypertrophy, pro-inflammatory state

Diabetes mellitus Especially if poor glycemic control

Hypothyroidism Unless treated

Nephrotic syndrome

Medications

Antiretroviral regimens (for HIV) Some phenothiazines and 2nd-generation antipsychoticsNonselective beta-blockers Thiazide diureticsOral estrogen, tamoxifenSystemic glucocorticoids, Isotretinoin

Recreational drugs Alcohol (esp. with fatty liver) and Marijuana

Lifestyle and Diet Can Improve Dyslipidemia

Diet / Lifestyle Change Lipid Profile Change

Smoking cessation HDL-C 4 mg/dL1

Weight loss (5%–10%) TG 20%, LDL-C 15%,HDL-C 10%2

Diet Fruits, vegetables & low-fat dairy; SugarTotal carb & Fat (to 33%–50% of calories)

LDL-C, HDL-C1

TG 9 mg/dL2

Brisk 30-min walk, 3x/wk LDL-C, HDL-C 5%–10%1

1Sampson UK et al. Curr Atheroscler Rep. 2012;14:1-10.2Miller M et al. J Am Coll Cardiol. 2008;51:724-30.min=minute; wk=week.

6

Pharmacologic Therapy for Very High TG Levels

Drug Class

Very High TG Indications*

Select Adverse EffectsTG >500

mg/dL

Type IVHyper-

lipidemia

Fenofibratea

Dyspepsia, various upper gastrointestinal complaints, cholesterol, gallstones, myopathy

(Gemfibrozil should not be combined with statins, and has limited use in current practice.)

Extended-release Niacin (ERN)b

Flushing, pruritus, diarrhea, vomiting, hyperglycemia, hyperuricemia/gout, dyspepsia/exacerbation of peptic

ulcer, hepatotoxicity

(HPS2-THRIVE study of ERN / LRPT did not achieve 1endpoint & showed significant ↑ in nonfatal serious AEs in

ERN / LRPT group)

*Data from individual product labeling for each drug in patients with very TG. a145 mg per day. b2 grams per day. AEs=adverse events; HPS2-THRIVE=Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events; LRPT= laropiprant. Fredrickson DS et al. Ann Intern Med. 1975;82:150-7. Miller M et al. Circulation. 2011;123:2292-333.

Pharmacologic Therapy for Very High TG Levels

Drug Class

Very High TG Indications*

Select Adverse EffectsTG >500

mg/dL

Type III Hyper-

lipidemia

Type IVHyper-

lipidemia

Om-3 FA (EPA / DHA)a Eructation, dyspepsia, taste

perversion

Om-3 FA (EPA only)a Arthralgia

Statins b cMyalgia, myopathy (rare),

rhabdomyolysis (very rare), A1c, cognitive impairment

*Data from individual product labeling for each drug in patients with very TG. a4 grams per day. bAtorvastatin, rosuvastatin, and simvastatin. cAtorvastatin and simvastatin. A1c=glycosylated hemoglobin; DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid. Fredrickson DS et al. Ann Intern Med. 1975;82:150-7. Miller M et al. Circulation. 2011;123:2292-333.

%TG not corrected for baseline TG. Since % in TG levels varies directly with baseline TG, these are only a rough approximation of relative TG-lowering effect.

Approximate TG Lowering Effect by Drug Class

Drug % TG Reduction

Fibrates 30–50

Immediate-release niacin 20–50

Om-3 20–50

ER Niacin 10–30

Statins 10–30

Ezetimibe 5–10

ER Niacin=extended-release niacin. AHA Statement, Miller M et al. Circulation. 2011;123:2292-333.

Statins Reduce CVD Events in HTG Patients (HTG Subgroup Data)

CARE=Cholesterol and Recurrent Events Trial; CTT= Cholesterol Treatment Trialists; JUPITER= Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; NS=not significant; PPP=Prospective Pravastatin Pooling; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland Coronary Prevention Study. Maki KC et al. J Clin Lipidol. 2012;6:413-26.

Statin Trial (Subgroup) Drug

↓ CVD Risk Total study

(HTG subjects)

P-valueTotal study

(HTG subjects)

WOSCOPS (TG) Pravastatin –31% (–32%) <0.001 (0.003)

CARE (TG) Pravastatin –24% (–15%) 0.003 (0.07)

PPP Project (Highest TG tertile) Pravastatin –23% (–15%) <0.001 (0.029)

4S (“Dyslipidemia”) Simvastatin –34% (–52%) <0.001 (<0.001)

JUPITER (Older subjects with TG) Rosuvastatin –44% (–21%) <0.001 (NS)

CTT (Highest TG tertile)Various statins

–21% (–24%) <0.001 (<0.001)

Fibrates Reduce CHD Risk by 35% in Patients with HTG and Low HDL-C

Subjects with HTG/low HDL-CDyslipidemia

B Complementary Subgroups Without Dyslipidemia

(HTG/low HDL-C = TG ≥204 mg/dL and HDL-C ≤34mg/dL)

*Did not meet primary endpoint. ACCORD=Action to Control Cardiovascular Risk in Diabetes; BIP=Bezafibrate Infarction Prevention; FIELD=Fenofibrate Intervention and Event Lowering in Diabetes; OR=odds ratio; VA-HIT=Veterans Affairs HDL Intervention Trial. Sacks FM et al. N Engl J Med. 2010;363:692-4.

Subjects w/o HTG/low HDL-CDyslipidemia

*

*

*

*

*

*

ACCORD (simvastatin + fenofibrate)

FIELD (fenofibrate)

ACCORD (simvastatin + fenofibrate)

FIELD (fenofibrate)

BIP (bezafibrate)

HHS (gemfibrozil)

VA-HIT (gemfibrozil)

HHS (gemfibrozil)

BIP (bezafibrate)

VA-HIT (gemfibrozil)

Study (treatment) OR (95% CI) Study (treatment) OR (95% CI)

A meta-analysis of randomized fibrate trials

Niacin Reduces Total CVD (Any CV Event): Trials before AIM-HIGH and HPS2

AFREGS=Armed Forces Regression Study; AIM-HIGH=Atherothrombosis Intervention in MetS with Low HDL/High TGs: Impact on Global Health Outcomes; ARBITER=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; CDP= Coronary Drug Project; CLAS=Cholesterol-Lowering Atherosclerosis Study; FATS=Familial Atherosclerosis Treatment Study; HALTS= HDL and LDL Treatment Strategies in Atherosclerosis; HATS=HDL-Atherosclerosis Treatment Study; STOCKHOLM=Stockholm Ischaemic Heart Disease Secondary Prevention Study; UCSF-SCOR=University of California San Francisco Arteriosclerosis Specialized Center of Research Intervention Trial. Bruckert E et al. Atherosclerosis. 2010;210:353-61.

↓27%

Note: Many of these trials were not monotherapy niacin trials.

7

Boden WE et al. N Engl J Med. 2011;365:2255-67.

Time (years)

Cu

mu

lati

ve %

wit

h P

rim

ary

Ou

tco

me

0

10

20

30

40

50

0 1 2 3 4

Monotherapy

Combination Therapy

HR 1.02, 95% CI 0.87, 1,21Log-rank P value=0.79

N at risk

Monotherapy

Combination Therapy

1696

1718

1581

1606

1381

1366

910

903

436

428

16.2%

16.4%

AIM-HIGH Primary Endpoint: CHD Death, Nonfatal MI, Ischemic Stroke, High-risk ACS, Hospitalization for Coronary or Cerebrovascular Revascularization

*Highest tertile of TG and lowest tertile of HDL-C. †Heterogeneity by treatment. All measurements in mg/dL. ERN=extended-release niacin. Guyton JR et al. Paper presented at: AHA SS; Nov. 6, 2012; Los Angeles, CA.

AIM-HIGH: ERN Beats Control in Patients with HTG & Low HDL-C

Niacin w/o ↓CVD in HPS2, but base TG 120 & HDL-C 44!

# Patients with CV Events ERN ERN HR(% of Category) Better Worse (95% CI) P-value†

*Non-fatal MI or coronary death, any non-fatal or fatal stroke, coronary or non-coronary artery surgery or angioplasty. LRPT= laropiprant; SDM=standard deviation of the mean. Armitage J. Paper presented at ACC.13: American College of Cardiology 62nd Annual Scientific Session. March 9, 2013.

Years of Follow-up

Pa

tien

ts S

uff

erin

g E

ven

ts (

%)

15.0%

0 1 2 3 4 0

5

10

15

20

14.5%

Placebo ERN/LRPT

Logrank P=0.29Risk ratio 0.96 (95% CI 0.90–1.03)

Effect of ERN / LRPT on Major Vascular Events (MVEs)*

LipidMean (SDM) at

baseline, mg/dL

TC 128 (22)

Direct-LDL 63 (17)

HDL-C 44 (11)

TG 125 (74)

Baseline Lipids on Statin-based Rx

HPS2-THRIVE: Randomized Placebo-controlled Trial of ERN and LRPT

“Significant excesses of serious AEs due to known and unrecognised side-effects of niacin. Over 4 years, ER niacin / laropiprant caused serious AEs in ~30 patients per 1000.”

N=25,673 with Pre-existing CVD

The average patient had NONE of the usual lipid indications for niacin

Om-3 FA Molecular Structure

PUFA=polyunsaturated FA. Adapted from Mozafarian D, Wu JH. J Am Coll Cardiol. 2011;58:2047-67.

Not for TG-lowering

Effective for TG-lowering

-60%

-40%

-20%

0%

20%

40%

60%

Om-3 Ethyl Esters: Lipid Effects in Patients with TG >500 mg/dL

Pooled analysis (N=82).Harris WS et al. J Cardiovasc Risk 1997;4:385-91 and Pownall HJ et al. Atherosclerosis 1999;143:285-97.

Placebo Om-3 Acid Ethyl Esters (EPA+DHA, 4 g/day)

Baseline(mg/dL)

TG816

HDL-C22

Non-HDL-C27

TC296

VLDL-C175

LDL-C89

P<0.0001 P=0.0002

P=0.0015 P=0.0059 P<0.0001

P<0.0001

–45.0

6.70.0

9.1

–3.6

–13.8– 9.7

– 1.7 – 0.9

– 42.0

– 4.8

45.0

Ch

ang

e in

Med

ian

Lev

els

Statin + EPA/DHA Om-3 AEEs: Lipid Efficacy in Patients with TG 200–500 mg/dL

Med

ian

Ch

ang

e fr

om

Bas

elin

e (%

)

TG LDL-C HDL-CVLDL-C

Additions to baseline simvastatin therapy:

5

–5

–10

–15

–20

–25

–30

3.4*

–6.3–7.2

–1.2–2.8

–29.5*

0.7‡

0

–27.5*

–4.2†–1.9

Apo BNon-HDL-C

–9.0*

–2.2

*P<0.0001 between groups. †P=0.0232 between groups. ‡P=0.0522 between groups.AEEs=acid ethyl esters; COMBOS=Combination of Prescription Omega-3 with Simvastatin.Davidson MH et al. Clin Ther. 2007;29:1354-67.

Om-3 (Rx) 4 g/d + simvastatin 40 mg/d (n=123)

Placebo + simvastatin 40 mg/d (n=133)

Note: Om-3 AEEs are not FDA approved for TG 200–500 mg/dL

COMBOS trial

8

Icosapent Ethyl (IPE/Pure EPA): Lipid Effects with TG >500 mg/dL(dose-response, placebo-adjusted)

The MARINE Study: TG >500 mg/dL

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

TG Non-HDL-C VLDL-C Lp-PLA2 Apo B TC

Med

ian

Pla

ceb

o-a

dju

sted

Ch

ang

e (%

)

LDL-CHDL-C

VLDL-TG

-33.1ǁ

-19.7 †

-17.7ǁ

-8.1*

-28.6‡

-15.3*

-13.6‡

-5.1NS -8.5

†

-2.6NS

-16.3ǁ

-6.8*

-2.3NS

NS5.2

-3.6NS

NS1.5

-25.8†

-17.3NS

4 g/d (n=76)–FDA approved dose

2 g/d (n=73) -36.0†

-10.1NS

hsCRP

CRP=C-reactive protein; hsCRP=high-sensitivity CRP; ITT=intention to treat; Lp-PLA=lipoprotein-associated phospholipase A; MARINE= Multi-center, Placebo-controlled, Randomized, Double-blind, 12-week Study with an Open-label Extension. Bays HE et al. Am J Cardiol. 2011;108:682-90. Bays HE et al. Paper presented at: European Society of Cardiology (ESC) Congress 2011; August 29, 2011; Paris, France.

ITT Population

*P<0.05. †P<0.01. ‡P<0.001. ǁP<0.0001. NS = P≥0.05.P-values reflect differences between icosapent ethyl vs placebo.

Icosapent Ethyl

Statin + IPE (Pure EPA): Lipid Effects with TG 200–500 mg/dL(dose-response, placebo-adjusted)

TG Non-HDL-C Apo B

Me

dia

n P

lac

eb

o-a

dju

ste

d C

ha

ng

e (

%)

LDL-C HDL-C

–21.5ǁ

– 10.1‡

– 13.6ǁ

– 5.5†

– 9.3ǁ

– 3.8*

– 6.2†

– 3.6NS

– 4.5†

– 2.2NS

254265 8282128128 9193 3837 Baseline values

(mg/dL)

12-week trial in high-risk statin-treated patients (N=702) with residually TG levels (≥200 and <500 mg/dL) despite LDL-C control (≥40 and <100 mg/dL). ANCHOR= Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in Patients on Statins With High Tg Levels (≥200 and <500 mg/dL). Ballantyne CM et al. Am J Cardiol. 2012;110:984-92.

*P<0.05. †P<0.01. ‡P<0.001. ǁP<0.0001. NS = P≥0.05.P-values reflect differences between icosapent ethyl vs placebo.

4 g/d (n=233)

2 g/d (n=236)

The ANCHOR Study: TG ≥200 and <500 mg/dL

Note: IPE is not FDA approved for TG 200–500 mg/dL

Icosapent Ethyl

Effect of Icosapent Ethyl on Markers of Inflammation (TG >500 and 200–500 mg/dL)

*P<0.01; †P<0.001; ‡P<0.0001 vs placebo.ICAM= intercellular adhesion molecule; IL=interleukin; Ox-LDL=oxidized LDL.Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-40.

-2.5

-6.6

-13.6

11.0

-36.0

-2.3 -1.4

-5.1

4.7

-10.1

-2.4

-13.3

-19.0

-1.0

-22.0

-2.2

-5.8-8.0

7.0

-6.8

-40

-30

-20

-10

0

10

20

MARINE 4 g/day

MARINE 2 g/day

ANCHOR 4 g/day

ANCHOR 2 g/day

Med

ian

Pla

ceb

o-a

dju

sted

Ch

ang

e (%

)

Icosapent ethyl

*

†

NS

‡

NS

‡

†

NS

‡

NS

ICAM-1 Ox-LDL Lp-PLA2

IL-6

hsCRP

NS

NS

NSNS

Note: IPE is not FDA approved for TG 200–500 mg/dL

JELIS: Effect of EPA-only on Major Coronary Events in Hypercholesterolemic Patients

EPA=eicosapentaenoic acid; JELIS=Japan EPA Lipid Intervention Study. Yokoyama M et al. Lancet. 2007;369:1090-8.

No. at Risk

Control

EPA

0 1 4 5 Years

9319 8931 8671 8433 8192 7958

9326 8929 8658 8389 8153 7924

Cu

mu

lati

ve

In

cid

en

ce

of

Ma

jor

Co

ron

ary

Ev

en

ts (

%)

4

P=0.011

Statin + EPA

Statin only3

2

1

0

HR (95% CI): 0.81 (0.69–0.95)

↓

2 3

–19%

18,645 pts with total cholesterol ≥251 mg/dL recruited in Japan between 1996 and 1999 received 1800 mg of EPA daily with statin or statin only. Statin dose was up to 20 mg pravastatin or 10 mg simvastatin.

CABG=coronary artery bypass graft; MCE=major coronary event.Saito Y et al. Atherosclerosis. 2008;200:135-40.

JELIS Patient Subgroup: IPE Effects onMCE in TG >150 mg/dL and HDL-C <40 mg/dL

Primary endpoint: sudden cardiac death, fatal and non-fatal MI, unstable angina pectoris, angioplasty, stenting, or CABG

HR and P-value adjusted for age, gender, smoking, diabetes, and HTN

AMR101 4 g/day

Placebo

Study duration ~4–6 yrs

Primary endpoint:

Prevention of 1st major CV

event

N=8000

Reduction of CV Events with EPA –Intervention Trial

• Randomized, double-blind, parallel group design

• Secondary outcome measures: Incidence of additional CV events, lipid and lipoprotein levels, subgroup analyses such as diabetes, etc.

• Multinational trial

• Anticipated completion 2016

Hx=history; RF=risk factor. NIH website. http://clinicaltrials.gov/ct2/show/NCT01492361?term=REDUCE-IT&rank=1

• Men & women ≥45 yo• Prior CHD (70% patients)

or T2DM + ≥1 RF)• Atherogenic dyslipidemia:

– Hx of ↑TC (at LDL-C goal on statin)

– TG 150–500 mg/dL

AMR101=icosapent ethyl

Note: EPA is notFDA approved for TG 200–500 mg/dL

9

GISSI-P1-2 ORIGIN3 JELIS4REDUCE-IT5

(Ongoing)

Om-3 Type/dose

EPA/DHA1 g/day2

EPA/DHA1 g/day

EPA1.8 g/day

EPA 4 g/day

Population Italian International Japanese InternationalN 11,324 12,536 18,645 ~8,000Gender 85% male 65% male 31% male Accrual ongoing

Risk Profile

Recent MI (≤3 mos; median 16 days)

High CV risk, and IFG, IGT, or T2DM

80% 1o prev; TC ≥6.5 mM; excl MI ≤6 mos prior

TG >150 mg/dL+CHD or ↑CHD risk

Follow-up 3.5 years 6.2 years (median) 4.6 years (mean) 4–6 years (planned)

Statin Use Minimal 53% in n-3 FA arm, 55% in pbo arm

All on statins(simva or pravastatin)

All on background statins

(LDL-C goal)Primary End Point

All-cause death, non-fatal MI, NF stroke

Death from CV causes MACE MACE

Result RRR 10% (P=0.048)/ 15% (P=0.023)

HR=0.98P=0.72

RRR 19% (no minimum TG level) P=0.011

Powered for 15% RRR

LDL-C 2%–3% >control groups 12% both arms 25% in both groups –

Select Om-3 CVD Outcome Studies

excl=excluded; GISSI= Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico; IFG=impaired fasting glucose; IGT=impaired glucose tolerance; MACE=major adverse cardiac event; mos=months; ORIGIN=Outcome Reduction with an Initial Glargine Intervention; pbo=placebo; prev=prevention; REDUCE-IT=Reduction of Cardiovascular Events with EPA-Intervention Trial; RR=relative risk; RRR=relative risk reduction. 1. GISSI-Prevenzione Investigators. Lancet. 1999;354:447-55. 2. www.trialresultscenter.org/study4440-GISSI-P.htm. 3. ORIGIN Investigators. N Engl J Med. 2012;367:309-18. 4. Yokoyama M et al. Lancet. 2007;369:1090-8. 5. http://www.clinicaltrials.gov.

Note: Trial designs differ so results can not be directly compared.

AHA Recommendations for Om-3 FA Intake

Kris-Etherton PM et al. Circulation. 2002;106:2747-57.

Population Recommendation

Patients without documented CHD

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).

Patients with documented CHD

Consume ~1 g of EPA+DHA per day, preferably from oily fish. EPA+DHA

supplements could be considered in consultation with the physician.

Patients needing TG lowering

2–4 grams of EPA+DHA per day provided as capsules under a physician’s care

Sources of Omega-3 Acid Ethyl Esters

*Freshwater trout is also a member of the Salmonidae family. As opposed to sea trout, freshwater trout are not marine fish.Bays HE. Drugs Today (Barc). 2008;44:205-46.

Fish family Common name

Engraulidae Anchovy

Carangidae Jack mackerel

Clupeidae Herring, sardine and menhaden

Osmeridae Smelt

Salmonidae* Salmon

Scombroidei Tuna, mackerel and marlin

Examples of fish families that largely contribute to the oils in prescription omega-3 (P-Om-3) acid ethyl esters

Prescription vs Dietary Supplement Om-3

Om-3 acid ethyl esters

Icosapent ethyl Om-3 Dietary Supplements

FDA product classification Drug Drug Food

FDA approval Yes Yes No

Ingredients EPA+ DHA EPA Variable amounts of DHA + EPA

(includes other PUFAs and SFAs)

Quantity of Om-3 per capsule 0.9 g 0.98 g Typically 300 mg – 800 mg EPA & DHA

Typically 100 – 400 EPA

Capsules/day to achieve ~4g Om-3

4 4 Typically 5 – 13 for EPA + DHATypically 10 – 40 EPA alone

Recommended dose 4 g/d 4 g/d

-In patients with CHD: ~1 g/d of EPA+DHA, preferably from oily fish. Consider EPA+DHA supplements in consultation with a physician.-In patients requiring ↓TG: EPA+DHA 2–4g/d as capsules under physician’s care.-When using prescription Om-3 agents to ↓TG levels: 4 g/d of Om-3

Tested in clinical trials Yes Yes Not required

SFAs=saturated fatty acids.

Conclusions

• HTG is likely a major RF for pancreatitis & CVD– Optimal TG level is <100 mg/dL– Rx required if TG >500 mg/dL– Consider Rx if TG 200–500 mg/dL in high-risk

patients (prior CVD, T2DM, MetS, etc.)

• Treatment modes:– Diet & Exercise– Weight control– Address 2o factors– Medications

• HTG meds may CVD in pts with HTG / low HDL-C, butdata are not robust and none are FDA approved for CVD reduction

Case 1: 62-yo Hispanic Woman with T2DM, no Prior CHD Events, with High TG

10

Case 1: 62-yo Hispanic Woman with T2DM and HTG, but No Prior CHD Events

Meds: None for lipids, BP, or platelets

Exam: BMI = 31 kg/m2, BP = 135/95 mm Hg, waist 36” Non-smoker

Labs:

A1c 6.2%

TC 200 mg/dL

TG 559 mg/dL

HDL-C 27 mg/dL

LDL-C 118 mg/dL

Non-HDL-C 173 mg/dL

BMI=body mass index.

Diabetes Is a CHD Risk Equivalent

• CVD accounts for ~2/3 of deaths in people with diabetes1

• Adults with diabetes have heart disease death rates about 2–4 times higher than adults without diabetes1

• NCEP ATP III Guidelines2

– Diabetes is a major, independent risk factor for CHD and other forms of CVD

– Patients with diabetes should be managed as a CHD risk equivalent

1CDC National Diabetes Fact Sheet 2005. http://www.cdc.gov/diabetes/pubs/factsheet05.htm. 2NCEP ATP III. Circulation. 2002;106:3143-421.

ATP III Treatment Recommendations for Elevated TG

TG (mg/dL)

ATP III Classification

Primary Target of Therapy Treatment Recommendations

150–199 Borderline high LDL-C goal Weight and Physical activity

200–499 High LDL-C goal

Weight and Physical activity

Consider non-HDL-C goal:LDL-C with statin or VLDL-C with niacin

or fibrateSugar/carbs*

≥500 Very high

TGto prevent

acute pancreatitis

Very low fat diet (fat ≤15% total calories)Weight and Physical activityAdd niacin or fibrates(+Om-3 as per FDA indication*)

*Not in ATP III statement.

NCEP ATP III. Circulation 2002;106:3143-421.

Treatment of Mixed Hyperlipidemia

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97.

High LDL-C and TG

Therapeutic Lifestyle Change

Drug Therapy

Achieve the LDL-C goal1STEP

Achieve the non-HDL-C goalIncrease LDL-C lowering orAdd a fibrate, niacin or fish oils

2STEP

Residual CVD Risk in Major Statin Trials

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-7.6 Downs JR et al. JAMA. 1998;279:1615-22.

14S Group. Lancet. 1994;344:1383-9.2LIPID Study Group. N Engl J Med. 1998;339:1349-57. 3Sacks FM et al. N Engl J Med. 1996;335:1001-9.

0

10

20

30

40

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6

N 4444 4159 20,536 6595 66059014

Secondary High Risk Primary

Pa

tie

nts

Ex

pe

rie

nc

ing

M

ajo

r C

HD

E

ve

nts

, % Placebo

Statin19.4

12.310.2

8.75.5 6.8

28.0

15.913.2 11.8

7.910.9

CHD events occur in patients treated with statins

AFCAPS= Air Force Coronary Atherosclerosis Prevention Study; LIPID= Long-term intervention with pravastatin in ischemic disease; TexCAPS=Texas Coronary Atherosclerosis Prevention Study.

Conclusions

• T2DM greatly risk for

– Microvascular disease

– Macrovascular disease (CVD)

• CVD risk is high in T2DM despite statin Rx

• Residual CVD risk might be with TG / HDL meds (fibrates, niacin, Om-3) as statin adjuncts

11

Case 2: 49-yo Caucasian Man with T2DM, MI, and PCI 2 yrs Ago with Modestly Elevated TG

William C. Cromwell, MD

Case 2: 49-yo Caucasian Man with T2DM, MI, and PCI 2 yrs Ago with Modestly Elevated TG

Meds: Metformin 1000 mg bid, ASA 81 mg/d, atorvastatin 40 mg/d

Exam: BMI=29 kg/m2, BP=129/82 mm Hg, Waist=41”

LabsA1c 6.5%

TG 248 mg/dL

LDL-C 75 mg/dL

HDL-C 38 mg/dL

Non-HDL-C 139 mg/dL

ASA=aspirin; Dx=diagnosis; PCI=percutaneous coronary intervention.

Case 2: Treatment Approach

First, establish the patient’s risk status:49-yo man, T2DM, previous MI with PCI 2 yrs ago, nonsmoker

Risk factor Patient

Gender: Male Yes: Male

Age: >45 years Yes: 49 years

Previous MI Yes

T2DM Yes: T2DM = CHD risk equivalent

MetS: 4 of 5 RFs1. Waist >40”2. Hyperglycemia3. HDL-C <40 mg/dL4. TG >150 mg/dL5. High BP

Yes: MetS1. 41”2. Yes3. 38 mg/dL4. 248 mg/dL5. No: BP 129/82 mm Hg

This patient is very high risk

Risk status established, set goals for therapy

Case 2: Goals for Therapy

Goal Patient Treatment

BP: 120/80 mm Hg may be optimal (JNC7)

129/82 mm Hg, Not on BP Rx

Consider low dose ACEI for renal protection in T2DM

LDL-C: <100 mg/dL, optional <70 mg/dL

75 mg/dLIs relatively low LDL-C misleading? Why? What to do?

Non-HDL-C: <130 (<100 optional)

139 mg/dLNon-HDL-C high on atorva 40! Needs non-HDL-C statin adjunct

TG: <150 mg/dL (target) 248 mg/dLAddress 2o factorsLikely needs TG statin adjunct

HDL-C >40 mg/dL (target) 38 mg/dL May need HDL-C statin adjunct

A1c: <6.5% 6.5% None: He is at goal on metformin

Waist: <40”BMI: 18.5–24.9 kg/m2

(Obese: >30 kg/m2)

41”29 kg/m2

Physical activity: 30–60 minutes of daily moderate aerobic activityDiet: ↓sugars, calories & alcohol

JNC= Joint National Committee.

Status of the ABCs of Risk Management

CDC. MMWR Morb Mortal Wkly Rep. 2011;60:1248-51.

Percent Compliant

AspirinPeople at risk of CV events who are taking aspirin 47%

Blood pressurePeople with HTN who have adequately controlled BP 46%

CholesterolPeople with cholesterol who are effectively managed 33%

SmokingPeople trying to quit smoking who get help 23%

Check / Encourage Medication Adherence at Each Visit

“Drugs don't work in patients who don't take them.”

C. Everett Koop, MD

Osterberg L, Blaschke T. N Engl J Med. 2005;353:487-97.

12

Conclusions

• 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

Question & Answer