clinical management of hypertriglyceridemia: state of the ... · clinical management of...

Clinical Management of Hypertriglyceridemia: State of the Art 2015

Eliot A. Brinton, MD, FAHA, FNLAPresident, American Board of Clinical Lipidology

Director, Atherometabolic ResearchUtah Foundation for Biomedical Research

President, Utah Lipid CenterSalt Lake City

[email protected]

National Lipid Association Clinical Lipid UpdateFebruary 28, 2015, Denver, Colorado

Speaker DisclosuresDr. Brinton has received:• Research funding: Aurora Foundation, Health

Diagnostic Laboratory• Honoraria as consultant/advisor: Amarin,

Amgen, Arisaph, AstraZeneca, Atherotech, Janssen, Kowa, Lilly, Merck, Novartis, Sanofi-Aventis, Synageva

• Honoraria as speaker: Aegerion, Amarin, AstraZeneca, Genzyme, Janssen, Kowa, Merck, Synageva, Takeda

Learning ObjectivesParticipants should be able to:1. Discuss the prevalence and pathophysiology

of hypertriglyceridemia (HTG)2. Appreciate the likely causal connection of

HTG with acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD)

3. Diagnose HTG and its atherogenic sequelae4. Acknowledge TG-lowering medications in

development5. Implement appropriate management of HTG

TG Categories: Names, Disease Risks, and Drug

Approval PathwaysTG Range (mg/dL) NCEP ATP-III 1 AHA Statement 2

NLA Statement 3 Disease Risk FDA

<100Desirable

Optimal None

No Rx interest<150 Normal Dyslipidemia

150-199 Borderline High Borderline More dyslipidemia

200-499 High High ↑CVD Approve if ↓CVD likely

>500 Very High Very High↑CVD & sl

↑pancreatitis 4(esp ↑if >2000)

Approve if reasonable

safety1. Grundy, S, for the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143‐3421.2. Miller, M, et al. AHA Statement, Circulation. 2011;123(20):2292‐2333.3. All but “Optimal” are in the NLA Statement: Jacobson, TA, et al. J Clin Lip 2014;8:473–488.4. ↑Risk of acute pancrea s at this level is mainly due to ↑TG variability.

Prevalence of HTG in US Adults

%

From Christian et al. Am J Cardiol 2011: 107: 891

3.4 million Americans have

very high TG

Triglyceride Level (mg/dL)

42.3

40.6

NHANES II (1976-1980) NHANES III (1988-1994) NHANES (1999-2006)

Adults aged 20-74 years Adults aged 60-74 years

Increasing Prevalence of HTG Parallels Increased Obesity in the US

Cohen J, et al. Poster at 2008 AHA Scientific Sessions. Ford ES, et al. Arch Intern Med. 2009;169:572-8.Christian JB, et al. Am J Cardiol. 2011;107:891-7.

0

5

10

15

Abno

rmal

TG (%

)

2.4 2.3

5.5

3.5

5x

8.7

1.8

2x

Very-High and Severe HTG are Usually Genetic

Adapted from Hegele et al. Lancet Diabetes & Endocrinology 2014; 2: 655. *Miller, M. Circulation 2011.

% o

f Gen

eral

Pop

ulat

ion

885 mg/dL **500 mg/dL *

*“Very High” cutoff per AHA Consensus Panel Statement. **“Severe” cutoff per EAS Consensus Panel.

Metabolism of TG-Rich Lipoproteins

RemnantReceptor

Hepatocyte

Fatty Acids

Small intestine

Chylomicron

ChylomicronRemnant

Liver

Bloodstream

Lipoprotein Lipase

Normal Metabolism of TGRLp: Exogenous (Dietary Origin)

1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333. 2. Grundy SM. Atlas of atherosclerosis and metabolic syndrome. Chapters 4 and 5. 4th edition. Current Medicine LLC. 2005.

Muscle and

adipose tissue

Normal Metabolism of TGRLp: Endogenous (Hepatic Origin)

Glycerol

Fatty Acids

Triglyceride

Cholesteryl ester

VLDLTG:CE =

5:1

Apo B

Apo, apolipoprotein; VLDL, very low-density lipoprotein; CE, cholesteryl ester

Kwiterovich PO. Johns Hopkins Textbook of Dyslipidemia. 2009.; Miller M, et al. Circulation. 2011;123:2292-2333.; Grundy SM. Atlas of atherosclerosis and metabolic syndrome. 2005.

TG within VLDL:• derived from glycerol + fatty acids from plasma• newly synthesized in the liver (fructose driven)

LDLreceptor

Hepatocyte

Normal Plasma Metabolism of TGRLp: Hepatic Origin

Fatty Acids

Bloodstream Muscle and

adipose tissueLipoprotein

Lipase

Lipoprotein Lipase

IDL

LDL

Normal Size VLDL

• LDL receptor clears VLDL remnants, IDL & LDL

IDL, intermediate-density lipoproteins; LDL, low-density lipoproteinKwiterovich PO. Johns Hopkins Textbook of Dyslipidemia. 2009. Miller M, et al. Circulation. 2011;123:2292-2333. Grundy SM. Atlas of atherosclerosis and metabolic syndrome. 2005.

BloodstreamMuscle

and adipose tissue

Cholesterol Enrichment of VLDL and Shrinkage of LDL & HDL Promoted by CETP in HTG

Hepatic TG Lipase

Hepatic TG Lipase

LDL

Increased Triglycerides

HDL

Small,DenseHDL

VLDL

• CETP-mediated exchange affects composition and metabolism of VLDL, LDL, and HDL

• Occurs at all TG levels but is greatly increased w/ HTG, causing “Atherogenic Dyslipidemia”

HDL, high-density lipoprotein; LDL, low-density lipoprotein; CETP, cholesteryl ester transfer proteinMiller M, et al. Circulation. 2011;123:2292-2333. Ginsberg HN. J Clin Invest. 2000;106(4):453-458.

Small,DenseLDL

Cholesterol-enriched

VLDL

Lipid Measurements in HTG Patients

Increasing Inaccuracy of Friedewald LDL-C with Increasing TG

LDL-C = Total Cholesterol – HDL-C –TG/5

On routine lipid panel, LDL-C is calculated using the Friedewald Formula:

0

10

20

30

40

50

0-100 101-200 201-300 301-400

Absolute underestimation of LDL-C (by Friedewald) by Fasting TG level


Abso

lute

diff

eren

ce (

mg/

dL)

Even modest increases in TG result in LDL-C underestimation using Friedewald formula

Lindsey CC, et al. Pharmacotherapy. 2004;24:167-172.

Increasing Inaccuracy of Friedewald LDL-C with Increasing TG

LDL-C = Total Cholesterol – HDL-C –TG/5

On routine lipid panel, LDL-C is calculated using the Friedewald Formula:

0

10

20

30

40

50

0-100 101-200 201-300 301-400

Absolute underestimation of LDL-C (by Friedewald) by Fasting TG level


Abso

lute

diff

eren

ce (

mg/

dL)

Even modest increases in TG result in LDL-C underestimation using Friedewald formula

Lindsey CC, et al. Pharmacotherapy. 2004;24:167-172.

Direct LDL-C solves this problem, but there may be a better solution…

What is Non-HDL-C?

16

HDL LDL IDL VLDL Chylomicron remnant

Apo AI Apo B100 Apo B100 Apo B Apo B48

CholesterolTriglyceride

All atherogenic lipoproteins

non-HDL

Non-HDL-C = Total cholesterol – HDL-C

Liu J, et al. Am J Cardiol. 2006;98:1363-1368. (Framingham Study)

0

0.5

1

1.5

2

2.5

Rel

ativ

e C

HD

Ris

k

LDL-C, mg/dL

Non-HDL-C, mg/dL

<130 130-159 ≥160

≥190160-189

<160

Non–HDL-C Is Stronger than LDL-C in Predicting CHD Risk

Non-HDL-C Advantagesvs other Lipid Parameters

• Stronger CVD risk predictor than TG (less variable, less loss w/ adjustments)

• Measures chol content of TG-rich lipos• Stronger CVD risk predictor than LDL-C• More stringent than LDL-C (only ~ ½ of pts at

LDL-C goal also at Non-HDL-C goal)• Valid non-fasting (not true for LDL-C)• Valid in HTG (not true for LDL-C)• ~Comparable to apo B/LDL-P, yet• Free with basic lipid panel• Guideline goal consensus (IAS, NLA, etc.)

TG Measurement: Summary• Fasting TG is standard (12 hr, water ok)• Non-fasting TG predicts CVD risk in

populations1 but too variable in individuals?• If NF TG <200 mg/dL fasting TG not neces.2• SD LDL remains important (see below)• Remnant particle testing controversial

– Post-prandial (cumbersome, no standards)– RLP-C—easy but ?accuracy ?validation– DGUC—apo A-I/Rem ratio?3

– Beta-quant best to R/O type III4– Other: NMR? ion mobility?– Friedewald VLDL-C (=TG/5) is NOT remnants!5

• Non-HDL-C incl. all, is free, has consensus1. Langsted A, et al. J Intern Med. 2011 Jul;270(1):65-75.2. Miller, M, et al. Circulation. 2011;123(20):2292-2333.3. May, HT. Lipids Health Dis. 2013 Apr 26;12:55. 4. Hopkins, PN. Current Athero Reports. 2014 in press.5. Varbo, A. Circulation. 2013 epub August 7.

Does HTG Cause Disease?

*After adjustment for covariates and removal of patients hospitalized for gallstones, chronic pancreatitis, alcohol-related morbidities, renal failure, and other biliary disease.1. Cybulska B, Klosiewicz-Latoszek L. Kardiol Pol. 2013;71(10):1007-1012; 2. Miller M et al. Circulation. 2011;123(20):2292-2333; 3. Murphy M et al. JAMA Intern Med. 2013;173(2):162-164. N=n=31,740, 31,887 and 3,642 for 3 TG strata w/ cutpoints150 and 500 mg/dL

Crud

e Incide

nce

(Cases/100

0 Patie

nt‐Years)

Group 1

Group 2

Group 3

• HTG is the 3rd

biggest cause of acute pancreatitis (~10%) after alcohol & gallstones1,2

• Acute pancreatitis risk ↑4%/100 mg/dL ↑ TG* (HR, 1.04)3

2.5

2.0

1.5

0.0

1.0

0.5

Incidence of Acute Pancreatitis by TG3

Triglycerides (mg/dL)<150 150–499 ≥500

21

Pancreatitis Risk ↑↑w/ TG >500 mg/dL

Proposed Mechanisms of VHTG-Induced Acute Pancreatitis*

*VHTG = very high triglyceride. Gan SI, et al. World J Gastroenterol. 2006;12:7197-7202.

Impaired pancreatic capillary blood flow

Modest pancreatic lipase leak→↑FFA production

Ischemia Inflammation(→↑FFA)

Pancreatic acinar cell injury

Large, TG-rich chylomicrons

HTG Predicts CHD Risk(Meta-analysis of 29 Studies, N=262,525*)

*3rd vs 1st tertile, adjusted for at least age, sex, smoking, other lipids & BP.Sarwar N et al. Circulation. 2007;115:450-8.

Groups CHD CasesDuration of Follow-up≥10 years 5902<10 years 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)

21 IncreasedRisk

Also: 22% ↑CVD/ 88 mg/dL ↑TG (61 studies N=330,566)Liu, J. Lipids in Health and Disease 2013, 12:159.

< 200 200 - 299300 +

0

5

10

15

20

< 3030 -39 40 -

49 50+

5.7

2.21.3

1.0

6.1

3.13.7

1.1

17.2

4.3 6.7 7.9

Triglycerides mg/dL

Odd

s R

atio

HDL-C mg/dL

TG Predicts CAD Risk Beyond HDL-C

Hopkins et al. J Am Coll Cardiol. 2005;45:1003-12. 653 Cases with Premature Familial CAD.

↑CHD Risk w/ TG 200, ↑↑ if > 500 mg/dL

*Triglyceride odds ratio adjusted for HDL-C; n=653 (FHx early CHD), n=1029 (control)

Hopkins, Hunt and Brinton. J Am Coll Cardiol. 2005;45:1003-1012.

Reduction of TG →↓Pancreatitis & ASCVD(After Baseline TG >500 mg/dL)

Repet TG at 6-24 wks. N=41,210 (2 large US claims databases).Christian J et al. Am J Med. 2014;127(1):36-44.

Pancreatitis<200

200-299300-399400-499

Cardiovascular Events<200

200-299300-399400-499

0.2 0.4 0.6 0.8 1.0 1.2Adjusted Incidence Rate Ratio

Triglycerides (mg/dL)

Triglycerides (mg/dL)

Similar CHD Results from Copenhagen 4y f/u; N= 75,725.Jorgensen AB et al. New Eng J Med. 2014; 371:32-41.

HTG As a Cause of Atherosclerosis & CVDBiological mechanisms (selected)• TGRLp Remnants → senescence of endothelial

precursors (→impaired endothelial repair) 1• Post-prandial TG →↑endothelial microparticles,2

inflammatory cytokines,3 apoptosis4

• TG lipolysis → FFA → ↑endothelial cell inflammation5*

• ↑Apo C-III → HTG AND → vascular endothelial activation & monocyte adhesion (pro-inflam.)6

• HTG → ↓LDL size, ↓HDL size/loss of apo A-I• ↑VLDL prod. → HTG and ↑apo B (pro-athero.)1. Liu L, Atherosclerosis. 2009;202:405– 414.2. Ferreira AC. Circulation. 2004;110: 3599–3603.3. Norata GD. Atherosclerosis. 2007;193:321–327.4. Shin HK. Circulation. 2004;109:1022–1028.5. Wang L. J Lipid Res. 2009;50:204–213.6. Zheng C. Eur Heart J 2013;34:615-24.7. Ginsberg, HN. J Clin Invest. 2000;106:453-8.

*Only factor specific for TG rather than TG-rich Lp

ApoC-III is Raises TG and is Anti-Endothelial, Pro-Inflammatory and Pro-atherogenic

ApoC-lll

LPL activityTRL clearance

VLDL production

adhesion molecules

NO production

vasoconstriction

ß1-integrin expression,

TLR2 activation, and monocyte

adhesion

TG & HDL metab Endothelial cells Monocytes

HTG/↑Remn/↓apo AI Endothelial Dysfunction/Inflammation

Atherosclerotic Cardiovascular DiseaseLPL, lipoprotein lipase; TRL, triglyceride-rich lipoprotein; NO, nitric oxide; TLR2, toll-like receptor, 2 (an immune receptor which produces cytokines when activated).Caron S, et al. Circ Res. 2008;103:1348-50. Pollin TI, et al. Science 2008;322;1702-1705. 28

HDL catabolism

Genetic Evidence• Mendelian randomization studies strongly

suggest HTG causes CVD1-3

Conclusion: “In mild-to moderate [HTG], intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.”2

1. Do R. Nature Genetics 2013, e-pub 6 October.2. Hegele RA. Lancet, 2013 epub 23 December.3. Holmes MV Eur HJ 2014, epub 27 January.

HTG As a Cause of Atherosclerosis & CVD (cont)

Mechanisms of Remnant Lipoprotein (RLP) Atherogenicity

After McPherson R. J Am Coll Cardiol. 2013;61:437-439 and Wang L J Lipid Res. 2009;50;204-213

Cholesterol-rich remnant Lipoprotein (RLP)

CETP &

LPL

Dysfunctional Endothelium

TG-rich LP RLP

Lipoprotein Lipase

RLPMacrophage

(MΦ) Foam Cell

MΦ Uptake → foam cells

Inflammatory FFA

-----A

rteria

l Lum

en---

---

↓NO production↑Adhesion Molecules↑Permeability↑Plt activation

Lipoprotein Lipase

Inflammatory FFA

Lipid & Protein

Oxidation

Lipid & Protein Oxidation

-----S

uben

doth

elia

l Spa

ce---

--

Genetic Causes of HTGSomewhat Common but Controversial• Familial combined hyperlipidemia (FCH)

– ↑TG and Cholesterol levels (possibly also w/ HBP) believed due to genetic defects in one or more factors of lipoprotein metabolism (including Apo C-II, Apo C-III & CETP?)

• Familial hypertriglyceridemia (FHT)– ↑TG levels only (nl cholesterol), related to ↑ hepatic VLDL

production and/or polygenic vs environmental ↓LPL activityRelatively Rare to Very Rare• Familial dysbetalipoproteinemia (Fredrickson Type III)• Lipoprotein lipase (LPL) deficiency• Apo C-II deficiency• GPIHBP1 deficiency• Others

CETP=cholesteryl ester transfer proteinAfter Bays HE. Chapter 21 in The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich, PO, Jr., ed. 2010; p 245-57.

Note: genetic testing for HTG is rarely usefulclinically and is not recommended for routine use

Does LDL Size Contribute to HTG

Management?

LDL-C Doubly Underestimates ↑CVD Risk With HTG/low HDL-C & Small, Dense LDL

Large LDL Small, Dense LDL

Apo B

SameLDL-C

(130 mg/dL)

Fewer Particles &Less Risk/Particle

More Particles &More Risk/Particle

CholesterolEster (CE)

More Apo B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

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


Less CE/particle

so more particles and

↑↑CVD Risk!

LDL-C Doubly Underestimates ↑CVD Risk With HTG/low HDL-C & Small, Dense LDL

Large LDL Small, Dense LDL

Apo B

SameLDL-C

(130 mg/dL)

Fewer Particles &Less Risk/Particle

More Particles &More Risk/Particle

CholesterolEster (CE)

More Apo B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.



Less CE/particle

so more particles and

↑↑CVD Risk!

Basic lipid panel shows differences

↑SD LDL Even at TG <100 mg/dL!

Packard, C. Intl. J Cardiol 2000;74:S17-S22

100 mg/dL

SD LDL Predicts CVD Regardless of LDL-C

Hoogeveen, RC. ATVB 2014;34:1069-77. ARIC Study, N≈11,000.

↑SDLDL+/-

↑LDL-C

↑LDL-C +/-

↑SDLDL

Non-HDL-C Best Predicts SD LDL

Risk Factor Pearson R R2 P valueNon-HDL-C 0.721 0.520 <0.0001Apo B 0.706 0.498 <0.0001TG (log) 0.641 0.411 <0.0001LDL-C 0.543 0.392 <0.0001HDL-C -0.291 0.085 <0.0001

Hoogeveen, RC. ATVB 2014;34:1069-77. ARIC Study, N≈11,000.

SD LDL SummaryBiology: SD LDL is pro-atherogenic• Easier into subendothelial space• Stickier to subendothelial matrix• More readily oxidized• Carries atherogenic proteins (e.g. apo C-III)• Harder to clear via LDL-REpidemiology: SD LDL predicts ASCVD• SD LDL was discounted since not predictive of ASCVD

w/ LDL-P; however,• Discordance between LDL-P and LDL-C makes sense

only re: LDL size, and• LDL-P is “weighted” towards SD LDL, and• SD LDL by new assay strongly predicts ASCVD;

however,• Non-HDL-C captures much of this assoc.

Bottom line: LDL size is important mechanisticallyHow to measure? Non-HDL-C, LDL-P, LDL sizing, new assay?

Management of HTG Patients

Statins do NOT Prevent All CHD Events (Residual Risk ~50-70%)

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 66059014Secondary High Risk Primary

Patie

nts

Expe

rienc

ing

Maj

or C

HD

Eve

nts,

%

PlaceboStatin

19.4

12.310.2 8.7

5.5 6.8

28.0

15.913.2 11.8

7.910.9

CHD events occur frequently in patients taking statins

Statins Reduce CVD Events in HTG PatientsHOWEVER…

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. Ballantyne et al. Circulation. 2001;104:3056-51. CTT Collaborators. Lancet. 2005;366:1267-78. Maki et al. J Clin Lipidol. 2012;6:413-26.

Trial (Subgroup, mg/dL)(Drug)

Risk differencevs placebo P-value

Main Study HTG Subgroup Main Study HTG Subgroup

WOSCOPS (TG ≥148)(Pravastatin) –31% –32% <0.001 0.003

CARE (TG ≥144)(Pravastatin) –24% –15% 0.003 0.07

PPP Project (TG ≥200)(Pravastatin) –23% –15% <0.001 0.029

4S (TG >159, HDL-C <39)(Simvastatin) –34% –52% <0.001 <0.001

JUPITER (TG ≥150)(Rosuvastatin) –44% –21% <0.001 NS

CTT (TG >177)(Various) –21% –24% <0.001 <0.001

Median follow-up: ≥5 yrs.

*CHD = Death, MI, and recurrent ACS. HR = Hazard RatioMiller M, et al. J Am Coll Cardiol. 2008;51:724-730. N=3718.

0

5

10

15

20

TG <150 TG ≥150

LDL-C <70

LDL-C ≥70

Lipid values in mg/dL

Ref

HR0.85

(0.67,1.08)

HR0.72

(0.54,0.94)

HR0.84

(0.65, 1.09)

P=0.017

P=0.180

P=0.192

Rat

e of

CH

D A

fter

30 d

ays

(%)

15.0%

17.9%

11.7%

16.5%

TG >150 mg/dL Increases CHD Risk* Even when LDL-C <70 on a Statin

(PROVE IT-TIMI 22 Subanalysis)

*CHD = Death, MI, and recurrent ACS. HR = Hazard RatioMiller M, et al. J Am Coll Cardiol. 2008;51:724-730. N=3718.

0

5

10

15

20

TG <150 TG ≥150

LDL-C <70

LDL-C ≥70

Lipid values in mg/dL

Ref

HR0.85

(0.67,1.08)

HR0.72

(0.54,0.94)

HR0.84

(0.65, 1.09)

P=0.017

P=0.180

P=0.192

Rat

e of

CH

D A

fter

30 d

ays

(%)

15.0%

17.9%

11.7%

16.5%

TG >150 mg/dL Increases CHD Risk* Even when LDL-C <70 on a Statin

(PROVE IT-TIMI 22 Subanalysis)

Statin monoRxis not enough in HTG/lowHDL-C

Patients!

Treatment of HTG: Begin with 2o Causes

• High fructose/sucrose/carbohydrate intake• Low fiber intake• Ethanol (also tobacco? also THC?)• Sedentary lifestyle/calorie excess• Central obesity/insulin resistance• DM2 (or 1)—esp. if poor glycemic control• Hypothyroidism (check TSH!!)• Nephrotic syndrome• Medications:

– Antiretrovirals– Oral estrogens– Systemic glucocorticoids– Retinoic acid derivatives– Minor effects (some antipsychotics, nonselective beta-blockers,

thiazide diuretics, etc.)After Bays HE. In The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich, PO Jr., ed. 2010;245-57.

TG-Lowering Medications

Drug/class ↓TriglyceridesFenofibrate 20-50%Omega-3 oil (EPA +/- DHA; EE vs FFA) (pharmacologic doses)

20-45%

Niacin 20-50%Statins** 7-30%

After:• *Expert Panel on Detection, Evaluation & Treatment of High Blood Cholesterol in Adults. JAMA 2001: 285:

2486-97. • Robinson JG, Stone NJ. Am J Cardiol 2006; 98(suppl):39i-49i.• Robinson JG, Davidson MH. Expert Rev Cardiovasc Ther 2006; 4: 461-76.• Briel M, et al. BMJ 2009: 338:b92.• Miller M et al. Circulation. 2011;123:2292-2333• *Chapman MJ et al. Eur Heart J. 2011;32(11):1345-1361.

“TG-Lowering”1o for TG ≥500

2o for TG 200-499

1o for TG 200-4992o for TG ≥500

**High-intensity statin Rx will ↓TG 20-50% in pts with HTG

TG Medications: Which? When?

• If TG 200-499 mg/dL: consider Rx to prevent ASCVD*• If TG ≥500 mg/dL: Rx all to prevent pancreatitis (& ASCVD)

Regular dose Reduced dose* Brand Name200 67** Lofibra®

160 54/50 Lofibra®/Triglide®

150 50 Lipofen®

145 48 Tricor®

135 45 Trilipix®***130 43 Antara®

120 40 Fenoglide®

90 30 Antara®

Fenofibrate Formulations: A Confusing Mess!Available Fenofibrate Doses (mg/day)

*primarily for renal or geriatric patients** also available at 134 mg***fenofibric acid(See FDA-approved prescribing information for further details)

Bottom line: pick the one that works best for your patient’s payer

Choice of Prescription Om-3EE EPA+DHA* EE EPA only** FFA EPA+DHA***

Generic available? Yes No NoEPA/DHA (total) 55/45 (84%) 100/0 (98%) 73/27 (75%)Bioavailability(short-term)

Good Good Excellent

Regimen 2 bid w/ meals 2 bid w/ meals 2 or 4 qd meal indep.Tolerability issues Fishy taste &

eruct, dyspeps±Arthralgia only Fishy eruct, dyspeps,

diarrhea, nauseaTG-lowering ++++ +++ +++LDL-C effects ↑↑/± ±/↓ ↑/±HDL-C effects ↑ ±/↓ ↑↓CVD? Not at low dose,

no ongoing trialsProbably (mid-

dose) +ongoing trialNo data,

but ongoing trial

*Lovaza PI. Davidson MH et al Clin Ther 2007;29:1354–1367. ORIGIN Investigators. N Engl J Med. 2012;367:309-18. 4. Risk & Prevention Investigators N Engl J Med 2013;358:1800-8.**Vascepa PI. Yokoyama M et al. Lancet. 2007;369:1090-8. Bays HE, et al. Am J Cardiol. 2011;108:682-90.Ballantyne CM et al Am J Cardiol 2012;110:984-992.***Epanova PI. Davidson MH, J Clin Lipidology, 2012, 6:573. Offman E, Vasc Health Risk Manag. 2013; 9; 563–573. Kastelein, JJP; J Clin Lip 2013 epub 10 Oct. . Maki KC et al Clin Ther 2013;35:1400–1411.

Fenofibrate Rx Omega-3 NiacinΔ TG ↓↓↓ ↓↓↓ ↓↓Δ LDL-C ↑↑↑ to → ↑↑↑ to → to ↓ ↓ to ↓↓Δ Non-HDL-C → to ↓ → to ↓ ↓ to ↓↓Δ HDL-C → to ↑ → to ↑ ↑ to ↑↑↓ CVD Efficacy 0 to + 0 to +++ 0 to +↓ Mortality 0 ++ +Non-CVD Benefits 0 to ++ 0 to ++? 0Access (cost/month) $60-250 $90-300 $10-400“Natural” 0 ++ +Safety + to – +++ – – – to 0Tolerability ++ to – ++ to – – – – to 0Ease of use +++ +++ – – to ++

71

Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts


72



73Bottom line: Feno or Om-3 are 1st line for TG, Niacin for HDL, combos good.


Investigational TG-Lowering Agents• ISIS-APOCIIIRx: apo C-III antisense (ISIS)• Pradigastat: intestinal DGAT1 inhibitor

(ISIS/Novartis)• ARI-3037MO: Niacin analog (Arisaph)• CAT-2003: oral -3 + niacin, intracellular

(Catabasis)• Diazoxide Choline Controlled Release (DCCR):

KATP channel agonist (Essentialis)

http://www.isispharm.com/Pipeline/index.htmhttp://onlinelibrary.wiley.com/doi/10.1111/dom.12002/abstracthttp://www.prnewswire.com/news-releases/arisaph-pharmaceuticals-reports-positive-results-from-two-

safety-clinical-trials-for-its-niacin-analog-ari-3037mo-177707481.htmlhttp://www.isispharm.com/Pipeline/Therapeutic-Areas/Metabolic-Disease.htm#ISIS-DGAT2Rxhttp://www.fiercebiotech.com/story/catabasis-nails-324m-triglyceride-busting-drug/2013-11-15http://www.Clinicaltrials.gov

HTG: Should We Treat? Yes!• TG>~100: assume ↑ASCVD risk (statin Rx)• TG 200-500—↑ASCVD risk even w/ statin!

– Test for remnants if TC≈TG & both > ~250– Diet: ↓calories, ↓fructose, ↓EtOH (in ~all)– ↑Physical activity (in ~all)– ↓Glycemia (if DM or IR)– Rx w/ medications:

• Statins (if ↑ASCVD risk), and• If HTG persists: consider fibrate, om-3, niacin

• TG >500—↑pancreatitis and ↑ASCVD!– Diet: ↓fat, ↓calories, ↓EtOH, (↓fructose) – ↑Physical activity– ↓Glycemia (if DM)– Rx: om-3, fibrate, (niacin, statin)

clinical management of hypertriglyceridemia: state of the ... · clinical management of...

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