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Dyslipidemia Management:

State of the Art 2013Cardiovascular Health Summit, 2013

Crowne Plaza, Billings, MTApril 12, 2013

Eliot A. Brinton, MD, FAHA, FNLAVice President, American Board of Clinical Lipidology;

Director, Atherometabolic Research Utah Foundation for Biomedical Research;

President, Utah Lipid Center;Salt Lake City

eliot.brinton@utah.edu

Speaker DisclosuresDr. Brinton has received:• Research funding: Amarin, Health Diagnostic

Laboratory, Merck, Roche• Honoraria as consultant/advisor: Abbott,

Aegerion, Amarin, Arisaph, Atherotech, Daiichi-Sankyo, Essentialis, Genzyme, Kowa, Merck, Novartis, Regeneron, Sanofi-Aventis, Takeda

• Honoraria as speaker: Abbott, Amarin, Daiichi-Sankyo, Janssen, Kowa, Merck, Takeda

Learning Objectives

• At the end of this learning activity, participants should be able to:– Discuss new developments in LDL-C

lowering agents– Evaluate new and controversial data in

management of patients with low HDL-C– Consider the impact of new medications

and ongoing trials in management of high TG

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Talk Outline• LDL/Non-HDL Lowering

– Statin adverse effects (myopathy & DM)– Lomitapide and Mipomersen approval—for

HoFH only– PCSK9 mAb in development– “ATP-IV” Guidelines—when?

• HDL Raising– Observational Data– Clinical Trial data

• AIM-HIGH sub-analysis• HPS-2 ACC presentation• CETP-I update

• TG/Non-HDL Lowering– Icosapent-ethyl approval, REDUCE-IT study– Epanova in development

Management of High LDL/Non-HDL

Statin Update• Statin Myopathy:

– New internet-based data (USAGE study)– Continued work on causes & Rx

• New-onset DM: FDA-mandated label update (all but pravastatin)

• Cognitive dysfunction: no solid data, butFDA-mandated label update

• Liver transaminase testing removed

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Statin Side Effects (esp. Myopathy): Most Common Reason to Discontinue

(but also common in pts who continued)USAGE: Internet survey, 10,138 US adults w/ prior statin Rx (2000-2011)Among the 12% who discontinued• Reasons for discontinuing:

– Side-effects—62% (86% w/ muscle pain/weakness = 53% of total)

– Cost—17% (despite many inexpensive generics now available)

– Lack of cholesterol lowering efficacy—12%

• When/how they stopped:– 57% stopped promptly after a side effect (no further Rx fill)

– One-third stopped w/o asking or telling their health-care provider

Among the 88% current users– Muscle pain or weakness reported by 25%

Cohen JD, J Clin Lip 2012.

Do Statins Increase New-Onset DM-2?Yes, Modest Increase w/ Certain Statins• ~ 9-25% ↑ DM risk• Higher with increased age (+other DM RFs)• Maybe no ↑ w/ pravastatin or lovastatin?• Few data w/ fluvastatin or pitavastatinBut Favorable Risk/Benefit Ratio Remains• NNH = 1 case of DM per 225 pts Rx’d x 4y• NNT = 1 MACE per 31 pts Rx’d x 4y*• Prevent >7 MACE:1 DM case (>3:1 at hi-dose)No need to avoid statin in med- to high-risk pts

Sattar N, et al. Lancet 2010; 375: 735-42; Mills, EJ, et al. QJMed 2011;104:109-124.*Cholesterol Treatment Trialists (CTT) Collaboration, Lancet 2010; 376:1670-81.

New LDL-C-Lowering Drugs

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Cuchel M, Lancet 2013;381;40-46 .

Lomitapide Lowers LDL-C in HoFH (N=29 no ctrls)

↓HDL-C 10-20% at 26 wks, gone at 56 wks↓Lp(a) 21% (sig at 56 wks only)

— Includes data from 6 dropouts—

Lomitapide (Juxtapid—Aegerion): Update

• MoA: MTP-inhib, blocks VLDL/chylo assembly

• What clinical impact in the “statin world”?– Approved December 2012, available 1/13– For “HoFH”: how many in US? how to Dx?

• N≈300 (?) per genetic studies, vs • N≈600 (?) LDL-apheresis (LDL-C >200 on-Rx), vs• N≈3000 (?) by study criteria (TC >500 pre-Rx)

– Concurrent LDL apheresis studied/allowed– Cost: $225-295K/yr (!) vs LDL-apher $50-

$125K/year

Lomitapide (Juxtapid—Aegerion): Update—cont.

• Safety and tolerability– Oral qd, but – Fatty intest/abd Sx in ~all– Fatty liver/↑transaminases in ~all

• Rx requirements:– REMS for Rx-ing MD, pt registry – Dose titration up and down, – Supplements (vit E, ALA, EPA, DHA)– Contraindications: pregnancy, strong CYP

inhib, hepatic insufficiency, intestinal disease – Precautions: warfarin, simvastatin – Paperwork: Rx forms, mail-order pharmacy,

insurance pre-auth (!)

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Mipomersen →↓LDL-C 21% in HoFH (N=34)

0 5 10 15 20 25 30Week

Raal, FJ. Lancet 2010;375:998-1006 HDL-C ↑11%; Lp(a) ↓23% (both sig)

Mipomersen (Kynamro—Isis): Update

• MoA: Apo B anti-sense oligonucleotide (blocks apo B-100 synth & hep VLDL prod)

• What clinical impact in the “statin world”?– Approved by FDA 1/29/13, available 2/13– For “HoFH”: how many in US? how to Dx?

• N≈300 (?) per genetic studies, vs • N≈600 (?) LDL-apheresis (LDL-C >200 on-Rx), vs• N≈3000 (?) by study criteria (TC >500 pre-Rx)

– ↓Apo C-III 45% (non FH pts)– Concurrent LDL apheresis “not recommended”

(not studied, but no other rationale)– Cost $176K/yr (vs $225-295K/y, or $50-

125K/y)Kynamro PI, Genzyme, January 2013; and Raal, FJ. Lancet 2010;375:998-1006

Mipomersen (Kynamro—Isis): Update—cont.

• Safety and tolerability– Once-weekly but req. sc shot– No fatty intestine, but– Fatty liver/↑transaminase (flu-like Sx in ~30%)– Injection site rxn (~76-84%, recur at old sites)– Rejected by EMEA (d/c’s; liver, skin & CV tox)– ~New Rx category: safety? immune effects?

• Rx requirements:– REMS for Rx-ing MD, pt registry – Contraindic: mod-severe hepatic impairment– Precautions: flu-like (30%; fever, myalg),

pregnancy category B– Rx forms, mail-order pharmacy, and insurance

pre-auth (!)Kynamro PI, Genzyme, January 2013; and Raal, FJ. Lancet 2010;375:998-1006

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New Cholesterol Guidelines• NCEP ATP-III 2001 (12 years old); many

new studies/approved agents since• New effort:

– NCEP discontinued, not “ATP-IV”– NHLBI requested “evidence based”, not an

update of ATP-III—likely very different– Few/no studies directly tested ATP-III goals– May delete lipid Rx goals, like anti-plt Rx?– Will use lifetime risk (not 10-y Framingham)

• Release: 2011—2012—2013—2014??

Relationship between HDL-C and CVD Risk:

General Population vs. Monogenic Disorders

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Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000.

Coronary Heart Disease Risk by Non-HDL-C and HDL-C Quintiles

Haz

ard

Rat

io

Haz

ard

Rat

io

Usual Mean Non-HDL-C Level, mg/dL Usual Mean HDL-C Level, mg/dL

Non-HDL-C by levels of HDL-C HDL-C by levels of Non-HDL-C

High CVD Risk in Patients with Low HDL-C

• Average HDL-C in CCU is 38 mg/dL (vs TG 167, LDL-C 103)1

• Post-PCI, low HDL-C predicts 3 x ↑mort.2• Statin Rx→LDL-C <70 + HDL-C <mid 30s:

– CVD in TNT: 1.5-1.9%/yr3

– CVD in AIM-HIGH: 5.4%/yr4

1. Sachdeva A et al. Am Heart J. 2009;157:111-117.e2.2. Wolfram RM et al. Am J Cardiol. 2006;98:711-717.3. Barter P et al. N Engl J Med. 2007;357:1301-1310.4. Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

Antioxidative Activity

AntithromboticActivity

Potential Antiatherogenic Actions of HDL

Anti-infectious Activity

EndothelialRepair

Chapman MJ et al. Curr Med Res Opin. 2004;20:1253-1268.Assmann G et al. Annu Rev Med. 2003;53:321-341.

AntiapoptoticActivity

ReverseCholesterolTransportCellular

CholesterolEfflux

Anti-inflammatoryActivity

VasodilatoryActivity

HDL

Apo A-I

Apo A-II

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ORM2 RBP4 TF FGA HPXITIH4TTR

Acute-phase Response

LCAT apoC-IapoC-II

apoC-IIIapoC-IV

PON3

SAA4

SAA2

SAA1

apoA-1PON1

apoHapoA-IV

Clusterin

apoA-II

apoL-I

apoD

apoE

apoFapoM

PLTPCETP

Lipid Metabolism

C3C4A

C4B

C9

VTN

ComplementRegulation

SERF2 SERF1AGT

AHSGHRP

SERA1

AMPKNG1

ProteinaseInhibitor

The HDL Proteosome

Adapted from Vaisar T et al. J Clin Invest. 2007;117:746-756.

Reconciling Observational Data Re: Low HDL-C

• Low HDL-C ≈↑CVD– In general populations– In ACS

• Low vs high HDL-C (isolated) ≠↑vs ↓CVD– Certain gene variants (LIPG + 14—HDL-C

only, ↓LCAT?)• Hypotheses:

– Low-HDL-C ≈↑CVD only when ↑TG?– Related to TG-rich remnant lipos

Clinical Trials of HDL-Raising Medications:

Recent CVD Results

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Available Agents for HDL-Raising (&↓TG)Available Agents for HDL-Raising (&↓TG)Agent HDL-C ↑ Primary UseNicotinic acid 15-35% HDL ↑Fibrates 5-20% TG ↓Statins 5-15% LDL ↓Prescr. Om-3* 2-10% TG ↓Bile-acid resins* 2-5% LDL ↓Ezetimibe* 1-3% LDL ↓Pioglitazone* 5-20% Glucose ↓Estrogens* 10-25% Hot flashes-blockers* 10-20% BPHAlcohol* 5-15% Social, etc.

*Lacking FDA-approved indication for HDL-raising.Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174.Insull W et al. Mayo Clin Proc. 2001;76:971-982.McKenney JM et al. Pharmacother. 2007;27:715-728.

Niacin Reduces Total CVD (CHD + CVA):Pre-AIM-HIGH Trials

Bruckert, E. Atherosclerosis 2010; 210:353-361.

stat sig 27%↓

1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH — ResultsPrimary Outcome

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AIM‐HIGH: Niaspan beats Control in HTG/low HDL‐C pts

Guyton, JR; AHA Presentation Nov 2012

AIM-HIGH—New Subgroup Analysis SummaryAIM-HIGH—New Subgroup Analysis SummarySubjects w/ HDL-C <32 mg/dL & TG >200 mg/dL had

37% ↓CVD w/ ERNA: HR 0.63 (95%CI 0.40-0.98, interaction p=.017)

[1st + 3rd HDL/TG tertile <33 & >198 had HR .74 p=.07]

Similar subpopulations showed 27-71% ↓CVD with:• Gemfibrozil: HHS*, VA-HIT*• Fenofibrate: FIELD, ACCORD-Lipid• Omega-3 (pure EPA): JELIS*

Bottom Line: TG/HDL drugs work in ↑TG/↓HDL-C!(Need to check ↑TG/↓HDL-C pts in HPS2/THRIVE)

Guyton, JR; AHA Presentation Nov 2012. *Lesser benefit seen in full study popul.

Niacin May Reduce CVD Better in Patients with Metabolic SyndromeNiacin May Reduce CVD Better in Patients with Metabolic Syndrome

Relative Hazard 0.78 0.30

Z(int) = –1.78

Placebo Niacin

MS– (0–2 RF’s) MS+ (3–5 RF’s)

n=243 n=99 n=111 n=39

Analysis of Coronary Drug Project. Canner PL et al. J Am Coll Cardiol. 2003;41:291A. [Abstract 845-2]

Patients With HDL-C at BL; N=354 (Placebo), 138 (Niacin)

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HPS-2/THRIVE: The PromiseAppeared to avoid most AIM-HIGH problems• ~True placebo-control ∴ good test of niacin?• Adequate duration (~5 yrs)• Adequate N (~23,000 subjects)• Little pre-study Rx “contamination” (vs. AIM-

HIGH)But might have kept two problems• NO selection for either low HDL-C or high TG pts• All niacin subjects also on laropiprant, so NOT a

test of niacin alone!

* Non‐fatal MI or coronary death, any non‐fatal or fatal stroke, coronary or non‐coronary artery surgery or angioplasty.

Years of follow‐up 

Patients  suffering events (%) 

15.0% 

0  1  2  3  4 0 

5 

10 

15 

20 

14.5% 

Placebo 

ERN/LRPT 

Logrank P=0.29

Risk ratio 0.96 (95% CI 0.90 – 1.03) 

Effect of ERN/LRPT on Major Vascular Events* 

Mean (SD) baseline

mg/dL

Total chol 128 (22)

Direct‐LDL 63 (17)

HDL 44 (11)

Triglycerides* 125 (74)

Baseline Lipids on Statin‐based Rx

HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease

“Significant excesses of serious adverse events (SAEs) due to known and unrecognised side‐effects of niacin. Over 4 years, ER niacin/laropiprant caused SAEs in ~3%”

http://www.thrivestudy.org/

Note: pts had NONE of the usual lipid indications for Niacin

0 2 4 6 8 10 12

Skin

Bleeding

Heart failure

Musculoskeletal

Gastrointestinal

Infection

New onset diabetes

Diabetic complication

Active

Placebo

Percentage of patients

Excess    p value

3.7%   <0.0001 

1.8%   <0.0001 

1.4%   <0.0001

1.0%   <0.0001

0.7%     0.0008

0.4%     0.05 

0.7%     0.0002

0.3%     0.0026

ERN/LRPT

Effect of ERN/LRPT on SERIOUS Adverse Events (median follow-up 3.9 years)

http://www.thrivestudy.org/

Note: majority of excess SAEs in DM‐2were “minor hyperglycaemic problem”

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Trend Towards MVE Benefit Among European Patients

Randomized allocation  Risk ratio & 95% CI Het or trend χ²

(uncorrected p value)PlaceboERN/LRPT

(12,835)(12,838)Age (years)< 65  740 (11.4%)  786 (12.2%)  0.00 

(p=0.98) ≥ 65 <70  392 (13.9%)  367 (13.1%) ≥ 70  564 (15.9%)  605 (17.0%) 

SexMale  1397 (13.2%)  1485 (14.0%)  3.21 

(p=0.07) Female  299 (13.4%)  273 (12.3%) 

RegionEurope  832 (11.3%)  913 (12.4%)  3.61 

(p=0.06) China  864 (15.8%)  845 (15.5%) 

Statin‐based therapySimvastatin 40mg  945 (14.0%)  949 (14.0%)  1.28 

(p=0.26) Ezetimibe/simvastatin   751 (12.4%)  809 (13.3%) 

All  1696 (13.2%) 1758 (13.7%)  3.5% SE 3.3 reduction 

1.0  1.2 0.8 

ERN/LRPT better  Placebo better 

Randomized allocation 

Risk ratio & 95% CI

Het or trend Χ²

(uncorrected p value)PlaceboERN/LRPT(12835)(12838)

HDL cholesterol <35  (0.9)  388 (15.8%) 399 (16.3%)  0.20 

(p=0.66) ≥35  <43  560 (13.7%) 546 (13.5%) ≥43  (1.1)  748 (11.9%) 813 (12.8%) 

LDL cholesterol <58  (1.5)  724 (14.7%) 679 (13.8%)  5.91 

(p=0.02) ≥58 <77  685 (12.4%) 761 (13.7%) 

≥77  (2.0)  287 (12.0%) 318 (13.5%) 

All  1696 (13.2%) 1758 (13.7%)  3.5% SE 3.3 reduction 

1.0  1.2 0.8 ERN/LRPT better  Placebo better 

mg/dL (mmol/L) 

Triglycerides

<89   (1.0)  541 (13.2%)  563 (13.4%)  0.66 (p=0.42) ≥89 <151  694 (12.8%)  712 (13.2%) 

≥151 (1.7)  461 (13.9%)  483 (14.8%) 

Trend Towards MVE Benefit Among Patients with LDL‐C > 58 mg/dL

Why no benefit of ERNL added to statin?• Did not study pts with lipid indication for niacin!

Avg. base: HDL-C 44 mg/dL, TG 125, LDL-C 63• Benefit in pts w/ LDL-C >57 mg/dL? (sig trend)• Benefit in low HDL-C/High TG? (analyses pend.)• Benefit in Caucasians? (close to sig 9%↓)• Harm from niacin (new DM-2, myopathy)• Harm from laropiprant?

– Pan-infections (anti-WBC effect?)– Hemorrhage (↑CVA due to ↑aneurysms vs anti-plt?)

HPS-2/THRIVE: The Reality

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HDL-Raising via CETP-Inhibition

CETP in HDL Metabolism and Atherosclerosis

• Human CETP deficiency: ↑↑HDL-C and ↓↓CVD• Decreasing CETP in animals: ↑↑HDL-C and ↓↓athero

Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167.

Contacos C et al. Atherosclerosis. 1998;141:87-98.

Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28:148-154.

LIVER PERIPHERAL TISSUE

CE

TG

Bile

Foamcells

RCT HDL

ABC-A1

VLDL LDL

PLASMA

LDL-R

ABC-G1

Free cholesterol

CETP

Athero-sclerosisLDL

Lipid Effects of CETP Inhibitors% Change from Baseline, added to statin RxLipid Effects of CETP Inhibitors% Change from Baseline, added to statin Rx

CETP AgentDose

(mg/day)HDL-C (%)

LDL-C (%)

TG (%)

Torcetrapib 60 61 -24 -9

Anacetrapib 100 138 -40 -7

Evacetrapib* 100 82 -13 -4

Dalcetrapib 600 31 -2 -3

*Dose of evacetrapib in clinical endpoint trial is 130 mg/d.Adapted from Cannon C et al. JAMA. 2011;306:2153-2155, and Nicholls SJ et al. JAMA. 2011;306:2099-109.

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Barter et al. N Engl J Med. 2007;357(13):2109-2122.http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc.http://www.ama-assn.org/ama1/pub/upload/mm/365/torcetrapib.doc.Qiu X et al. Nat Struct Mol Biol. 2007;14(2):106-113.

http://www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf.http://www.roche.com/media/media_releases/med-cor-2012-05-07.htm.*Dalcetrapib development stopped May 7, 2012 due to lack of efficacy in the Dal-Outcomes CVD endpoint trial.

CETP Inhibitors: 2 Down, 2 RemainCETP Inhibitors: 2 Down, 2 Remain

CETP

Evacetrapib

↑CVD (25%) but OK HDL

function(off-target eff.?)

*No ↓CVD,but OK HDL function, +/-anti athero?

--------------------↑HDL-C----------------------~60% ~80% ~140% ~30%

Torcetrapib Caused Off-target Hyperaldosteronism (ILLUMINATE data)

• Torcetrapib arm of ILLUMINATE:1– ↑ Systolic Blood Pressure:

• Mean ↑5.4 mmHg• >15 mmHg ↑SBP: 19.5% torcet (vs 9.4% placebo, P<0.001)

– ↓ serum potassium– ↑ serum bicarbonate– ↑ serum sodium– ↑ serum aldosterone

• ↑ CVD in ILLUMINATE correlated with adrenal dysfunction

• Inverse relationship of CVD and on-Rx-HDL-C preserved

• Conclusion: ↑CVD likely due to off-target actions of torcetrapib, not related to CETP inhibition1,2

1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.

dal-OUTCOMES Results: No ↓CVD

Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].

Year

Cum

ulat

ive

Inci

denc

e of

Prim

ary

Out

com

e (%

of p

atie

nts)

No. at riskPlacebo 7933 7386 6551 1743Dalcetrapib 7938 7372 6495 1736

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dal-OUTCOMES Results: HDL Was Likely Still Functional

Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].

Quintiles of Change in HDL-C (mg/dL) Baseline to Month 1

Annu

aliz

ed E

vent

Rat

e (%

)

Small stat. sig. ↑BP (0.6 mm) suggested small adverse adrenal effect, which may have overcome small benefit from modest ↑HDL.

Does Anacetrapib Reduce CVD Events?DEFINE Results

Cannon CP, et al. N Engl J Med. 2010;363(25):2406-15.

“Hard” CVD

No net ∆

“Soft” CVD↓71%

Cardiovascular Events During the Treatment Phase of the Study

Ongoing Clinical Trials of CETP-Inhibitors

REVEAL• Anacetrapib 100mg/d• N=30,000• Stable CHD• Background atorva• 1o endpoint: fatal

CHD, MI, cor revasc• Start 6/11• 4 yr min f/u• End ~1/17

ACCELERATE• Evacetrapib 130mg/d• N=11,000• ACS 30d-1y, or non

CHD, or DM+CAD• Background statin• 1o endpoint: fatal

CHD, MI, CVA, cor revasc, hosp for USA

• Start 2H12• 1.5 yr min f/u• End ~2H15

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Revisiting the HDL HypothesisCon• Recent trials of HDL-raising have been neutral• Genetic isolated ∆HDL-C may not predict CVDPro• CVD risk reduction only ~1/3 w/ statin monoRx, so• Statin monoRx is not enough for high-risk patients• Low HDL-C predicts high CVD risk, even w/ statin Rx• HDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG pts

Revisiting the HDL HypothesisCon• Recent trials of HDL-raising have been neutral• Genetic isolated ∆HDL-C may not predict CVDPro• CVD risk reduction only ~1/3 w/ statin monoRx, so• Statin monoRx is not enough for high-risk patients• Low HDL-C predicts high CVD risk, even w/ statin Rx• HDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG pts(My) Current Recommendation• Consider HDL/TG meds (fibrate, Om-3, niacin)

Revisiting the HDL HypothesisCon• Recent trials of HDL-raising have been neutral• Genetic isolated ∆HDL-C may not predict CVDPro• CVD risk reduction only ~1/3 w/ statin monoRx, so• Statin monoRx is not enough for high-risk patients• Low HDL-C predicts high CVD risk, even w/ statin Rx• HDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG pts(My) Current Recommendation• Consider HDL/TG meds (fibrate, Om-3, niacin) in

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Revisiting the HDL HypothesisCon• Recent trials of HDL-raising have been neutral• Genetic isolated ∆HDL-C may not predict CVDPro• CVD risk reduction only ~1/3 w/ statin monoRx, so• Statin monoRx is not enough for high-risk patients• Low HDL-C predicts high CVD risk, even w/ statin Rx• HDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG pts(My) Current Recommendation• Consider HDL/TG meds (fibrate, Om-3, niacin) in• New analyses and trials must address:

– Does Rx with each particular HDL-raising med →↓CVD?– Is HDL a causal factor or a biomarker of risk?

How Should We Measure HDL?• Plasma concentration

– HDL-C– Apo A-I– HDL-P—independent (not rel. to TG/LDL-P)

• HDL Composition/Structure—in devel.– HDL size (including pre-beta HDL)– HDL proteome, TG, other?

• HDL Function—in development– Cholesterol efflux– Inflammation, oxidation, etc.

Bottom line: HDL metrics are a “moving target”HDL-C is ok for routine clinical use for now

Update on Management of Hypertriglyceridemia

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Can Hypertriglyceridemia Cause Atherosclerosis?

Con• HTG assoc. w/ CVD weaker than LDL-C, partly HDL-C

dependent• Severe HTG from ↑chylos not related to ↑CVD• TG accumulation not seen in atherosclerotic plaque• TG-lowering drugs not completely proven to ↓CVDPro• TG-rich lipos are atherogenic (esp. chol-rich remnants)• TG lipolysis by LPL → pro-inflammatory FFA (uptake

by CD36 and FA binding proteins to nucleus)• Apo C-III raises TG and is pro-inflammatory• HTG causes atherogenic changes in LDL and HDL• TG-lowering meds →↓CVD in HTG/low HDL-C pts• EPA →↓CVD in general population on-top of statin!

TG Levels Predict CHD Risk: Meta-analysis of 29 Observational 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.

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)

21Increased

Risk

Increased CHD Risk with TG >150 mg/dL (even w/ LDL-C < 70!)Increased CHD Risk with TG >150 mg/dL (even w/ LDL-C < 70!)

CH

D E

ven

taR

ate

Aft

er 3

0 D

aysc ,

%

TG <150TG ≥150

LDL-C ≥70

LDL-C <70

HR: 0.85P=.180

Referent

HR: 0.72P=.017

HR: 0.84P=.192

N = 4162

PROVE IT-TIMI 22 Trial:• Patients w/ acute coronary syndrome (ACS) • Rx atorvastatin 80 mg or pravastatin 40 mg. • Primary endpoint: death, MI, and recurrent ACS (adjusted for age, gender, low HDL-C,

smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment). Lipid values are in mg/dL.

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

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19

CETP = cholesterol ester transfer protein

FattyLiver

VLDL

TG

TG

CE

CE

CETP

CETP HDL

Hepatic Lipase

Kidney

Rapid Lossof Apo A-I

HDL & A-I

SDLDL

LDL size

Apo B & LDL-P

TG

VLDL-C

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

“Atherogenic Dyslip.”1. ↑TG/VLDL-C2. SD LDL/↑LDL-P3. ↓HDL-C & Apo A-I

FFA/TGand

Fructose(glucose)

Hepatic Lipase

Three Atherogenic Consequences of Hypertriglyceridemia

CentralAdiposity

LDL

SDHDL

1

3

2

FFA/TG

↑VLDL Synth

Fibrates Reduce CHD Risk ~35% in Patients with High TG and Low HDL-C

A meta-analysis of randomized fibrate trials

A Subjects with Dyslipidemia B Complementary Subgroups Without Dyslipidemia

“With Dyslipidemia”= TG ≥ 204mg/dL and HDL-C ≤ 34mg/dL

After Sacks FM, Carey VJ, Fruchart JC. N Engl J Med. 2010;363(7):692-694. Copyright © 2010 Massachusetts Medical Society.

B Subjects without Dyslipidemia

Adjusted for age, sex, smoking diabetes, and hypertension.Saito Y et al. Atherosclerosis. 2008;200:135-40. 57

EPA Reduces CVD in JELIS Subgroup: TG >150mg/dL and HDL <40mg/dL

(↓57% vs ↓19% in total study population)

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20

Trial(Drug)

Primary Endpoint: Entire Cohort (P-value)

Lipid Subgroup Criterion

Primary Endpoint: Subgroup (P-value)

Pre-statin era

HHS (Gemfibrozil)-34% (0.02)

TG > 204 mg/dlLDL-C/HDL-C > 5.0 -71% (0.005)

BIP (Bezafibrate) -9.4% (0.26)

TG > 200 mg/dl HDL-C <35 mg/dl -42% (0.02)

Some statin use

FIELD(Fenofibrate) (no statins at entry)

-11% (0.16) TG > 150 mg/dl -12% (0.07)

Statin add-on

ACCORD(Fenofibrate/simva) -8% (0.32)

TG > 204 mg/dlHDL-C < 34 mg/dl -31% (0.0567)

JELIS(ethyl EPA)(simva & prava)

-19% (0.011)

TG > 150 mg/dlHDL-C < 40 mg/dl -53% (0.043)

↓CVD with “TG/HDL Drugs” in High TG/Low HDL-C Subgroups

Gemfibrozil Reduces CVD In Patients w/ Average to Elevated Insulin Levels

Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604 VA-HIT Results.

+15

+10

+5

0

-5

-10

-15

-20

-25

-30

-35

-40

≤23

n = 434

24-29 30-38 39

Fa

vo

rs G

em

fib

rozi

lF

av

ors

Pla

ce

bo

CV

D R

isk

Re

duct

ion,

%

P=.04 Versus Placebo

n = 431n = 426n = 442

Baseline Fasting Insulin Quartile----1---- ----2---- ----3---- ----4----

Fibrates reduce CVD best in Insulin Resistance

Statin + EPA/DHA (Lovaza): COMBOS Lipid Endpoints

Med

ian

ch

ang

e fr

om

bas

elin

e (%

)

TG LDL-C HDL-CVLDL-C

Additional changes to baseline simvastatin therapy

P-OM3 4 g/d + simvastatin 40 mg/d

Placebo + simvastatin 40 mg/d

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.

TG 200-500 baseline on statin.Davidson MH et al. Clin Ther. 2007;29:1354-67.

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21

Statin + EPA (Vascepa): ANCHOR Lipid Endpoints

****P<0.0001; ***P<0.001; **P<0.01; *P<0.05;NS = not significant (P≥0.05), icosapent ethyl vs placebo

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

-21.5****

-10.1***

-13.6****

-5.5**

-9.3****

-3.8* -6.2

**

-3.6NS

-4.5**

-2.2NS

254265 8282128128 9193 3837 Baseline (mg/dL)

4 g/day2 g/day

Icosapent Ethyl

12-week trial in high-risk statin-treated patients (n = 702) with TG 200-500 and LDL-C 40-100. Ballantyne CM et al. Am J Cardiol. 2012;110:984-92.

Bottom line: EPA/DHA better for ↓TG & ↑HDL-C. EPA better for ↓LDL-C, ↓Non-HDL-C, ↓Apo B (↓CVD?)

Effect of Icosapent Ethyl on Inflammatory Markers

*P<0.01; †P<0.001; ‡P<0.0001 vs placebo. hs-CRP=high-sensitivity C-reactive protein; 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

Icosapent ethyl 2g bid

Placebo

Study duration ~4–6 years

Primary endpoint:

1st major CV event

composite

Reduction of Cardiovascular Events with EPA – Intervention Trial: REDUCE-IT

• Randomized, double-blind, multinational• 2o outcomes: individual CVD events, lipid/lipoprotein levels, safety,

subgroup analyses (diabetics, etc.) • Completion ~Nov 2016

http://www.clinicaltrials.gov/ct2/show/NCT01492361?term=icosapent+ethyl&rank=9

• N=8000 M&F ≥45 y/o• High CVD risk:

• Prior CHD (70% pts), or• DM-2 + ≥1 RF

• Dyslipidemic:– H/O ↑Chol, but at LDL-C

goal on statin, and– TG 150-500 mg/dL

Icosapent ethyl = Vascepa = AMR101

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22

Omefas (Epanova) Update• Omefas (omega-3 fatty acids—Epanova,

Omthera) in phase III• Plan to file NDA mid 2013• Composition: EPA 50-60%, DHA 15-25%,

+other om-3 FAs• ECLIPSE (Jan 2011)

– Design: N=54, 4-way cross-over 24 h PK of EPA & DHA, 24 h post 4 g Omefas (Epanova) or O3AEE (Lovaza) on low- or high-fat diets.

– Results: • Plasma EPA+DHA w/ Omefas 4x > vs O3AEE on low-fat

diet (also > on high-fat)• EPA w/ Omefas 13x >;

Omefas (Epanova) Update—cont.• EVOLVE (Nov 2012)

– Design: N=399 TG 500-2000 mg/dL on 2, 3, or 4 g/d Omefas vs 4 g/d olive oil (control) x 12 wks

– Results: • TG ↓26% at 2 g/d and ↓31% at 4g/d; • Non-HDL-C ↓8% at 2 g/d and ↓ 10% at 4g/d• Apo C-III ↓ 11% at 2g/d and ↓14% at 4g/d• Some mild GI Sx

• ESPRIT– Design: N=647 “HTG” statin-Rx, Omefas 2g/d vs

4g/d vs Olive oil 4g/d x 6 wks– Results:

• TG ↓15% at 2g/d, ↓21% at 4g/d• Non-HDL-C ↓4% at 2g/d, ↓7% at 4g/d• LDL-C ↑5% at 2g/d, ↑1% at 4g/d• Apo C-III ↓8% at 2g/d, ↓13% at 4g/d

Lipid Update 2013: Summary• New concerns re: statins• New statin adjuncts/alternatives (to ↓LDL-C)• New HDL controversies:

– Relationship of HDL with athero & CVD – New observational and clinical trial data– Ongoing development of HDL-raising meds

• New TG developments:– Appreciation for High TG epi. & mech.– New omega-3 approved– Another omega-3 in late-stage phase 3

• Still OK to consider HDL & TG Rx as statin adjunct or alternative (statin intolerant)