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HDLHDLHDLHDL----Cholesterol Versus Cholesterol Versus Cholesterol Versus Cholesterol Versus HDLHDLHDLHDL----Function: What is the Science Function: What is the Science Function: What is the Science Function: What is the Science and What is the Best Clinical and What is the Best Clinical and What is the Best Clinical and What is the Best Clinical

ApproachApproachApproachApproach????

Eliot A. Brinton, MD, FAHA, FNLAImmediate Past President,

American Board of Clinical LipidologyDirector, Atherometabolic Research

Utah Foundation for Biomedical ResearchPresident, Utah Lipid Center

Salt Lake Cityeliot.brinton@utah.edu

Baptist Health South Baptist Health South Baptist Health South Baptist Health South FloridaFloridaFloridaFlorida14th 14th 14th 14th Annual International Symposium onAnnual International Symposium onAnnual International Symposium onAnnual International Symposium on

Cardiovascular Cardiovascular Cardiovascular Cardiovascular Disease Disease Disease Disease PreventionPreventionPreventionPreventionFebruary 20, 2016; February 20, 2016; February 20, 2016; February 20, 2016; Miami, Miami, Miami, Miami, FloridaFloridaFloridaFlorida

Speaker DisclosuresSpeaker DisclosuresSpeaker DisclosuresSpeaker DisclosuresDr. Brinton has receivedDr. Brinton has receivedDr. Brinton has receivedDr. Brinton has received::::• Grants/Research Grants/Research Grants/Research Grants/Research Support: Support: Support: Support: Amarin, Aurora

Foundation, National Institutes of Health • Honoraria as Consultant: Honoraria as Consultant: Honoraria as Consultant: Honoraria as Consultant: Alexion, Amarin,

Amgen, Aralez, AstraZeneca, Kowa, Merck, PTS Diagnostics, Regeneron, Sanofi-Aventis

• Honoraria as Speaker:Honoraria as Speaker:Honoraria as Speaker:Honoraria as Speaker: Amarin, Amgen, AstraZeneca, Janssen, Kowa, Merck, Regeneron, Sanofi-Aventis, Takeda

DrDrDrDr. Brinton will reference unlabeled. Brinton will reference unlabeled. Brinton will reference unlabeled. Brinton will reference unlabeled/ unapproved / unapproved / unapproved / unapproved uses of drugs in his presentationuses of drugs in his presentationuses of drugs in his presentationuses of drugs in his presentation....

Learning ObjectivesLearning ObjectivesLearning ObjectivesLearning Objectives• Explain how HDL-C predicts CVD in

populations but not in studies of genetic variants (Environmental only? Only w/ HTG?)

• Appreciate the heterogeneity of HDL structure and composition

• Discuss the apparent anti-atherogenic effects of HDL

• Discuss the “neutral” ASCVD effects of “HDL-raising” treatment in randomized clinical trials

• Implement clinically feasible approaches to ASCVD prevention in low HDL-C patients

Talk Outline• Epidemiology• Physiology and Pathophysiology• Anti-Atherogenic Mechanisms• Genetics of HDL-C vs ASCVD• “HDL-Raising” Treatment

– Niacin– CETP-I– Apo A-I infusion– HDL-delipidation

• Summary and Conclusion

Low HDLLow HDLLow HDLLow HDL----C Predicts ↑CHD C Predicts ↑CHD C Predicts ↑CHD C Predicts ↑CHD Independent of LDLIndependent of LDLIndependent of LDLIndependent of LDL----C C C C

Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a.

HDLHDLHDLHDL----CCCCmg/dL mg/dL mg/dL mg/dL

4yr CAD Risk*4yr CAD Risk*4yr CAD Risk*4yr CAD Risk*

LDLLDLLDLLDL----C, mg/C, mg/C, mg/C, mg/dLdLdLdL

8565

4525

100 160 2200

1

2

3

*Framingham Study: men aged 50-70 years HDLHDLHDLHDL----C is C is C is C is inverseinverseinverseinverse to CAD to CAD to CAD to CAD

at at at at allallallall LDLLDLLDLLDL----C LevelsC LevelsC LevelsC Levels Emerging Risk Factors Collaboration. Emerging Risk Factors Collaboration. Emerging Risk Factors Collaboration. Emerging Risk Factors Collaboration. JAMA.JAMA.JAMA.JAMA. 2009;302:19932009;302:19932009;302:19932009;302:1993----2000.2000.2000.2000.

Coronary Heart Disease Risk by Coronary Heart Disease Risk by Coronary Heart Disease Risk by Coronary Heart Disease Risk by NonNonNonNon----HDLHDLHDLHDL----C and HDLC and HDLC and HDLC and HDL----C QuintilesC QuintilesC QuintilesC Quintiles

Haz

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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

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Early and Late Mortality Post-DES Low HDL-C vs High HDL-C at Baseline

Wolfram RM et al. Am J Cardiol. 2006;98:711-717.

High HDL-C

Low HDL-C

0

2

4

6

8

10

HDLHDLHDLHDL----C Quintiles,C Quintiles,C Quintiles,C Quintiles,aaaa

mg/dLmg/dLmg/dLmg/dL

5-Ye

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isk

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ajor

CVD

Ev

ents

, %

Low HDLLow HDLLow HDLLow HDL----C Still Predicts Residual CVD Risk C Still Predicts Residual CVD Risk C Still Predicts Residual CVD Risk C Still Predicts Residual CVD Risk AfterAfterAfterAfter Optimal Statin RxOptimal Statin RxOptimal Statin RxOptimal Statin Rx

LDLLDLLDLLDL----C ≤70 mg/dL on C ≤70 mg/dL on C ≤70 mg/dL on C ≤70 mg/dL on statinstatinstatinstatina,ba,ba,ba,b (Treating to New Targets Study)(Treating to New Targets Study)(Treating to New Targets Study)(Treating to New Targets Study)

aaaaOnOnOnOn----treatment level (3 months statin therapy); n = 2661treatment level (3 months statin therapy); n = 2661treatment level (3 months statin therapy); n = 2661treatment level (3 months statin therapy); n = 2661bbbbMean LDLMean LDLMean LDLMean LDL----C, 58 mg/dL; mean TG, 126 mg/dL C, 58 mg/dL; mean TG, 126 mg/dL C, 58 mg/dL; mean TG, 126 mg/dL C, 58 mg/dL; mean TG, 126 mg/dL ****PPPP=0.03 =0.03 =0.03 =0.03 for differences among quintiles of HDLfor differences among quintiles of HDLfor differences among quintiles of HDLfor differences among quintiles of HDL----CCCC Barter Barter Barter Barter P et P et P et P et al. al. al. al. N Engl N Engl N Engl N Engl J Med.J Med.J Med.J Med. 2007;357:13012007;357:13012007;357:13012007;357:1301----1310.1310.1310.1310.

Q1Q1Q1Q1<37<37<37<37

Q2Q2Q2Q237 to <4237 to <4237 to <4237 to <42

Q3Q3Q3Q342 to <4742 to <4742 to <4742 to <47

Q5Q5Q5Q5≥55≥55≥55≥55

Q4Q4Q4Q447 to <5547 to <5547 to <5547 to <55

HR vs HR vs HR vs HR vs Q1*Q1*Q1*Q1* 0.850.850.850.85 0.570.570.570.57 0.550.550.550.55 0.610.610.610.61

HDL Are HDL Are HDL Are HDL Are Heterogeneous Heterogeneous Heterogeneous Heterogeneous

in in in in Composition Composition Composition Composition and and and and Structure, Structure, Structure, Structure, (Their (Their (Their (Their Functions Functions Functions Functions Remain Unclear)Remain Unclear)Remain Unclear)Remain Unclear)

HDLHDLHDLHDL----C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL Function, Function, Function, Function, butbutbutbut HDL Composition HDL Composition HDL Composition HDL Composition Must Must Must Must

DetermineDetermineDetermineDetermine HDL FunctionHDL FunctionHDL FunctionHDL Function

HDL Function

HDL Composition (and Structure)

HDLHDLHDLHDL----C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL Function, Function, Function, Function, butbutbutbut HDL Composition HDL Composition HDL Composition HDL Composition Must Must Must Must

DetermineDetermineDetermineDetermine HDL FunctionHDL FunctionHDL FunctionHDL Function

HDL Function???? HDL Composition (and Structure)

HDLHDLHDLHDL----C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL Function, Function, Function, Function, butbutbutbut HDL Composition HDL Composition HDL Composition HDL Composition Must Must Must Must

DetermineDetermineDetermineDetermine HDL FunctionHDL FunctionHDL FunctionHDL Function

HDL Function

HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, Their functions MUST be determinedTheir functions MUST be determinedTheir functions MUST be determinedTheir functions MUST be determined

by their compositionby their compositionby their compositionby their composition

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HDL Composition (and Structure)

HDLHDLHDLHDL----C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL Function, Function, Function, Function, butbutbutbut HDL Composition HDL Composition HDL Composition HDL Composition Must Must Must Must

DetermineDetermineDetermineDetermine HDL FunctionHDL FunctionHDL FunctionHDL Function

HDL Function

HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, Their functions MUST be determinedTheir functions MUST be determinedTheir functions MUST be determinedTheir functions MUST be determined

by their compositionby their compositionby their compositionby their composition

The term “functionality” refers primarily to electronic devices.“FunctionFunctionFunctionFunction” is the best term for what HDL does.

HDLHDL2a2aHDLHDL2b2b HDLHDL3c3cHDLHDL3b3bHDLHDL3a3a

--------------------------------------Particle Particle SizeSizeSizeSizeSizeSizeSizeSize & Electrophoretic & Electrophoretic MobilityMobilityMobilityMobilityMobilityMobilityMobilityMobility--------------------------------

ApolipoproteinApolipoproteinApolipoproteinApolipoproteinApolipoproteinApolipoproteinApolipoproteinApolipoprotein ContentContentParticle Particle ShapeShapeShapeShapeShapeShapeShapeShape

DiscoidalDiscoidal

SphericalSphericalAA--I HDLI HDL AA--I/AI/A--II HDLII HDL

LipidLipid--poor apoApoor apoA--II

HDL HDL HDL HDL HDL HDL HDL HDL Structure & Composition HeterogeneityStructure & Composition HeterogeneityStructure & Composition HeterogeneityStructure & Composition HeterogeneityStructure & Composition HeterogeneityStructure & Composition HeterogeneityStructure & Composition HeterogeneityStructure & Composition Heterogeneity

+other apos: A+other apos: A--IV, C, D, E, etc.IV, C, D, E, etc.+non+non--apo proteins: inflam, thromb, etc.apo proteins: inflam, thromb, etc.

--------------------------Alpha-migrating------------------------- ----PrePre--betabeta--migratingmigrating----Globular Discoidal

Globular

Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.

AntioxidantAntioxidantAntioxidantAntioxidantActivityActivityActivityActivity

AntithromboticAntithromboticAntithromboticAntithromboticActivityActivityActivityActivity

Potential Antiatherogenic Actions of HDLPotential Antiatherogenic Actions of HDLPotential Antiatherogenic Actions of HDLPotential Antiatherogenic Actions of HDL

AntiAntiAntiAnti----infectious infectious infectious infectious ActivityActivityActivityActivity

EndothelialEndothelialEndothelialEndothelialRepairRepairRepairRepair

AfterAfterAfterAfter Chapman MJ et Chapman MJ et Chapman MJ et Chapman MJ et al. al. al. al. Curr Med Res Opin.Curr Med Res Opin.Curr Med Res Opin.Curr Med Res Opin. 2004;20:12532004;20:12532004;20:12532004;20:1253----1268126812681268. . . . AssmannAssmannAssmannAssmann G G G G et al. et al. et al. et al. Annu Rev Med.Annu Rev Med.Annu Rev Med.Annu Rev Med. 2003;53:3212003;53:3212003;53:3212003;53:321----341.341.341.341.

AntiapoptoticAntiapoptoticAntiapoptoticAntiapoptoticActivityActivityActivityActivity

ReverseReverseReverseReverseCholesterolCholesterolCholesterolCholesterolTransportTransportTransportTransportCellularCellularCellularCellular

CholesterolCholesterolCholesterolCholesterolEffluxEffluxEffluxEfflux

AntiAntiAntiAnti----inflammatoryinflammatoryinflammatoryinflammatoryActivityActivityActivityActivity

VasodilatorVasodilatorVasodilatorVasodilatorActivityActivityActivityActivity

HDLHDLHDLHDL

Apo A-I

Apo A-II

Processes Processes Processes Processes Promoting Efflux Promoting Efflux Promoting Efflux Promoting Efflux of of of of Cholesterol Cholesterol Cholesterol Cholesterol from from from from Cells Cells Cells Cells to to to to HDL ParticlesHDL ParticlesHDL ParticlesHDL Particles

Adapted from Barter P, Rye KA. High density lipoprotein cholesterol: the new target. A handbook for clinicians. 3rd ed.Birmingham, UK: Sherbourne Gibbs, 2007:31.Rosen R et al. Circulation. 2012.

Extracellular space Cell membrane

Unesterified (Free) C

holesterolU

nesterified (Free) Cholesterol

Unesterified (Free) C

holesterolU

nesterified (Free) Cholesterol

Mem

brane and IntracellularM

embrane and Intracellular

Mem

brane and IntracellularM

embrane and Intracellular

ABCA1

DiffusionSR-B1

DiffusionSR-B1ABCG1

DiffusionSR-B1ABCG1

Discoidal Discoidal Discoidal Discoidal Discoidal Discoidal Discoidal Discoidal HDLHDLHDLHDLHDLHDLHDLHDL(PL(PL(PL(PL(PL(PL(PL(PL--------rich)rich)rich)rich)rich)rich)rich)rich)

Small Small Small Small Small Small Small Small sphericalsphericalsphericalsphericalsphericalsphericalsphericalspherical

HDLHDLHDLHDLHDLHDLHDLHDLLCAT

LCAT

LipidLipidLipidLipidLipidLipidLipidLipid--------poor Apo Apoor Apo Apoor Apo Apoor Apo Apoor Apo Apoor Apo Apoor Apo Apoor Apo A--------I I I I I I I I (globular?)(globular?)(globular?)(globular?)(globular?)(globular?)(globular?)(globular?)

Large Large Large Large Large Large Large Large sphericalsphericalsphericalsphericalsphericalsphericalsphericalspherical

HDLHDLHDLHDLHDLHDLHDLHDL

Potential Antiatherogenic Potential Antiatherogenic Potential Antiatherogenic Potential Antiatherogenic Actions of Actions of Actions of Actions of HDLHDLHDLHDL

MCP-1 = monocyte chemoattractant protein-1

Adapted from Barter PJ et al. Circ Res. 2004;95:764-772.

Monocyte

MacrophageFoam

cell

Vessel Lumen

Endothelium

IntimaCytokines

Adhesion molecule

Oxidized LDL

LDL

LDL

HDL inhibits expression of endothelial cell adhesion molecules and MCP-1

MCP-1

HDL inhibits oxidation of LDL-C

HDL promotes efflux of cholesterol from foam cells

HDL Protects Arterial HDL Protects Arterial HDL Protects Arterial HDL Protects Arterial Endothelial CellsEndothelial CellsEndothelial CellsEndothelial Cells

• ↑ Vasodilatation– ↑ NO (production)– ↑ PGI2– ↓ ET-1

• ↑ Endothelial Integrity– ↑ EC precursors– ↑ EC migration – ↑ EC proliferation– ↓ Apoptosis

• ↓ Inflammation– ↓ CAMs– ↓ PAF

• ↓ Coag/Thrombosis– ↑ NO– ↑ PGI2– ↑ TFPI– ↓ PAF– ↓ vWF– ↓ TF– ↓ tPA

AfterAfterAfterAfter CalabresiCalabresiCalabresiCalabresi L et al. L et al. L et al. L et al. ATVB ATVB ATVB ATVB 2003;23:17242003;23:17242003;23:17242003;23:1724----1731173117311731....

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ORM2 RBP4 TF FGA HPXITIH4TTR

Acute-phase Response

LCAT apoC-IapoC-II

apoC-III

apoC-IV

PON3

SAA4

SAA2

SAA1

apoA-1PON1

apoHapoA-IV

Clusterin

apoA-II

apoL-I

apoD

apoE

apoF

apoMPLTP

CETP

Lipid Metabolism

C3

C4A

C4B

C9

VTN

Complement

Regulation

SERF2 SERF1AGT

AHSGHRP

SERA1

AMPKNG1

Proteinase

Inhibitor

The HDL Proteome: Important to HDL Function

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

*Camont L ATVB 2013;33;2715-23.

HDL HDL HDL HDL LipidomeLipidomeLipidomeLipidome is also complex and key to HDL Function!*is also complex and key to HDL Function!*is also complex and key to HDL Function!*is also complex and key to HDL Function!*

Other Other Other Other Apparent Disease Reduction Apparent Disease Reduction Apparent Disease Reduction Apparent Disease Reduction via HDLvia HDLvia HDLvia HDL

(+/(+/(+/(+/---- atheroatheroatheroathero----related)related)related)related)

• ↑Longevity (cellular): ↑WBC Telomeres w/ ↑HDL-C

• ↑β-cell function w/ ↑apo A-I & ↑ABCA1– ↓DM-2 w/ torcetrapib– ↑DM-2 w/ genetic high HDL-C/

• Helps w/ TG-Rich Lp metabolismChen, W. Atherosclerosis 205 (2009) 620–625Kruit JK CurrOpinLipid 2010;21;178-85Barter P Circ 2011;124;555-62Qi, Q. Diabetes, epub February 7, 2012

Epidemiology: HDLEpidemiology: HDLEpidemiology: HDLEpidemiology: HDL----C → ↓MIC → ↓MIC → ↓MIC → ↓MIGenetics: Genetics: Genetics: Genetics: NoNoNoNo AssociationAssociationAssociationAssociation

Voight, BF, Peloso, GM et al. Lancet 2012 epub May 17

Can NOT assume that ↑ HDLCan NOT assume that ↑ HDLCan NOT assume that ↑ HDLCan NOT assume that ↑ HDL----C → ↓ ASCVD!C → ↓ ASCVD!C → ↓ ASCVD!C → ↓ ASCVD!

Lipids → MI? (positive or inverse) Lipids → MI? (positive or inverse) Lipids → MI? (positive or inverse) Lipids → MI? (positive or inverse) For LDLFor LDLFor LDLFor LDL----C: Epidemiologic C: Epidemiologic C: Epidemiologic C: Epidemiologic ≈ Genetic Genetic Genetic Genetic For HDLFor HDLFor HDLFor HDL----C: EpidemC: EpidemC: EpidemC: Epidemiologiciologiciologiciologic ≠ ≠ ≠ ≠ GeneticGeneticGeneticGenetic

Voight, BF, Peloso, GM et al. Lancet 2012 epub May 17

N>25,000. Genetic score of 13 SNPs for LDL-C, 14 SNPs for HDL-C

HDL as Risk HDL as Risk HDL as Risk HDL as Risk FactorFactorFactorFactor(vs Risk Marker (vs Risk Marker (vs Risk Marker (vs Risk Marker onlyonlyonlyonly))))

ConConConCon• Many genetic studies show no HDL-CVD

correlation w/o corresponding TG ∆• Many HDL-raising trials showed +/- or no ↓CVDProProProPro• Low HDL-C predicts high CVD Risk• High HDL-C predicts anti-atherogenicity:

– Anti-inflammatory– Antioxidant– Antithrombotic– Pro-endothelial, etc.

• Some HDL-raising trials have shown ↓atheroPossible resolution: part factor/part marker Possible resolution: part factor/part marker Possible resolution: part factor/part marker Possible resolution: part factor/part marker (HDL function? via TG(HDL function? via TG(HDL function? via TG(HDL function? via TG----Rich Lp Remnants?)Rich Lp Remnants?)Rich Lp Remnants?)Rich Lp Remnants?)

“Failed“Failed“Failed“Failed” HDL” HDL” HDL” HDL----Raising Raising Raising Raising TrialsTrialsTrialsTrials• Niacin• Fibrates• CETP-I• Postmenopausal hormone

replacement• Apo A-I Infusion/Reinfusion

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StudyStudyStudyStudyTreatmeTreatmeTreatmeTreatme

ntntntntn/Nn/Nn/Nn/N

ControlControlControlControln/Nn/Nn/Nn/N

PetoPetoPetoPeto OROROROR95% 95% 95% 95% ClClClCl

PetoPetoPetoPeto OROROROR95% 95% 95% 95% ClClClCl

ARBITERARBITERARBITERARBITER----6666----HALTSHALTSHALTSHALTS 2/1872/1872/1872/187 9/1769/1769/1769/176 0.25 (0.08,0.25 (0.08,0.25 (0.08,0.25 (0.08,

0.84)0.84)0.84)0.84)Guyton JR et alGuyton JR et alGuyton JR et alGuyton JR et al 1/6761/6761/6761/676 1/2721/2721/2721/272 0.35 (0.02, 0.35 (0.02, 0.35 (0.02, 0.35 (0.02,

7.56)7.56)7.56)7.56)AFREGSAFREGSAFREGSAFREGS 0/710/710/710/71 1/721/721/721/72 0.14 (0.00, 0.14 (0.00, 0.14 (0.00, 0.14 (0.00,

6.92)6.92)6.92)6.92)ARBITERARBITERARBITERARBITER----2222 2/872/872/872/87 2/802/802/802/80 0.92 (0.13, 0.92 (0.13, 0.92 (0.13, 0.92 (0.13,

6.65)6.65)6.65)6.65)HATSHATSHATSHATS 1/381/381/381/38 5/385/385/385/38 0.24 (0.05, 0.24 (0.05, 0.24 (0.05, 0.24 (0.05,

1.26)1.26)1.26)1.26)UCSF_SCORUCSF_SCORUCSF_SCORUCSF_SCOR 0/480/480/480/48 1/491/491/491/49 0.14 (0.00, 0.14 (0.00, 0.14 (0.00, 0.14 (0.00,

6.96)6.96)6.96)6.96)STOCKHOLMSTOCKHOLMSTOCKHOLMSTOCKHOLM 72/27972/27972/27972/279 100/276100/276100/276100/276 0.61 (0.43, 0.61 (0.43, 0.61 (0.43, 0.61 (0.43,

0.88)0.88)0.88)0.88)CLASCLASCLASCLAS 1/941/941/941/94 5/945/945/945/94 0.250.250.250.25 (0.05, (0.05, (0.05, (0.05,

1.29)1.29)1.29)1.29)CDPCDPCDPCDP 287/1119287/1119287/1119287/1119 839/2789839/2789839/2789839/2789 0.81 (0.69, 0.81 (0.69, 0.81 (0.69, 0.81 (0.69,

0.94)0.94)0.94)0.94)TotalTotalTotalTotal

Test for heterogeneity: P = 0.24, ITest for heterogeneity: P = 0.24, ITest for heterogeneity: P = 0.24, ITest for heterogeneity: P = 0.24, I2222 = = = = 23.0%23.0%23.0%23.0%

Test for overall effect: P < 0.0001Test for overall effect: P < 0.0001Test for overall effect: P < 0.0001Test for overall effect: P < 0.0001

0.75 (0.65, 0.75 (0.65, 0.75 (0.65, 0.75 (0.65, 0.86)0.86)0.86)0.86)

Subtotal excluding CDPSubtotal excluding CDPSubtotal excluding CDPSubtotal excluding CDP 0.53 (0.38, 0.53 (0.38, 0.53 (0.38, 0.53 (0.38, 0.73)0.73)0.73)0.73)

0.1 0.2 0.5 1 2 5 10 Log scale

Meta-Analysis: Effects of Nicotinic AcidMajor Coronary Events

Many of these trials were tests of drug combinations that included niacinBruckert E et al. Atherosclerosis. 2010;210:353-361.

AIM-HIGH: ERNA beats Control in HTG/low HDL-C pts

Guyton JR JACC 2013 62(17)1580–1584

AIM-HIGH: ERNA beats Control in HTG/low HDL-C pts

Guyton JR JACC 2013 62(17)1580–1584

Niacin →↓CVD in

patients with

HTG/low HDL-C

*Non-fatal MI or coronary death, any non-fatal or fatal stroke, coronary or non-coronary artery surgery or angioplasty. HPS2-THRIVE=Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events; LRPT=laropiprant; SDM=standard deviation of the mean.

LipidMean (SDM) at

baseline, mg/dL

TC 128 (22)

Direct LDL 63 (17)

HDL-C 44 (11)

TG 125 (74)

HPS2HPS2HPS2HPS2----THRIVE: No THRIVE: No THRIVE: No THRIVE: No OverallOverallOverallOverall↓CVD w/ ERN + LRPT↓CVD w/ ERN + LRPT↓CVD w/ ERN + LRPT↓CVD w/ ERN + LRPT

Years of Follow-up P

atie

nts

Suf

ferin

g E

vent

s (%

)

15.0%

0 1 2 3 4 0

5

10

15

20

14.5%

Placebo ERN / LRPT

Log-rank P=0.29Risk ratio 0.96 (95% CI 0.90–1.03)

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

N=25,673 with Pre-existing CVDBaseline Lipids on Statin Rx

HPS2 studied niacin in patients without lipid

indication

Landray et al. N Engl J Med. 2014;371:203-12.

HPS2 stopped when curves started to diverge!

HPS2: MVE by age, sex, region & statin therapy

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%)

Sex

Male 1397 (13.2%) 1485 (14.0%) 3.21 (p=0.07) Female 299 (13.4%) 273 (12.3%)

Region

Europe 832 (11.3%) 913 (12.4%) 3.61 (p=0.06) China 864 (15.8%) 845 (15.5%)

Statin-based therapy

Simvastatin 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

HPS2: MVE by age, sex, region & statin therapy

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%)

Sex

Male 1397 (13.2%) 1485 (14.0%) 3.21 (p=0.07) Female 299 (13.4%) 273 (12.3%)

Region

Europe 832 (11.3%) 913 (12.4%) 3.61 (p=0.06) China 864 (15.8%) 845 (15.5%)

Statin-based therapy

Simvastatin 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

Regional difference is Biologically Plausible, but Gender Difference is Not

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HPSHPSHPSHPS----2/THRIVE: Good & Bad2/THRIVE: Good & Bad2/THRIVE: Good & Bad2/THRIVE: Good & BadAppeared to Appeared to Appeared to Appeared to avoidavoidavoidavoid most most most most AIMAIMAIMAIM----HIGH HIGH HIGH HIGH problemsproblemsproblemsproblems• ~True placebo-control ∴ good test of niacin?• Longer duration (~4 yrs)• Large N (~23,000 subjects)• Little pre-study Rx “contamination”But had But had But had But had new new new new problemsproblemsproblemsproblems• NoNoNoNo selection selection selection selection for either low HDLlow HDLlow HDLlow HDL----C C C C orororor high high high high TG TG TG TG pts

(base HDL-C 44, TG 125—no niacin indication!); need AIM-HIGH-style subanalysis

• NoNoNoNo need for further LDLneed for further LDLneed for further LDLneed for further LDL----C loweringC loweringC loweringC lowering (base 63)• NotNotNotNot a test of niacin niacin niacin niacin alone alone alone alone (ERNA given w/

laropiprantlaropiprantlaropiprantlaropiprant (↑novel SAEs in Rx arm)• Chinese had ↑myopathy and no CVD benefit

Armitage, J. Oral Presentation, ACC Scientific Sessions, March 2013.

Niacin and CVD: SummaryNiacin and CVD: SummaryNiacin and CVD: SummaryNiacin and CVD: Summary• Monotherapy benefit well documented: useful for

statin-intolerant pt• Benefit as statin adjunct not shown clearly in

recent trials; howeverhoweverhoweverhowever,• AIM-HIGH appeared to show ↓CVD in HTG/low

HDL-C pts, like fibrates (must confirm)• HPS2-THRIVE

– Benefit begins after 2 years? (results suggestive)– Benefit in Caucasians? (results suggestive)– Benefit if LDL-C ≥58? (results suggestive)– Benefit in HTG/low HDL-C? (not tested beyond

>150/<40)– Lack of overall benefit from concurrent laropiprant?

“Failed“Failed“Failed“Failed” HDL” HDL” HDL” HDL----Raising Raising Raising Raising TrialsTrialsTrialsTrials• Niacin• Fibrates

Fibrates →↓CHD in Patients Fibrates →↓CHD in Patients Fibrates →↓CHD in Patients Fibrates →↓CHD in Patients w/ High TG w/ High TG w/ High TG w/ High TG andandandand Low HDLLow HDLLow HDLLow HDL----CCCC

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

Fibrates →↓CHD in Patients Fibrates →↓CHD in Patients Fibrates →↓CHD in Patients Fibrates →↓CHD in Patients w/ High TG w/ High TG w/ High TG w/ High TG andandandand Low HDLLow HDLLow HDLLow HDL----CCCC

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

“PROMINENT” CVOT of “PROMINENT” CVOT of “PROMINENT” CVOT of “PROMINENT” CVOT of PemafibratePemafibratePemafibratePemafibrate starting soon: HTG + low HDLstarting soon: HTG + low HDLstarting soon: HTG + low HDLstarting soon: HTG + low HDL----C subjectsC subjectsC subjectsC subjects

ACCORDACCORDACCORDACCORD----Lipid: Entire Fenofibrate ASCVD Lipid: Entire Fenofibrate ASCVD Lipid: Entire Fenofibrate ASCVD Lipid: Entire Fenofibrate ASCVD Benefit Confined to HTG + Low HDLBenefit Confined to HTG + Low HDLBenefit Confined to HTG + Low HDLBenefit Confined to HTG + Low HDL----C Patients C Patients C Patients C Patients

Maj

or

Fat

al +

No

n-F

atal

C

V E

ven

ts, %

HTG (>204 mg/dL and Low HDL-C (<34 mg/dL) All Others

28.6%RRRP = 0.057

Ginsberg, HN for The ACCORD Study Group. NEJM 2010; 362:1563-1574. Prespecified analysis.

N=941 (18% of Entire Cohort) N=4548 (82%) of Entire Cohort

79456

60485

2292264

2312284

Entire CVD benefit from fenofibrate was in HTG/Low HDL-C subgroup (<18% of the ACCORD-LIPID subjects).

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“Failed“Failed“Failed“Failed” HDL” HDL” HDL” HDL----Raising Raising Raising Raising TrialsTrialsTrialsTrials• Niacin• Fibrates• CETP-I

CETP in HDL Metabolism and AtherosclerosisCETP in HDL Metabolism and AtherosclerosisCETP in HDL Metabolism and AtherosclerosisCETP in HDL Metabolism and Atherosclerosis

• Human CETP deficiency: ↑↑HDLHuman CETP deficiency: ↑↑HDLHuman CETP deficiency: ↑↑HDLHuman CETP deficiency: ↑↑HDL----C and ↓CVDC and ↓CVDC and ↓CVDC and ↓CVD• Decreasing CETP in animals: ↑↑Decreasing CETP in animals: ↑↑Decreasing CETP in animals: ↑↑Decreasing CETP in animals: ↑↑HDLHDLHDLHDL----C and C and C and C and ↓athero↓athero↓athero↓atheroBarter 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 Rx

Lipid 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

Dalcetrapib 600 31 -2 -3

Evacetrapib* 100 82 -13 -4

Anacetrapib 100 138 -40 -7

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

Torcetrapib Caused OffTorcetrapib Caused OffTorcetrapib Caused OffTorcetrapib Caused Off----target target target target Hyperaldosteronism (ILLUMINATE data)Hyperaldosteronism (ILLUMINATE data)Hyperaldosteronism (ILLUMINATE data)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 onInverse relationship of CVD and onInverse relationship of CVD and onInverse relationship of CVD and on----RxRxRxRx----HDLHDLHDLHDL----C C C C preservedpreservedpreservedpreserved

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

1. Barter PJ et al. 1. Barter PJ et al. 1. Barter PJ et al. 1. Barter PJ et al. N Engl J Med. N Engl J Med. N Engl J Med. N Engl J Med. 2007;357:21092007;357:21092007;357:21092007;357:2109----2122.2122.2122.2122.2. Rosenson RS. 2. Rosenson RS. 2. Rosenson RS. 2. Rosenson RS. Curr Athero Rep. Curr Athero Rep. Curr Athero Rep. Curr Athero Rep. 2008;10:2272008;10:2272008;10:2272008;10:227----229.229.229.229.

Inverse Relationship between On-Rx HDL-C and CVD Suggests HDL Remains Functional w/ CETP-I

(Torcetrapib—ILLUMINATE)

Barter, P. Am J Card 2009.

Increased CVD appeared due to

↑Aldosterone Despite Beneficial ↑HDL-C

Schwartz G NEJM 2012 367;22;2089-99. Inverse relationship was not stat-sig.

High HDLHigh HDLHigh HDLHigh HDL----C Remains Protective, soC Remains Protective, soC Remains Protective, soC Remains Protective, soCETPCETPCETPCETP----I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function

(Dalcetrapib(Dalcetrapib(Dalcetrapib(Dalcetrapib————daldaldaldal----OUTCOMES)OUTCOMES)OUTCOMES)OUTCOMES)

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Schwartz G NEJM 2012 367;22;2089-99. Inverse relationship was not stat-sig.

High HDLHigh HDLHigh HDLHigh HDL----C Remains Protective, soC Remains Protective, soC Remains Protective, soC Remains Protective, soCETPCETPCETPCETP----I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function

(Dalcetrapib(Dalcetrapib(Dalcetrapib(Dalcetrapib————daldaldaldal----OUTCOMES)OUTCOMES)OUTCOMES)OUTCOMES)

Schwartz G NEJM 2012 367;22;2089-99. Inverse relationship was not stat-sig.

High HDLHigh HDLHigh HDLHigh HDL----C Remains Protective, soC Remains Protective, soC Remains Protective, soC Remains Protective, soCETPCETPCETPCETP----I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function

(Dalcetrapib(Dalcetrapib(Dalcetrapib(Dalcetrapib————daldaldaldal----OUTCOMES)OUTCOMES)OUTCOMES)OUTCOMES)

Modest CVD Benefit from ↑HDLModest CVD Benefit from ↑HDLModest CVD Benefit from ↑HDLModest CVD Benefit from ↑HDL----C?C?C?C?

Schwartz G NEJM 2012 367;22;2089-99. Inverse relationship was not stat-sig.

High HDLHigh HDLHigh HDLHigh HDL----C Remains Protective, soC Remains Protective, soC Remains Protective, soC Remains Protective, soCETPCETPCETPCETP----I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function I Does NOT Block HDL Function

(Dalcetrapib(Dalcetrapib(Dalcetrapib(Dalcetrapib————daldaldaldal----OUTCOMES)OUTCOMES)OUTCOMES)OUTCOMES)

Modest CVD Benefit from ↑HDLModest CVD Benefit from ↑HDLModest CVD Benefit from ↑HDLModest CVD Benefit from ↑HDL----CCCCNegatedNegatedNegatedNegated by Modest ↑Adrenal? by Modest ↑Adrenal? by Modest ↑Adrenal? by Modest ↑Adrenal?

(↑SBP 0.6 mm p<0.001)(↑SBP 0.6 mm p<0.001)(↑SBP 0.6 mm p<0.001)(↑SBP 0.6 mm p<0.001)

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.

• Dal-Outcomes stopped May 7, 2012 due to lack of CVD efficacy.

• ACCELERATE stopped October 12, 2015 due to “futility” for CVD efficacy.

CETP Inhibitors: 3 Down, 1 RemainsCETP Inhibitors: 3 Down, 1 Remains

CETP

Evacetrapib

↑CVD (25%): ↑↑HDL funct, but↑↑↑off-target eff.?

*No ∆CVD:↑HDL funct, but ↑off-target eff.?

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

*No ↓CVD: WHY??

Why Have CETPWhy Have CETPWhy Have CETPWhy Have CETP----Inhibitors Inhibitors Inhibitors Inhibitors Failed to ↓CVD (Failed to ↓CVD (Failed to ↓CVD (Failed to ↓CVD (so farso farso farso far)?)?)?)?

--------------Beneficial------------- ------Adverse------ Net Effect

CETP-IAgent

↑HDL-C HDL-C →↓CVD

↓LDL-C ↓Lp(a) ↑Aldost. (↑BP etc.)

↑CRP ∆ CVD

Torcetrapib1 ++++ +++ ++ ? ++++ 0? Adverse

Dalcetrapib2 ++ + 0 ? ++ +2 Neutral

Evacetrapib4 ++++ ? ++ ? ---- 5 ? Neutral6

Anacetrapib3 ++++++ ? +++ ++ ---- ++ ?

1. Barter PJ. N Engl J Med. 2007;357:2109-2122.2. Schwartz GG. N Engl J Med. 2012 Nov 5. [Epub ahead of print].3. Cannon CP. N Engl J Med. 2010;363(25):2406-15.4. Nicholls SJ. JAMA 306;2099-2109.5. Cao, G. JLR 2011 52(12)2169-76.6. E. Lilly Press release, October 12, 2015

(Also likely beneficial (Also likely beneficial (Also likely beneficial (Also likely beneficial ↓glucose w/ torcetrapib & anacetrapib.)glucose w/ torcetrapib & anacetrapib.)glucose w/ torcetrapib & anacetrapib.)glucose w/ torcetrapib & anacetrapib.)

Anacetrapib benefits vs harms unknown (ongoing RCT)

CETP-I Update, October 2015• Torcetrapib—Pfizer (ILLUMINATE stopped early for

harmharmharmharm, 1.5 vs 4.5 y planned) – ↑25% CVD & ↑40% Fatal CVD but– ↑BP 0.6 mm &↓35% CVD if ↑aldo and– ↓57% if HDL-C >93 mg/dL on-Rx (top quint)

• Dalcetrapib—Roche (dal-OUTCOMES stopped early for futilityfutilityfutilityfutility at 70% of events)– ↑4% CVD (NS) but– ↑BP 0.6 mm & ↑CRP 0.2 mg/L (both p <0.001) and– ↓21% CVD if HDL↓21% CVD if HDL↓21% CVD if HDL↓21% CVD if HDL----C ↑26%C ↑26%C ↑26%C ↑26% (top quint)

• Evacetrapib—Lilly (ACCELERATE stopped 8 mos early, 10/12/15, for insufficient insufficient insufficient insufficient efficefficefficeffic.... at 70 vs 90% durat.?)– No Δ CVD– ?Δ BP (“no ↑BP” in early/small studies—as torcetrapib!)

• Anacetrapib—Merck (REVEAL is ongoingongoingongoingongoing)– ↓24% CVD (↓71% cor revasc) @ 1.6y; ↓16% @ 3½ y

(DEFINE)• TA-8995—Amgen

– ↓LDL-C ~50% in monoRx + ~150% ↑HDL-C

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9

My CETP-I Take-Away?• Don’t stop RCT early for futility (or benefit)!!—

curves may diverge late for “non-LDL” trials• CETP-Inhibition does NOT eliminatedoes NOT eliminatedoes NOT eliminatedoes NOT eliminate ((((or even

reduce) ↑HDL-mediated ↓CVD• Adrenal effects are common and hard to see

but powerfully ↑CVD• CETP-I may yet prove beneficial via

– ↑HDL-C– ↓LDL-C– ↓Lp(a)– ↓DM2– And in certain patient subgroups (?)

“Failed“Failed“Failed“Failed” HDL” HDL” HDL” HDL----Raising Raising Raising Raising TrialsTrialsTrialsTrials• Niacin• Fibrates• CETP-I• Postmenopausal hormone

replacement• Apo A-I Infusion/Reinfusion

Pooled analysis of E and E+P arms of Pooled analysis of E and E+P arms of Pooled analysis of E and E+P arms of Pooled analysis of E and E+P arms of WHI WHI WHI WHI (www.medscape.com)(www.medscape.com)(www.medscape.com)(www.medscape.com)

HRT HRT HRT HRT ReducesReducesReducesReduces CHD When Started CHD When Started CHD When Started CHD When Started BeforeBeforeBeforeBefore 60 years old60 years old60 years old60 years old

* Duration of treatment.1.Nissen SE, et al. Am J Cardiol. 2005;96(5A):61F-68F. 3. Nissen SE, et al. JAMA. 2003;290(17):2292-2300.2. Nissen SE, et al. JAMA. 2006;295(13):1556-1565.

Beneficial Effect of LDLBeneficial Effect of LDLBeneficial Effect of LDLBeneficial Effect of LDL----C and HDLC and HDLC and HDLC and HDL----C C C C Interventions on Atheroma by IVUSInterventions on Atheroma by IVUSInterventions on Atheroma by IVUSInterventions on Atheroma by IVUS

Prava40 mg

Atorva80 mg

Rosuva40 mg

Placebo Combineddoses

Reversal1

18 months*ASTEROID2

24 months*ApoA-1 Milano3

5 weeks*

10

5

0

-5

-10

-15

-20 n = 249 243 349 11 36

Tota

l ath

ero

ma

volu

me

Mea

n c

han

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m b

asel

ine

(mm

3 )

JJ6

A-I

αHDL Preβ-HDL95% 5%

Plasma From Patient

Preβ-HDL Enriched Plasma Obtained by HDL Selective Delipidation

A-I A-I

A-I

A-I

A-I

αHDL Preβ-HDL20% 80%

Treated Plasma To Patient

Waksman R, et al. J Am Coll Cardiol. 2010;55(24):2727-2735.

Preβ Enriched Plasma Obtained By Selective HDL Delipidation

A-I

Preβ-HDL

Pre-ß HDL readily accepts cholesterol

HDL HDL HDL HDL DelipidationDelipidationDelipidationDelipidation: Safe, Well: Safe, Well: Safe, Well: Safe, Well----Tolerated, and Trending Towards Tolerated, and Trending Towards Tolerated, and Trending Towards Tolerated, and Trending Towards

↓Atherosclerosis ↓Atherosclerosis ↓Atherosclerosis ↓Atherosclerosis

Waksman, R; JACC 2010;55:2727-35

HDL Delipidation Recombinant HDL Atorva 80 mg

q wk x 7 weeks q wk x 5 weeks q day x 18 mos

Slide 52

JJ6 Dr Brinton:You mentioned you would like these studies switched around. Please guide.Julie Johnson, 6/11/2012

2/12/2016

10

Clinical TakeClinical TakeClinical TakeClinical Take----Away MessagesAway MessagesAway MessagesAway Messages

HDL Function Can’t (Yet) Be Measured Practically

(Clinically)HDL Composition

(and Structure)

HDLHDLHDLHDL----C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL C Tells Very Little About HDL Function, Function, Function, Function, butbutbutbut HDL Composition HDL Composition HDL Composition HDL Composition Must Must Must Must

DetermineDetermineDetermineDetermine HDL FunctionHDL FunctionHDL FunctionHDL Function

HDL Function

HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, HDL Particles cannot “Think” for themselves, Their functions MUST be determinedTheir functions MUST be determinedTheir functions MUST be determinedTheir functions MUST be determined

by their compositionby their compositionby their compositionby their composition

The term “functionality” refers primarily to electronic devices.“FunctionFunctionFunctionFunction” is the best term for what HDL does.

How Should We Measure HDL?How Should We Measure HDL?How Should We Measure HDL?How Should We Measure HDL?• Plasma concentration

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

but uses not established– HDL subfractions—controversial, not estab.

• HDL Composition/Structure—in develop.• HDL Function—in development

– Cholesterol efflux– Inflammation, oxidation, etc.

Bottom line: HDL and its metrics are very complexHDL-C is still best for routine clinical use

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

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

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

Revisiting the HDL HypothesisRevisiting the HDL HypothesisRevisiting the HDL HypothesisRevisiting the HDL HypothesisConConConCon• Recent trials of HDL-raising have been neutral• Genetic isolated ∆HDL-C may not predict CVDProProProPro• CVD risk reduction only ~1/3 w/ statin monoRx, so• Statin monoRx is not enough for high-risk patients• ↓Low HDL↓Low HDL↓Low HDL↓Low HDL----C predicts ↑CVD riskC predicts ↑CVD riskC predicts ↑CVD riskC predicts ↑CVD risk, even w/ statin Rx, even w/ statin Rx, even w/ statin Rx, even w/ statin Rx• HDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG ptsHDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG ptsHDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG ptsHDL↑(+TG↓) Rx shows ↓CVD in ↓HDL/HTG pts(My) Current Recommendation(My) Current Recommendation(My) Current Recommendation(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?– When is HDL a causal factor, not a biomarker?

Summary and Conclusion: Summary and Conclusion: Summary and Conclusion: Summary and Conclusion: Clinical Approach to HDLClinical Approach to HDLClinical Approach to HDLClinical Approach to HDL----CCCC

MeasureMeasureMeasureMeasure::::• HDLHDLHDLHDL----C, fasting TG, fasting glucose (no HDL C, fasting TG, fasting glucose (no HDL C, fasting TG, fasting glucose (no HDL C, fasting TG, fasting glucose (no HDL subfractssubfractssubfractssubfracts))))• BP, waist (good); hsCRP & A1c (both optional)BP, waist (good); hsCRP & A1c (both optional)BP, waist (good); hsCRP & A1c (both optional)BP, waist (good); hsCRP & A1c (both optional)• CAC if 1CAC if 1CAC if 1CAC if 1oooo prevprevprevprev andandandand >45/55 y/o (M/W), >45/55 y/o (M/W), >45/55 y/o (M/W), >45/55 y/o (M/W), espespespesp if +FHx or DM2if +FHx or DM2if +FHx or DM2if +FHx or DM2Worry ifWorry ifWorry ifWorry if:• HDL-C <40/50 (M/W), ↑ASCVD risk even if LDL-C at goal• Metabolic Syndrome/Insulin Resist/DM2, ↑risk ASCVD & DM TreatTreatTreatTreat::::• LDL-C/Non-HDL-C w/ statin (if indicated)• Residual low HDL-C w/

– Smoking cessation– Exercise & diet (↓calories & sugar, EtOH?)– Fenofibrate (consider—easier but less effective)? Rx contain. DHA?– Niacin (consider—harder but more effective)?– DM meds (esp. pioglitazone, metformin, SGLT2)– HRT (consider—start in early postmenopause)