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“Smoldering” Insulin Resistance: Early Diagnosis

and Treatment to Prevent Cardiovascular Disease

Eliot A. Brinton, MD, FAHA, FNLADirector, Atherometabolic Research

Utah Foundation for Biomedical ResearchPresident, Utah Lipid Center

Salt Lake Cityeliot.brinton@utah.edu

Speaker Disclosures

Dr. Brinton has received:

• Research funding: Amarin, Health Diagnostic Laboratory, Merck, Roche

• Honoraria as consultant/advisor : Abbott, Aegerion, Amarin, Atherotech, Daiichi-Sankyo, Essentialis, Kowa, Merck, Novartis, Takeda

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

Learning Objectives• Explain how visceral adiposity leads to low-

grade systemic inflammation, fatty liver, and insulin resistance.

• Discuss how fatty liver and insulin resistance lead to dyslipidemia, atherosclerosis and increased risk of cardiovascular disease (CVD) events

• Implement evidenced-based best-practice strategies for diagnosis and treatment of insulin resistance for CVD risk reduction

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2

6

14

17

2122

0

5

10

15

20

25

Num

ber o

f CH

D D

eath

s O

ut o

f To

tal P

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n (N

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70)

Pyörälä M, et al. Diabetes Care. 2000;23:1097-1102.

AUC Fasting Plasma Insulin Quintiles, pmol/L/h

Insulin Resistance (Ins. Levels)Predicts ↑CHD Mortality

Insulin Sensitive Insulin Resistant

≤237 238-337 338-437 438-669 >669

Parameters of Insulin ResistanceParameters of Insulin ResistanceParameters of Insulin ResistanceParameters of Insulin Resistance• Fasting insulin

– how high? (95th vs 50th %ile)• Plasma/serum glucose

– Fasting > 110 vs > 100 mg/dL– OGTT (75g, 2h) > 140 mg/dL

• HOMA-IR• Lipids

– ↑TG and/or ↓HDL-C (ratio > ~3?)• Central Adiposity

– BMI, – Waist, waist/hip ratio– MRI for visceral adiposity

• Inflammatory Markers (hsCRP, LpPLA2…)

Adiposity as a Key Factor in Inflammation, Fatty Liver and Insulin Resistance

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1998

Increases in Obesity Among U.S. Adults

1990 Through 2006

(*BMI ≥≥≥≥30, or about 30 lbs. overweight for 5’4” person)

BRFSS, Behavioral Risk Factor Surveillance System http: //www.cdc.gov/brfss/

2006

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

↑Obesity coincides w/ ↑DM-2 & flattening of CVD↓

“It’s all fat, no muscle”

Adipocytes and Macrophages are 1Adipocytes and Macrophages are 1Adipocytes and Macrophages are 1Adipocytes and Macrophages are 1oooo

Sources Sources Sources Sources of Inflammatory of Inflammatory of Inflammatory of Inflammatory CytokinesCytokinesCytokinesCytokines

Modified from Rader. N Engl J Med 2000;343:1179.

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Visceral Obesity & Adipocyte Hypertrophy ER Stress and Pro-inflammatory State

After Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112:1785-8.

Hypertrophic (enlarged) adipocytes secrete more inflammatory adipokines and recruit more macrophages

Adipokines Link Obesity with Atherosclerosis

CRP (marker systemic inflam)

IL-6 (pro-inflammatory)

PAI-1 (pro-thrombotic)

Angiotensinogen (pro-hypertens.)

Leptin (endocrine coordination)

Resistin (pro-athero?)

MCP-1 (pro-inflammatory)

TNFα (pro-inflammatory)

Adiponectin (anti-athero)

Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

↑Atherogenic ↓Antiatherogenic

Excess Adipose Tissue (cell # and size)

Lp-PLA 2 and CRP Additively Predict Stroke Risk (ARIC Study)

High (>3)Medium (1-3)

Low (<1)

Low (<310)

Medium (310-422)

High (>422)

0

2

4

6

8

10

12

hs-CRP, mg/L

95% CI 2.99-39.55 p<0.001

5.74

10.88

5.815.37

4.304.09

2.79

1.00

4.01

Ischemic stroke hazard ratio

Abstract 2979, AHA Meeting, November 2004. New Orleans, LA.

Circulation, Vol. 110, Supplement III 641.

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Interactions Among Adiposity, Insulin Resistance and Atherosclerosis

Adapted from de Luca C, Olefsky JM. Nat Med. 2006;12:41-2.

Macrophages

Endocrine inflammatory signals

Paracrine and autocrine

inflammatory signals

Adipocyte IR and ER Stress

Muscle insulin resistance

Liver insulin resistance

Systemicinsulin resistance

Overnutrition, underexertion, polygenics

Dyslipidemia, hypertension, hyperglycemia

Accelerated atherosclerosis and CVD

Healthy, Quiescent Visceral Adipocytes

Normal Type 2 Diabetes

Courtesy of Wilfred Y. Fujimoto, MD.

Quantitation of Visceral/Intraperitoneal

Adipose Tissue:Abdominal MRI of Patient Without

vs With Diabetes Mellitus-2

Visceral vs Peripheral Adipocytes

• Androgens & polygenic factors predispose

• Unique access to liver via Portal Vein• ↑ FFA/TG turnover (↑insulin resistance?)• ↑ Pro-inflammatory tendencies?

– Adipocyte hypertrophy vs. hyperplasia– Increased ER stress due to cytoplasmic

stretch?– Greater adipocytokine secretion?– Greater inflammatory cell recruitment?

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Fatty Liver and Insulin Resistance

as Causes of Dyslipidemia,

Atherosclerosis and CVD

Causes and Effects of Fatty LiverCauses of Hepatic FFA/TG Excess• Excess portal FFA & TG from visceral

adipocytes →hepatic storage• Excess systemic FFA & TG (excess intake vs

utilization) →hepatic storage• Excess fructose (portal & systemic) → ↑hepatic FFA synthesis

Effects of Hepatic FFA/TG Excess• ↑ VLDL synthesis → ↑TG & apo B, ↓LDL size• ↑ Hepatic Insulin resistance → ↑Glycemia• ↑ NASH/hepatic inflammation• ↑ Cirrhosis and hepatic failure??

CETP = cholesterol ester transfer protein

Fatty Liver

VLDL

TG

TG

CE

CECETP

LDL

CETP HDL SDHDL

Hepatic Lipase

Kidney

RapidFiltration of

Apo A-I

HDL

SDLDL

LDL size

TG

VLDL-C11

22

33

Also, ↑VLDL synthesis is assoc. w/ ↑apo B & ↑LDL-P

“Atherogenic Dyslip”1. ↑ TG/VLDL-C2. ↓ LDL size3. ↓ A-I/HDL-C

↑CentralAdiposity

InsulinResistance

FFA/TG

Hepatic Lipase

Three Atherogenic Consequences Three Atherogenic Consequences Three Atherogenic Consequences Three Atherogenic Consequences of Hypertriglyceridemiaof Hypertriglyceridemiaof Hypertriglyceridemiaof Hypertriglyceridemia

After Ginsberg HN. J Clin Invest. 2000;106(4):453-457.

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High Triglycerides Are Strongest Predictor of Small, Dense LDL

(Pattern B)

40 80 120 160 200 240 280

TG (mg/dL)

0

20

40

60

80

100

Cum

ulat

ive

Perc

ent Pattern A

Pattern B

LDL=low-density lipoprotein; TG=triglyceride.

Austin MA, King MC, Vranizan KM, Krauss RM. Circulation. 1990;82:495-506

<147<147 >147>147 <116<116 >116>116 <142<142 >142>1420.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Rel

ativ

e R

isk

of C

AD

Small, Dense LDL May Predict CAD Better than LDL-C, Apo B, and TG

St-Pierre AC, et al. Circulation. 2001;104:2295-2299.

LDL-C(mg/dL)

Apolipoprotein B (mg/dL)

Triglycerides(mg/dL)

≥≥39.6%39.6%<<39.6%39.6%

Small, dense Small, dense LDL (<255 Å)LDL (<255 Å)

4.04.0p<0.001p<0.001(N=35)(N=35)

1.01.0(N=35)(N=35)

6.56.5p<0.001p<0.001(N=50)(N=50)

6.56.5p=0.13p=0.13(N=15)(N=15)

3.93.9p<0.001p<0.001(N=27)(N=27)

1.01.0(N=9)(N=9)

5.95.9p<0.001p<0.001(N=58)(N=58)

2.02.0p=0.12p=0.12(N=14)(N=14)

1.01.0(N=12)(N=12)

3.33.3p<0.001p<0.001(N=20)(N=20)

1.91.9p=0.15p=0.15(N=11)(N=11)

5.65.6p<0.001p<0.001(N=65)(N=65)

CAD, coronary artery disease; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol.

ExtraExtraExtraExtra Atherogenicity Atherogenicity Atherogenicity Atherogenicity of of of of Small Dense Small Dense Small Dense Small Dense LDL (pattern B)LDL (pattern B)LDL (pattern B)LDL (pattern B)

EndothelialChemoattractants

Highly oxidizedSmooth Muscle Cell

Mildly oxidizedFoam CellFoam CellFoam CellFoam Cell

LDLLDLLDLLDL

LDLLDLLDLLDLENDOTHELIUM MonocyteMonocyteMonocyteMonocyte

MacrophageMacrophageMacrophageMacrophageThrough endothelium easier

Stays on matrix longer

More readily oxidized

Associates w/ Metabolic Syndrome/DM:↓HDL, ↑TG, ↑Inflam., ↑Thromb., ↑Oxid.

↓LDL-Recep. uptake, ↑ Levels & Modific.

AndAfter Carmena et al. Circulation. 2004;109(23 Supplement 1):111-112

OxLDLOxLDLOxLDLOxLDL

Ox Ox Ox Ox LDLLDLLDLLDL

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1.0 1.2 1.1 1.72.8

10.7

0

2

4

6

8

10

12

CH

D O

dds

Rat

io

<100 100-149 150-199 200-299 300-499 500+

Serum Triglycerides (mg/dL)

TGs are independently associated withpremature familial CHD*

CHD Risk Is Increased WithCHD Risk Is Increased WithCHD Risk Is Increased WithCHD Risk Is Increased WithTG Levels TG Levels TG Levels TG Levels ≥≥≥≥222200 mg/dL00 mg/dL00 mg/dL00 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.

TG >150 mg/dL Increases CHD Risk TG >150 mg/dL Increases CHD Risk TG >150 mg/dL Increases CHD Risk TG >150 mg/dL Increases CHD Risk Even w/ LDLEven w/ LDLEven w/ LDLEven w/ LDL----C < 70 mg/dL on a C < 70 mg/dL on a C < 70 mg/dL on a C < 70 mg/dL on a StatinStatinStatinStatinaaaa

PROVE ITPROVE ITPROVE ITPROVE IT----TIMI 22 TIMI 22 TIMI 22 TIMI 22 SubanalysisSubanalysisSubanalysisSubanalysisbbbb

Miller M et al. Miller M et al. Miller M et al. Miller M et al. J Am Coll J Am Coll J Am Coll J Am Coll Cardiol. Cardiol. Cardiol. Cardiol. 2008;51:7242008;51:7242008;51:7242008;51:724----730730730730....

aaaaDeath, MI, and recurrent ACS Death, MI, and recurrent ACS Death, MI, and recurrent ACS Death, MI, and recurrent ACS bbbbACS patients on atorvastatin 80 mg or pravastatin 40 mgACS patients on atorvastatin 80 mg or pravastatin 40 mgACS patients on atorvastatin 80 mg or pravastatin 40 mgACS patients on atorvastatin 80 mg or pravastatin 40 mgccccAdjusted for age, gender, low HDLAdjusted for age, gender, low HDLAdjusted for age, gender, low HDLAdjusted for age, gender, low HDL----C, smoking, hypertension, obesity, C, smoking, hypertension, obesity, C, smoking, hypertension, obesity, C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatmentdiabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatmentdiabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatmentdiabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatmentLipid values are in mg/dLLipid values are in mg/dLLipid values are in mg/dLLipid values are in mg/dL

CH

D E

vent

CH

D E

vent

CH

D E

vent

CH

D E

vent

aa aaR

ate

%

Rat

e %

R

ate

%

Rat

e %

(A

fter

(Afte

r (A

fter

(Afte

r 30 30

30

30 D

ays

Day

sD

ays

Day

scc cc)) ))

N = N = N = N = 3718371837183718

0

5

10

15

20

11.7%

16.5%15.0%

17.9%

TG <150TG <150TG <150TG <150 TG ≥150TG ≥150TG ≥150TG ≥150

LDLLDLLDLLDL----C ≥70C ≥70C ≥70C ≥70

LDLLDLLDLLDL----C <70C <70C <70C <70

HR: 0.72HR: 0.72HR: 0.72HR: 0.72PPPP=.017=.017=.017=.017

HR: 0.85HR: 0.85HR: 0.85HR: 0.85PPPP=.180=.180=.180=.180

HR: 0.84HR: 0.84HR: 0.84HR: 0.84PPPP=.192=.192=.192=.192

ReferentReferentReferentReferent

1.32

1.14

1.76

1.37

1

1.2

1.4

1.6

1.8

2

Nonadjusted Adjusted

Metaanalysis of 17 studiesMetaanalysis of 17 studiesMetaanalysis of 17 studiesMetaanalysis of 17 studiesAustin MA, et al. Am J Cardiol. 1998;81:7B-12B.

†Per 89 mg/dL increase in triglyceride*P<.05

Rel

ativ

e C

VD R

isk

Rel

ativ

e C

VD R

isk

Rel

ativ

e C

VD R

isk

Rel

ativ

e C

VD R

isk†† ††

TG is CVD Risk Factor: Women>Men TG is CVD Risk Factor: Women>Men TG is CVD Risk Factor: Women>Men TG is CVD Risk Factor: Women>Men Partially Partially Partially Partially InInInIndependent of HDLdependent of HDLdependent of HDLdependent of HDL----CCCC

*

*

**

Men (n = 46 413)Women (n = 10 864)

Men (n = 22 293)Women (n = 6345)

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Insulin Resistance May Insulin Resistance May Insulin Resistance May Insulin Resistance May Increase CVD More in WomenIncrease CVD More in WomenIncrease CVD More in WomenIncrease CVD More in WomenGreater relative ↑CVD risk in women

• ↑TG• ↓HDL-C• IFG• Central Adiposity• HBP• DM-2Narrows gender-gap (CVD risk still < men)

LDL-C Doubly Underestimates CVD Risk in Cases of Small, Dense LDL

Large LDLLarge LDLLarge LDLLarge LDL Small, Dense LDLSmall, Dense LDLSmall, Dense LDLSmall, Dense LDL

Apo BLDL-C

130 mg/dL

Fewer Particles &Less Risk/Particle

More Particles &More Risk/Particle

CholesterolEster

More Apo B

After 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

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

Insulin Resistance as a Mechanism of CVD Risk

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Mandarino, DeFronzo, et al. JCI 2000;105:311-20 and Diabetes 2003;52:1943-50.

Insulin Resistance Blocks IRS-1 Induction ofFavorable Arterial Effects of Insulin

Mandarino, DeFronzo, et al. JCI 2000;105:311-20 and Diabetes 2003;52:1943-50.

Insulin Resistance/Insulin-Providing Rx Causes Allows Increased Harmful MAP Kinase Effects

Mandarino, DeFronzo, et al. JCI 2000;105:311-20 and Diabetes 2003;52:1943-50.

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How Does Insulin Resistance Cause Atherometabolic Disease?

• ↑FFA release – ↑peripheral FFA →↓glucose uptake– ↑portal FFA → fatty liver

• Fatty liver → – Hepatic insulin resistance ( → ↑hepatic glucose

output)– ↑ synth VLDL, apo B, TG, which causes – “Atherogenic dyslip.” ( ↑LpB#, ↓LDL size, ↓LpA-I)– Other lipoprot. abnl. ( ↓Apo C-II, ↑Apo C-III, etc.)

• ↑Fat cell size ( ↓adiponect., ↑adipokines, ↑inflam.)• Skel Musc pathology ( ↑TG , ↓glucose utiliz.)• Pancreatic beta-cell dysfunction• Pro-inflammatory effect in artery wall

Practical Treatment of the Practical Treatment of the Practical Treatment of the Practical Treatment of the Atherometabolic SyndromeAtherometabolic SyndromeAtherometabolic SyndromeAtherometabolic Syndrome

NCEP ATP III Definition of Insulin Resistance Syndrome

(“Metabolic Syndrome”)

National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol

in Adults (ATP III). Circulation. 2002;106:3143-3421.

Presence of 3 or more = Metabolic syndrome ICD-9-CM code: 277.7

Men Women

Waist circumference, inches >40 >35

Triglycerides, mg/dL ≥150 ≥150

HDL-C, mg/dL <40 <50

BP, mm Hg ≥130/≥85 ≥130/≥85

FPG, mg/dL* 100-125 100-125

*ADA cutpoint for IFG is ≥100 mg/dL.

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34

Subcutaneous fat

Abdominal muscle

layer

Intra-abdominal fat

Abdominal Adiposity:The Critical Adipose Depot

Modified by EA Brinton from M. Davidson, MD.

Best to measure• Just above anterior iliac crest• Fully relaxed = extend then relax• At end-expiration• Tape in contact w/ but not compressing, skin

PopulationPopulationPopulationPopulation----Specific Waist Specific Waist Specific Waist Specific Waist Cutoffs Cutoffs Cutoffs Cutoffs for the Metabolic Syndromefor the Metabolic Syndromefor the Metabolic Syndromefor the Metabolic Syndrome

Population Men Women

Caucasian 40 (37) 35 (31½)

Mid-East/Mediter. 37 31½

SubSaharan Afric 37 31½

Latin American 35½ 31½

East Asian 35½/33½ 31½

Alberti, KGMM, et al Circulation 2009;120:1640-1645.

Metabolic Abnormalities

vs BMI% of Patients with % of Patients with % of Patients with % of Patients with “Metab Abnl”= “Metab Abnl”= “Metab Abnl”= “Metab Abnl”= >>>> 2:2:2:2:1.1.1.1. HBPHBPHBPHBP2.2.2.2. HTGHTGHTGHTG3.3.3.3. IFGIFGIFGIFG4.4.4.4. ↓HDL↓HDL↓HDL↓HDL----CCCC5.5.5.5. ↑hsCRP↑hsCRP↑hsCRP↑hsCRP6.6.6.6. ↑↑↑↑HOMAHOMAHOMAHOMA----IRIRIRIRA=Men, B=WomenA=Men, B=WomenA=Men, B=WomenA=Men, B=Women

BMI: <25 25BMI: <25 25BMI: <25 25BMI: <25 25----30 30 30 30 >30 >30 >30 >30

↑↑↑↑Met.AbnMet.AbnMet.AbnMet.Abn: Hisp, ↑Waist, : Hisp, ↑Waist, : Hisp, ↑Waist, : Hisp, ↑Waist, ↑Age, + Smok.↑Age, + Smok.↑Age, + Smok.↑Age, + Smok.↓↓↓↓Met.AbnMet.AbnMet.AbnMet.Abn: Afr. Amer, : Afr. Amer, : Afr. Amer, : Afr. Amer, +EtOH, ↑Phys. Act.+EtOH, ↑Phys. Act.+EtOH, ↑Phys. Act.+EtOH, ↑Phys. Act.Wildman, RP. Arch Int Med 2008; 168:1617-24.

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Rx of Small, Dense LDL

Increase LDL Size• Niacin• Fibrates• Omega-3• PioglitazoneLower LDL-C/Non-HDL-C/apo B• Statins, etcRx Insulin Resistance• Diet, exercise, weight loss• Pioglitazone, metformin• ACEI’s? Fibrates? Statins?

Insulin Resistance as a Insulin Resistance as a Insulin Resistance as a Insulin Resistance as a Therapeutic Target Therapeutic Target Therapeutic Target Therapeutic Target in CVD Preventionin CVD Preventionin CVD Preventionin CVD Prevention

Lifestyle and Diet Can Improve Dyslipidemia

Diet/Lifestyle Change Lipid Profile Change

Smoking cessation � HDL-C 4 mg/dL1

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

Diet --�Fruits, vegetables & low-fat dairy; ↓sugar--�Total carb & �fat (to 33-50% of calories)

� LDL-C, � HDL-C1

� TG 9.4 mg/dL2

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

1. Sampson UK, Fazio S, Linton MF. Curr Atheroscler Rep. 2012;14(1):1–10. 2. Miller M, et al. J Am Coll Cardiol. 2008;51:724-730.

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Rx Insulin Resistance to Rx Insulin Resistance to Rx Insulin Resistance to Rx Insulin Resistance to Prevent Athero and CVD?Prevent Athero and CVD?Prevent Athero and CVD?Prevent Athero and CVD?

Decrease IRDecrease IRDecrease IRDecrease IR• ↓CVD:CVD:CVD:CVD:

– ↓WeightWeightWeightWeight– ExerciseExerciseExerciseExercise– PioglitazonePioglitazonePioglitazonePioglitazone– ERT/HRT?ERT/HRT?ERT/HRT?ERT/HRT?– Fibrates?Fibrates?Fibrates?Fibrates?

• ↑CVD:– Rosiglitazone – Muraglitazar

Increase IRIncrease IRIncrease IRIncrease IR• ↓CVD:CVD:CVD:CVD:

– Statins (?)Statins (?)Statins (?)Statins (?)– NiacinNiacinNiacinNiacin

• ↑CVD:– ↑Weight/visceral

adiposity– Sedentary lifestyle– Metabolic syndrome– DM-2

Fibrates: Fibrates: Fibrates: Fibrates: WellWellWellWell----Established Treatment Established Treatment Established Treatment Established Treatment

for Metabolic Syndromefor Metabolic Syndromefor Metabolic Syndromefor Metabolic Syndrome

VA-HIT: Gemfibrozil Prevents CVD With Average to Elevated Insulin Levels

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

+15

+10

+5

0

-5

-10

-15

-20

-25

-30

-35

-40

≤23

n = 434

24-29 30-38 ≥39

Fav

ors

Gem

fibro

zil

Fav

ors

Pla

cebo

CV

D R

isk

Red

uctio

n, %

P=.04 Versus Placebo

n = 431n = 426n = 442

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

Fibrates reduce CVD best in Insulin Resistant Pts.

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ACCORD Subgroup & Prior Fibrate Studies: ↓CVD if HTG/Low HDL-C

Trial(Drug)

Primary Endpoint: Entire Cohort

(P-value)

Lipid Subgroup Criteria

Primary Endpoint: Subgroup

Publication Date(s)

HHS (Gemfibrozil) -34% (0.02)

TG > 200 mg/dlLDL-C/HDL-C > 5.0

-71% (0.005)1987 (1988,1992)

VA-HIT (Gemfibrozil) -22% (0.0006)

HDL-C < 40 mg/dL -22% (0.0006)

(Subgroup = all)

1999 (2002, 2003, 2006)

BIP (Bezafibrate) -7.3% (0.24)

TG > 200 mg/dl-39.5% (0.02)

2000 (MetSynd 2005)

FIELD(Fenofibrate) -11% (0.16)

TG > 204 mg/dlHDL-C < 42 mg/dl

-27% (0.005)2005 (HDL+TG 2009)

ACCORD(Fenofibrate) -8% (0.32)

TG > 204 mg/dlHDL-C < 34 mg/dl

-31% 2010

After Ginsberg, HN. ACC Presentation 3/10

Data from FIELD Study. Rajamani, K, et al. Lancet 2009; 373:1780-88.

↓Lower-Extremity Amputations w/ Fenofibrate(Esp. “Minor” = Below Ankle; w/o Large-Vessel Disease

FIELD 2007 Ophthalmology Substudy(1o Outcome: Retinopathy Progression a ↓22%, p=0.2)

11.4

14.6

11.7

3.1

0

2

4

6

8

10

12

14

16

18

No Pre-existing Retinopathy Pre-existing Retinopathy

Pro

gres

sion

of R

etin

opat

hya ,

%

a2 step-progression of retinopathy grade by ETDRS criteria, 2 y f/u

P=.87

P=.004

Keech A, et al. Lancet. 2007;370:1687-1697.

Placebo (n = 500)Fenofibrate (n = 512)

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Pioglitazone: A Logical (but novel)

Treatment for Metabolic Syndrome

TZD Activates Favorable IRS-1 Effects and Blocks MAP Kinase (via ↓Insulin)

Mandarino, DeFronzo, et al. JCI 2000;105:311-20 and Diabetes 2003;52:1943-50.

Pioglitazone for Diabetes and Pre-Diabetes?

Pros• Strongest available insulin sensitizer• ↓ Fatty liver (~50%) & visceral fat• ↑ Beta-cell survival/function• Prevents DM-2 ~3/4↓• ↓ TG, ↑ HDL-C• Direct anti-inflammatory/anti athero effect• Decreases CVD (std. MACE—2o endpt.)Cons• ↑ Bladder cancer (not causal? &1:23 vs CVD)• ↑ CHF (water retention only)• ↑ Adiposity (peripheral only—good?)• ↑ Osteoporosis (women only)

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Niacin: A Paradoxical Treatment for Metabolic Syndrome

Niacin Briefly Worsens Glycemic Niacin Briefly Worsens Glycemic Control Control in in DMDM--22——Likely via ↑Likely via ↑Insulin Insulin ResistanceResistance

Fasting Blood Glucose*

0

50

100

150

200

250

Placebo Niaspan 1 gram Niaspan 1.5 grams

Glu

cose

mg/

dL

Baseline Week 4 Week 8 Week 12 Week 16

ADVENT trial; Grundy et al, Arch Int Med 162:1568-7 6, 2002* median values

0

5

10

15

20

<95 95-104 105-125

CDP at 6 yr: Nonfatal MI by Baseline FBG*

mg/dL

RelativeHazard 0.70 0.74 0.73 0.44

*Z for interaction = –0.35. Indicates homogeneity

≥126

Placebo Niacin

Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.

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0

5

10

15

20

25

Niacin 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 (Ni acin)

Niacin Reduces Niacin Reduces Niacin Reduces Niacin Reduces Total CVD Total CVD Total CVD Total CVD (CHD + CVA):(CHD + CVA):(CHD + CVA):(CHD + CVA):PrePrePrePre----AIMAIMAIMAIM----HIGH TrialsHIGH TrialsHIGH TrialsHIGH Trials

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

stat sig 27%stat sig 27%stat sig 27%stat sig 27%↓

AIMAIMAIMAIM----HIGH: Rationale and DesignHIGH: Rationale and DesignHIGH: Rationale and DesignHIGH: Rationale and Design• 5 Decades of consistent niacin trial data:

– ↓Atherosclerosis – ↓CHD – ↓Stroke

• Niaspan as a means, not an end: “AIM-HIGH was designed to provide a rigorous test of the HDL hypothesis”

• Selected ↓HDL-C subjects (ok TG & LDL)• Active comparator design—no “placebo”:

– Match LDL-C lowering (↑statin & CAI in ctrl)– Maintain study blind (low-dose IRNA in ctrl)

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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

• NotNotNotNot placebo-controlled ∴ ∴ ∴ ∴ notnotnotnot a true test of Niaspan (actually tested HDL hypothesis)

• Goes against many prior niacin studies• Study too short to see benefit?• Prior statin & niacin Rx blunted benefit?

Lowering Our Interpretation Lowering Our Interpretation Lowering Our Interpretation Lowering Our Interpretation of AIMof AIMof AIMof AIM----HIGHHIGHHIGHHIGH

Brinton, EA, J Clinical Lipidology, 6 (4):312-317, 2012.

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HPSHPSHPSHPS----2/THRIVE: The 2/THRIVE: The 2/THRIVE: The 2/THRIVE: The PromisePromisePromisePromiseAppeared 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?• Adequate duration (~5 yrs)• Adequate N (~23,000 subjects)• Little pre-study Rx “contamination” (vs. AIM-

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

test of niacin alone!

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

Guyton, JR; AHA Presentation Nov 2012

AIM-HIGH—New Subgroup Analysis Summary*AIM-HIGH—New Subgroup Analysis Summary*

Subjects 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**

TG/HDL drugs work in ↑TG/↓HDL-C (=IR/MetSynd)!(Need to check ↑TG/↓HDL-C pts in HPS2/THRIVE)

*Guyton, JR; AHA Oral talk Nov 2012. **Benefit (less) also seen in full study population

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What We Know So FarWhat We Know So FarWhat We Know So FarWhat We Know So Far• Merck press-release 12/24/12: ERNA +

laropiprant “did not meet its primary endpoint” and “Merck does not plan to seek regulatory approval for the medicine in the US.”

• Tredaptive withdrawn worldwide Jan. 2013• Presentation/publication of results expected

March 2013Why no benefit?Why no benefit?Why no benefit?Why no benefit?• Benefit only in low HDL-C/High TG pts?—avg.

baseline: HDL-C 44, TG 120, LDL-C 63 mg/dl • Harm from laropiprant? (↑SAEs in Rx arm)

HPSHPSHPSHPS----2/THRIVE: The 2/THRIVE: The 2/THRIVE: The 2/THRIVE: The RealityRealityRealityReality

Percent of US Patients w/ CHD Risk Equivalentsa and Low HDL-C or High TG

Taking Niacin or Fibrates

Alsheikh-Ali AA, et al. Am J Cardiol. 2006;98:1231-1233.

Pat

ient

s, %

4.7

8.2

4.9

9.5

0.91.9

0

5

10

15

20

a96% had diabetesbTG ≥200 mg/dL

Low HDL-Cn = 577

Elevated TG b

n = 158

NiacinFibrates

Niacin + Fibrates

• Make the Diagnosis:– >3 of 5 Met/Synd factors + BMI, insulin, inflam.

• TLC (diet and exercise) – 1st-line Rx– Addresses underlying cause, but – Difficult, and – Usually not enough

• Drug Rx (anti-obesity vs specific) – 2nd-line Rx after TLC – Generally easier & more effective, but– No clinical trial evid. for ↓CVD w/ TLC or antiobesity Rx– Fibrates, om-3 & niacin (statin adj) may ↓CVD, but– This evidence is mainly subgroup/post-hoc

• Combination meds may be needed

Summary: Dx and Management of Insulin Resistance/Metabolic Syndrome

Adapted from Grundy, S. et al., Circulation 2005;112:1-18.