update on management of atherogenic dyslipidemia of insulin resistance, obesity, and type 2...

Source: www.myhealthywaist.org

UPDATE ON MANAGEMENT OF ATHEROGENIC DYSLIPIDEMIA OF

INSULIN RESISTANCE, OBESITY, AND TYPE 2 DIABETES:

BEYOND LDL CHOLESTEROL

Ronald M. Krauss, MD

Children’s Hospital Oakland Research Institute

UC Berkeley and UCSF


Atherogenic Dyslipidemia in Obesity, Insulin Resistance, and Metabolic Syndrome

High triglyceride (TG) levels TG-rich remnant lipoproteins (VLDL) Altered metabolism of LDL and HDL particles

Absolute levels of LDL cholesterol are commonly not significantly increased, number of LDL particles Predominantly small, dense LDL particles

Low levels of HDL cholesterol (may reduce reverse cholesterol transport)

Adapted from Haffner SM Diabetes Care 2003; 26: S83-6and Garvey WT et al. Diabetes 2003; 52: 453-62

Source: www.myhealthywaist.orgSource: www.myhealthywaist.org

Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL and Small LDL and Reduction of HDL

SmallerLDL

HL

Apo AI

Renalclearance

LPL

RemnantsLPL/HL

VLDL

TG TG CETP

Cholesterol

HDL

TGTGLDL

TGTG SmallerHDL

Apo AI: apolipoprotein AI

CETP: cholesteryl ester transfer protein

HL: hepatic lipase

LPL: lipoprotein lipase

TG: triglycerides


Residual Cardiovascular Risk in Major Statin Trials

Reprinted from J Am Coll Cardiol, Vol 46, Libby P. The forgotten majority: Unfinished business in cadiovascular risk reduction, 1225-8, Copyright © 2005, with permission from Elsevier

LDLN 4,444 4,159 20,536 6,595 6,6059,014

-36% -28% -29% -26% -27%-25%

Secondary High risk Primary

Pat

ien

ts e

xper

ien

cin

g

maj

or

coro

nar

y ev

ents

(%

)


Re

lati

ve

CV

D r

isk

†

Triglyceride Level is an Independent Cardiovascular Disease (CVD) Risk Factor – Meta-Analysis of 17 Studies

Adapted from Austin MA et al. Am J Cardiol 1998; 81: 7B-12B

Men (n=22,293)

Women (n=6,345)

Men (n=46,413)

Women (n=10,864)

*

*

*

*

†Associated with an 89 mg/dl (1.00 mmol/l) increase in triglycerides

*p<0.05


Triglyceride Level Remains a Cardiovascular Disease (CVD) Risk Factor in Patients Treated With Statins - CARE and LIPID

Adapted from Sacks FM et al. Circulation 2000; 102: 1893-900

CV

D e

ven

t ra

te*

Placebo

Pravastatin

<98 99-126 127-158 159-207 >207

Triglyceride levels (mg/dl)

Slope=0.018p=0.02

Slope=0.029p<0.001

n=13,173

*Coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty


Coronary Heart Disease (CHD) Risk: HDL Cholesterol vs. LDL Cholesterol as Predictor*

Adapted from Castelli WP Can J Cardiol 1988; 4 (Suppl A): 5A-10A

*Data represent men aged 50 – 70 from the Framingham Heart StudyR

elat

ive

risk

of

CH

D a

fter

4 y

ears

LDL cholesterol (mg/dl)

8565

4525

HDL

cholesterol

(mg/dl)


Statin Therapy Does Not Eliminate Cardiovascular Disease (CVD) Risk Associated With Low HDL Cholesterol

Adapted from HPS Collaborative Group Lancet 2002; 360: 7-22and Sacks FM et al. Circulation 2000; 102: 1893-900

CARE: Cholesterol and Recurrent Events

HPS: Heart Protection Study

LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease

CV

D e

ven

t ra

te (

%)

High HDL cholesterol + statin

Low HDL cholesterol + statin


Relative Risk of Myocardial Infarction (MI) According to Triglycerides (TG) and HDL Cholesterol: Case-Control Study in CAD Patients

Adapted from Gaziano et al. Circulation 1997; 96: 2520-5

Quartiles of TGQuartiles of TG, adjusted for HDL cholesterolQuartiles of log TG/HDL cholesterol


Apo B

Similar LDLcholesterol

Slower plasma clearance Greater artery uptake & retention Faster oxidation More particles

Cholesterylester

LDL Cholesterol Underestimates the Number of LDL Particles When Levels of Small LDL Are Increased

Larger LDL (phenotype A)More cholesterol/particle

Smaller LDL (phenotype B)Less cholesterol/particle


Favourable Shift in LDL Particle Size is Strongly Associated With End-of-Treatment Triglyceride (TG) Values

Adapted from Davidson MH et al. Clin Cardiol 2006; 29: 268-73

Med

ian

in

crea

se i

n L

DL

par

ticl

e d

iam

eter

(n

m)

TG level† (mg/dl)

<200 200-299 ≥300 Ch

ang

e f

rom

bas

elin

e (%

)

TG

*

Small LDL cholesterol

Large LDL cholesterol

LDL particle concentration

*

*

TG† <200 mg/dl

TG† ≥200 mg/dl

†End-of-treatment TG level

*p<0.03 vs. TG level ≥200 mg/dl

Triglyceride reduction in metabolic syndrome (TRIMS)

Significant inverse relationshipp value for trend =0.019


Pharmacologic Options for Management of Atherogenic Dyslipidemia

LDL lowering: statin, ezetimibe, resin

Triglyceride reducing, HDL raising: niacin, fibrates, omega-3 fatty acids


Coronary Drug Project: Niacin Effects on 6-Year Cardiovascular Disease (CVD) and 15-Year Mortality

Reprinted from Am J Cardiol, Vol 95, Canner PL et al. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug

Project), 254-7 Copyright © 2005, with permission from Elsevier

CHD: coronary heart disease

MI: myocardial infarction

Hazardratio

0.83 0.71 0.84 0.86p<0.005 p<0.005 p<0.005 p<0.05

Niacin

Placebo


Coronary Drug Project: Niacin Effects on 6-Year Nonfatal Myocardial Infarction by Fasting Plasma Glucose

Reprinted from Am J Cardiol, Vol 95, Canner PL et al. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug

Project), 254-7 Copyright © 2005, with permission from Elsevier

<95 95-104 105-125 ≥126

Fasting plasma glucose (mg/dl)

Hazardratio

0.70 0.76 0.75 0.43

Niacin

Placebo


ADVENT: Safety of Niacin for Dyslipidemia Associated With Type 2 Diabetes

Reprinted from Arch Intern Med, Vol 162, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial), 1568-76

Copyright © 2002, with permission from Elsevier

*

Baseline Week 4 Week 8 Week 12 Week 16

n=148

*p=0.048 vs. placebo


Primary Prevention With Gemfibrozil The Helsinki Heart Study

Adapted from Manninen V et al. Circulation 1992; 85: 37-45

Inci

den

ce

of

car

dia

c e

ven

tsp

er

1,0

00 p

ers

on

-ye

ars

0

5

10

15

20

HDL cholesterol 42 HDL cholesterol 42

TG 200 TG 200 TG 200 TG 200mg/dl

Gemfibrozil

TG: triglycerides

Placebo

Incidence of coronary heart disease events


VA-HIT: Gemfibrozil Effect on Primary Endpoint - Lipids

Adapted from Rubins HB et al. N Engl J Med 1999; 341: 410-8

LDL cholesterol TG

HDL cholesterol

Primary endpoint occurrence*†

Ch

ang

e fr

om

bas

elin

e (%

)

%

Placebo Gemfibrozil

*Nonfatal myocardial infarction or death from coronary causes

†22% relative risk reduction (95% CI: 7%–35%, p=0.006)

TG: triglycerides


VA-HIT: LDL and HDL Particle Subclasses Are Favourably Affected by Fibrate Treatment

Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63

IDL: intermediate-density lipoprotein

B: baseline

Placebo Fibrate

5% reduction

13641463

1352 1290*

LD

L p

arti

cle

nu

mb

er (

nm

ol/l

)

B 7 months B 7 months

20

% d

ec

rea

se

36

% i

nc

rea

se

*

*

HD

L p

arti

cle

nu

mb

er (m

ol/l

) 25.2 25.126.6 27.6*

Placebo Fibrate

B 7 months B 7 months

21

% i

nc

rea

se

*

*

10% increase

*p≤0.0005 vs. placebo at 7 months

IDL Large HDL Large LDL Medium HDL Small LDL Small HDL


Rel

ativ

e o

dd

s ra

tio

†

LDL particle number

LDL particle size

**

Rel

ativ

e o

dd

s ra

tio

†

HDL particle number

HDL particle size

**

VA-HIT: LDL and HDL Particle Numbers Are Significant, Independent Predictors of New Coronary Heart Disease Events

Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63

Baseline

7 months

†Calculated for a 1-SD increment of each lipoprotein particle in separate logistic regression models adjusted for treatment group, age, hypertension, smoking, body mass index, and diabetes

*p<0.05


VA-HIT: Cardiovascular Disease Risk Reduction in Nondiabetic Patients

Adapted from Rubins HB et al. Arch Intern Med 2002; 162: 2597-604

Ris

k re

du

ctio

n

≤23

n=434

24-29 30-38 ≥39

n=431n=426n=442

Quartiles of fasting plasma insulin (µU/ml)

Fav

ou

rs g

emfi

bro

zil

Fav

ou

rs p

lace

bo

p=0.04 vs. placebo


Myocardial Infarction Prevention With Bezafibrate in Metabolic Syndrome

Reprinted from Arch Intern Med, Vol 165, Tenenbaum A et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome, 1154-60


0

Myo

card

ial

infa

rcti

on

(%

)

Car

dia

c m

ort

alit

y (%

)

Time (years) Time (years)

Log-rank p=0.02 Log-rank p=0.07

5

10

15

20

0

5

10

15

PlaceboBezafibrate

1 2 3 4 5 6 7 8 901 2 3 4 5 60


Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)

Subjects: 9,795 (37% female) patients with type 2 diabetes aged 50-75 years with and without coronary heart disease (CHD)

Entry lipid criteria: cholesterol = 116-251 mg/dl (3.00-6.50 mmol/l), plus either Cholesterol/HDL cholesterol ratio >4

or Triglycerides >89 mg/dl (1.00 mmol/l)

Treatment: fenofibrate 200 mg once daily or placebo for 5 years

Primary endpoint: CHD death plus nonfatal myocardial infarction

Adapted from Keech AC and the FIELD Study Investigators Cardiovasc Diabetol 2004; 3: 9-24


FIELD: End of Study Lipid Results

Adapted from Keech A et al. Lancet 2005; 366: 1849-61

Placebo (P)Fenofibrate (F)

113

LDLcholesterol

HDLcholesterol

Triglycerides

Baseline (mg/dl)

117 43 43 164 167

119

LDLcholesterol

HDLcholesterol

Triglycerides

Baseline (mg/dl)

119 43 43 171 173

128

LDLcholesterol

HDLcholesterol

Baseline (mg/dl)

125 42 40 184 197

Triglycerides

Did not start other lipid-lowering therapyn= 3,124 (P) 3,951 (F)

Total population

Started other lipid-lowering therapyn= 1,776 (P) 944 (F)


Ev

ent

rate

(%

)

FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events*


11% reductionp=0.16

*Nonfatal myocardial infarction or CHD death


24% reductionp=0.01

19% increasep=0.22

FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events*


PlaceboFenofibrate

*Nonfatal myocardial infarction or CHD death


FIELD Primary Prevention Population: Effects on Coronary Heart Disease (CHD) Events and Total Cardiovascular Disease (CVD) Events


Ris

k re

du

ctio

n (

%)

(n=7,664) (n=7,664)

p=0.014

p=0.004

CHD events Total CVD


FIELD: Microvascular Disease


Progression RegressionP

ati

en

ts (

%)

P F P F

14% reductionp<0.001

30% reductionp=0.0003

Placebo Fenofibrate

Pa

tie

nts

(%

)

*Progression of albuminuria was defined as the proportion of patients who progressed either from normoalbuminuria to microalbuminuria or from microalbuminuria to macroalbuminuria.

Placebo (P)Fenofibrate (F)

Laser treatment for retinopathy Progression and regression of albuminuria*


FIELD: Clinically Important Adverse Events

Adverse EventPlacebo, %

n=4,900

Fenofibrate, %

n=4,895

Newly diagnosed cancer 7.6 8.0

Deep-vein thrombosis 1.0 1.4

Pulmonary embolism 0.7 1.1‡

Pancreatitis 0.5 0.8§

Myositis* 0.02 0.04

Rhabdomyolysis† 0.02 0.06

Renal disease requiring dialysis 0.4 0.3

ALT 3-5x ULN 0.5 0.2

>5x ULN 0.2 0.2

CPK 5-10x ULN 0.1 0.2

>10x ULN 0.06 0.08

Creatinine increase >2.26 mg/dl 1.0 1.5

ALT: alanine aminotransferase

CPK: creatine phosphokinase

ULN: upper limit of normal

*Myositis was experienced by 1 placebo and 2 fenofibrate patients†Rhabdomyolysis was experienced by 1 placebo and 3 fenofibrate patients (none were taking a statin)‡p=0.022§p=0.031



Pharmacologic Options for Atherogenic Dyslipidemia

LDL lowering: statin, ezetimibe, resin

Triglyceride reducing, HDL raising: niacin, fibrates; omega-3 fatty acids

Combination therapy


SAFARI: Combination Therapy in Patients With Combined Hyperlipidemia

Reprinted from The American Journal of Cardiology, Vol 95, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial), 462-8

Copyright © (2005), with permission from Elsevier

**

*

*Simvastatin 20

Simvastatin 20 + Fenofibrate 160

n=618

*p<0.001 vs. simvastatin


SAFARI: Effects on LDL Particle Subclasses

Adapted from Grundy SM et al. Am J Cardiol 2005; 95: 462-8Reproduced with permission

Simvastatin +Fenofibrate

Simvastatin Simvastatin

Ch

an

ge

fro

m b

ase

line

in

LD

L p

att

ern

(%

)

Baseline Week 12*

Incr

ease

d p

arti

cle

siz

e

n=618

*Significantly different pattern between the 2 treatment groups (p<0.001)

B (Smaller, dense)

AB (Intermediate)

A (Larger, buoyant)

Simvastatin +Fenofibrate


Atorvastatin and Fenofibrate Alone or in Combination in Patients With Type 2 Diabetes

Adapted from Athyros VG et al. Diabetes Care 2002; 25: 1198-202

TriglyceridesLDL

cholesterolHDL

cholesterol

Ch

an

ge

fro

m b

ase

line

(%

)

*

*

*

*‡

*

*

*†

Atorvastatin 20 mgFenofibrate 200 mgCombination

*†

n=120

*p <0.0001 vs. baseline

†p <0.05 vs. both monotherapies

‡p <0.05 vs. atorvastatin


Statin-Fibrate Combination Therapy: Pharmacokinetic Interactions

Adapted from:

TriCor [package insert]. Abbott Laboratories; 2004

Kyrklund C et al. Clin Pharmacol Ther 2001; 69: 340-5

Pan W J et al. J Clin Pharmacol 2000; 40: 316-23

Backman JT et al. Clin Pharmacol Ther 2000; 68: 122-9

Backman JT et al. Clin Pharmacol Ther 2002; 72: 685-91

Abbott Laboratories. Data on file; 2005

Davidson MH Am J Cardiol 2002; 90 (suppl): 50K-60K

Prueksaritanont T et al. Drug Metab Dispos 2002; 30: 1280-7

Martin PD et al. Clin Ther 2003; 25: 459-71

Bergman AJ et al. J Clin Pharmacol 2004; 44: 1054-62

Gemfibrozil Fenofibrate

Atorvastatin Expected in Cmax No effect

Simvastatin Cmax by 2-fold No effect

Pravastatin Cmax by 2-fold No effect

Rosuvastatin Cmax by 2-fold No effect

Fluvastatin No effect No effect

Lovastatin Cmax by 2.8-fold Not available

Cerivastatin Cmax by 2-3-fold No effect

Cmax: maximum concentrations


Effects of Lovastatin or Lovastatin and Niaspan on Lipid Parameters

Adapted from Hunninghake DB et al. Clin Cardiol 2003; 26: 112-8

Ch

an

ge

fro

m b

ase

line

(%

)

LDL cholesterol

HDL cholesterol

Triglycerides

Lovastatin 40 mg

Lovastatin 20 mg + 1,000 mg niaspan (Advicor)


Analysis of the HDL-Atherosclerosis Treatment Study (HATS): Angiographic and Clinical Endpoints After 3 Years – Simvastatin + Niacin vs. Placebo

Adapted from Brown BG et al. N Engl J Med 2001; 345: 1583-92

Placebo

Mea

n c

han

ge

in s

ten

osi

s (%

)

*p<0.001 vs. placebo

‡p=0.04 vs. placebo

Coronary death, myocardial infarction, stroke or

revascularization

Simvastatin + Niacin

Co

mp

osite even

t rate (%)

3.923.7

-0.4

2.6*‡

89% reduction

-0.5

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Nine proximal lesions

25

20

15

10

5

0


ARBITER 2: Statin Plus Placebo vs. Statin Plus Extended-Release Niacin (ERN)

12 monthsP value

BL vs. 12 months

Lipid (mg/dl)Statin +Placebo

Statin + ERN

P Value

Statin +Placebo

Statin + ERN

n 71 78

LDL cholesterol 86 20 85 25 NS NS NS

HDL cholesterol 40 9 47 16 0.003 NS <0.001

Triglycerides 164 83 134 87 0.03 NS 0.009

Non-HDL cholesterol

115 21 107 34 NS 0.03 0.02

Values are mean SD BL: baseline

Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7


ARBITER 2: Statin + Placebo vs. Statin + Extended-Release Niacin 1,000 mg/d Primary Endpoint – Carotid Intima-Media Thickness (CIMT) Change

Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7

Statin + Placebo(n=71)

Statin + Extended release niacin

(n=78)

Bas

elin

e C

IMT

(m

m)

Ch

ang

e in

CIM

T (

mm

)Statin + Extended

release niacin(n=78)

p=0.23*

Statin + Placebo(n=71)

p<0.001*

*Within-group comparisons

Baseline CIMT after 1 year


Kaplan-Meir Estimates of Incidence of Coronary Events on Patients Receiving Statin or Statins and Omega-3 Fatty Acid (EPA)

Reprinted from The Lancet, Vol 369, Yokoyama M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis, 1090-98


All patients Primary prevention

Secondary prevention

18,645 Japanese (70% women, 61 years) randomized to statin alone or statin + EPA (1.8 g/d) and followed for 5 years

update on management of atherogenic dyslipidemia of insulin resistance, obesity, and type 2...

Health & Medicine

small ldl

metabolism of ldl

ldl cholesterolronald

elsevier ldl n

reduction of hdl smaller

number of ldl particles

women n

b relative cvd risk