1

Lipid Management: p gBeyond LDL

Lisa R. Tannock MDDivision of Endocrinology andDivision of Endocrinology and

Molecular MedicineUniversity of Kentucky

Overview

• Discuss the concept of residual risk• Discuss the concept of residual risk

• Review current evidence-based medicine for therapies other than statins

2

Major CVD Risk Factors

• High LDL/ Low HDL• High LDL/ Low HDL

• Smoking

• Diabetes

• Hypertension

• Age• Age

• Gender

Prevalence of CVD* in Adults

* Includes CHD, CHF, stroke and HTN

3

Burden of Coronary Artery Disease in the US

• 2400 Americans die of CVD2400 Americans die of CVD each day

• CVD deaths equal cancer, respiratory diseases, accidents and diabetes combined

• If all forms of major CVD were• If all forms of major CVD were eliminated, life expectancy would increase 7 yrs; cancer –3 yrs

American Heart Association. 2002 Heart and Stroke Statistical Update.

Secondary Prevention

Primary Prevention 4S-PL

LDL-C Lowering With Statins: Reduced CHD Events

y

CARE-Rx

4S-Rx

LIPID-Rx

CARE-PLLIPID-PL

WOSCOPS-PL10

15

20

25

TNT-10HPS-Rx

HPS-PL

50

AFCAPS-Rx

AFCAPS-PL

WOSCOPS-RxWOSCOPS-PL

70 90 110 130 150 170 190 210

0

5

Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.

LDL Cholesterol (mg/dL)

TNT-10TNT-80

ASCOT-RxASCOT-PL

4

Lipid LevelsLipid Levels SimvastatinSimvastatin PlaceboPlacebo

Risk ratio and 95% CIRisk ratio and 95% CI

STATIN PLACEBO

HPS: Statin Benefit Independent of Baseline LDL

Lipid LevelsLipid Levelsat Entryat Entry

SimvastatinSimvastatin(10,269)(10,269)

Placebo Placebo (10,267)(10,267)

LDL cholesterol (mg/dl)

< 100 282 358

100 < 130 668 871

130 1083 1356

STATINBetter

PLACEBOBetter

ALL PATIENTS 2033 2585

24% SE 3reduction(2P<0.00001)

0.6 0.8 1.0 1.2 1.40.4

HPS Collaborative Group. Lancet. 2002;360:7-22.

Summary of Clinical Trial Findings

• in LDL-C results in in CHD morbidity/ mortality

• Studies support treatment in various patient groups– women

– elderly

– diabetics

– more moderate hyperlipidemia

5

Risk Assessment - LDL GoalsRisk Category 10 Year

RiskLDL Goal (mg/dl)

LDL level for Drug Rx

CHD or equivalent (Diabetes)

>20% <100

Optional: <70*

≥100*

(>100 optional)

2+ risk factors ≤20% <130

<100 optional*

≥130 (10-20% risk)

(>100 optional)

≥160 (<10% risk)optional ≥160 (<10% risk)

0-1 risk factor <10% <160 ≥190

NCEP ATP III guidelines, with 2004 update*

ATP III: JAMA 2001; 2004 update: Circulation 2004

Despite LDL Lowering:Residual Risk

0

4S CA

RE

WO

SCO

PS

LIP

ID

AFC

AP

S

HPS

PR

OSP

ER

ASC

OT

36%

19%27%

40%

24%31%

24%

34%

20

40

60

80

Re

lati

ve

Ris

k R

ed

uc

tio

n

Ma

jor

Co

ron

ary

Ev

en

ts, %

Residual Risk

10

100

Rin

M

6

Patients at or Below LDL-C of 100 mg/dL Have Events

– Of 2,191 statin-treated patients who experienced a CV/CB event 67% were at LDL-C of

n=2,191

33%

67%

event, 67% were at LDL-C of 100 mg/dL

– Among patients with a CV/CB event and

• With LDL-C <100 mg/dL, 38.6%had low HDL-C and/or elevated triglycerides

• With LDL-C >100 mg/dL, 43.9%had low HDL C and/or elevated

LDL-C <100 mg/dL

LDL-C >100 mg/dL

had low HDL-C and/or elevated triglycerides

CV=cardiovascular; CB=cerebrovascular.Patients were on statin therapy ≥6 weeks; >2 years pre- and post-statin history with laboratory data; no concomitant lipid-lowering drugs; and ≥1 complete lipid profile pre- and post-statin initiation. Patients were followed for up to 5 years.Phatak H et al. Poster presented at the European Atherosclerosis Society Congress; June 10–13, 2007: Helsinki, Finland. Poster P016-441.

Beyond LDL• Low HDL and elevated TG and sdLDL

closely correlateT i ll i t l b it d• Typically seen in central obesity and metabolic syndrome patients

• TG: Non-HDL is secondary target with goal 30 mg/dl higher than LDL goalgoal

• Low HDL: Levels > 40 mg/dl “desirable” but no target yet defined

• Other lipid parameters

7

CV Risk: HDL-C and LDL-C Interaction

For any level of LDL-C, HDL-C is inversely related

Data From Framingham Study

yto CHD risk

isk o

f C

HD

1.0

2.0

3.0

Gordon T et al. Am J Med 1977;62:707-714.

R

LDL-C(mg/dL)

0.0100 160 220 85

6545

25

Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels

Prospective Cardiovascular Münster Study

245250 *

s)

TG < 200 mg/dL

116

245

100

150

200

Inci

den

ceper

1,0

00 (

in 6

yea

rs

TG 200 mg/dL

* Bar represents 5% of subjects in which 25% of CHD events occurred.Assmann G, Schulte H. Am J Cardiol 1992;70:733–737.Copyright ©1992, with permission from Excerpta Medica Inc.

24 310

50

5.0 > 5.0LDL-C/HDL-C ratio

p

8

Non-Fasting TGs Predictive of Risk

h,

MI,

io

n)

Women’s Health Initiative

• 20,118 Fasting

• 6,319 Non-fasting

Women’s Health Initiative

• 20,118 Fasting

• 6,319 Non-fasting Non-Fasting TG

Fasting TG2

2.5O

dds

Rat

io (

CV D

eath

CVA,

Rev

ascu

lari

zati (<8 hr)

• Baseline demographics

• Baseline bloods

• 11.4-year mean F/U

• Fasting time documented

• Endpoint: CV death, MI CVA

(<8 hr)

• Baseline demographics

• Baseline bloods

• 11.4-year mean F/U

• Fasting time documented

• Endpoint: CV death, MI CVA

Fasting TG

P-trend = 0.9

P-trend = 0.001

0.5

1

1.5

Tertile of Baseline TG

Bansal S et al. JAMA 2007;298:309316.

1st

MI, CVA, Revascularization

• 1,001 events

• Best risk discriminant = TG drawn @ 2–4 hours

MI, CVA, Revascularization

• 1,001 events

• Best risk discriminant = TG drawn @ 2–4 hours

2nd 3rd

CVD=cardiovascular disease; TG=triglyceride; CV=cardiovascular; MI=myocardial infarction; CVA=cerebrovascular accident; F/U=follow-up

0

• Reverse cholesterol transport

Mechanisms By Which HDLMay Be Anti-atherogenic

• Antioxidant effects

• Inhibition of adhesion molecule expression

I hibiti f l t l t ti ti• Inhibition of platelet activation

• Prostacyclin stabilization

• Promotion of NO production

9

HDL-C, RCT and Atherosclerosis

Bile

A-IM h

Mature HDL-C SR-BI

SR-BI

LDL-CReceptor

LiverFC

CE LCAT

FCA-I

CEHL, EL

Macrophage

FC

Nascent HDL-C

CE

TP

17

BCE

RCT=reverse cholesterol transport; CE=cholesteryl ester; FC=free cholesterol; LCAT=lecithin-cholesterol acyltransferase; CETP=cholesteryl ester transfer protein; VLDL=very low-density lipoprotein; SR-BI=scavenger receptor class B type I; HL=hepatic lipase; EL=endothelial lipase.

Reproduced with permission from Cuchel M et al. Arterioscler Thromb Vasc Biol. 2003;23:1710–1712.

VLDL/LDL-C

Declining HDL-C in the Population

>12,000 respondents to a biennial population survey in

1.5

1.4

1.3

1.2

1 1

1.3

1.2

1.1

1 0

MenWomen

Nonsmokers

Smokers

Nonsmokers

Smokersthe Pawtucket Heart Health Program

Between 1981 and 1993, 0.08 mmol/L (3.1 mg/dL) decline H

DL-

C (

mm

ol/

L)

1.1

0.0

1.3

1.3

1.2

1.1

1.0

0.0

1.0

0.0

1.5

1.5

1.4

1.3

1.2

1.1

0.0

Smokers

Alcohol

No AlcoholNo Alcohol

Alcohol

BMI <22.9 BMI <24.5

Adjusted for other risk factor changes

Reprinted from Ann Epidemiol, Vol. 8, Derby CA et al., 84-91, copyright 1998, with permission from Elsevier.

1.2

1.1

1.0

0.0

1.4

1.3

1.2

1.1

0.0

5

BMI 27.6 BMI 27.9

1981 - 1993 1981 - 1993

10

Treating HDL:Non-pharmacologic Methods

• Exercise overrated

–HDL only when TG high

7P=0.015P=0.015

high

–HDL only with intense, frequent exercise

• Alcohol

– Raises TG Chan

ges

in H

DL-

Conce

ntr

atio

n (

mg/d

L)

4

1ControlControl

Infrequent Infrequent exerciseexercise

Frequent, intense Frequent, intense exerciseexercise

Couillard C et al. Arterioscler Thromb Vasc Biol 2001;21:1226-1232. | Kraus WE et al. N Engl J Med 2002;347:1483-1492. Copyright 2002 Massachusetts Medical Society. All rights reserved.

• Affects CETP activity

– Modest HDL changes

• Smoking cessation

• Weight loss

Co

0

-2

IntenseIntense

ControlControl

ModerateModerate

How Do We Increase HDL?

• Strategies to raise HDL• Strategies to raise HDL– Niacin

– Fibrates

– Thiazolidinediones

– CETP Inhibitor - ?

11

Lipid Effects of Niacin Extended-Release (ER)

han

ge

from

Bas

elin

e (%

)

-8 -13-22 -21-16

293024

2116

10

-21

-32

-14

-5

-26

-3

-12

-30-25

-17

HDLHDL--CC

LDLLDL--CC

Lp(a)Lp(a)

TGTG

3020100

-10-20-30-40

Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U.

Ch -44-39 TGTG40

-50

mg500 1000 1500 2000 2500 3000

Niacin Monotherapy: Coronary Drug Project

• 1966–1975, men with prior MI

Event Rate (%)

–1435

prior MI• 5 lipid-influencing

drugs– Niacin 1 g TID (n=1119);

TC 10%, TG 27%• 6 years: reduction in

MI only in niacin

Placebo

Niacin

–27–26

–4710

15

20

25

30

Coronary Drug Project. JAMA 1975; 231:360-381. | Canner PL et al. J Am Coll Cardiol 1986;8:1245-1255.

group• 15 years: 4% absolute

reduction in mortality– NNT = 25

CVSurgery

Nonfatal MI/

CHD Death

Nonfatal MI

Stroke/TIA

47

0

5

12

Niacin

• Reasonable alternate in statin-intolerant patients

• Possible consideration for combination therapy

• Limited by side effects– Flushing

– Gout

– Peptic ulcer disease

– Insulin resistance

HDL-Atherosclerosis Treatment Study (HATS)Niacin and Statin Outcome Trial

89%89%ReductionReduction

21.4

*P<.05vs Placebo23.725

2.6*

14.3

5

10

15

20

Placebo S + N + AVS + N

Brown BG et al. N Engl J Med 2001;345:1583-1592.

AV

Coronary Death, MI, Coronary Death, MI, Stroke Stroke or Revascularizationor Revascularization

0

13

HATS: Primary Clinical EndpointCAD Death, NonCAD Death, Non--fatal MI, CVA or Revascularizationfatal MI, CVA or Revascularization

%)

Si i i i

100 1

en

ts F

ree o

f Even

ts ( Simvastatin-niacin

Relative Risk = 0.40

90

80

No simvastatin-niacin

78%

91%

Pati

e

1st

p = 0.02

Years2nd 3rd0

70

0~~

Brown BG et al. N Engl J Med 2001;345:15831592.

HATS=HDL-atherosclerosis treatment study; CAD=coronary artery disease; MI=myocardial infarction; CVA=cerebrovascular accident

0

Niacin + Statin: ARBITER 2

g/d

L)

Statin + placebo

0

100

200

300

al ero

l

LD

L

HD

L

TG

Co

nce

ntr

atio

ns

(mg

Statin + niacin ER

**

h

10

12

P = .20

9.6 60%

To

tach

ole

st

H

ARBITER 2 study; Circulation 2004Statin +Placebo

Statin +Niacin ER

Pat

ien

ts w

ith

Eve

nt

(%)

0

2

4

6

8P .20

3.8

14

Niacin Therapy

• Start low and titrate dose• Start low and titrate dose

• Take in the middle of a meal

• Avoid alcohol and hot drinks with dose

• Pre-treat with ASA 30 mins before dose

• Warn patients about the flush!• Warn patients about the flush!

Meyers et al; Ann Int Med, 2003

Niacin Brands

• Brands labeled “No Flush” or “Flush-free” have no effectfree” have no effect– Inositol hexaniacinate not metabolized

by humans

• Sustained release or timed release forms have variable effects and increased liver toxicity

Meyers et al; Ann Int Med, 2003

15

Niacin + Statin:Current Recommendations

• Pending Outcomes Trials• Pending Outcomes Trials– AIM HIGH

– HPS-THRIVE

• Monotherapy is a suitable alternative in statin intolerant patientsp

• Probable benefit from statin combination therapy in high risk

e (%

)

2° Prevention:Incidence of Death from CHD and Nonfatal MI

20

25

Fibrate Monotherapy: VA HIT

Placebo Rx

mu

lati

ve I

nci

den

ce

Placebo

Gemfibrozil

5

10

15

20

P=0.006

HDL 32 34*

LDL 113 113

TG 166 115*

Year

Cu

m

* Lipid values significantly different, P<0.05

Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.

01 2 3 4 5 6

16

Fibrate Monotherapy: Helsinki Heart Study

ents

s)20

Gemfibrozil

cid

ence

of

card

iac

eve

(per

1,0

00 p

erso

n-y

ears

5

10

15 Placebo

1° Prevention; Manninen V et al. Circulation. 1992;85:37–45

In(

0

HDL-C 42 HDL-C 42

TG 200 TG 200 TG 200 TG 200mg/dL:

Fibrate Combination Therapy: FIELD

Primary Endpoint Secondary Endpoint

Lancet, 2005Non-significant 19% increase in cardiac mortality with feno vs. placebo

17

FIELD: Outcomes

• Greater use of t ti i l bstatins in placebo

than fibrate groups

• Less ↑HDL than expected

• Not clear if statin + fib t b fi i lfibrate beneficial

Statin + Fibrate

• Data to establish benefit in outcomes pending (ACCORD trial)pending (ACCORD trial)

• Most benefit in Metabolic Syndrome and low HDL patients

• Safety: no increased risk of rhabdo or renal failure in trial settingsor renal failure in trial settings

• Choice of agents doesn't matter; use lower statin doses

Statin-Fibrate Safety Report, 2004

18

Thiazolidinediones

TG HDL-C Non–HDL-C LDL-C

20

30

†

†‡

Pioglitazone

Rosiglitazone

ang

e fr

om

bas

elin

e at

24

wee

ks (

mg

/dL

)

-30

-20

-10

0

10†

†

Data from Goldberg RB et al. Diabetes Care. 2005;28:1547-1554.

Ch

a

-50

-40

-60

TZDs: CHD Prevention

• PROactive (Prospective PioglitazoneClinical Trial in Macrovascular Events)Clinical Trial in Macrovascular Events)

• 5,238 subjects with type 2 DM and macrovascular disease on best usual care

• Baseline lipids: HDL 42; LDL 112; TG 159; baseline HbA1c 7.8%

• Concurrent medication use– B blockers: 55%

– ACE inhibitors/ ARBs: 70%

– Statins: 43%

– Fibrates: 10%

19

PROactive: 1° EndpointComposite of death, nonfatal MI, stroke, ACS, leg amputation, coronary or leg revascularization

PROactive: 2° EndpointComposite of death, nonfatal MI or stroke

20

Pioglitazone: CVD RiskDeath, MI or Stroke

Lincoff et al; JAMA 2007; 298:1180-1188

Summary

• Statins remain the initial therapy

L HDL/ Hi h TG lik l t ib t t• Low HDL/ High TG likely contributes to residual risk

• Probable benefit to niacin + statins

• Evidence unclear for fibrates in monotherapy or with statins

• Probable benefit to pioglitazone in diabetics

21

Encourage Compliance…Medications that aren’t taken

don’t work