1 Challenges in Lipid Management. 2 Objectives Provide an overview of the effects of lipid-lowering drugs on lipoprotein levels and clinical results.

1

Challenges in Lipid Management

2

Objectives

Provide an overview of the effects of lipid-lowering drugs on lipoprotein levels and clinical results

Detail the effects of fibrates on lipoprotein levels, atherosclerotic disease, and coronary end points

Describe the mechanism of action of niacin and how it affects plasma lipids, lipoproteins, and its anti-inflammatory actions

Review the results of clinical trials of niacin alone or combined with colestipol or statins

Describe the side effects of niacin

3

Effects of Lipid-Lowering Drugs

Challenges in Lipid Management

4

Drug Therapy Options for Treating Dyslipidemia

Drug/Class Lipid Effects Clinical Results Side Effects

StatinsLDL-C 18%–55%HDL-C 5%–15%TG 7%–30%

Major coronary events, CHD deaths, stroke, total mortality, and coronary procedures

Myopathy Liver enzymes

NiacinLDL-C 5%–25%HDL-C 15%–35%TG 20%–50%

Major coronary events Total mortality (possibly)

FlushingHyperglycemiaHyperuricemia (gout)Upper GI distressHepatotoxicity

Fibric acidsLDL-C 5%–20%a

HDL-C 10%–20%TG 20%–50%

Major coronary events

DyspepsiaGallstonesUnexplained CHD deaths (WHO study)

Bile acid sequestrants

LDL-C 15%–30%HDL-C 3%–5%TG No

Major coronary events and CHD deaths

GI distressConstipation Absorption of other drugs

aMay be increased in patients with high TGLDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides; WHO=World Health Organization; CHD=coronary heart disease; GI=gastrointestinalExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

5

Fibrates and Their Benefits on Management of Lipids

MOA Fibrates inhibit fatty acid synthesis in the liver and increase the elimination of TG-rich particles from plasma. They also increase the synthetic rate of HDL-C.

Efficacy TC:

TG: (by 25%–45%)

LDL-C: (by 10%–20%)

HDL-C: (by 10%–15%)

LDL-C/HDL-C:

VLDL:

apo B:

Side effects Abnormal liver function tests, dyspepsia, gallstones, myopathy

Indications Treatment of hypercholesterolemia, hypertriglyceridemia

Contraindications Hypersensitivity to fenofibrate, hepatic or severe renal dysfunction, preexisting gallbladder disease

MOA=mechanism of action; TG=triglycerides; HDL-C=high-density lipoprotein cholesterol; TC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; VLDL=very low-density lipoprotein cholesterol; apo B=apolipoprotein BYoung CE et al. Cardiol Rev. 2004;12:107–119; LOFIBRA® [package insert]; 2005.

6

Effects of Gemfibrozil on CHD Events: VA-HIT Trial

CHD=coronary heart disease; VA-HIT=Veterans Affairs HDL Intervention Trial; MI=myocardial infarctionRubins HB et al. N Engl J Med. 1999;341:410–418.

23%P=0.02

22%P=0.07

22%P=0.006

n=184 n=146 n=118 n=93 n=275 n=219

0

5

10

15

20

25

Nonfatal MI CHD Deaths Combined

CH

D E

ve

nts

, %

Placebo

Gemfibrozil

In a 5-year, randomized, double-blind placebo-controlled trial of 2531 CHD patients

7

5-Year Incidence of CHD Events and Lipid Levels: VA-HIT Trial

CHD=coronary heart disease; VA-HIT=Veterans Affairs HDL Intervention Trial; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterolReprinted with permission from Robins SJ et al. JAMA. 2001;285:1585–1591. Copyright © 2001, American Medical Association. All rights reserved.

Placebo

Gemfibrozil

5-Y

ea

r C

HD

Ev

en

t R

ate

, %

5-Y

ea

r C

HD

Ev

en

t R

ate

, %

5-Y

ea

r C

HD

Ev

en

t R

ate

, %

Quintile Trial Concentrations, mmol/L

Quintile Trial Concentrations, mmol/L

HDL-C Triglycerides

LDL-C

Quintile Trial Concentrations, mmol/L

10

13

16

19

22

25

0.50 1.00 1.50 2.00 2.50 3.00

10

13

16

19

22

25

2.00 2.40 2.80 3.20 3.60 4.00

10

13

16

19

22

25

0.60 0.70 0.80 0.90 1.00 1.10

8

Effects of Fibrates on Coronary End Points: Results of a Meta-analysis

-10

-5

0

5

10

15

20

25

30

MajorCoronaryEvents

CoronaryDeaths

CV Deaths Non-CVDeaths

All-CauseDeaths

Re

lati

ve

Ris

k R

ed

uc

tio

n,

%

NS=not significant; CV=cardiovascularBirjmohun RS et al. J Am Coll Cardiol. 2005;45:185–197.

P<0.001

53 trials/16,802 patientsusing fibrates or placebo

P=NSP=NS

P=NSP=NS

9

Cumulative Risk Curve of Time to First Event Showing Nonsignificant Risk Reduction in CHD Events—FIELD Study

CHD=coronary heart disease; FIELD=Fenofibrate Intervention and Event Lowering in Diabetes; MI=myocardial infarction; HR=hazard ratio; CI=confidence intervalFIELD study investigators. Lancet. 2005;366:1849–1861.

In a 5-year, randomized, placebo-controlled study of 9795 diabetic patients 50–75 years old, CHD events (nonfatal MI plus CHD death)

Numbers at risk

Placebo 4900 4835 4741 4646 4547 2541 837

Fenofibrate 4895 4837 4745 4664 4555 2553 850

PlaceboFenofibrate

HR 0.89 (95% CI 0.75–1.05)P=0.16

0

5

10

15

0 1 2 3 4 5 6

Time Since Randomization, Years

Cu

mu

lati

ve R

isk,

%

10

Challenges in Lipid Management

Niacin Effects on Lipids and Other Cardiovascular Disease (CVD) Risk Factors

11

Beneficial Effects of ER Niacin on Plasma Lipids, Lipoproteins, and Lp (a)

P<0.001 for all groupsER=extended release; TC=total cholesterol; TG=triglycerides; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; Lp (a)=lipoprotein (a)Adapted with permission from Carlson LA. J Intern Med. 2005;258:94–114; Morgan JM et al. Am J Cardiol. 1998;82:29U–34U.

-60

-40

-20

0

20

40

60

80

TC TG LDL-C HDL-C HDL HDL Lp (a)

Ch

an

ge

Fro

m B

as

eli

ne

, %

2 3

Effects of ER niacin 2 g/d (NIASPAN™ 2000 mg/d) on 31 dyslipidemic patients for 12 weeks

12

ER Niacin for Treatment of Dyslipidemia

-21

-28 -28

-6

-15-20

1723

28

-40

-30

-20

-10

0

10

20

30

40

1000 mg/d 2000 mg/d ≤3000 mg/d

Ch

an

ge

Fro

m B

as

eli

ne

, %

TG

LDL-C

HDL-C

12 weeks(N=96)

96 weeks (N=225)

All, significant change from baseline, P<0.001ER=extended release; TG=triglycerides; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterolMorgan JM et al. Am J Cardiol. 1998;82(12A):29U–34U; Capuzzi DM et al. Am J Cardiol. 1998;82(12A):74U–81U.

n=35

n=31

13

ER Niacin for Treatment of Dyslipidemia

-6

13

-24

-15

19

-31-40

-30

-20

-10

0

10

20

30

LDL-C HDL-C TG

Dif

fere

nc

e i

n P

lac

eb

o(A

dju

ste

d M

ea

n,

%)

1000 mg/d, n=35

2000 mg/d, n=31

12 weeks (N=96)

ER=extended release; TG=triglycerides; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterolMorgan JM et al. Am J Cardiol. 1998;82(12A):29U–34U.

Placebo-Adjusted ER Niacin:

14

Effects on HDL-C, LDL-C, and TG Levels of Niacin in Combination With Colestipol or Statins

-50

-40

-30

-20

-10

0

10

20

30

40

50

HDL-C LDL-C TG

Ch

an

ge

Fro

m P

retr

ea

tme

nt,

%

Colestipol (30 g/d), IR Niacin (3–12 g/d), n=94

Colestipol (15–30 g/d), IR Niacin (0.25–4 g/d), n=36

Fluvastatin (20 mg/d), IR Niacin (<3 g/d), n=38

Pravastatin (20 mg/d), IR Niacin (3 g/d), n=27

Lovastatin (20 mg/d), IR Niacin (1.5 g/d), n=14

Simvastatin (10–20 mg/d), SR Niacin (2 g/d), n=33

HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; TG=triglycerides; IR=immediate release; SR=slow releaseCarlson LA. J Intern Med. 2005;258:94–114; Blankenhorn DH et al. JAMA. 1987;257:3233–3240; Brown G et al. N Engl J Med. 1990;323:1289–1298; Jacobson TA et al. Am J Cardiol. 1994;74:149–154; O’Keefe JH Jr et al. Am J Cardiol. 1995;76:480–484; Gardner SF et al. Pharmacotherapy. 1996;16:419–423; Brown BG et al. N Engl J Med. 2001;345:1583–1592.

15

Effect of ER Niacin on the Distribution of LDL and HDL Subclasses

-46-40

26

-23

6

20

39

70

-50-57

19

-29

0

14

75

89

0.2

-10-1

-14

614

-6 -5

-75

-50

-25

0

25

50

75

100

L1 L2 L3 H1 H2 H3 H4 H5

Ch

an

ge

Fro

m B

as

eli

ne

, %

ER Niacin 1000 mg/dER Niacin 2000 mg/dPlacebo

L1 subclass represents highly atherogenic small dense LDL particles. H4 and H5 subclasses represent the cardioprotective HDL particlesER=extended release; LDL=low-density lipoprotein; HDL=high-density lipoprotein Reprinted from Am J Cardiol, Vol. 91, Morgan JM et al, Effects of extended-release niacin on lipoprotein subclass distribution, 1432–1436, Copyright 2003, with permission from Elsevier.

LDL Subclasses HDL SubclassesP=0.364 P=0.067 P=0.277 P=0. 778 P=0. 415 P=0. 996 P<0. 001 P<0. 001

In a 12-week, randomized, double-blind, placebo-controlled trial of 60 primary hypercholesterolemic patients

16

Plasma Levels of LP-A1 During Treatment With ER Niacin or Gemfibrozil

50

60

70

80

90

100

110

120

130

140

0 7 11 19

Weeks of Treatment

Ba

se

lin

e,

%

ER Niacin

Gemfibrozil

aP<0.01 vs week 0bP<0.01cP=<0.05 for niacin and gemfibrozil at each time pointER=extended releaseTo convert HDL from mg/dL to mmol/L, multiply by 0.0259Adapted from Sakai T et al. Arterioscler Thromb Vasc Biol. 2001;21:1783–1789.

a,ba,b,c

a,b

a

In a 19-week, randomized, double-blind trial of 139 patients with HDL less than 1.04 mmol/L

17

Effect of ER Niacin vs Gemfibrozil on Lipid Parameters

-60

-40

-20

0

20

40

HDL-C LDL-C TG

ER=extended release; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; TG=triglycerides; apo A-1=apolipoprotein A-1; Lp (a)=lipoprotein (a)Adapted with permission from Guyton JR et al. Arch Intern Med. 2000;160:1177–1184. Copyright © 2000, American Medical Association. All rights reserved.

-25

-20

-15

-10

-5

0

LDL-C/HDL-C TG/HDL-C

ER Niacin 2000 mg

Gemfibrozil 600 mg BID

Ch

ang

e F

rom

Bas

elin

e, %

-15

-10

-5

0

5

10

15

apo A-1 apo B

-30

-20

-10

0

10

20

Lp (a) Fibrinogen

P<0.001

P=0.004P=0.02

P=0.001

P=0.06

P<0.001 P=0. 005

P=0.01

P<0.001

In a randomized, double-blind trial of 173 patients 21–75 years old

18

Challenges in Lipid Management

Niacin Mechanism of Action

19

Niacin Acts Through Nicotinic Acid Receptors on Multiple Tissues

Adipocytes Immune Cells (Spleen, Lymphoid Cells, Lung)

Epidermal Langerhans’ Cells

Niacin

Antilipolytic effects

Probableantiinflammatory

effectPLA2

Arachidonic acid

PGD2

GPR109A

Flushing

NiacinNiacin

PLA2=phospholipase A2; PGD2=prostaglandin D2

Adapted from Pike NB. 2005;115:3400–3403. Journal of Clinical Investigation. Online by Pike. Copyright 2005 by American Society for Clinical Investigation. Reproduced with permission of American Society for Clinical Investigation in the format presentation via Copyright Clearance Center; Yu BL et al. Med Hypotheses. 2007;69:90–94.

20

HDL-C Removes CE From Peripheral Tissues in a Process Called Reverse Cholesterol Transport

ABCA1

Macrophage

CE

FC

11HDL2 HDL3 Nascent

HDL-C

HDL pathway

apo A-1apo A-1apo A-1

apo A-2 apo A-2

LCATLCAT

22

CE

VLDLIDLLDL-C

Non–HDL-C pathway

apo B apo B apo B

CE

TG

CETP

3Bile acids

and cholesterols

Bile

5

HDL-C=high-density lipoprotein cholesterol; CE=cholesteryl esters; FC=free cholesterol; ABCA1=adenosine triphosphate-binding cassette transporter A1; SR-BI=scavenger receptor class B type I; apo A-1=apolipoprotein A-1; LCAT=lecithin-cholesterol acyltransferase; CETP=cholesteryl ester transfer protein; TG=triglycerides; LDL-C=low-density lipoprotein cholesterol; IDL=intermediate density lipoprotein; VLDL=very low-density lipoprotein; LDL-R=LDL receptorReprinted from Drug Discov Today, Vol. 10, Brousseau ME, Emerging role of high-density lipoprotein in the prevention of cardiovascular disease, 1095–1101, Copyright 2005, with permission from Elsevier.

4

Liver

CEFC

CE

LDL-R

4

SR-BI

21

Niacin Significantly Increases Cholesterol Exporter ABCA1

aP<0.05bP<0.01 ABCA1=adenosine triphosphate-binding cassette transporter A1; SEM=standard error of mean; dHDL=delipidated HDLReprinted from Biochem Pharmacol, Vol. 67, Rubic T et al, Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin, 411–419, Copyright 2004, with permission from Elsevier.

0

50

100

150

200

250

300

Control Niacin

Co

ntr

ol

(SE

M),

%

3 h

48 h

0

20

40

60

80

100

120

Co

ntr

ol

(SE

M),

%

Baseline After Exposure to:

dHDL Niacin Both

a

aa

b

b

ABCA1 Cellular Cholesterol Content

22

Niacin and Reverse Cholesterol Transport

Bile acidsand cholesterols

Bile

HDL2 HDL3 Nascent HDL-C

HDL pathway

CE

Liver

CEFC

CE

ABCA1

Macrophage

VLDLIDLLDL-C

Non–HDL-C pathway

CE

FC

apo A-1apo A-1apo A-1

apo A-2 apo A-2

LCATLCAT

SR-BI

LDL-R

apo B apo B apo B

CE

TG

CETP

11

22

3

4

4

5

Nascent HDL-C

Nascent HDL-C

Niacinapo A-1

apo A-1

HDL-C=high-density lipoprotein cholesterol; CE=cholesteryl esters; FC=free cholesterol; ABCA1=adenosine triphosphate-binding cassette transporter A1; SR-BI=scavenger receptor class B type I; LDL-R=LDL receptor; apo A-1=apolipoprotein A-1; LCAT=lecithin-cholesterol acyltransferase; CETP=cholesteryl ester transfer protein; TG=triglycerides; LDL-C=low-density lipoprotein cholesterol; IDL=intermediate density lipoprotein; VLDL=very low-density lipoproteinReprinted from Drug Discov Today, Vol. 10, Brousseau ME, Emerging role of high-density lipoprotein in the prevention of cardiovascular disease, 1095–1101, Copyright 2005, with permission from Elsevier; Rubic T et al. Biochem Pharmacol. 2004;67:411–419; McKenney J. Am J Health-Syst Pharm. 2003;60:995–1005.

23

Effects of Niacin on Lipoprotein Metabolism Summary

Partial inhibition of release of FFAs from adipose tissue, leading to a decrease in TG synthesis by the liver

– Decreased TG synthesis reduces the synthesis of VLDL, the precursor of LDL-C, and eventually decreases LDL-C

Inhibition of synthesis of apo B, which is needed for the formation of VLDL particles and enhanced VLDL catabolism

Favorable LDL particle size transformation, with shift from small, dense to large, bouyant particles

Reduced extraction and catabolism of apo A-1 from HDL-C, maintaining structure and function of HDL-C particles

Stimulation of the expression of membrane cholesterol transporter ABCA1

FFAs=free fatty acids; TG=triglyceride; VLDL=very low-density lipoprotein; LDL-C=low-density lipoprotein cholesterol; apo B=apolipoprotein B; apo A-1=apolipoprotein A-1; HDL-C=high-density lipoprotein cholesterol; ABCA1=adenosine triphosphate-binding cassette transporter A1McKenney J. Am J Health-Syst Pharm. 2003;60:995–1005; Carlson LA. J Intern Med. 2005;258:94–114.

24

Antiinflammatory Actions of ER Niacin That May Be Beneficial Against Atherosclerosis

Emerging clinical studies suggest that ER niacin may reduce inflammation by a variety of mechanisms unrelated to its antiatherosclerotic lipid-altering effects

ER niacin appears to attenuate overexpression of NOS

ER niacin has been shown to reduce plasma CRP levels

ER niacin has been shown to decrease levels of lipoprotein-associated phospholipase A2

ER niacin has been shown to increase levels of the antiinflammatory adipokine, adiponectin

ER=extended release; NOS=nitric oxide synthase; CRP=C-reactive proteinYu BL et al. Med Hypotheses. 2007;69:90–94.

25

Randomized Controlled Clinical Trials of Nicotinic Acid and Effect on HDL-C and Atherosclerosis

Nicotinic Acid and Atherosclerosis: A Positive Effect in Imaging Studies

SourceImaging Studies

Special Agent(s)

Patients Receiving Treatment n/Total (%)

Increase in HDL-C Levels

%

Follow-up

Duration y Outcomesa

CLAS I Niacin + colestipol 94/188 (50.0) 37 2 Decreased coronary atherosclerosis

CLAS II Niacin + colestipol 75/138 (54.3) 37 4 Decreased coronary atherosclerosis

FATS Niacin + colestipol 48/146 (32.9) 43 2.5 Decreased coronary atherosclerosis;Decreased death, MI, or revascularization (secondary outcome)

CLAS Fem Niacin + colestipol 80/162 (49.4) 38 2 Decreased femoral atherosclerosis

CLAS IMT Niacin + colestipol 39/78 (50.0) 38 4 Decreased carotid IMT (regression also observed at 1 and 2 y)

SCRIP Niacin + colestipol + gemfibrozil + lovastatin + aggressive lifestyle modification

145/300 (48.3) 12 4 Decreased coronary atherosclerosis; Decreased frequency of new coronary lesion formation

ARBITER 2 Niacin + statin 87/167 (52.1) 21 1 Decreased carotid IMT (P>0.05)

ARBITER 3 Niacin + statin 87/167 (52.1) 23 2 Decreased carotid IMT

ARBITER=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; CLAS=Cholesterol-Lowering Atherosclerosis Study; CLAS Fem=femoral atherosclerosis group of CLAS; CLAS IMT=carotid ultrasound group of CLAS; FATS=Familial Atherosclerosis Treatment Study; HDL-C=high-density lipoprotein cholesterol; IMT=intima-media thickness; MI=myocardial infarction; SCRIP=Stanford Coronary Risk Intervention ProjectaDeath indicates all-cause mortality

Adapted with permission from Singh IM et al. JAMA. 2007;298:786–798. Copyright © 2007, American Medical Association. All rights reserved.

26

CLAS: Changes in Carotid Artery Intima-Media Thickness

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

0.08

Year 2 vs Baseline Year 4 vs Baseline Year 4 vs Year 2

Me

an

Ch

an

ge

, m

m

Placebo, n=22

Niacin + Colestipol, n=24

aVs drug groupCLAS=Cholesterol-Lowering Atherosclerosis StudyBlankenhorn DH et al. Circulation. 1993;88:20–28.

P<0.0001a

P<0.0001a

P=0.06a

In a randomized, placebo-controlled angiographic trial of 188 nonsmoking men with progressive atherosclerosis

27

Average Changes in Coronary Artery Stenosis With 3 Treatment Regimens: FATS

2.01.1

2.2

-0.3

-2.6

0.4

-1.1

-6.4

0.1

-8

-6

-4

-2

0

2

4

All Lesions Lesions ≥50% Lesions <50%

Ch

an

ge

, %

ConventionalLovastatin-colestipolNiacin-colestipol

FATS=Familial Atherosclerosis Treatment StudyConventional therapy = diet + counseling, and colestipol if HDL-C was elevatedBrown G et al. N Engl J Med. 1990;323:1289–1298.

28

ARBITER 2: The Effect of a Combination of ER Niacin With Statin on CIMT Was Superior to Statin Alone

0.00

0.02

0.04

0.06

0.08

0.10

Statin + Placebo Statin + ER Niacin

Ch

ang

e in

CIM

T,

mm

± S

EM

0.044 mm(P<0.001)

0.014 mm(P=0.23)

ARBITER 2=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; ER=extended release; CIMT=carotid intima-media thickness; SEM=standard error of meanReprinted with permission from Taylor AJ et al. Circulation. 2004;110:3512–3517.

N=167

29

Nicotinic Acid and Atherosclerosis: A Positive Effect on Clinical Outcomes

Randomized Controlled Clinical Trials of Nicotinic Acid and Effect on HDL-C and Clinical Outcomes

SourceClinical

Outcome Studies

Special Agent(s)

Patients Receiving Treatment n/Total (%)

Increase in HDL-C Levels

%

Follow-up Duration

y Outcomesa

CDP Niacin 1119/8341 (13.4) NR 6 Decreased (27%) nonfatal MI

CDP follow-up

Niacin 1119/8341 (13.4) NR 15 Decreased (11%) death

Stockholm Niacin + clofibrate

279/555 (50.3) NR 5 Decreased (26%) death; decreased (36%) CAD death

HATS Niacin + simvastatin

38/160 (23.8) 26 3 Decreased (90%) first death, MI, stroke, or revascularization

AFREGS Niacin + gemfibrozil + cholestyramine

71/143 (49.7) 36 2.5 Decreased (13%) composite clinical outcome of angina, MI, TIA, stroke, death, and cardiovascular procedures; decreased focal coronary stenosis (secondary outcome)

HDL-C=high-density lipoprotein cholesterol; CDP=Coronary Drug Project; Stockholm=Stockholm Ischemic Heart Disease Secondary Prevention Study; HATS=HDL Atherosclerosis Treatment Study; AFREGS=Armed Forces Regression Study; NR=not reported; MI=myocardial infarction; CAD=coronary artery disease; TIA=transient ischemic attackaDeath indicates all-cause mortality

Adapted with permission from Singh IM et al. JAMA. 2007;298:786–798. Copyright © 2007, American Medical Association. All rights reserved.

30

CDP: 15-Year Follow-up

Mortality for a Mean Follow-up of 15 Years in Niacin 3 g/d and Placebo Groups

CDP=Coronary Drug ProjectCanner PL et al. J Am Coll Cardiol. 1986;8:1245–1255.

58.2

52.0

48

50

52

54

56

58

60

Placebo Niacin

Mo

rta

lity

, %

11%P=0.0004

n=2789 n=1119

31

HATS—Niacin and Statin Outcome Trial

aComposite of coronary death, nonfatal MI, revascularization, hospitalization for confirmed ischemiaHATS=HDL Atherosclerosis Treatment StudyBrown BG et al. N Engl J Med. 2001;345:1583–1592.

12

1

11

6

0

2

4

6

8

10

12

14

Placebo Simvastatin-Niacin

AntioxidantVitamins

Simvastatin-Niacin Plus

Antioxidants

Ev

en

ts,

n

P=0.003vs Placebo

a

n=38 n=38 n=42 n=42

32

ARBITER 2—The Effect of Niacin Plus Statin on CHD Events (Secondary End Point)

aComposite clinical cardiovascular eventsARBITER 2=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; CHD=coronary heart disease; ER=extended releaseAdapted from Taylor AJ et al. Circulation. 2004;110:3512–3517.

9.6

3.8

0

2

4

6

8

10

12

Statin + Placebo Statin + ER Niacin

Ca

rdio

va

sc

ula

r E

ve

nts

, %

a

n=71 n=78

33

Niacin Side Effects

Challenges in Lipid Management

34

Major Side Effects of Niacin

ER=extended releaseCarlson LA. J Intern Med. 2005;258:94–114; Niaspan® [package insert]; 2007.

A temporary, dose-dependent skin flush—pronounced cutaneous vasodilation—induced by niacin occurs shortly after oral dosing– The niacin flush is thought to be the side effect that has limited

niacin’s clinical use

An increase in plasma uric acid levels is also seen regularly during niacin treatment– This effect is most clinically significant in patients with joint

problems and/or high pretreatment urate levels

Gastrointestinal side effects (gastritis-like) may occur in patients taking niacin

Other adverse events that have been reported with ER niacin in ≥5% of patients include– Headache – Rhinitis – Rash

– Pain (myalgia) – Pruritis

35

ER Niacin—Contraindications and Warnings

ER=extended release; IR=immediate release; HMG-CoA=hepatic hydroxymethyl glutaryl coenzyme ANiaspan® [package insert]; 2007.

Contraindicated in patients with

– Known hypersensitivity to niacin or its components

– Significant or unexplained hepatic dysfunction

– Active peptic ulcer disease

– Arterial bleeding

Warnings

– ER niacin should not be substituted for equivalent doses of IR niacin

– Cases of severe hepatic toxicity have occurred in patients substituting sustained release niacin products for IR niacin at equivalent doses

– Patients should be warned against substantial quantities of alcohol intake

– ER niacin should be used with caution in patients with a past history of liver disease

– Liver tests should be performed on all patients during therapy

– Rare cases of rhabdomyolysis have been associated with concomitant administration of niacin and HMG-CoA reductase inhibitors

36

Effect of ER Niacin on Glycemic Control in Diabetes Mellitus

0

2

4

6

8

10

Placebo ER Niacin 1000 mg/d ER Niacin 1500 mg/d

Baseline Week 4 Week 8 Week 12 Week 16aP=0.05ER=extended release; HbA1C=glycosylated hemoglobinReprinted with permission from Grundy SM et al. Arch Intern Med. 2002;162:1568–1576. Copyright © 2002, American Medical Association. All rights reserved.

Hb

A1C

, %

a

n=49 n=45 n=52

37

Summary

Niacin decreases FFA release and stimulates RCT, resulting in decreased triglycerides and LDL-C and increased HDL-C

Niacin also favorably affects HDL and LDL particle size and has antiinflammatory effects

These varied effects make niacin unique in its ability to broadly modify lipoprotein levels in a way that is beneficial for CVD risk

An important drawback to niacin use is the skin flush that occurs in some patients shortly after dosing

FFA=free fatty acid; RCT=reverse cholesterol transport; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CVD=cardiovascular disease

38

Bibliography

39

Bibliography (continued)

40

Challenges in Lipid Management

Before prescribing, please consult the manufacturers’ prescribing information.

Merck does not recommend the use of any product in any different manner than as described

in the prescribing information.

Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA.

All rights reserved. 12-08 M524A-2007-W-1245907-SS Printed in USA

VISIT US ON THE WORLD WIDE WEB AT WWW.MERCK.COM

41

Back-up

42

Beneficial Effects of Niacin on Plasma Lipids, Lipoproteins, and Lp (a)

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

C TG VLDL LDL-C HDL-C HDL HDL Lp (a)

Effects of niacin 4 g/d on 31 dyslipidemic patients for 6 weeks

C=cholesterol; TG=triglycerides; VLDL=very low-density lipoprotein; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; Lp (a)=lipoprotein (a)Adapted from Carlson LA. J Intern Med. 2005;258:94–114.

Incr

ease

, %

Dec

reas

e, %

9.0 3.0 1.4 6.2 1.1 0.4 0.7 232Mean Pretreatment Levels

2 3