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Efficacy of Extended-Release Niacin
HDL-C
Change from Baseline
30
20
10
10%
0
–3%
-10
-20
–5%
-30
22%
–9%
–14% –17%
–12%
–22%
–17%
–11%
–24%
–28%
-40
-50
15%
500
mg
26%
30% 29.5%
–30%
–35%
–39%
–21%
LDL-C
Lp(a)
–26%
–44%
TG
1000 1500 2000 2500 3000
mg
mg
mg
mg
mg
Goldberg A et al. Am J Cardiol 2000;85:1100-1105.
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Addition of Extended-Release Niacin
to a Statin because of Persistently
Low HDL-C
30
20
10
0
-10
-20
-30
TC
LDL-C
HDL-C
Wolfe ML et al. Am J Cardiol 2001;87:476-479.
Copyright ©2001, Excerpta Medica Inc. Reprinted with permission.
TG
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HDL-Atherosclerosis Treatment Study (HATS)
Niacin and Statin Outcome Trial
25
23.7
89%
Reduction
21.4
*P<.05
vs Placebo
20
14.3
15
10
2.6*
5
0
Placebo
S+N
AV
S + N + AV
Coronary Death, MI, Stroke, or Revascularization
Brown BG et al. N Engl J Med 2001;345:1583-1592.
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What treatment would you
recommend?
A. Atorvastatin 10 mg/day
B. Colesevelam 3.8 gr/day
C. Ezetimibe 10 mg qd
D. Niacin extended-release 1000 mg/day
E. Statin (other than atorvastatin)
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What is the next treatment option?
A. Increase atorvastatin to 40 mg/day
B. Add colesevelam 3.8 gr/day
C. Add ezetimibe 10 mg qd
D. Add extended-release niacin 1000
mg/day
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What is the next treatment option?
 Increase rosuvastatin to 40 mg
 Add colesevelam 3.8 gr
 Add ezetimibe 10 mg
 Add extended-release niacin 1000 mg
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Change from Baseline
(%)
Lipid Effects of Niacin ExtendedRelease (ER)
30
20
10
0
-10
-20
-30
-40
-50
HDL-C
10
-3
-5
-8
-12
-13
-17
-14
-21
29
-22
-21
24
21
16
30
-16
-25
-32
-30
-39
500
1000
1500
 Lipid effects
2000
mg
2500
LDL-C
Lp(a)
-26
-44
TG
3000
– Most potent agent for  HDL: 20%+; nonlinear
– Favorable effects on LDL-particle density
–  LDL (linear), TG, and Lp(a)
 Tolerability with concomitant statin therapy
– No change in rate of liver adverse effects or myositis versus statin
monotherapy
Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U.
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Cumulative % of Patients
Flushing Episodes per Patient:
Niacin IR versus Niacin ER
100
90
80
70
60
50
40
30
20
10
0
Niacin IR (n=76)
Niacin ER (n=74)
 ~ 28% of patients
never flushed
 ~ 50% of patients
flushed 3 times
 ~ 80% of patients
flushed 6 times
0
5
10
15
20
25
30
35
40
45
50
Number of Flushes
Kos Pharmaceuticals, Inc. Data on file, 2003.
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Effect of Niacin ER on Lipids and
Glycemic Control in Diabetes
Mellitus: ADVENT
*P=.048
*
8
Hb A1C (%)
7
6
5
4
3
2
1
0
Placebo
Baseline
Week 4
Niacin ER 1 g
Week 8
Grundy SM et al. Arch Intern Med 2002;162:1568-1576.
Niacin ER 1.5 g
Week 12
Week 16
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ARBITER 2
 Objective
– Compare effects of niacin ER 1000 mg/d with
placebo on carotid intima–media thickness
(primary endpoint) over 12 months
 Study population
– Patients with known CHD with good LDL-C on
statin therapy
 Design
– Randomized, double-blind, placebo-controlled,
single-center, investigator-initiated study
 Timeline
– Enrollment: December 2001 through May 2003
– Final follow-up: May 2004
Taylor AJ et al. Circulation 2004;110:3512-3517.
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ARBITER 2: Baseline Characteristics
Placebo
(n=80)
Niacin ER
(n=87)
Male, n (%)
74 (93)
78 (90)
Age, y, mean ± SD
68 ± 10
67 ± 10
Hypertension, n (%)
61 (76)
64 (74)
Tobacco use, n (%)
5 (6)
12 (14)
Diabetes mellitus, n (%)
22 (28)
24 (28)
Metabolic syndrome, n (%)
42 (53)
42 (49)
80 (100)
87 (100)
Myocardial infarction
42 (53)
41 (47)
Percutaneous coronary revascularization
35 (44)
42 (49)
Coronary artery bypass
28 (35)
40 (46)
Angina with documented ischemia
27 (34)
26 (30)
Coronary heart disease, n (%)
P=NS for all.
Taylor AJ et al. Circulation 2004;110:3512-3517.
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ARBITER 2: Baseline Therapies
Medication, n (%)
unless noted
Placebo
(n=80)
Niacin ER
(n=87)
80 (100%)
87 (100%)
36 ± 22
34 ± 19
Beta-blocker
63 (79%)
69 (79%)
ACE inhibitor
42 (58%)
54 (62%)
Aspirin
68 (85%)
75 (86%)
Vitamin E
14 (18%)
22 (25%)
Vitamin C
8 (10%)
10 (12%)
Statin [simvastatin 93%]
Mean statin dose, mg
P=NS for all.
Taylor AJ et al. Circulation 2004;110:3512-3517.
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ARBITER 2: Lipid and CRP Values
Mean 
SD;
mg/dL
unless
noted
Baseline
Placebo
Niacin
ER
71
78
LDL-C
91  22
87  17
HDL-C
40  7
TG
12 Months
Placebo
Niacin
ER
71
78
NS
86  20
39  7
NS
172 
104
154 
82
NonHDL-C
121 
27
hs-CRP,
mg/L
3.0 
4.7
n
P (baseline vs
12 months)
P
Placebo
Niacin
ER
85  25
NS
NS
NS
40  9
47  16
.002
NS
<.001
NS
164 
83
134 
87
.03
NS
.009
115 
26
NS
115 
21
107 
34
NS
.03
.02
3.8 
4.3
NS
3.5 
4.7
4.0 
5.8
NS
NS
NS
P
Taylor AJ et al. Circulation 2004;110:3512-3517.
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Change in CIMT
(mm ± SEM)
ARBITER 2:  CIMT at 12 Months
versus Baseline
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
Within-Group
Comparison
0.044 mm
(P<.001)
Statin + Niacin ER
 Safe
 Flushing common,
occurred in 2/3 of
patients
0.014 mm
(P=.23)
 Adherence >90%
Statin +
Niacin ER
Statin +
Placebo
Between-group comparison: P=.08, intent-to-treat analysis of
placebo > niacin ER, P=.048.
Taylor AJ et al. Circulation 2004;110:3512-3517.
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 Composite clinical event
endpoint
– Unstable angina/MI
hospitalization
– Stroke
– Sudden cardiac death
– Percutaneous coronary
revascularization,
CABG, or peripheral
revascularization
Taylor AJ et al. Circulation 2004;110:3512-3517.
Patients with Event (%)
ARBITER 2: Secondary Efficacy
Endpoint—Clinical Events
12
10
9.6
 60%
8
P = .20
6
3.8
4
2
0
Statin +
Placebo
Statin +
Niacin ER
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ARBITER 2: Subgroup Changes in
CIMT
 Placebo
Placebo
Change in CIMT (mm  SEM)
.065
.055
P <.05
for all
Niacin ER
P = NS
for all
– Significant CIMT progression
in normal, MS, and DM
 Niacin ER
– No significant CIMT
.045
progression in normal, MS,
and DM
.035
– Effect in subgroups similar to
.025
all niacin ER–treated patients
.015

.005
– Less CIMT progression in all
-.005
-.015
-.025
Potential lesser effect in MS
and DM explained by worse
cardiovascular risk profiles?
Normal
(n=70)
MS (n=51)
DM (n=46)
Taylor AJ et al. J Am Coll Cardiol 2005;45:3A.
subgroups vs placebo

Normal: 109% (P < 0.05)

MS: 33% (P = NS)

DM: 53% (P = NS)
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ARBITER 2: Baseline Measured CV
Risk Variables
 Worse CV risk profile of metabolic syndrome
– Lower HDL-C, higher BP than normal or DM
Normal
MS
DM
70
51
46
LDL-C, mg/dL
91  21
85  15
89  24
NS
HDL-C, mg/dL
43  6
35  4
40  7
<.001
131  62
181  99
188  104
96  12
101  11
130  44
<.001
Systolic BP, mm Hg
127  19
141  20
135  23
.001
Diastolic BP, mm Hg
73  12
78  12
71  14
.012
30.6  6.2
.005
N
TG, mg/dL
Blood glucose, mg/dL
Body mass index, kg/m2 27.8  5.7 30.8  5.3
Taylor AJ et al. J Am Coll Cardiol 2005;45:3A.
P
.001
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ARBITER 2: Multivariate Linear
Regression—Changes in CIMT and HDL-C
Independent variable: CIMT
 In a similar
Partial
Correlation
P
Change in HDL-C
–.16
.05
Gender
–.09
.29
Waist girth
–.08
.33
.09
.27
–.12
.15
.04
.61
–.01
.87
SBP
Baseline HDL-C
Baseline TG
Baseline blood glucose
Taylor AJ et al. J Am Coll Cardiol 2005;45:3A.
model limited
to participants
with metabolic
syndrome,
baseline blood
glucose was
directly related
to CIMT
 R = 0.30
 P = .04
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ARBITER 2: Conclusions
 Statin monotherapy: significant progression of IMT
 Combination therapy with statin + niacin ER 1000 mg/d
– Slowed IMT progression among individuals with

Known CHD

Well-controlled LDL-C (<100 mg/dL)

Moderately low HDL-C (40 mg/dL)
 First clinical trial to show:
– Superiority of combination therapy over
monotherapy for a validated surrogate endpoint
– Incremental benefit of adding niacin ER to existing
statin therapy
Taylor AJ et al. Circulation 2004;110:3512-3517.
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ARBITER 2: Conclusions
 Greater increases in HDL-C independently
associated with superior effects on CIMT
 Metabolic syndrome:
– Effect of  HDL-C may be blunted in
setting of poorly controlled risk factors

Highlights need to control all lipid and
nonlipid risk factors concurrent with
efforts to increase HDL-C
Taylor AJ et al. Circulation 2004;110:3512-3517.
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ARBITER 3:  CIMT at 24 Months
after Open-Label Conversion to
Niacin ER 1 g qhs
 N=130
0.08
– Additional 12-
0.06
CIMT Change (mm)
month open-label
observation period
– Total 24 months
– 104 patients
completed year 2
 Laboratory results
– HDL-C  total 9.5
mg/dL
– LDL-C 81 mg/dL
– No glycemic effects
*
*P < 0.05
vs baseline
0.04
0.02
0.00
-0.02
-0.04
Placebo/niacin ER
-0.06
-0.08
Niacin ER/niacin ER
Baseline
Taylor AJ et al. Circulation 2005;112:II-179.
P
R
O
G
R
E
S
S
I
O
N
R
E
G
R
E
S
S
I
O
N
12 months 24 months
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Take-Home Points
 Niacin
– Most potent drug currently available to HDL-C
– Niacin ER better tolerated than niacin IR
 Niacin and coronary risk
– Niacin alone: effective
– Combined niacin/statin therapy: highly effective
– Added value over statin monotherapy now shown
for first time in ARBITER 2
 Atherosclerosis progression
 Benefit directly related to increase in HDL-C
 More data in ARBITER 3
 CHD outcomes data next
 AIM-HIGH: NHLBI/Kos–cosponsored trial
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What other advice do you recommend?
A. Add extended release niacin
B. Consider LDL apheresis
C. Lipid screening on her two children
D. Add Vitamin E 400-800 units/day
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Extended-Release Niacin and Lovastatin:
Long-Term Study
50
41
40
26
Change (%)
30
20
10
0
-10
11
−2
−10
−16
Week 0
−16
−27
−25
−25
−41
−42
−34
−25
−34
-40
-50
HDL-C
18
-20
-30
30
−47
−41
4
500/10
(n=753)
8
1000/20
(n=706)
12
1500/30
(n=676)
16
2000/40
(n=655)
−45
Lp(a)*
TG
LDL-C
52
2000/40
(n=226)
*N = ~200; point at week 16 is extrapolated
HDL-C=high-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); TG=triglyceride;
LDL-C=low-density lipoprotein cholesterol
Kashyap ML, et al. Am J Cardiol. 2002;89:672–678.
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AIM - HIGH
 Patients: 3,300 men and women with vascular disease and
HDL-C <40 and 50 mg/dL, respectively; TG 150–400; and LDLC <180 mg/dL, 3–5-year follow-up
 Centers: 90 centers (~36 patients per center) in US and
Canada (20%)
 Funding: NHLBI, Kos (Abbott) Pharmaceuticals
 Therapy: Simvastatin vs. Simvastatin + Extended-release
niacin
 Primary Endpoint: Coronary heart disease death, myocardial
infarction, stroke, or high-risk acute coronary syndrome
hospitalization
AIM-HIGH=Atherothrombosis Intervention in Metabolic Syndrome with Low
HDL/High Triglycerides and Impact on Global Health Outcomes
ClinicalTrials.gov Web site. Available at:
http://clinicaltrials.gov/ct/show/NCT00120289.
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ARBITER 3:
Changes in CIMT – Pooled, 12-Month Data

Aggregate Change in CIMT for
All Drug Periods (mm)
0.075
Overall CIMT
regression
0.05
ANOVA p<0.001

0.025
−0.027 ± 0.011
−0.041 ± 0.021
0
-0.025

-0.05
Mean ± SEM
-0.075
Placebo
Phase
(+ Statin)
First 12 mos. Total 24 mos.
ERN (+ statin)
ERN
Treatment Period (+ statin)
Placebo + statin phase
 n = 61
 Significant CIMT progression
Initial 12 months ERN + statin
 n = 125
 Pooled ARBITER 2 and 3
results
 Net CIMT regression
 −0.027 ± 0.011 mm
 p<0.001 vs.
placebo
24 month ERN + statin effect
 n = 57
 Continuous ERN treatment
 CIMT regression
 −0.041 ± 0.021 mm
 p<0.001 vs. placebo
CIMT = carotid intima-media thickness; ERN = extended-release niacin
Reprinted from Taylor AJ, et al. Curr Med Res Opin. 2006;
22:2243–2250, with permission from Informa Healthcare.
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MK-0524 (laropiprant) Suppresses
Niacin-Induced Increases in Skin Blood Flow
1.4
9
Laser Doppler Perfusion Imaging
Placebo-Corrected LDPI
Measurement (Volt)
1.2
Laropiprant 30mg + ER niacin 1500 mg
Laropiprant 100 mg + ER niacin 1500 mg
Laropiprant 300 mg + ER niacin 1500 mg
Aspirin 325 mg Pretreatment + ER niacin 1500 mg
ER niacin 1500 mg
1
0.8
0.6
0.4
0.2
0
2
0
0
30
60
90
120 150
180 210 240
270 300
330 360
Time (minute, post dose)
ER = extended release
Reprinted from Lai E, et al. Clin Pharmacol Ther. 2007;81:
849-857, with permission from Nature Publishing Group.
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Kathy Berra, MSN, ANP, FAAN,
illustrates the importance of
educational resources as a follow-up
to the counseling process . . .
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Statins and Other Lipid-Modifying Therapies:
Results from the COMPELL Study
Atorvastatin 40/Niacin ER 2000
Simvastatin/Ezetimibe 40/10 mg
Rosuvastatin 20/Niacin ER 1000
Rosuvastatin 40 mg
25
Change from Baseline
At 12 Weeks
20
15
10
5
0
High-Density Lipoprotein Cholesterol
COMPELL = Comparative Effects on Lipid Levels of Combination Therapy With a Statin
and Extended Release Niacin or Ezetimibe Versus a Statin Alone; ER = extended release
Created from McKenney JM, et al. Atherosclerosis. 2007;19:432-437.
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Niacin: Efficacy
 In patients with mixed dyslipidemia, niacin has been
shown to:
– Decrease LCL-C levels by 5% to 25%
– Increase HDL-C levels by 15% to 35%
– Decrease triglyceride levels by 20% to 50%
 The effects of niacin on lipids are dose-related
– 1,500 mg/day is typically required for an
appreciable beneficial effect
HDL-C = high-density lipoprotein cholesterol;
LDL-C = low-density lipoprotein cholesterol
Adult Treatment Panel III. Circulation. 2002;106:3143–3421. |
Grundy SM, et al. Arch Intern Med. 2002;162:1568–1576.
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SEACOAST I Efficacy End Points at 24 Weeks
*
Median % Change from Baseline
30
*
S20
N/S 1000/20
24.9
18.3
20
10
N/S 2000/20
6.7
*Superior to S20; P < 0.05 versus S20
0
-4.0
-10
-7.1
-7.4
-13.1 -14.2
-13.9
-20
-7.6
*
-13.8
-15.3
*
-22.5
-30
*
-16.7
*
-25.0
-26.5
*
*
*
-40
-18.1
-38.0
Non–HDL-C
LDL-C
HDL-C
TG
*
Lp(a)
Apo B
Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density
lipoprotein cholesterol; Lp(a) = lipoprotein (a); TG = triglycerides
Reprinted in a slightly modified form from Ballantyne CM et al. Am J
Cardiol 2008;101:1428–1436, with permission from Elsevier Limited.
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