Download Effects of Laropiprant on Nicotinic Acid

Effects of Laropiprant on Nicotinic Acid-Induced Flushing
in Patients With Dyslipidemia†
John F. Paolini, MD, PhDa,*, Yale B. Mitchel, MDa, Robert Reyes, BAa, Uma Kher, PhDa,
Eseng Lai, MD, PhDa, Douglas J. Watson, PhD, MSPHb, Josephine M. Norquist, MSb,
Alan G. Meehan, PhDa, Harold E. Bays, MDc, Michael Davidson, MDd,
and Christie M. Ballantyne, MDe
Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated
primarily by prostaglandin D2, which leads to poor patient compliance and suboptimal
dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin
D2 receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release
niacin (ERN)–induced flushing in dyslipidemic patients and (2) support a novel accelerated
ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the
study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a
9-week, 2-period crossover study. Patients who completed part A (n ⴝ 122) entered part B
(after a 2-week washout), together with additional patients who entered part B directly (n
ⴝ 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous
titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks,
with doubling of the respective doses for the remaining 4 weeks. Patients treated with
LRPT plus ERN experienced significantly less ERN-induced flushing than those treated
with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance
treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in
inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN.
LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERNinduced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients. © 2008 Elsevier
Inc. All rights reserved. (Am J Cardiol 2008;101:625– 630)
Elevated low-density lipoprotein (LDL) cholesterol is a
key risk factor for atherosclerotic coronary heart disease.
Statins reduce coronary heart disease mortality by approximately 1/3. To further reduce the residual coronary
heart disease event risk in dyslipidemic patients, the
regulation of other lipid parameters beyond low-density
lipoprotein cholesterol alone may be of benefit. Niacin
(nicotinic acid) lowers low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a), and it is the most
effective agent approved for increasing high-density lipoprotein cholesterol levels.1 As monotherapy or in combination with other lipid-altering agents, niacin reduces
cardiovascular events and atherosclerosis progression in
a
Merck Research Laboratories, Rahway, New Jersey; bMerck Research
Laboratories, North Wales, Pennsylvania; cLouisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky; dChicago Center for
Clinical Research, Chicago, Illinois; and eBaylor College of Medicine,
Houston, Texas. Manuscript received June 19, 2007; revised manuscript
received and accepted October 3, 2007.
This study was supported by a grant from Merck & Company, Inc.,
Rahway, New Jersey.
*Corresponding author: Tel: 732-594-2246; fax: 732-594-9866.
E-mail address: [email protected] (J.F. Paolini).
†
A list of study investigators appears in the Appendix.
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjcard.2007.10.023
patients with cardiovascular disease and dyslipidemia.1–3
However, clinical lipid efficacy in dyslipidemic patients
requires titration over 12 weeks to niacin doses of ⱖ1
g/day, which are frequently associated with flushing.2– 8
This cutaneous adverse reaction limits patient acceptance of
niacin and the widespread use of the drug in the management of patients with coronary heart disease and dyslipidemia. Indeed, a recent retrospective observational study of
prescription patterns of extended-release niacin (ERN) use
in 14,386 dyslipidemic patients in a clinical practice setting
in the United States reported that ⬍15% of newly initiated
ERN users were still receiving ERN therapy at the end of 1
year, and of those, ⬍15% were receiving doses of ⱖ1.5 g.9
These clinical practice data clearly illustrate the need for the
development of a novel method of administering niacin that
is better tolerated. Niacin-induced flushing is mediated primarily by prostaglandin D2, which activates prostaglandin
D2 receptor 1, leading to cutaneous vasodilatation.10 Laropiprant (LRPT; MK-0524) is a once-daily, selective prostaglandin D2 receptor 1 antagonist.11 The present placebocontrolled study in dyslipidemic patients assessed whether
LRPT would (1) reduce niacin-induced flushing at the initiation of ERN therapy and during long-term maintenance
therapy and (2) support a novel, accelerated ERN dosing
paradigm: initiating ERN at the 1-g dose and advancing
rapidly to the 2-g therapeutic dose.
www.AJConline.org
626
The American Journal of Cardiology (www.AJConline.org)
Table 1
Demographics and baseline characteristics
Demographic/Baseline Parameter
Age (yrs)
Gender
Women
Men
Race
White
Black
Hispanic
Other
Body mass index (kg/m2)
Low-density lipoprotein cholesterol (mg/dl)
High-density lipoprotein cholesterol (mg/dl)
Median triglycerides (mg/dl)
Non-high-density lipoprotein cholesterol (mg/dl)
Fasting plasma glucose (mg/dl)
Statin therapy
Placebo
(n ⫽ 68)
ERN 1 g ¡ ERN 2 g
(n ⫽ 72)
LRPT (Pooled Doses) ⫹
ERN 1 g ¡ ERN 2 g
(n ⫽ 272)
All Patients
(n ⫽ 412)
52.1 ⫾ 10.4
54.3 ⫾ 10.6
52.5 ⫾ 11.0
52.8 ⫾ 10.8
21 (30.9)
47 (69.1)
26 (36.1)
46 (63.9)
109 (40.1)
163 (59.9)
156 (37.9)
256 (62.1)
55 (80.9)
5 (7.4)
5 (7.4)
3 (4.4)
29.7 ⫾ 5.4
129.6 ⫾ 49.7
46.8 ⫾ 12.6
152
163.7 ⫾ 54.3
99.4 ⫾ 17.6
21 ⫾ 30.9
57 (79.2)
8 (11.1)
6 (8.3)
1 (1.4)
29.3 ⫾ 5.4
132.0 ⫾ 44.3
45.5 ⫾ 11.4
163
168.4 ⫾ 45.5
99.8 ⫾ 16.6
30 ⫾ 41.7
226 (83.1)
26 (9.6)
13 (4.8)
7 (2.6)
30.2 ⫾ 5.7
129.1 ⫾ 39.7
48.0 ⫾ 13.0
158
164.0 ⫾ 43.8
100.2 ⫾ 21.3
91 ⫾ 33.5
338 (82.0)
39 (9.5)
24 (5.8)
11 (2.7)
29.9 ⫾ 5.6
129.7 ⫾ 42.2
47.3 ⫾ 12.7
160
164.7 ⫾ 45.9
100.0 ⫾ 20.0
142 ⫾ 34.5
Data are expressed as mean ⫾ SD or number (percentage) except as noted.
Methods
This study enrolled dyslipidemic men and women aged 18
to 75 years for whom treatment with niacin was appropriate
as determined by the investigator. Exclusion criteria included conditions or medications (including aspirin [with
the exception of the use of aspirin 81 mg/day for cardioprotection] and nonsteroidal anti-inflammatory drugs) that
might have confounded or interfered with the reporting of
flushing; diseases, conditions, or medications that could
have affected lipid levels; patients with newly diagnosed
(within 6 months of randomization) or poorly controlled
type 1 or type 2 diabetes mellitus (glycosylated hemoglobin
⬎8.5%); patients with histories of gout who were not taking
allopurinol; patients taking niacin ⬎50 mg/day; inability to
complete an electronic diary on a daily basis; triglycerides
ⱖ500 mg/dl; alanine aminotransferase and/or aspartate aminotransferase ⱖ1.5 times the upper limit of normal; creatinine phosphokinase (CK) ⱖ2 times the upper limit of normal; thyroxine ⬍4 ␮g/dl; thyroid-stimulating hormone ⬎10
␮U/ml; or any of the contraindications specified in the
product label for Niaspan (Abbott Laboratories, Abbott
Park, Illinois).12
This was a 2-part study. In part A of the study, 154
dyslipidemic patients were randomized to either LRPT 150
mg/day or placebo for 4 weeks, followed by a 1-week
washout and crossover to the other treatment for an additional 4 weeks. Patients who completed part A (n ⫽ 122)
were washed out for 2 weeks and then entered part B,
together with 290 additional dyslipidemic patients who
were randomized directly into part B (after a 2-week placebo run-in), for a total of 412 patients in part B. All part B
patients were randomized to placebo, ERN 1 g (Niaspan,
with no previous titration), or ERN 1 g coadministered with
LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling
of the respective doses for the remaining 4 weeks. Patients
were instructed to take study therapy with their evening
meals. In part B of the study, patients reported flushing
Figure 1. Maximum GFSS in week 1, presented as percentage of
patients.
intensity daily with the validated Flushing Symptom Questionnaire13 using a handheld electronic diary. The Flushing
Symptom Questionnaire is composed of 11 questions that
assess aspects of the frequency, severity, duration, and
bother of flushing. One of the 11 items assesses the intensity
of all 4 flushing symptoms (skin redness, warmth, tingling,
and itching) in the aggregate using an 11-point numerical
rating scale, termed the Global Flushing Severity Score
(GFSS), which was labeled with the following intensity
categories: none (score 0), mild (score 1 to 3), moderate
(score 4 to 6), severe (score 7 to 9), and extreme (score 10).
The study protocol was reviewed and approved by the
appropriate ethics committees and institutional review
boards. All patients provided written informed consent. The
study was performed in accordance with the Declaration of
Helsinki and Good Clinical Practice standards.
The key efficacy end points in part A of the study were
the percent change from baseline in low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol, and triglyc-
Preventive Cardiology/Laropiprant Reduces ERN-Induced Flushing
627
Figure 2. Mean ⫾ SE percentage of days during which patients had moderate or greater flushing (GFSS ⱖ4), by study week.
Figure 3. Percent change from baseline at week 8 for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and
triglycerides (TG). Data are expressed as mean ⫾ SE percent change from baseline for high-density lipoprotein cholesterol and low-density lipoprotein
cholesterol and as median ⫾ SE percentage change from baseline for triglycerides.
erides. In part B of the study, flushing intensity was assessed
using the GFSS during treatment initiation (week 1) and
maintenance treatment (weeks 2 to 8). Additional end points
in part B included the percent change from baseline in
low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides.
Safety assessments included the collection of adverse
experiences, physical examination, vital signs, and 12-lead
electrocardiography. Laboratory safety measurements included blood chemistry, hematology, and urinalysis. Blood
chemistry included aspartate aminotransferase, alanine aminotransferase, CK, serum creatinine, and fasting plasma
glucose.
Efficacy analyses of lipid and flushing end points were
performed in the all-patients-treated analysis population,
which included all patients who had taken ⱖ1 dose of
randomized medication and who had lipid measurements or
GFSS measurements for ⱖ1 day after the first dose of
treatment. Efficacy end points were analyzed using an analysis-of-variance model with terms for treatment and center.
Results
The demographics and baseline characteristics were generally similar across the treatment groups in this study
(Table 1). Of the 412 patients who entered part B, a total of
63 (15.3%) discontinued the study drug before completing
the trial: 9 of 68 patients (13.2%) taking placebo, 14 of 72
patients (19.4%) taking ERN alone, and 40 of 272 patients
(14.7%) taking LRPT plus ERN.
Treatment with LRPT plus ERN 1 g led to a significant
reduction relative to ERN 1 g alone in the intensity of
628
The American Journal of Cardiology (www.AJConline.org)
ERN-induced flushing reported during the treatment initiation period as determined by the percentage of patients with
maximum GFSS ⱖ1 (mild or greater flushing) during week
1 (p ⬍0.001 for between-group comparison for LRPT plus
ERN 1 g vs ERN 1 g alone across all doses of LRPT tested;
data not shown). All steps of the step-down trend test were
significant, indicating that there was no apparent dose-response relation for the reduction in the maximum intensity
of acute ERN-induced flushing with LRPT (data not
shown); therefore, data for the LRPT plus ERN group were
pooled across LRPT doses for subsequent analyses. In addition to evaluating GFSS ⱖ1 (any ERN-induced flushing),
the effects of treatment in the treatment initiation period
(week 1) in part B on the clinically important ERN-induced
flushing intensity categories of moderate or greater flushing
(GFSS ⱖ4), were also examined. Treatment with LRPT
plus ERN led to a smaller percentage of patients reporting
maximum scores of moderate or greater ERN-induced
flushing compared with ERN alone (Figure 1).
During the maintenance treatment period in part B, treatment with LRPT plus ERN led to a significant reduction in
ERN-induced flushing relative to ERN alone, as determined
by the percentage of days with GFSS ⱖ1 during weeks 6 to
8 (p ⬍0.001 for between-group comparison for LRPT plus
ERN 1 g vs ERN 1 g alone across all doses of LRPT tested;
data not shown). The higher frequency of moderate or
greater flushing in the ERN alone group relative to that in
the placebo group reported in week 1 of part B persisted
throughout the maintenance period to week 8 (Figure 2).
During weeks 6 to 8, the incidence of moderate or greater
ERN-induced flushing in patients treated with LRPT plus
ERN was similar to that for patients treated with placebo
(Figure 2).
In part B, the incidence of discontinuation because of
flushing in the LRPT plus ERN group (8 of 272 [2.9%]) was
numerically lower than that for the ERN alone group (5 of
72 [6.9%]); no patients in the placebo group discontinued
because of flushing in part B.
At week 8 in part B, treatment with LRPT had no
significant effect on the beneficial lipid-altering effects of
ERN (Figure 3). In part A of the study, treatment with
LRPT 150 mg alone had no effect relative to placebo on
mean high-density lipoprotein cholesterol and low-density
lipoprotein cholesterol levels and median triglycerides levels (data not shown).
In part B, the overall safety profile of the LRPT plus
ERN group was generally comparable with that for the ERN
alone group. There were no deaths or drug-related serious
adverse experiences in this study. The incidence of discontinuations because of drug-related adverse experiences that
were not associated with flushing was similar across the 3
groups (data not shown). In part A, the incidence of discontinuation because of drug-related adverse experiences in the
LRPT 150 mg group was similar to that for the placebo
group (data not shown).
There were no cases of hepatitis in this study. No patients
in part A had consecutive or presumed consecutive alanine
aminotransferase and/or aspartate aminotransferase elevations ⱖ3 times the upper limit of normal (data not shown).
In part B, consecutive or presumed consecutive alanine
aminotransferase and/or aspartate aminotransferase eleva-
tions ⱖ3 times the upper limit of normal were reported by
5 of 268 patients (1.9%) taking LRPT plus ERN, 0 of 72
patients (0%) taking ERN alone, and 0 of 68 patients (0%)
taking placebo (p ⫽ 0.588 for LRPT plus ERN vs ERN
alone). Of the 5 cases reported in the LRPT plus ERN
group, 2 were drug related. None of the cases were associated with clinical symptoms, and all reversed with treatment
discontinuation; there was no evidence of a relation to
LRPT dose.
There were no cases of myopathy (i.e., muscle symptoms
associated with CK ⱖ10 times the upper limit of normal) or
rhabdomyolysis in the study. In part B, CK elevations ⱖ10
times the upper limit of normal were reported in 6 of 269
patients (2.2%) taking LRPT plus ERN, 1 of 72 patients
(1.4%) taking ERN alone, and 1 of 68 patients (1.5%) taking
placebo (p ⬎0.999 for LRPT plus ERN vs ERN alone).
These CK elevations were asymptomatic and generally transient and reversible, resolving either during continued study
treatment or after the discontinuation of study treatment;
there was no evidence of a relation to LRPT dose. Three of
the 6 cases in the LRPT plus ERN group (1.1% of the 269
patients in that group) were determined by the investigators
to be possibly drug related; the other 3 cases in the LRPT
plus ERN group as well as the 2 cases in the ERN alone and
placebo groups were determined to be not drug related. One
additional patient in the LRPT plus ERN group had an
asymptomatic CK elevation ⱖ10 times the upper limit of
normal that had started during part A (when the patient was
randomized to placebo) and continued into part B.
In part A and part B, the laboratory adverse experience of
fasting blood glucose increased was reported at a similar
incidence across the treatment groups (data not shown). In
part B, there were small least squares mean increases from
baseline at week 8 in fasting plasma glucose of 3.4, 7.4, and
8.7 mg/dl in the placebo, ERN alone, and LRPT plus ERN
groups, respectively (p ⫽ 0.556 for LRPT plus ERN vs
ERN alone). No clinically meaningful differences in change
from baseline at week 8 were observed across the treatment
groups in pulse rate, electrocardiographic results, systolic
blood pressure, diastolic blood pressure, body weight, or
body mass index (data not shown).
Discussion
In the present study, ERN coadministered with the prostaglandin D2 receptor 1 antagonist LRPT was given according
to a new paradigm of initiation at ERN 1 g/day for 4 weeks
and then advanced to 2 g/day for another 4 weeks in dyslipidemic patients. Treatment with LRPT plus ERN was
well tolerated and led to a significant reduction in ERNinduced flushing at the initiation of therapy and with the
long-term maintenance of therapy, without affecting niacin’s beneficial effects on lipids. In addition, there was a
lower incidence of discontinuations because of flushing
with LRPT plus ERN compared with ERN alone.
Patients treated with LRPT plus ERN experienced a
significantly lower incidence of ERN-induced flushing, including clinically meaningful moderate or greater flushing,
compared with those taking ERN alone during the treatment
initiation and maintenance periods. Treatment with LRPT
plus ERN led to an immediate and significant reduction in
Preventive Cardiology/Laropiprant Reduces ERN-Induced Flushing
the percentage of patients experiencing moderate or greater
ERN-induced flushing compared with ERN alone during
week 1 (the initiation of therapy) at ERN 1 g. Whereas
ERN-induced flushing persisted in the ERN alone arm
throughout the 8 weeks of the study, LRPT plus ERN
treatment provided a sustained reduction in ERN-induced
flushing throughout the maintenance treatment period
(weeks 2 to 8 in part B). The incidence of moderate or
greater ERN-induced flushing for LRPT plus ERN during
weeks 6 to 8 of the study approximated that of patients
treated with placebo.
Study therapy was dosed with the evening meal rather
than at bedtime to ensure adequate time during the wakeful
hours to fully assess the effects of LRPT on ERN-induced
flushing. Although this trial had been designed as a doseranging study, all LRPT doses tested were maximally effective in reducing ERN-induced flushing.
Fewer patients discontinued because of flushing in the
LRPT plus ERN group compared with the ERN alone
group; because of the small size of this study, demonstration of statistical significance was not intended. In
this study, patients receiving ERN therapy had a relatively high level of treatment compliance compared with
what would typically be expected in actual clinical practice9 because of intensive follow-up through daily downloading of their electronic diaries, frequent clinic visits,
drug intake accountability, and patient education regarding the occurrence of flushing and the importance of
remaining in the trial through to completion. As a result,
the low incidence of discontinuations in the LRPT plus
ERN group in the first week of therapy indicates that the
attenuation in flushing over this period was due to an
actual beneficial effect of LRPT rather than a potential
confounding effect of early discontinuations with initiation at the ERN 1 g dose.
LRPT plus ERN therapy had no significant effect on the
high-density lipoprotein cholesterol–increasing or low-density lipoprotein cholesterol– and triglycerides-lowering effects of ERN, and LRPT alone had no effect relative to
placebo on high-density lipoprotein cholesterol, low-density
lipoprotein cholesterol, or triglycerides level.
LRPT, given alone or coadministered with ERN, was
generally well tolerated. The incidence of consecutive or
presumed consecutive alanine aminotransferase and/or aspartate aminotransferase elevations ⱖ3 times the upper
limit of normal in the LRPT plus ERN group was not
significantly different from that in the ERN alone group.
None of the drug-related alanine aminotransferase and/or
aspartate aminotransferase elevations in the LRPT plus
ERN group were associated with clinical symptoms, and
there was no evidence of a relation to LRPT dose for these
elevations. There were no cases of myopathy reported in
this study, and the incidence of CK elevations ⱖ10 times
the upper limit of normal in the LRPT plus ERN group was
also not significantly different from that in the ERN alone
group. Slight alterations in glycemic regulation have been
reported with ERN therapy and other niacin products.14 The
small increase in mean fasting blood glucose in the LRPT
plus ERN group was not significantly different from that in
the ERN alone group, indicating that LRPT had no clini-
629
cally meaningful impact on the known glycemic effects of
ERN.
In summary, the reductions in flushing seen with LRPT
support a novel dosing paradigm for ERN therapy that
should facilitate the more widespread use of niacin therapy
at a more effective dose and thereby reduce the risk for
cardiovascular disease in patients with dyslipidemia.
Acknowledgment: We wish to thank Olga Kuznetsova for
statistical input in the development of the study, Kelly
McQuarrie for development and support of the electronic
diary, Sally Thompson-Bell and her team (Abigaile Betteridge, Robin Roberts, and Andrew Trovato) for facilitating the timely completion of the trial, and Dr. Jonathan
Tobert for his input and guidance during the early phase of
the LRPT clinical development program.
Appendix
Study Investigators: Stephen Aronoff, MD, Central Research Institute of Dallas, Dallas, Texas; Christie Ballantyne, MD, Baylor College of Medicine, Houston, Texas;
Harold Bays, MD, L-MARC Research Center, Louisville,
Kentucky; Eliot A. Brinton, MD, University of Utah
School of Medicine, Salt Lake City, Utah; David
Capuzzi, MD, Lipid Disorders Research Center, Thomas
Jefferson University, Philadelphia, Pennsylvania; Scott
Conard, MD, Tiena Health Research, Irving, Texas; Michael Davidson, MD, Radiant Research Chicago, Chicago, Illinois; Adrian Dobs, MD, Johns Hopkins University, Baltimore, Maryland; Samuel Engel, MD, Soundview
Research Associates, Norwalk, Connecticut; Alan Forker,
MD, Saint Luke’s Lipid & Diabetes Research Center, Kansas City, Missouri; Neil Fraser, MD, Troy Internal Medicine, Troy, Michigan; Elizabeth Gallup, MD, Radiant Research Kansas City, Overland Park, Kansas; Linda M.
Gaudiani, MD, Marin Endocrine Associates, Greenbrae,
California; Henry Ginsberg, MD, Columbia University,
New York, New York; Charles Harper, MD, Atlanta, Georgia; David Hassman, MD, Comprehensive Clinical Research, Berlin, New Jersey; Charles Herring, MD, New
Hanover Medical Research Associates, Wilmington, North
Carolina; Victor N. Howard, MD, Heart Center Research
Casa Grande Medical Plaza, Port Charlotte, Florida; William Insull, MD, Baylor College of Medicine, Houston,
Texas; Michael B. Jacobs, MD, Radiant Research Las Vegas, Las Vegas, Nevada; Scott Kleber, MD, Laureate Clinical Research Group, Atlanta, Georgia; Robert Knopp, MD,
Northwest Lipid Research Center, Seattle, Washington; Michael J. Koren, MD, Jacksonville Center for Clinical Research, Jacksonville, Florida; William Kraus, MD, Duke
University, Durham, North Carolina; Wayne Larson, MD,
Radiant Research Tacoma, Lakewood, Washington; Andrew Lewin, MD, National Research Institute, Los Angeles,
California; Thomas W. Littlejohn, MD, Piedmont Medical
Research Associates, Winston-Salem, North Carolina;
Barry Lubin, MD, Hampton Roads Center for Clinical Research, Inc., Norfolk, Virginia; James McKenney, PharmD,
National Clinical Research, Inc., Richmond, Virginia;
Thomas Pearson, MD, Strong Heart Program Rehabilitation
630
The American Journal of Cardiology (www.AJConline.org)
Center, Rochester, New York; Terry Poling, MD, Heartland
Research Associates, LLC, Wichita, Kansas; George Raad,
MD, Metrolina Medical Research, Charlotte, North Carolina; Jennifer Robinson, MD, University of Iowa College of
Public Health, Lipid Research Clinic, Iowa City, Iowa; Eli
Roth, MD, Sterling Research Group, Ltd., Cincinnati, Ohio;
Mohammed Saad, MD, University of California, Los Angeles, Diabetes Center, Alhambra, California; Edward
Schwager, MD, Carondelet Medical Group, Tucson, Arizona; Evan A. Stein, MD, Metabolic & Atherosclerosis
Research Center, Cincinnati, Ohio; Allen Sussman, MD,
Rainier Clinical Research Center, Inc., Renton, Washington; Melvin Tonkon, MD, Apex Research Institute, Santa
Ana, California; Philip Toth, MD, MidWest Institute for
Clinical Research, Indianapolis, Indiana; Kris Vijayaraghavan, MD, Scottsdale Cardiovascular Research Institute,
Scottsdale, Arizona; Mervyn Weerasinghe, MD, Rochester
Clinical Research, Inc., Rochester, New York; Scott Yates,
MD, North Texas Medical Research, The Colony, Texas;
James Zavoral, MD, Radiant Research Minneapolis, Edina,
Minnesota; Howard Zisser, MD, Sansum Medical Research
Institute, General Research, Santa Barbara, California.
1. Third report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.
2. The Coronary Drug Project Research Group. Clofibrate and niacin in
coronary heart disease. JAMA 1975;231:360 –381.
3. Knopp RH, Ginsberg J, Albers JJ, Hoff C, Ogilvie JT, Warnick GR,
Burrows E, Retzlaff B, Poole M. Contrasting effects of unmodified and
time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin. Metabolism 1985;34:
642– 650.
4. Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES. Increasing HDL
cholesterol with extended-release nicotinic acid: from promise to practice. Neth J Med 2004;62:229 –234.
5. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA,
Brusco OA, Brody J. Efficacy and safety of an extended-release
niacin (Niaspan): a long-term study. Am J Cardiol 1998;82(suppl):
74U– 81U.
6. Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin
(Niaspan): efficacy, tolerability, and safety in hypercholesterolemic
patients. Am J Cardiol 1998;82(suppl):29U–34U.
7. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp
RH, Tun P, Zupkis RV, Greguski RA. Comparative effects of lovastatin and niacin in primary hypercholesterolemia: a prospective trial.
Arch Intern Med 1994;154:1586 –1595.
8. Mills E, Prousky J, Raskin G, Gagnier J, Rachlis B, Montori VM,
Juurlink D. The safety of over-the-counter niacin. A randomized placebo-controlled trial. BMC Clin Pharmacol 2003;3:4 –11.
9. Kamal-Bahl S, Burke T, Watson D, Wentworth C, Ma L. Dosage and
titration patterns of extended release niacin in clinical practice. Circulation 2006;113:(Poster No. e814) [AHA 7th Scientific Forum on
Quality of Care and Outcomes Research in Cardiovascular Disease and
Stroke, Washington, DC, 2006]
10. Cheng K, Wu TJ, Wu KK, Sturino C, Metters K, Gottesdiener K,
Wright SD, Wang Z, Lai E, Waters MG. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation
in mice and humans. Proc Natl Acad Sci U S A 2006;103:6682– 6687.
11. Sturino CF, O’Neill G, Lachance N, Boyd M, Berthelette C, Labelle
M, Li L, Roy B, Scheigetz J, Tsou N, et al. Discovery of a potent and
selective prostaglandin D(2) receptor antagonist, [(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]
indol-3-yl]-acetic acid (MK-0524). J Med Chem 2007;50:794 – 806.
12. Product label for Niaspan® (Kos Pharmaceuticals, Inc., Miami, Florida). In: Physicians’ Desk Reference. 61st ed. Montvale, New Jersey:
Thompson PDR; 2007:1730 –1735.
13. Norquist JM, Yu Q, Paolini JF, McQuarrie K, Santanello NC,
Watson DJ. Development and validation of a questionnaire to
assess niacin-induced cutaneous flushing. Curr Med Res Opin
2007;23:1549 –1560.
14. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in
noninsulin-dependent diabetes mellitus. JAMA 1990;264:723–726.