© 1998 American Heart Association, Inc.
Original Contributions |
Effect of the Novel Antiplatelet Agent Cilostazol on Plasma Lipoproteins in Patients With Intermittent Claudication
From the Departments of Pharmacology and Medicine, University of Tennessee Health Science Center and Veterans Affairs Medical Center, Memphis, Tenn (M.B.E.); Otsuka America Pharmaceutical, Inc, Rockville, Md (J.H., E.B.B., W.P.F.); the Department of Medicine, Bowman Gray Medical Center, Winston-Salem, NC (J.R.C.); the University of California Irvine Medical Center, Orange, and Veterans Affairs Medical Center Long Beach, Long Beach, Calif (I.L.G.); the Heart Disease Prevention Clinic, University of Minnesota, Minneapolis (D.B.H.); Baylor Medical Center, Houston, Tex (J.A.H.); and the Chicago Center for Clinical Research, Chicago, Ill (M.D.).
Correspondence to Marshall B. Elam, PhD, MD, Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, University of Tennessee Health Science Center, 874 Union Ave, Memphis, TN 38163. E-mail melam{at}utmem1.utmem.edu
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Abstract |
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Abstract—Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (P<0.001). Cilostazol also increased plasma high density lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (P<0.001 and P<0.01, respectively). Both HDL3 and HDL2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL2. Individuals with baseline hypertriglyceridemia (>140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, P<0.002) increase in the apoA1 to apoB ratio. Low density lipoprotein cholesterol and lipoprotein(a) concentrations were unaffected. Cilostazol treatment resulted in a 35% increase in treadmill walking time (P=0.0015) and a 9.03% increase in ankle-brachial index (P<0.001). These results indicate that in addition to improving the symptoms of IC, cilostazol also favorably modifies plasma lipoproteins in patients with peripheral arterial disease. The mechanism of this effect is currently unknown.
Key Words: HDL • intermittent claudication • triglycerides • cilostazol • apoA1
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Cilostazol is a vasodilator and platelet aggregation inhibitor that has been marketed since 1988 in Japan for treatment of ischemic symptoms of peripheral vascular disease. Cilostazol {6[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2-(1H)-quinolinone} is a 2-oxoquinolone derivative (molecular weight, 369.47) that has a plasma half-life of 10.5±4.4 hours after oral administration (Figure 1
). Cilostazol inhibits both primary and
secondary platelet aggregation in response to ADP, collagen,
epinephrine, and arachidonic
acid.1 2 The antiplatelet and vasodilator
properties of cilostazol have been attributed to its ability to elevate
intracellular levels of cAMP.3 Cilostazol is
currently being evaluated in the United States for treatment of
symptomatic intermittent claudication (IC). Japanese
studies performed in diabetic patients have indicated that, in addition
to its vasodilator and antiplatelet properties, cilostazol may also
favorably modify plasma lipoproteins by increasing HDL
cholesterol (HDL-C) and reducing
triglycerides.4 The purpose of the
present study was to determine whether cilostazol favorably
modifies plasma lipoproteins in a general population of patients with
stable IC.
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Methods |
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Patient Population
The study included subjects with documented chronic, stable, symptomatic IC secondary to peripheral arterial disease (PAD). PAD was defined as an ankle-brachial index (ABI)
0.90; termination of walking on a
variable-load, constant-speed treadmill due to IC (>54 and <805
m); and a Doppler-measured drop of 
10 mm Hg in blood
pressure of 1 ankle after the treadmill test. For patients without a
qualifying ABI, a 20–mm Hg drop in postexercise ankle artery pressure
was required for entry. Patients with documented IC underwent 2 fasting
blood draws (at least 1 week apart) in which plasma
triglyceride concentration (average of 2 determinations)
was <350 mg/dL, and plasma LDL-C was between 100 and 190 mg/dL in all
subjects. Subjects were men and women >40 years of age. Women were not of child-bearing potential (they either had been surgically sterilized or were at least 1 year postmenopausal). Subjects with gross obesity (>60% above ideal body weight), poorly controlled hypertension (systolic pressure >200 mm Hg; diastolic pressure >100 mm Hg), poorly controlled diabetes, a history of malignancy, current alcohol or drug abuse, renal disease (creatinine >2.5 mg/dL), or bleeding tendencies were excluded. Antiplatelet, anticoagulant, vasoactive, hemorheologic, or lipid-modifying medications were not allowed during the 12-week-study treatment period. Therapy with ß-blockers and thiazide diuretics was allowed if held at a constant dose for 8 weeks before the trial and if the dosage was maintained during the 12-week treatment period. All study participants discontinued lipid-lowering therapy at least 4 weeks before screening, with the exception of probucol, which was to be discontinued 6 months before screening. Enrollees were instructed to maintain stable dietary patterns during the 12-week study period.
Study Design
This study was a multicenter, randomized, parallel, double-blind
trial with the administration of either cilostazol, 100 mg PO, BID, or
placebo PO, BID, for a period of 12 weeks. Study participants were
evaluated at study weeks 2, 4, 6, 8, and 12. Standardized treadmill
walking tests were conducted at 2 baseline visits and weeks 8 and 12.
The primary outcome variables from lipid profiling were as follows:
total cholesterol, LDL, HDL-C (total HDL-C,
HDL2, and HDL3),
lipoproteina (Lpa, when
30 mg/dL), apoA1, apoB, and triglycerides. All
lipid analyses were blinded to the investigators and patients
after randomization. The primary outcome variables for exercise
tolerance were pain-free walking distance and maximal walking distance.
Pain-free walking distance was defined as the distance walked before
initial onset of pain. Maximal walking distance was defined as the
maximum distance walked.
Lipid Assays
Plasma cholesterol, triglycerides,
HDL-C, and LDL-C were determined by the central laboratory at Bowman
Gray School of Medicine (Winston-Salem, NC). Blood for analysis
of plasma concentrations of lipids and lipoproteins was obtained from
fasting participants (12 hours without food, 24 hours without alcohol).
Plasma was immediately isolated by low-speed
centrifugation. Samples were shipped on wet ice to the
Bowman Gray Lipid Analytic Laboratory and analyzed using
methods standardized by the Centers for Disease Control and Prevention,
Atlanta, Ga. Cholesterol and triglyceride
analyses were performed on whole plasma with and without
heparin-MnCl2 precipitation using a Technicon RA
1000 Auto-analyzer.5 HDL-C was determined
by the heparin-manganese precipitation method, first reported by
Burstein and Samaille.6
HDL2/HDL3 subtypes were
analyzed using the dextran sulfate precipitation method of
Gidez et al.7 LDL was calculated using the method
of Friedewald et al.8 ApoA1 and apoB were
measured on human plasma immunoturbidimetrically using a Cobas Fara II
centrifugal analyzer and antibodies against human apoA1 and
apoB provided by Sigma Chemical Co (for apoA1, Sigma procedure 356; for
apoB, Sigma procedure 357). Lpa was measured on
human plasma by automated immunoprecipitin analysis
using a Cobas Fara II centrifugal analyzer and antibodies
against human Lpa provided by INCSTAR Corp
(catalog No. 86084).
Statistical Analysis
Continuous efficacy measures were analyzed by ANOVA and
the Wilcoxon rank sum test. The former method was used when the
residuals for the response variables were normally distributed;
otherwise, the Wilcoxon rank sum test was used. Sample size was
based on determination of a clinically meaningful difference in HDL
between groups (4 mg/dL). The minimum sample size chosen (n=75)
provided >80% power based on a 5% significance level (2-sided). The
primary analysis for lipids was the change from baseline to the
last observation. Secondary analyses of the effect of
pretreatment HDL and triglycerides and of ß-blocker and
diuretic therapy on the lipoprotein response to cilostazol were
conducted to provide additional information regarding the potential
mechanism of the lipid effect. The protocol was approved by the
Institutional Review Board at each study center. Written, informed
consent was obtained from each patient before entry into the study.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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One hundred eighty-nine study participants were randomized to receive therapy with either cilostazol (n=95) or placebo (n=94). The 2 treatment groups were similar with regard to demographics, PAD severity, concurrent illnesses, concurrent medications, and baseline lipoproteins, with the following exceptions: Significantly more patients randomized to placebo reported prior coronary artery bypass grafting and diuretic therapy, and baseline levels of total cholesterol, apoA1, and apoB were higher in the placebo group (Table 1
). As expected in a
population of claudicants, there was a high prevalence of comorbid
disease including hypertension, coronary heart disease, and
diabetes mellitus. Although the cohort was predominantly white and
male, significant numbers of female (n=30) and minority (n=28)
participants were included as well. Of the 189 patients who were
randomized, 170 (89.9%) completed the study (ie, had a week-12 visit).
The number of patients who completed the study was comparable between
the treatment groups: 86.3% cilostazol (n=82) and 93.6% placebo
(n=88).
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The most commonly reported adverse effects reported by study
participants during the 12-week study period were headache, diarrhea,
musculoskeletal pain, abnormal stools, dizziness, and
peripheral edema (Table 2).
Significantly more participants in the cilostazol treatment group
reported headache compared with placebo. In most cases these symptoms
were transient, responded to symptomatic treatment, and did
not require discontinuation of treatment. Four patients discontinued
cilostazol treatment because of persistent headache, and 1 patient
discontinued cilostazol therapy due to diarrhea. No increases 2-fold or
greater in liver transaminases were seen in either treatment group.
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Effect of Cilostazol Treatment on Plasma Lipoproteins
After 12 weeks of treatment with cilostazol, there was a
significant decrease (15%) in plasma triglycerides and an
increase (9.5%) in plasma HDL-C compared with placebo (Figure 2). These lipoprotein effects were
observed after 2 and 4 weeks of cilostazol treatment for HDL-C and
triglycerides, respectively, and continued throughout the
remaining 8 weeks of treatment. By comparison, plasma HDL-C and
triglycerides remained stable during the 12-week treatment
period in the placebo group. LDL-C levels were not significantly
different with cilostazol treatment (Figure 2). In addition to
significant changes in triglycerides and HDL-C, cilostazol
therapy was accompanied by a significant increase in plasma apoA1
(Table 3). There was a small but
significant decrease in plasma apoB, which when combined with the
increased apoA1, resulted in an increase in the apoA1 to apoB ratio.
The increase in HDL-C appeared to result from increases in both
HDL2 and HDL3, although the
former did not reach statistical significance. The apoB to LDL-C ratio,
an index of LDL density, was unchanged by cilostazol treatment (Table 3). Plasma cholesterol, LDL-C, and
Lpa (measured in patients with baseline
Lpa >30 mg/dL) were unchanged after cilostazol
treatment (Table 3). There were no significant changes in plasma
lipoproteins between weeks 0 and 12 in the placebo group.
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Effect of Baseline HDL-C and Triglycerides on
Lipoprotein Response to Cilostazol
The population of patients studied included individuals with a
wide range of HDL and triglyceride levels, including a
significant number of normolipidemic subjects. To determine whether
patients with low HDL-C or
hypertriglyceridemia were more likely to
benefit from the lipoprotein-modifying effect of cilostazol, the HDL
and triglyceride response to the drug was examined after
stratifying the patients by baseline HDL-C <0.94 mmol/L (<36
mg/dL) and triglycerides >1.58 mmol/L (>140 mg/dL).
The HDL response to cilostazol was unaffected by baseline HDL levels.
Patients with low HDL-C experienced increased HDL-C with cilostazol
treatment equivalent to that of subjects with higher baseline HDL-C. In
contrast, plasma triglyceride was decreased and HDL-C
increased to a greater extent in patients whose baseline
triglyceride was elevated (Table 4).
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Correlation of Change in Physical Activity and Glycemic Measures
With Lipoprotein Response to Cilostazol
To determine whether the observed changes in plasma HDL-C and
triglycerides might have been the result of increased
exercise level or improved glycemic control in cilostazol-treated
patients rather than a direct hypolipidemic effect of the drug, the
observed changes in HDL-C and triglycerides were correlated
with indices of IC and glycemic control across all patients (Table 5). Both treadmill distance (maximal) and
ABI improved significantly (P=0.004 and P<0.001,
respectively, versus placebo) in cilostazol-treated patients compared
with placebo-treated patients; however, there was no significant
correlation of change in either maximal walking distance or ABI with
change in the lipoprotein variables. Neither fasting glucose nor
glycosylated hemoglobin was influenced by cilostazol treatment.
Moreover, cilostazol had little effect on glycosylated hemoglobin
regardless of diabetic status. There was no correlation of either of
these variables with change in the lipoprotein variables.
Finally, to determine whether the observed increase in HDL-C after
cilostazol treatment was related to decreased
triglycerides, we examined the relationship of the change
in triglycerides with the change in HDL-C. Surprisingly,
there was no significant correlation between change in
triglycerides and in HDL-C.
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Effect of ß-Blocker and Diuretic Therapy on Lipoprotein
Response to Cilostazol
Both ß-blockers and diuretics are known to modify plasma
triglycerides and HDL-C. Because of the prevalence of
concomitant hypertension and coronary heart disease among study
participants, many patients were being treated with these agents and
this was allowed, provided the dose was held constant during the
12-week treatment period. On the other hand, it is possible that these
agents might have prevented or blunted the effect of cilostazol on
plasma lipoproteins. In particular, if cilostazol exerted its
lipoprotein-modifying effects by increasing intracellular cAMP as a
result of its ability to inhibit phosphodiesterase, that response might
be altered by blockade of ß-receptors. Analysis of the
HDL-C and triglyceride response to cilostazol in subjects
being treated with diuretics or ß-blockers showed no effect
of either agent on the lipoprotein response to cilostazol, with the
exception of patients on diuretic therapy, who had a reduced
triglyceride-lowering effect compared with those not on
diuretic therapy (-6% versus -16%). This may reflect
antagonism of cilostazol's triglyceride-lowering effect by
diuretic therapy. Alternatively, the reduced
triglyceride response in the group of study participants on
diuretic therapy may merely reflect the lower baseline
triglyceride values in that group. Individuals with low
baseline triglycerides had a lower decrease of
triglycerides with cilostazol, as discussed earlier. The
absence of an effect of ß-antagonist therapy on
lipoprotein response to cilostazol does not eliminate the possibility
that increased intracellular cAMP levels may mediate the lipoprotein
effects of cilostazol, but it argues against a requirement for
ß-adrenoceptor–mediated increases in cAMP.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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This study demonstrates that, in addition to its vasodilator and antiplatelet properties, the phosphodiesterase inhibitor cilostazol also favorably modifies plasma lipoproteins. Specifically, plasma levels of HDL-C and apoA1 are significantly increased and plasma triglycerides are decreased. Both the triglyceride-lowering and HDL-raising effects of cilostazol are more pronounced in individuals with baseline hypertriglyceridemia. The only previous report of the lipid-modifying effect of cilostazol is a study of a limited number of diabetic subjects in the Japanese literature.4 This prior study reported effects of cilostazol on plasma lipoproteins, which were comparable to those reported here.
Current treatment guidelines recommend aggressive cholesterol lowering and risk-factor modification in individuals with known coronary heart disease and other symptomatic vascular disease, including PAD.9 Individuals with PAD are at high risk of death and disability from coronary and cerebrovascular disease, in addition to the morbidity associated with PAD itself. The risk of fatal cardiovascular events in subjects with PAD is increased from 2- to 15-fold, depending on the severity of the underlying PAD.10 11 12 Therefore, patients with IC have great potential to benefit from lipoprotein modification, not only to alter the clinical course of PAD itself, but also to modify coexisting atherosclerotic vascular disease. The ability of cilostazol to favorably modify plasma triglycerides and HDL-C is particularly significant for patients with IC, in that both hypertriglyceridemia and low HDL-C are observed with increased frequency in such patients.13 14 15 16 17 Reduced plasma triglycerides may be desirable in this patient population, as elevated plasma triglyceride levels are associated with increased risk of cardiovascular disease independent of HDL-C.18 19
The exact mechanisms involved in the ability of cilostazol to lower plasma triglycerides and increase HDL are at present unknown. The lipoprotein effects of cilostazol that we have observed appear to be independent of changes in physical activity or glucose tolerance and are unaffected by concomitant ß-antagonist therapy. It is likely that the lipoprotein effects of cilostazol are a result of its ability to inhibit cyclic nucleotide phosphodiesterase and thereby elevate intracellular cAMP. Cyclic nucleotide phosphodiesterases regulate intracellular levels of cAMP (and cGMP) by catalyzing their degradation.20 There are several possible mechanisms by which increased cAMP might result in lowered plasma triglycerides. One possible mechanism is by reducing hepatic triglyceride (ie, VLDL) secretion, either directly, or indirectly by potentiating the effect of glucagon to inhibit VLDL secretion.21 On the other hand, increased cAMP levels have been shown to promote release of lipoprotein lipase from rat adipocytes,22 which could reduce plasma triglycerides. Although plasma lipoprotein lipase was not measured as part of the present study, increased plasma lipoprotein lipase has been observed in streptozotocin diabetic rats treated with cilostazol (Otsuka America Pharmaceutical, unpublished data, 1994).
In the present study, the time course of the effect of cilostazol on HDL-C differed from that of its effect on triglycerides. In addition, the change in HDL-C was not correlated with the decrease in triglycerides during cilostazol treatment. This suggests that different mechanisms may be responsible for the effect of cilostazol on triglycerides and HDL. In this regard, there are no published studies of the effect of cAMP on expression of apoA1 by the liver or gut. On the other hand, the previous observation that increased cAMP levels enhance HDL3-mediated sterol efflux from cholesterol-loaded human skin fibroblasts23 indicates 1 possible mechanism for increased HDL-C after phosphodiesterase inhibitor treatment.
The observed beneficial lipoprotein-modifying effect of cilostazol, in addition to its previously reported antiplatelet properties, offers the possibility that long-term therapy with this agent will not only alleviate the symptoms of IC but may also favorably alter the clinical course of atherosclerotic peripheral vascular disease. This remains to be determined and will require long-term study of the effects of cilostazol.
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Acknowledgments |
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This study was supported in part by Otsuka America Pharmaceutical, Inc.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Treatment Centers and Study Investigators
H. Beebe, MD, Jobst Vascular Center, Toledo, Ohio; Lt Col D.L. Dawson, MD, Wilford Hall USAF Medical Center, San Antonio, Tex; L.K. Smith, MD, Arizona Heart Institute, Phoenix, Ariz; S.E. Wilson, MD, University of California at Irvine, Orange, Calif; R. Hobson, MD, UMDNJ, Newark, NJ; I. Gordon, MD, VA Medical Center, Long Beach, Calif; J.R. Crouse, MD, Bowman Gray Medical Center, Winston-Salem, NC; J.A. Herd, MD, The Methodist Hospital, Houston, Tex; D.B. Hunninghake, MD, University of Minnesota, Minneapolis; M.B. Elam, MD, PhD, VAMC/University of Tennessee, Memphis; A.B. Alvaro, MD, California Clinical Trials Medical Group, Beverly Hills, Calif; J. Regensteiner, PhD, University of Colorado Health Sciences Center, Denver, Colo; M. Davidson, MD, Chicago Center for Clinical Research, Chicago, Ill; E. Dyckman, MD, CRF Inc, Atlanta, Ga; M. Rendell, MD, Creighton Diabetes Center, Omaha, Neb; R. Ratner, MD, Washington Center Hospital, Washington, DC; P. Comp, MD, PhD, Oklahoma Memorial Hospital, Oklahoma City, Okla.
Received January 27, 1998; accepted June 2, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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