Starting with rosuvastatin in primary hyperlipidemia--Is there more than lipid lowering?

Abstract

The authors investigated the effects of rosuvastatin, beyond its lipid-lowering activity, on several nonlipid metabolic variables, along with its safety and tolerability, in patients treated for primary hyperlipidemia. Patients (n = 55) with primary hyperlipidemia were open-label assigned to the recommended starting dose of rosuvastatin 10 mg/day, and serum metabolic variables were measured at baseline and after 8 and 20 weeks. Treatment with rosuvastatin produced significant reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, nonhigh-density lipoprotein cholesterol (non HDL-C), and triglyceride concentrations, whereas HDL-C, apolipoprotein A-I, and lipoprotein(a) levels did not change significantly from baseline. The LDL-C treatment target was achieved in 71% of patients. No significant variations in renal function parameters (serum creatinine and creatinine clearance), insulin resistance estimates, and serum concentrations of uric acid, total homocysteine, vitamin B12, and folic acid were observed during the period of treatment. High-sensitivity C-reactive protein levels were significantly lowered by rosuvastatin therapy (median values, 3.1 vs 2.0 vs 1.9 mg/L, at 0, 8, and 20 weeks, respectively; p < 0.0001). In conclusion, rosuvastatin at 10 mg/day is a highly effective, safe, and well-tolerated monotherapy option for patients with primary hyperlipidemia, with a favorable antiinflammatory potential and nondeteriorating effects on renal function.

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Angiology
http://ang.sagepub.com/content/56/5/585
The online version of this article can be found at:
DOI: 10.1177/000331970505600510
2005 56: 585ANGIOLOGY
Konstantine Seferiadis and Moses S. Elisaf
Haralampos J. Milionis, Irene F. Gazi, Theodosios D. Filippatos, Vasilios Tzovaras, George Chasiotis, John Goudevenos,
: Is There More Than Lipid Lowering?−−Starting with Rosuvastatin in Primary Hyperlipidemia
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Starting with Rosuvastatin in Primary
Hyperlipidemia —
Is There More Than Lipid Lowering?
Haralampos J. Milionis, MD,* Irene F. Gazi, MD,* Theodosios D. Filippatos, MD,*
Vasilios Tzovaras, MD,* George Chasiotis, PhD,
†
John Goudevenos, MD,*
Konstantine Seferiadis, PhD,
†
and Moses S. Elisaf, MD, FRSH, FASA,*
Ioannina, Greece
The authors investigated the effects of rosuvastatin, beyond its lipid-lowering activity, on
several nonlipid metabolic variables, along with its safety and tolerability, in patients treated
for primary hyperlipidemia. Patients (n = 55) with primary hyperlipidemia were open-label
assigned to the recommended starting dose of rosuvastatin 10 mg/day, and serum metabolic
variables were measured at baseline and after 8 and 20 weeks. Treatment with rosuvastatin
produced significant reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C),
apolipoprotein B, nonhigh-density lipoprotein cholesterol (non HDL-C), and triglyceride concen-
trations, whereas HDL-C, apolipoprotein A-I, and lipoprotein(a) levels did not change signifi-
cantly from baseline. The LDL-C treatment target was achieved in 71% of patients. No signif-
icant variations in renal function parameters (serum creatinine and creatinine clearance), insulin
resistance estimates, and serum concentrations of uric acid, total homocysteine, vitamin B12,
and folic acid were observed during the period of treatment. High-sensitivity C-reactive protein
levels were significantly lowered by rosuvastatin therapy (median values, 3.1 vs 2.0 vs 1.9
mg/L, at 0, 8, and 20 weeks, respectively; p <0.0001). In conclusion, rosuvastatin at 10 mg/day
is a highly effective, safe, and well-tolerated monotherapy option for patients with primary
hyperlipidemia, with a favorable antiinflammatory potential and nondeteriorating effects on
renal function.
Introduction
Rosuvastatin, a 3-hydroxy-3-methylglutaryl coen-
zyme A reductase inhibitor (statin), in its current-
ly recommended start dose of 10 mg/day, is con-
sidered highly effective in minimizing the need for
titrations to higher doses in order to achieve low-
density lipoprotein cholesterol (LDL-C) treatment
goals, thus reducing the frequency of medical con-
tacts.
1-3
There is less information with respect to
the actions of rosuvastatin on nonlipid variables,
which are associated with an increased risk of car-
Angiology 56:585–592, 2005
From the *Department of Internal Medicine, School of
Medicine, University of Ioannina,
†
Laboratory of Biochemistry,
University Hospital of Ioannina, Ioannina, Greece
Correspondence: Moses S. Elisaf, MD, Professor of Medicine,
Department of Internal Medicine, School of Medicine,
University of Ioannina, 451 10 Ioannina, Greece
Email: hmilioni@cc.uoi.gr
©2005 Westminster Publications, Inc, 708 Glen Cove Avenue,
Glen Head, NY 11545, USA
585
Angiology Volume 56, Number 5, 2005

diovascular disease, such as indices of renal func-
tion, glycemic status, serum uric acid concentra-
tions, and high-sensitivity CRP (hsCRP), as well as
serum total homocysteine (tHcy), folate, and vita-
min B12 concentrations. In this study, we assessed
the effects of rosuvastatin (at the recommended
start dose of 10 mg/day) on several serum meta-
bolic variables, beyond its lipid-lowering capaci-
ty, along with its safety and tolerability in patients
treated for primary hyperlipidemia.
Subjects and Methods
Patients attending the Outpatient Lipid Clinic of
the University Hospital of Ioannina, Greece, were
recruited for the study. Men and women with
dyslipidemia were screened for eligibility by med-
ical history, physical examination, and clinical
laboratory evaluation, including the lipid profile.
No participant had either symptomatic ischemic
heart disease or any other vascular disease. Any
lipid-lowering medications had to have been dis-
continued for at least 6 weeks before enrollment.
All participants gave their informed consent and
the study protocol was approved by the institu-
tional ethics committee.
Patients were assigned to the National
Cholesterol Education Program (NCEP) diet for 6
weeks and were advised to follow this diet
throughout the study.
4
Fasting serum lipid con-
centration entry criteria were total cholesterol
(TC) >240 mg/dL (>6.2 mmol/L) at weeks –4
and –2, and triglycerides (TG) <350 mg/dL (4.0
mmol/L).
Patients with (1) abnormal hepatic function
(aminotransferase levels >2 times the upper limit
of normal, and/or history of chronic liver disease,
such as cirrhosis or alcohol abuse); (2) impaired
renal function (serum creatinine concentrations
>1.8 mg/dL, 159 µmol/L); (3) diabetes mellitus
(fasting blood glucose >126 mg/dL, 7.0 mmol/L);
(4) raised TSH levels (greater than 5.0 µU/L);
and (5) any medical conditions that might pre-
clude successful completion of the study protocol
were excluded.
Patients taking drugs such as angiotensin-
converting enzyme inhibitors, angiotensin II re-
ceptor antagonists, or calcium channel blockers
on a stabilized dose for at least 8 weeks before
entry to the study were considered eligible. Those
receiving drugs possibly affecting the laboratory
parameters tested were also excluded.
5,6
After a mean 6-week baseline period the pa-
tients were assigned to rosuvastatin 10 mg daily
for 20 weeks. A food record rating score was cal-
culated from 3-day diaries kept by the partici-
pants in order to assess compliance with the diet
throughout the study. Blood samples were taken
after a 14-hour overnight fast for the determina-
tion of serum lipid concentrations (including
apolipoproteins), urea, creatinine, glucose, in-
sulin, uric acid, hs-CRP, tHcy, vitamin B12, and
folic acid, as well as liver and muscle enzymes at
baseline and at 8 and 20 weeks following treat-
ment initiation.
Laboratory Determinations
The laboratory determinations were performed
by use of an Olympus AU 600 analyzer as previ-
ously described.
5,6
The creatinine clearance was
estimated by the Cockcroft-Gault formula:
Creatinine clearance (CrCl) = ([140-age] xbody
weight)/(72 xserum creatinine), where body
weight is in kg, age is in years, and serum creati-
nine is in mg/dL. For women, the result is multi-
plied by a factor of 0.85 to compensate for the
lower average muscle mass.
7
Glucose was measured by the hexokinase
method and serum insulin concentrations by the
AxSYM Insulin assay, which is based on the
Microparticle Enzyme Immunoassay technology
(Abbott Laboratories, Diagnostic Division, USA).
The HOmeostasis Model Assessment (HOMA)
was used to predict the homeostatic concentra-
tions of fasting insulin and glucose, which arise
from varying degrees of beta-cell deficiency and
insulin resistance.
8
The model is known to be
nonlinear but can be approximated by simple
mathematical approximations: insulin resistance
= (fasting insulin in µU/mL) x(fasting serum
glucose in mg/dL) x0.06/405.
9
Serum concentrations of hsCRP were mea-
sured by the N High-Sensitivity CRP method,
which is an in vitro diagnostic assay (provided
by Dade Behring Marburg GmbH, Marburg,
Germany) based on particle-enhanced immuno-
nephelometry. The reference range of this assay
is 0.175–55 mg/L.
5,6
The AxSYM Homocysteine assay, a fluores-
cence polarization immunoassay (Axis-Shield,
Oslo Norway, Abbott Laboratories), was used for
the quantitative measurement of total L-homo-
cysteine in human serum. Serum folate was mea-
sured by AxSYM Folate, an ion capture assay
(Abbott Laboratories, Illinois, USA). A chemilu-
minescent microparticle intrinsic factor assay was
Angiology Volume 56, Number 5, 2005
586

used for the quantitative determination of vita-
min B12 in human serum (The ARCHITECT B12
assay, Abbott Laboratories, Illinois, USA).
5,6
The concentrations of TC and TG were deter-
mined enzymatically on the Olympus AU 600
clinical chemistry analyzer (Olympus Diagnostica,
Hamburg, Germany). High-density lipoprotein
cholesterol (HDL-C) was determined in the su-
pernatant, after precipitation of the ApoB-con-
taining lipoproteins with dextran sulfate–Mg
2+
(Sigma Diagnostics, St. Louis, MO, USA). LDL-C
was calculated by using the Friedewald formula.
Apolipoproteins (Apo) A-I and B were measured
with a Behring Nephelometer BN100, and re-
agents (antibodies and calibrators) from Dade
Behring Holding GmbH (Liederbach, Germany).
The ApoA-I and ApoB assays were calibrated ac-
cording to the International Federation of Clinical
Chemistry (IFCC) standards. Lipoprotein(a)
[Lp(a)] levels were determined by means of par-
ticle-enhanced immunonephelometry using a
Behring Nephelometer BN100 and N Latex Lp(a)
Reagent from Dade Behring Marburg GmbH
(Liederbach, Germany). The lower limit of the
assay was 2.4 mg/dL (0.024 g/L). Liver and mus-
cle enzymes were measured by use of conven-
tional methods.
Statistical Analysis
All parameters were expressed as mean values ±
SD, except for Lp(a) and hsCRP, which were ex-
pressed as median values (range). Relationships
between variables were assessed by the Pearson’s
correlation coefficient, and Spearman correlation
coefficients for parametric and nonparametric
variables, respectively. Analysis of variance
(ANOVA) for repeated measurements was used
to assess post-rosuvastatin treatment changes in
parametric variables and Friedman’s ANOVA for
nonparametric variables as appropriate.
Significance was defined as p<0.05. Analyses
were performed using the SPSS 11.0 statistical
package for Windows (SPSS Inc, 1989–2001),
and Statistica 6.0 (Statsoft, Inc, 1984–2001).
Results
In total, 55 patients were included in the study
(29 men and 26 women) with a mean age of 52.5
±13.7 years and a body mass index of 25.8 ±4.6
kg/m
2
.
At baseline, serum tHcy concentrations corre-
lated positively with serum creatinine concentra-
tions (r=0.36, p=0.071), and inversely with
serum folic acid concentrations (r=–0.53,
p=0.010) and vitamin B12 levels (r=–0.49,
p=0.012).
Rosuvastatin therapy resulted in a significant
reduction in TC (by 37%), LDL-C (by 46.5%),
Apo B (by 35%), non HDL-C (ie, TC minus HDL-
C, by 44.2%), and TG (by 25%). HDL-C, Apo A-I,
and Lp(a) levels did not change significantly from
baseline following statin therapy (Table I). In
total, 39 of 55 patients (71%) achieved the LDL-
C treatment target of less than 130 mg/dL (3.4
mmol/L).
Glycemic parameters (fasting glucose, insulin,
HOMA index) and serum uric acid concentrations
were not significantly influenced by rosuvastatin
treatment (Table I).
Statin treatment produced no significant
changes in serum creatinine concentrations as
well as in the calculated creatinine clearance
(CrCl) measurements. (Figure 1, Table I). A sub-
group analysis of patients with baseline CrCl
equal to 70 mL/minute or less (n=15) revealed
no significant variations in serum creatinine (0.93
±0.15 vs 0.98 ±0.17 vs 0.92 ±0.16 mg/dL; 82
±13 vs 87 ±15 vs 81 ±14 µmol/L, p=NS) or
CrCl (61 ±8 vs 58 ±9 vs 59 ±7 mL/minute, p=
NS) following rosuvastatin therapy.
Rosuvastatin treatment resulted in a signifi-
cant reduction of serum hsCRP levels by 38.7%
(Table I).
Serum concentrations of tHcy were not mod-
ified in patients receiving rosuvastatin, and this
was also noted for serum folate and vitamin B12
values (Table I). There were no correlations be-
tween “posttreatment minus baseline” changes of
serum tHcy (DtHcy) concentrations and changes
in serum lipid concentrations, and between DtHcy
and changes in serum creatinine and/or creati-
nine clearance estimates. Finally, posttreatment
tHcy did not correlate with serum creatinine, fo-
late, or vitamin B12 concentrations after 20
weeks on rosuvastatin 10 mg/day.
Safety and Tolerability of Rosuvastatin
Treatment
Rosuvastatin treatment (10 mg/day) was gener-
ally well tolerated. All participants completed the
study protocol. Clinically significant elevations in
alanine aminotransferase (ALT, values >3 times
the upper limit of normal on 2 consecutive occa-
sions) or in creatine kinase (CK) levels (values
Milionis Rosuvastatin in Primary Hyperlipidemia
587

Angiology Volume 56, Number 5, 2005
588
Table I. Serum parameters at baseline and after 8 and 20 weeks of treatment with
rosuvastatin 10 mg/day (n=55)
Variable Baseline Posttreatment p
8 weeks 20 weeks
Glucose, mg/dL 98 ±19 100 ±16098 ±18 NS
Insulin, µU/mL 9.6 ±4.7 9.6 ±4.2 9.5 ±3.1 NS
HOMA index 2.7 ±1.5 2.7 ±1.8 2.6 ±1.2 NS
TC, mg/dL 295 ±420186 ±260188 ±320<0.0001
LDL-C, mg/dL 213 ±420111 ±260114 ±300<0.0010
TG, mg/dL 148 ±690113 ±400111 ±370<0.0001
HDL-C, mg/dL 53 ±8053 ±8054 ±80NS
non-HDL-C, mg/dL 242 ±430133 ±230135 ±300<0.0001
Apo A-I, mg/dL 132 ±310132 ±330135 ±210NS
Apo B, mg/dL 122 ±36077 ±22 80 ±24 <0.0001
Lp(a), mg/dL 18 (2–131) 17 (2–119) 17 (2–116) *NS*
Creatinine, mg/dL 0.88 ±0.13 0.88 ±0.17 0.86 ±0.13 NS
CrCl, mL/minute 89 ±26 89 ±27 89 ±26 NS
Uric acid, mg/dL 5.0 ±1.3 5.0 ±1.4 4.9 ±1.2 NS
hsCRP, mg/L .3.1 (0.7–7.2) .2.0 (0.9–5.0) .1.9 (0.8–4.4) *<0.0001*
tHcy, µU/L 10.2 ±3.2010.1 ±3.0010.2 ±3.40NS
Vitamin B12, pg/mL 340 ±133 342 ±141 339 ±122 NS
Folate, ng/mL 6.3 ±2.5 6.4 ±2.1 6.3 ±2.0 NS
*Friedman’s ANOVA
To convert values for glucose to mmol/L, multiply by 0.05551. To convert values for insulin
to pmol/L, multiply by 6.945. To convert TC, LDL-C, non HDL-C, and HDL-C levels from
mg/dL to mmol/dL, multiply by 0.02586. To convert TG levels from mg/dL to mmol/L
multiply by 0.01129. To convert values for creatinine to mmol/L, multiply by 88.40. To
convert serum uric acid levels from mg/dL to µmol/L, multiply by 59.48.
HOMA: homeostasis model assessment; TC: total cholesterol; LDL-C: low-density lipoprotein
cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; Apo: apolipopro-
tein; Lp(a): lipoprotein(a); CrCl: creatinine clearance; hsCRP: high-sensitivity C-reactive
protein; tHcy: total homocysteine; NS: nonsignificant.

>10 times the upper limit of normal) were not
observed during follow up.
One female patient reported muscle pain in
both upper limbs 3 days after rosuvastatin was
initiated. Physical examination was unremark-
able, and laboratory evaluation, including deter-
minations of aspartate aminotransferase (AST),
ALT, CK, lactic dehydrogenase (LDH), and al-
dolase levels, were within normal limits. Treat-
ment was not discontinued and the patient’s
symptoms resolved after 6 days.
Discussion
The study confirmed the efficacy of rosuvastatin
in improving the lipid profile (TC, LDL-C, Apo B,
non HDL-C, and TG reduction) in patients with
primary hyperlipidemia.
1-3
It is notable that a sig-
nificant proportion of patients (71%) achieved
the LDL-C treatment goal with rosuvastatin 10
mg/day. On the other hand, there was no signifi-
cant effect on serum HDL-C, Apo A-I, and Lp(a)
concentrations. This is in contrast to a previously
reported HDL-C-raising effect with rosuvastatin;
this difference could be attributed to the relative-
ly high pretreatment HDL-C levels.
1-3,10
Glycemic parameters and insulin resistance
estimates were not significantly altered by rosu-
vastatin. There are some reports suggesting that
statins can improve insulin resistance and de-
crease the long-term incidence of diabetes melli-
tus in dyslipidemic patients.
11,12
However, short-
term rosuvastatin treatment (10 mg/day for 20
weeks) did not seem to have any impact on in-
Milionis Rosuvastatin in Primary Hyperlipidemia
589
Figure 1.
Changes in serum creatinine
concentrations (A), and
creatinine clearance (B) at
baseline and after 8 and 20
weeks of treatment with
rosuvastatin 10 mg/day in the
study population (n=55).
A
B

sulin sensitivity in nondiabetic subjects with dys-
lipidemia. This finding is in agreement with re-
cently published data demonstrating that rosu-
vastatin does not enhance insulin sensitivity or
lower day-long glucose and insulin concentra-
tions in insulin-resistant, nondiabetic subjects
with combined hyperlipidemia.
13
No significant variations in renal function pa-
rameters (ie, serum creatinine and creatinine
clearance) were observed during the treatment
period. Dipstick-positive proteinuria has been de-
scribed in some patients who received 80 mg/day
of rosuvastatin in phase III trials.
14
However, fur-
ther assessment of the clinical program safety
database failed to show that this mild proteinuria
was predictive of any acute or progressive change
in renal function or that rosuvastatin therapy was
associated with deteriorating renal function.
14,15
The absence of change in renal function after a
5-month period of rosuvastatin therapy in our
study is in line with the findings of Vidt et al
15
in-
dicating an arrest in progression of renal disease
in dyslipidemic patients receiving rosuvastatin. In
terms of safety, it appears that the start dose (10
mg/day) of rosuvastatin does not have any im-
pact on kidney function in patients with primary
hyperlipidemia. Nevertheless, our results must be
interpreted within the context of certain limita-
tions, such as the short duration of our study (20
weeks) and lack of testing for hematuria or mi-
croalbuminuria.
There is evidence that statin therapy exerts
beneficial effects in patients with different types
of renal disease.
16
These effects include improve-
ment in renal function, decreased microalbumin-
uria, and a fall in blood pressure.
16-19
The under-
lying mechanism remains undefined and may in-
volve an increase in renal blood flow following
the lipid-lowering effect, which in turn may be
due to an increased production of nitric oxide
(NO).
20
A subgroup analysis in the Heart Protec-
tion Study showed that simvastatin significantly
reduced the fall in glomerular filtration rate in
high-risk patients with and without diabetes mel-
litus.
21
Atorvastatin shares this favorable effect as
shown in smaller as well as larger studies, in-
cluding the GREek Atorvastatin and Coronary
heart disease Evaluation (GREACE) Study.
22,23
The favorable effects on renal function with other
statins not seen with rosuvastatin 10 mg/day may
be ascribed to the administration of higher doses
of these agents and/or to patients with higher
levels of serum creatinine. Moreover, the “nonag-
gravating” effect of rosuvastatin on renal function
as shown in our study, favors cardiovascular dis-
ease protection, since there is evidence that ele-
vated serum creatinine concentrations, even with-
in normal range, are strong and independent pre-
dictors of coronary heart disease adverse out-
comes and stroke in high-risk patients.
24
Serum uric acid concentrations did not sig-
nificantly change from baseline after rosuvastatin
treatment. The pathophysiological mechanisms
underlying the association of serum uric acid with
vascular disease and all-cause mortality are not
fully clarified.
25
There is evidence that atorvas-
tatin may exert a hypouricemic effect, but this has
not been described with other statins.
6,26
Whether
higher doses of rosuvastatin affect serum urate
concentrations could be the subject of further in-
vestigation.
Rosuvastatin therapy had a neutral effect on
Hcy. Prospective and retrospective studies have
shown that elevated plasma concentrations of
tHcy are associated with a high prevalence of
cardiovascular disease, independently of con-
ventional risk factors.
5,27
Hcy is an intermediate
amino acid resulting from the metabolism of me-
thionine and is known to be toxic to vascular en-
dothelium.
5,27
tHcy concentrations are mainly de-
termined by folate and cobalamin status and by
renal function, which was also evident in our
study.
5,28
Pharmacologic agents, including lipid-
lowering drugs, may influence tHcy levels.
5,28,29
Fibrates have been shown to raise tHcy levels,
and this has been partly attributed to the impair-
ment of renal function,
5,30,31
whereas statin ther-
apy appears to exert a neutral effect on tHcy lev-
els, with the exception of high-dose simvastatin
(80 mg/day), which has been reported to lower
tHcy plasma concentrations.
5,32-36
In agreement
with our findings, in a placebo-controlled study
of 46 hypercholesterolemic patients, rosuvastatin
at 10 mg/day did not significantly affect tHcy
levels.
37
The lack of any influence on serum folic
acid and vitamin B12 levels together with the
nondeteriorating effect on renal function para-
meters may account for the “neutral” effect of ro-
suvastatin on tHcy.
A substantial decrease in hsCRP levels, which
are considered strong predictors of ischemic heart
disease and the severity of atherosclerosis, was
noted following statin treatment.
38
This CRP-low-
ering effect seems to be a shared property among
statins.
6,39
It has been shown that patients who
have low CRP levels after statin therapy have bet-
ter clinical outcomes than those with higher CRP
levels, regardless of the resultant level of LDL-C.
40
Moreover, in patients with coronary artery dis-
ease, intensive statin treatment leading to greater
Angiology Volume 56, Number 5, 2005
590

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Even at the starting dose of 10 mg/day,
rosuvastatin constitutes a potent lipid-lowering
and antiinflammatory therapeutic regimen.
In conclusion, rosuvastatin at the recom-
mended starting dose of 10 mg/day appears to be
a highly effective, safe, and well-tolerated mono-
therapy option for patients with primary hyper-
lipidemia. Its “neutral” effects on renal function
indices, glycemic control, and other “biomarkers,”
including serum uric acid and homocysteine, as
well as a CRP-related potential antiinflammatory
action offer considerable advantages.
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