European Journal of Heart Failure (2009) 11, 11951201

doi:10.1093/eurjhf/hfp144

Effect of simvastatin vs. rosuvastatin on

adiponectin and haemoglobin A1c levels in
patients with non-ischaemic chronic heart failure
Takayoshi Tsutamoto*, Masayuki Yamaji, Chiho Kawahara, Keizo Nishiyama,
Masanori Fujii, Takashi Yamamoto, and Minoru Horie
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
Received 12 May 2009; revised 7 August 2009; accepted 9 September 2009; online publish-ahead-of-print 4 November 2009

To compare the effects of lipophilic simvastatin and hydrophilic rosuvastatin on plasma adiponectin and glycated haemoglobin A1c (HbA1c) levels in patients with non-ischaemic chronic heart failure (NICHF).
.....................................................................................................................................................................................
Methods
Seventy-one stable outpatients with NICHF, who were already receiving standard therapy for CHF, were randomized
to simvastatin (n 35) or rosuvastatin (n 36). Plasma levels of brain natriuretic peptide (BNP), total adiponectin,
and results
high-sensitive C-reactive protein, HbA1c, and oxidized low-density lipoprotein (oxLDL), a marker of oxidative stress,
were measured before and 4 months after treatment with simvastatin or rosuvastatin. There was no difference in the
baseline characteristics including left ventricular ejection fraction (LVEF) and biochemical parameters between the
two groups. In both groups, plasma BNP levels and LVEF did not change after 4 months. Plasma levels of adiponectin
and oxLDL did not change and HbA1c level was slightly increased (6.0 + 0.9 vs. 6.1 + 0.9%, P 0.053) in the simvastatin group. In contrast, plasma adiponectin level was significantly increased (12.3 + 7.3 vs. 14.0 + 8.2 mg/mL,
P 0.012) concomitant with a significant reduction in oxLDL and HbA1c (oxLDL: 8.8 + 4.7 vs. 7.6 + 4.7 U/mL,
P 0.0059; HbA1c: 6.0 + 0.7 vs. 5.9 + 0.7%, P 0.002) in the rosuvastatin group.
.....................................................................................................................................................................................
Conclusion
These findings suggest that hydrophilic rosuvastatin but not lipophilic simvastatin increases adiponectin and decreases
HbA1c levels in patients with NICHF.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Heart failure Statin Glycated haemoglobin Adiponectin Brain natriuretic peptide

Introduction
Chronic heart failure (CHF) is characterized by a complex syndrome of haemodynamic, neurohumoral, and metabolic abnormalities with high mortality. Recently, in diabetic and non-diabetic
patients with CHF, the haemoglobin A1c (HbA1c) level was
reported to be an independent risk factor for mortality in the
CHARM study population,1 suggesting the important role of
insulin resistance in CHF. Adiponectin, which is an adipocytespecific cytokine, is abundant in plasma and has important metabolic effects including insulin sensitivity2,3 and may predict cardiovascular events in CHF patients.4,5
Metabolic effects of lipophilic and hydrophilic statins may be
different in patients with hypercholesterolaemia,6 8 type 2

diabetes mellitus (DM),9,10 and coronary artery disease.11 In

addition, cardiac effects of lipophilic and hydrophilic statins may
be different on ischaemia-induced myocardial stunning.12
However, there has not been any report about differences
between the effects of lipophilic and hydrophilic statins on
plasma adiponectin and HbA1c levels in patients with CHF. Furthermore, insulin resistance and abnormal glucose tolerance are
often observed in patients with non-ischaemic CHF (NICHF),13
suggesting that insulin resistance is a potential therapeutic target
in patients with NICHF.
The present study compared the effects of lipophilic simvastatin
and hydrophilic rosuvastatin on plasma adiponectin and HbA1c
levels in patients with NICHF who were already receiving standard
therapy.

* Corresponding author. Tel: 81 77 548 2213, Fax: 81 77 543 5839, Email: tutamoto@belle.shiga-med.ac.jp
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Downloaded from http://eurjhf.oxfordjournals.org/ by guest on April 25, 2012

Aims

1196

Methods
Patients
The subjects were 71 stable NICHF outpatients who had already
received standard therapy for .6 months (mean follow-up period
2.2 + 0.15 years). Left ventricular ejection fraction (LVEF) was
measured by two-dimensional echocardiography or ventriculography
using contrast medium or radioisotope and LVEF was ,45% at the
initial diagnosis in all subjects. Aetiology of systolic CHF was dilated
cardiomyopathy or hypertensive heart disease. Patients with coronary
artery disease, valvular heart disease, malignancy, or renal failure
(serum creatinine .2.0 mg/dL) were excluded. Moreover, patients
who were already receiving pioglitazone hydrochloride or telmisartan,
which are ligands of the peroxisome proliferator-activated receptor g,
were also excluded. Informed consent was obtained from all patients
for participation in the study, according to the protocol approved by
the Committee on Human Investigation at our institution.

Seventy-one stable outpatients with NICHF, who were already

receiving standard therapy for CHF, were randomized to simvastatin
(5 mg/day, n 35) or rosuvastatin (2.5 mg/day, n 36). Blood
samples were drawn from the antecubital vein, after at least 30 min
of supine bed rest, and LVEF was measured by the biplane disc summation method on echocardiography (Simpsons rule) before and
after 4 months of simvastatin or rosuvastatin treatment. The levels
of HbA1c in the plasma, and serum total cholesterol, triglyceride, highdensity lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL)
cholesterol, and creatinine, were determined before and 4 months
after either simvastatin or rosuvastatin.

Measurements of oxidized low-density

lipoprotein, brain natriuretic peptide,
high-sensitive C-reactive protein,
and adiponectin
Blood for measurement of the plasma level of oxidized LDL (oxLDL), a
marker of oxidative stress, was placed into a plain tube, centrifuged at
1900 g for 15 min at 48C until assayed. Plasma level of oxLDL was
measured with a specific immunoradiometric assay using a commercial
kit (Kyowa Medex, Tokyo, Japan), as reported previously.14 Plasma
total adiponectin level was measured by a sandwich ELISA system as
reported previously.5 The plasma concentrations of brain natriuretic
peptide (BNP) were measured with a specific immunoradiometric
assay for human BNP using a commercial kit as reported previously.15
Blood for measurement of the serum level of high-sensitive C-reactive
protein was transferred to a chilled tube, then centrifuged at 1900 g for
15 min at 48C, and the serum thus obtained was stored at 2308C
until assay. Serum high-sensitive C-reactive protein was measured by
a sensitive nephelometric assay (Behring Diagnostics, Marburg,
Germany) as reported previously.16

Statistical analysis
All results are expressed as mean + SD. Categorical data were compared against a x 2 distribution. Univariate analysis was performed
using Students t-test. Responses after rosuvastatin therapy were compared with those after simvastatin therapy using ANOVA. Because
BNP and high-sensitive C-reactive protein levels were not normally
distributed, differences between the groups were analysed by
Mann Whitney U-test and differences in mean levels of these
before and after administration of simvastatin or rosuvastatin were

tested by non-parametric Wilcoxons rank-sum test for paired

values. Pearsons correlation coefficient was used to determine correlations and regression analysis. A two-tailed probability value of 0.05
was considered as significant. A P-value of ,0.05 was regarded as
significant.

Results
Patient characteristics
There was no difference in baseline characteristics between the
two groups (Table 1). At entry into the study, most patients
were receiving ACE-inhibitors or ARBs and b-blockers. There
was no difference in baseline biomarkers such as lipid profile,
BNP, HbA1c, high-sensitive C-reactive protein, oxLDL, and adiponectin level between the two groups.

Comparison of adiponectin and

haemoglobin A1c before and after
randomized treatment
In both groups, body mass index (BMI), NYHA functional class,
LVEF, and plasma BNP level did not change and serum total cholesterol, triglyceride, and LDL cholesterol were significantly
decreased after 4 months compared with the baseline value
(Table 2). Plasma levels of high-sensitive C-reactive protein
(2.0 + 2.9 vs. 1.2 + 1.3 mg/L, P 0.006 within-group, P 0.041
with ANOVA) and oxLDL (8.8 + 4.7 vs. 7.6 + 4.7 U/mL, P
0.0059 within-group, P 0.032 with ANOVA) were significantly
decreased in the rosuvastatin group but not in the simvastatin
group. In patients receiving simvastatin, HbA1c level was slightly
increased (6.0 + 0.9 vs. 6.1 + 0.9%, P 0.053). In contrast,
HbA1c level was significantly decreased in patients receiving rosuvastatin (6.0 + 0.7 vs. 5.9 + 0.7%, P 0.002 within-group, P
0.0003 with ANOVA). In both groups, plasma LDL cholesterol
levels were significantly decreased with more reduction in the
rosuvastatin group than the simvastatin group (P 0.0192 with
ANOVA). Plasma levels of adiponectin did not change (adiponectin: 10.2 + 5.7 vs. 10.0 + 5.0 mg/mL, P 0.591) in the simvastatin
group. In contrast, the plasma adiponectin level was significantly
increased
(12.3 + 7.3
vs.
14.0 + 8.2 mg/mL,
P 0.012
within-group, P 0.01 with ANOVA) in the rosuvastatin group.

Correlation between the changes in

adiponectin and those in haemoglobin
A1c, in non-ischaemic chronic heart
failure patients receiving rosuvastatin
In patients receiving simvastatin, there was no correlation between
delta change of adiponectin (adiponectin after 4 monthsadiponectin at baseline) and that of HbA1c (HbA1c after 4 months
HbA1c at baseline). In patients receiving rosuvastatin, there was
a significant correlation between delta change of adiponectin and
that of HbA1c (r 20.416, P 0.011) (Figure 1). In both
groups, there was no significant correlation between delta
change of adiponectin and that of HDL cholesterol. In patients
receiving simvastatin, there was no correlation between delta
change of adiponectin and that of oxLDL. In patients receiving

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Study protocol

T. Tsutamoto et al.

1197

Effect of rosuvastatin on adiponectin and HbA1c in CHF

Table 1 Comparisons of baseline characteristics between chronic heart failure patients treated with simvastatin and
rosuvastatin
Variables

Simvastatin (n 5 35)

Rosuvastatin (n 5 36)

P-value

Age (years)
Gender (male/female)

64.0 + 9.9
32/3

66.8 + 10.9
30/6

0.837
0.478

DCM/HHD (n)

32/3

29/7

0.307

Diabetes Mellitus, n (%)

Hyperlipidaemia, n (%)

9 (26)
6 (17)

14 (39)
9 (25)

0.312
0.562

I/II/III (n)
LVEF (%)

7/24/4
44.4 + 10

7/26/3
44.7 + 8.8

0.927

BMI (kg/m2)

23.6 + 3.6

23.6 + 3.0

0.303

Creatinine (mg/dL)
Haemoglobin A1c (%)

1.1 + 0.4
6.0 + 0.9

1.1 + 0.4
6.0 + 0.7

0.972
0.911

BNP (pg/mL) (median)

195 + 213 (108)

135 + 154 (85)

0.385

Total cholesterol (mg/dL)

Triglyceride (mg/dL)

179 + 36
186 + 96

193 + 40
176 + 80

0.105
0.659

HDL cholesterol (mg/dL)

42.6 + 12

44 + 13

0.633

LDL cholesterol (mg/dL)

High-sensitive C-reactive protein (mg/L) (median)

104 + 26
1.2 + 1.2 (0.6)

113 + 33
2.0 + 2.9 (1.0)

0.224
0.251

oxLDL (U/mL)

7.4 + 4.3

8.8 + 4.7

0.184

Adiponectin (mg/mL)
Treatments

10.2 + 5.7

12.3 + 7.3

0.185

Digitalis, n (%)

9 (25)

9 (26)

0.999

Loop diuretics, n (%)

Spironolactone, n (%)

22 (63)
31 (89)

20 (57)
25 (69)

0.631
0.133

ACE-I or ARB, n (%)

34 (97)

34 (94)

0.999

b-Blockers, n (%)

33 (94)

32 (91)

0.673

...............................................................................................................................................................................

NYHA class

0.900

rosuvastatin, there was a significant correlation between delta

change of adiponectin and that of oxLDL (r 20.391, P 0.02)
(Figure 2).

Discussion
The effects of statins on insulin sensitivity in patients with metabolic syndrome or type 2 diabetes are controversial.17 19 Lipophilic statins, particularly at high doses, may cause unfavourable
pleiotropic effects such as reduction of insulin secretion and
exacerbation of insulin resistance.9,10 Indeed, recent large-scale
clinical studies demonstrate that lipophilic statins, particularly at a
high dose, may increase the rate of onset of new diabetes.6,20,21
Therefore, in the present study we used a low dose of simvastatin
and rosuvastatin in patients with NICHF. Recently, Qu et al. 8
reported that rosuvastatin but not atorvastatin increased serum
adiponectin levels in patients with hypercholesterolaemia, which
is consistent with our finding in patients with NICHF.
Plasma levels of adiponectin are negatively correlated with adiposity and insulin resistance.2,3 In the present study, rosuvastatin
increased adiponectin levels and decreased HbA1c levels without

changing BMI. Thus, decreased levels of adiponectin may

promote insulin resistance rather than simply serving as a biomarker for insulin sensitivity. In addition, Desjardins et al. 22
recently reported that rosuvastatin increased vascular endothelial
PPARg expression and corrected blood pressure variability in
obese dyslipidaemic mice, supporting our findings.
Previous studies have reported that hydrophilic pravastatin
decreased HbA1c level in non-diabetic hypercholesterolaemia23 or
in patients with coronary artery disease,24 which is consistent with
our finding. However, in the recent JUPITER trial,25 rosuvastatin
therapy caused a small but significant increase in HbA1c levels in
apparently healthy persons without hyperlipidaemia but with elevated
high-sensitive C-reactive protein. The mechanism of the increase in
HbA1c in the JUPITER trial is unknown, but it has been suggested
that statins may deteriorate glycaemic control by decreasing various
metabolites, including isoprenoid, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. In the present study, a small but significant
decrease in HbA1c was observed 4 months after rosuvastatin therapy
(2.5 mg/day) in CHF patients. The reasons for this discrepancy are
unclear, but differences in the doses of rosuvastatin, follow-up
periods, and disease severity may contribute.

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ACE-I, angiotensin-converting inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BNP, brain natriuretic peptide; HDL cholesterol, high-density lipoprotein
cholesterol; LDL cholesterol, low-density lipoprotein cholesterol; DCM, dilated cardiomyopathy; HHD, hypertensive heart disease; LVEF, left ventricular ejection fraction; oxLDL,
oxidized LDL.

1198

T. Tsutamoto et al.

Table 2 Clinical and biochemical markers before and after randomized treatment
Treatment

Baseline

4 months

P-value (ANOVA)

............................................................

Group effect

Time effect

Group time
interaction

...............................................................................................................................................................................
Simvastatin
Rosuvastatin

23.6 + 3.6
23.6 + 3.0

23.7 + 3.1
23.6 + 3.9

NS

NS

NS

LVEF (%)

Simvastatin
Rosuvastatin

44.4 + 10
44.8 + 8.8

45.1 + 10
43.9 + 8.8

NS

NS

NS

BNP (pg/mL) (median)

Simvastatin
Rosuvastatin

195 + 213 (108)

135 + 154 (85)

193 + 239 (110)

149 + 221 (98)

NS

NS

NS

Total cholesterol (mg/dL)

Simvastatin
Rosuvastatin

179 + 36
193 + 40

144 + 28$
145 + 20$

NS

,0.0001

0.056

Triglyceride (mg/dL)

Simvastatin
Rosuvastatin
Simvastatin
Rosuvastatin
Simvastatin
Rosuvastatin
Simvastatin
Rosuvastatin
Simvastatin
Rosuvastatin
Simvastatin
Rosuvastatin
Simvastatin
Rosuvastatin

186 + 96
176 + 80
42.6 + 12
44 + 13
104 + 26
113 + 33
7.4 + 4.3
8.8 + 4.7
1.2 + 1.2(0.6)
2.0 + 2.9(1.0)
10.2 + 5.7
12.3 + 7.3
6.0 + 0.9
6.0 + 0.7

155 + 92*
138 + 60#
43.3 + 10
47.3 + 12#
75 + 21$
72 + 16$
6.9 + 3.0
7.6 + 4.7#
0.9 + 1.0 (0.6)
1.2 + 1.3 (0.7)#
10.0 + 5.0
14.0 + 8.2*
6.1 + 0.9
5.9 + 0.7#

NS

0.003

NS

NS

0.031

0.164

NS

,0.0001

0.0192

NS

0.0003

0.032

NS

0.016

0.041

NS

0.025

0.01

NS

0.054

0.0003

HDL cholesterol (mg/dL)

LDL cholesterol (mg/dL)
oxLDL (U/mL)
High-sensitive C-reactive protein
(mg/L) (median)
Adiponectin (mg/mL)
Haemoglobin A1c (%)

BMI, body mass index; BNP, brain natriuretic peptide; HDL cholesterol, high-density lipoprotein cholesterol; LDL cholesterol, low-density lipoprotein cholesterol; LVEF, left
ventricular ejection fraction; oxLDL, oxidized LDL.
*P , 0.05, #P , 0.01, and $P , 0.001 vs. the baseline value within each group.

Figure 1 (A) Comparison between delta change of adiponectin (adiponectin after 4 months adiponectin at baseline) and that of haemoglobin A1c (haemoglobin A1c after 4 months haemoglobin A1c at baseline) in patients receiving simvastatin. (B) Correlation between delta
change of adiponectin (adiponectin after 4 months adiponectin at baseline) and that of haemoglobin A1c (haemoglobin A1c after
4 months haemoglobin A1c at baseline) in patients receiving rosuvastatin.

Simvastatin therapy did not affect circulating adiponectin levels

without changing BMI, which is consistent with a previous study
in patients with metabolic syndrome.19 Other studies have
shown that simvastatin therapy significantly decreased adiponectin

levels without a corresponding change in BMI.7,26 In the present

study, HbA1c levels were slightly increased after simvastatin
therapy, suggesting the possible exacerbation of insulin
resistance.10

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BMI (kg/m2)

1199

Effect of rosuvastatin on adiponectin and HbA1c in CHF

Figure 2 (A) Comparison between delta change of oxidized low-density lipoprotein (oxidized low-density lipoprotein after 4 months oxi-

In CHF patients, plasma adiponectin levels are regulated by

various factors including up-regulators (BNP, female) and downregulators (BMI, DM). Recently, a high level of plasma oxLDL, as
a marker of oxidative stress and a prognostic predictor,14,27 was
reported to be an independent predictor of a high adiponectin
level in CHF patients.28 In the present study, rosuvastatin
therapy decreased oxLDL in association with a correlation
between delta change of adiponectin and that of oxLDL. The
effect of rosuvastatin therapy on oxLDL was reported in patients
with hypercholesterolaemia.29 The mechanism of the differential
effect on oxLDL between rosuvastatin and simvastatin remains
uncertain. It has been suggested that intermolecular differences
between statins contribute to differences in pleiotropic effects
such as nitric oxide bioavailability, anti-inflammatory activity, and
inhibition of oxidative stress.30
Node et al. 31 reported that low-dose simvastatin therapy
improved LVEF and decreased plasma BNP levels in patients with
NICHF. Krum et al. 32 reported that high-dose rosuvastatin had
no effect on LVEF or BNP in patients with CHF mainly due to nonischaemic aetiology. In the present study, low-dose rosuvastatin
had no effect on LVEF or BNP in patients with NICHF, but
decreased plasma high-sensitive C-reactive protein, which is an
independent prognostic predictor in patients with NICHF.16 The
reasons for an absence of benefit on LVEF and BNP in this study
remain uncertain. There are, however, a number of possibilities
that may be considered. It may be that the anti-ischaemic effects
of statins are the major driver of benefit on LVEF and BNP, and
this benefit was apparently observed in an ischaemic patient population. However, the effects of statins on cardiovascular endpoints
were neutral in CORONA33 and GISSI-HF.34
Heart failure itself is an insulin-resistant state,13,35 and insulin
resistance increases the incidence of heart failure36 and has been
shown to be independently associated with worsening
New York Heart Association functional class37 and poor prognosis.38 Adiponectin has a cardioprotective effect and plasma

adiponectin levels are negatively correlated with insulin resistance.

Furthermore, as direct evidence, a previous report demonstrated
that administration of adiponectin decreased the plasma glucose
levels in normal mice.39 Therefore, our finding that rosuvastatin
increased adiponectin and decreased HbA1c levels might indicate
that hydrophilic rosuvastatin treatment is more useful than lipophilic simvastatin for the management of CHF with or without DM.

Study limitations
Several limitations should be noted in the interpretation of these
results. First, the small number of patients with NICHF and the
relatively short-term follow-up period were limitations. Second,
most patients in the present study had mild CHF (NYHA functional class I or II), therefore our conclusions may be limited to
patients with mild CHF. Third, we did not measure or evaluate
markers of glucose metabolism such as the fasting blood sugar
or insulin level. Further studies are needed to evaluate the influence of the increase in adiponectin levels by administration of
rosuvastatin on glucose metabolism in patients with CHF. Finally,
we did not measure inflammatory cytokines such as tumour necrosis factor-a and interleukin-6, which may interact with adiponectin
levels in patients with CHF. Further studies are needed to clarify
this issue.
In conclusion, hydrophilic rosuvastatin but not lipophilic simvastatin increased adiponectin and decreased HbA1c levels in patients
with NICHF who were already receiving standard therapy,
suggesting that the metabolic effects of lipophilic and hydrophilic
statins are not similar in patients with CHF.

Acknowledgements
We wish to thank Ms Yohko Watanabe for excellent technical
assistance. We also express thanks to Mr Daniel Mrozek for assistance in preparing the manuscript.

Downloaded from http://eurjhf.oxfordjournals.org/ by guest on April 25, 2012

dized low-density lipoprotein at baseline) and that of adiponectin (adiponectin after 4 months adiponectin at baseline) in patients receiving
simvastatin. (B) Correlation between that of oxidized low-density lipoprotein (oxidized low-density lipoprotein after 4 months oxidized lowdensity lipoprotein at baseline) and that of adiponectin (adiponectin after 4 months adiponectin at baseline) in patients receiving rosuvastatin.

1200

Funding
This study was supported by a Grant-in-Aid for Scientific Research in
Japan.
Conflict of interest: none declared.

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