Comparative effect of olmesartan and candesartan on lipid metabolism and renal function in patients with hypertension: a retrospective observational study.

Abstract

Angiotensin II receptor blockers (ARBs), including olmesartan and candesartan, are widely used antihypertensive agents. Many clinical studies have demonstrated that ARBs have organ-protecting effects, e.g., cardioprotection, vasculoprotection and renoprotection. However, the effect of prolonged olmesartan monotherapy on lipid metabolism in patients with hypertension is less well studied. We performed a retrospective observational study to compare the effects of olmesartan with those of candesartan, focusing on lipid metabolism and renal function.
We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and Feb 28, 2011, to identify cohorts of new olmesartan users (n = 168) and candesartan users (n = 266). We used propensity-score weighting to adjust for differences in all covariates (age, sex, comorbid diseases, previous drugs) between olmesartan and candesartan users, and compared serum chemical data including serum triglyceride (TG), LDL-cholesterol (LDL-C), total cholesterol (TC), potassium, creatinine and urea nitrogen. The mean exposure of olmesartan and candesartan users was 126.1 and 122.8 days, respectively.
After adjustment, there were no statistically significant differences in all covariates between olmesartan and candesartan users. The mean age was 60.7 and 61.0 years, and 33.4% and 33.7% of olmesartan and candesartan users were women, respectively. There were no statistically significant differences in mean values for all laboratory tests between baseline and during the exposure period in both olmesartan and candesartan users. In olmesartan users, the reduction of serum TG level was significant in comparison with that in candesartan users. Other parameters of lipid profile and renal function showed no statistically significant difference in the change from baseline to during the exposure period between olmesartan and candesartan users.
In this study, we observed a more beneficial effect on lipid metabolism, a reduction of serum TG, with olmesartan monotherapy than with candesartan monotherapy. However, there were no clinically significant changes in the levels of all test parameters between baseline and during the exposure period with both drugs. These results suggest that the influence of olmesartan or candesartan monotherapy on lipid metabolism and renal function is small, and that they can be safely used in patients with hypertension.

Full text

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ORIGINAL INVESTIGATION Open Access
Comparative effect of olmesartan and
candesartan on lipid metabolism and renal
function in patients with hypertension:
a retrospective observational study
Yayoi Nishida1,2, Yasuo Takahashi1,2*, Tomohiro Nakayama4, Masayoshi Soma5and Satoshi Asai2,3
Abstract
Background: Angiotensin II receptor blockers (ARBs), including olmesartan and candesartan, are widely used
antihypertensive agents. Many clinical studies have demonstrated that ARBs have organ-protecting effects, e.g.,
cardioprotection, vasculoprotection and renoprotection. However, the effect of prolonged olmesartan monotherapy
on lipid metabolism in patients with hypertension is less well studied. We performed a retrospective observational
study to compare the effects of olmesartan with those of candesartan, focusing on lipid metabolism and renal
function.
Methods: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained
between Nov 1, 2004 and Feb 28, 2011, to identify cohorts of new olmesartan users (n = 168) and candesartan
users (n = 266). We used propensity-score weighting to adjust for differences in all covariates (age, sex, comorbid
diseases, previous drugs) between olmesartan and candesartan users, and compared serum chemical data
including serum triglyceride (TG), LDL-cholesterol (LDL-C), total cholesterol (TC), potassium, creatinine and urea
nitrogen. The mean exposure of olmesartan and candesartan users was 126.1 and 122.8 days, respectively.
Results: After adjustment, there were no statistically significant differences in all covariates between olmesartan
and candesartan users. The mean age was 60.7 and 61.0 years, and 33.4% and 33.7% of olmesartan and
candesartan users were women, respectively. There were no statistically significant differences in mean values for
all laboratory tests between baseline and during the exposure period in both olmesartan and candesartan users. In
olmesartan users, the reduction of serum TG level was significant in comparison with that in candesartan users.
Other parameters of lipid profile and renal function showed no statistically significant difference in the change
from baseline to during the exposure period between olmesartan and candesartan users.
Conclusions: In this study, we observed a more beneficial effect on lipid metabolism, a reduction of serum TG,
with olmesartan monotherapy than with candesartan monotherapy. However, there were no clinically significant
changes in the levels of all test parameters between baseline and during the exposure period with both drugs.
These results suggest that the influence of olmesartan or candesartan monotherapy on lipid metabolism and renal
function is small, and that they can be safely used in patients with hypertension.
Keywords: angiotensin II receptor blocker (ARB), olmesartan, candesartan, lipid metabolism, renal function, retro-
spective observational study
* Correspondence: takahashi.yasuo@nihon-u.ac.jp
1Division of Genomic Epidemiology and Clinical Trials, Advanced Medical
Research Center, Nihon University School of Medicine, 30-1 Oyaguchi-
Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan
Full list of author information is available at the end of the article
Nishida et al. Cardiovascular Diabetology 2011, 10:74
http://www.cardiab.com/content/10/1/74
CARDIO
VASCULAR
DIABETOLOGY
© 2011 Nishida et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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Introduction
Angiotensin II receptor blockers (ARBs) are widely used
antihypertensive agents that act through inhibition of
angiotensin II type 1 (AT1) receptors. In addition to
antihypertensive effects, ARBs have been shown to have
organ-protecting effects, including vasculoprotection [1],
cardioprotection [2] and renoprotection [3,4]. Peroxi-
some proliferator activated receptor gamma (PPAR-g),
an intracellular receptor that regulates glucose and lipid
metabolism, is modulated by different ARBs. Thereby,
ARBs have been considered to improve insulin resis-
tance [5,6], and we reported that monotherapy with
ARBs had a favorable effect on glucose metabolism [7].
Differences in pharmacology and pleiotropic effects
appear to exist across ARBs [5,6], which may be of clini-
cal importance and help physicians make decisions on
drug selection.
Hypertension and dyslipidemia are conditions that fre-
quently coexist. They are both major determinants of
cardiovascular disease, and together cause an increase in
coronary heart disease-related events [8]. In experimen-
tal models, some ARBs have demonstrated the ability to
affect lipid metabolism in a modest but significant way
[9]. Whether ARBs have a favorable effect on lipid
metabolism in humans may be of clinical significance,
especially in treating patients with dyslipidemia. Cande-
sartan, which binds more tightly to and dissociates more
slowly from the AT1receptor than other ARBs, had the
weakest PPAR-g modulatory activity [5,6]. Our recent
study showed that candesartan monotherapy at a thera-
peutic dosage had a minimal effect on lipid metabolism
for long periods up to 12 months [10]. Olmesartan
medoxomil is an ARB that is characterized by strong
blood pressure-lowering efficacy with a fast onset, pro-
longed duration of action and good tolerability. Olme-
sartan has moderate PPAR-g modulator activity [5,6],
and thereby has the possibility of affecting lipid metabo-
lism. Some clinical studies have demonstrated that
olmesartan has organ-protecting effects, including long-
term renoprotection in patients with type 2 diabetes,
and beneficial effects to reduce cardiovascular risk in
patients with atherosclerosis [11,12]. A few clinical stu-
dies reported the effect of olmesartan on lipid metabo-
lism [13-15]. However, their subjects were patients who
were treated with olmesartan combined with other anti-
hypertensive drugs or lipid-lowering drugs. Therefore,
the effect of prolonged olmesartan monotherapy on
lipid metabolism in patients with hypertension is less
well studied. In this study, we examined changes in the
plasma lipid profile of new users of generally prescribed
doses of olmesartan medoxomil, and compared them
with those in new users of candesartan cilexetil at doses
that have previously shown a minimal effect on lipid
metabolism. We also examined changes in serum potas-
sium level in addition to serum creatinine level and
serum urea nitrogen, as parameters of renal function.
Methods
Data source
This was a retrospective database study using the Nihon
University School of Medicine (NUSM) Clinical Data
Warehouse (CDW), which is a centralized data repository
that integrates separate databases, such as an order entry
database and a laboratory results database, from the hos-
pital information systems at three hospitals affiliated with
NUSM. The prescription database in the CDW contains
information from over 0.5 million patients, and prescrib-
ing data are linked longitudinally to detailed clinical
information such as patient demographics, diagnosis, and
laboratory data. Several epidemiological studies examin-
ing the effects of antihypertensive drugs on metabolic
and electrolyte changes using NUSM’s CDW have been
published [7,10,16].
Study population
Patients with mild to moderate hypertension, aged over
20 years who had been newly treated with olmesartan
medoxomil or candesartan cilexetil for at least four
weeks between November, 2004 and February, 2011,
were identified for the study. We identified 6,724
patients with olmesartan treatment and 11,069 patients
with candesartan treatment who fulfilled the above cri-
teria. We excluded patients who had been treated with
other antihypertensive drugs (ARB other than olmesar-
tan or candesartan, ARB combination drug, calcium
channel blocker, angiotensin-converting enzyme inhibi-
tor (ACEI), diuretic, alpha-blocker, beta-blocker, alpha
and beta-blocker, alpha-agonist, reserpine, vasodilator,
renin inhibitor) during the study period. We also
excluded patients who had received the following drugs
that affect the serum levels of parameters of lipid meta-
bolism or renal function: lipid-lowering drugs, potas-
sium preparations, and ion-exchange resins (e.g. sodium
polystyrene sulfonate), in the 60 days preceding the date
of a laboratory test. Consequently, the study cohorts
included 168 new users of olmesartan monotherapy
(who received 5-40 mg/day) and 266 new users of can-
desartan monotherapy (who received 1-12 mg/day). The
experimental protocol was approved by the Ethical
Committee of Nihon University School of Medicine.
Exposure and measurements
The baseline measurement period (non-exposure period)
was defined as 90 days before the start of olmesartan or
candesartan monotherapy. The exposure period (out-
come measurement period) was defined as between
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1 and 6 months after the start of olmesartan or cande-
sartan monotherapy. The mean exposure of olmesartan
users and candesartan users was 126.1 days and 122.8
days, respectively. Blood test data, including serum low-
density lipoprotein-cholesterol (LDL-C), triglyceride
(TG), total cholesterol (TC), potassium, creatinine and
urea nitrogen, were collected for each individual at the
date nearest the start of olmesartan or candesartan
monotherapy in the baseline period, and at the date
nearest six months after the start of olmesartan or can-
desartan monotherapy in the exposure period.
Data elements
For each patient, we collected information of patient
demographics (age and sex), medical history, use of
drugs, and laboratory results. Medical history included
cerebrovascular disease (ICD-10 code, I60-I69), ischemic
heart disease (I20-I25), other heart disease (I30-I52),
liver disease (K70-K77), kidney disease (N00-N19), gout
(M10), thyroid gland disorder (E00-E07), hyperlipidemia
(E78.0-E78.5), diabetes mellitus (E10-E14), and malig-
nant neoplasm (C00-C97) diagnosed in the 365 days
preceding the first date of prescription of olmesartan or
candesartan. Drugs used during the 60 days before the
start of olmesartan or candesartan monotherapy
included chemotherapeutic drugs, immunosuppressive
drugs, steroids, insulin, oral hypoglycemic drugs, and
thyroid drugs.
Statistical analysis
All statistical analyses were performed with SAS soft-
ware, version 9.1.3 (SAS Institute Inc., Cary, NC). To
compare differences in baseline characteristics, we used
t-test for continuous variables and chi-squared test for
categorical data. Adjustments for differences as observed
in Table 1 were performed using a propensity-score
weighting technique to balance treatment groups and
address the potential for treatment selection bias
[17-19]. This method is also known as the inverse prob-
ability of treatment weighted (IPTW) estimator,
described by Robins and colleagues [20]. To apply this
method, the propensity score for each subject was
obtained by fitting a logistic regression model that
includes the predictor variable (i.e., olmesartan user or
candesartan user) as an outcome and all baseline covari-
ates as shown in Table 1. After the propensity score was
constructed, we calculated the propensity score weight
as the inverse of the propensity score. Paired t-test and
a propensity score-weighted t-test were used to compare
the differences in means between baseline and during
the exposure period, and between olmesartan users and
candesartan users, respectively. All reported p-values are
two sided. A result was considered statistically signifi-
cant if the p value was less than 0.05.
Results
Table 1 shows the characteristics of the patients who
had been treated with olmesartan monotherapy or can-
desartan monotherapy, before and after IPTW adjust-
ment. Before adjustment, olmesartan users were more
likely to have ischemic heart disease and diabetes, utiliz-
ing more antidiabetic agents including insulin and oral
hyperglycemic drugs, than candesartan users. After
IPTW adjustment, the mean age was 60.7 and 61.0
years, and 33.4% and 33.7% of olmesartan and candesar-
tan users were women, respectively. There was no statis-
tically significant difference in all covariates between
olmesartan users and candesartan users.
Table 2 shows the results of laboratory tests at base-
line and during the exposure period. There were no sta-
tistically significant differences in the mean values for all
laboratory tests between baseline and during the expo-
sure period in both olmesartan users and candesartan
users. Serum urea nitrogen and creatinine levels tended
to increase in both users. Serum TG level tended to
decrease in olmesartan users, while it tended to increase
in candesartan users. Mean values of all laboratory tests
remained within normal limits during the study period
in both olmesartan users and candesartan users.
Table 3 shows the mean changes in the values of
laboratory test parameters during the exposure period
compared with baseline after IPTW adjustment. In
olmesartan users, the reduction of serum TG level was
significant in comparison with that in candesartan users.
Other tests showed no statistically significant difference
in the change from baseline to during the exposure per-
iod between olmesartan users and candesartan users.
We further examined the differences between olmesar-
tan users and candesartan users in patients with a pre-
vious diagnosis of diabetes or hyperlipidemia (Table 4),
because these diseases are leading risk factors for cardi-
ovascular disease. We found the same outcome in
patients with diabetes or hyperlipidemia as that in the
overall population, with a significant reduction of serum
TG level in olmesartan users in comparison with cande-
sartan users.
Discussion
In this study, we evaluated and compared the effects of
olmesartan and candesartan monotherapy on lipid meta-
bolism and renal function. We found that the reduction
of serum TG level in olmesartan users was significantly
greater than that in candesartan users, although there
were no significant differences in the mean values of all
test results between baseline and during the exposure
period in both users. These results suggest minimal
effects of olmesartan monotherapy on lipid metabolism
and renal function, the same as with candesartan
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Table 1 Baseline characteristics of patients before and after IPTW adjustment
Number of patients Percent distribution*
Characteristics Olmesartan (n = 168) Candesartan (n = 266)Before adjustment
Olmesartan
After adjustment
Olmesartan CandesartanCandesartan
Age (years, mean ± SD)
Sex (women, %)
Medical history
Cerebrovascular disease
Ischemic heart disease
Other heart disease
Liver disease
Kidney disease
Thyroid disease
Diabetes mellitus
Hyperlipidemia
Gout
Malignant neoplasm
Previous drugs
Chemotherapeutic drugs
Immunosuppressive drugs
Steroids
Thyroid drugs
Insulin
Oral hypoglycemic drugs
61.6 ± 12.4
32.7
60.9 ± 3.7
36.1
60.7 ± 13.9
33.4
61.0 ± 13.4
33.75596
30
39
55
61
76
29
141
144
2
49
49
34
87
99
104
61
171
215
12
99
17.9
23.2†
32.7
36.3
45.2
17.3†
83.9†
85.7
1.2†
29.2†
18.4
12.8
32.7
37.2
39.1
22.9
64.3
80.8
4.5
37.2
18.5
17.5
33.2
37.4
43.9
21.7
72.6
82.2
1.6
36.0
17.7
16.7
32.6
36.4
42.1
20.6
71.8
82.6
3.2
34.7
2
2
8
5
3
2
1.2
1.2
4.8
3.0
15.5†
32.1†
1.1
0.8
5.3
3.0
7.9
24.1
0.9
0.8
5.1
3.2
10.4
27.4
1.0
0.8
5.1
3.0
10.1
27.5
14
8
21
64
26
54
*Data are percent distribution of patients unless otherwise stated. †p < 0.05 (candesartan vs olmesartan).
Table 2 Summary of serum chemical data
Laboratory test Olmesartan (n = 168)Candesartan (n = 266)
Mean 95% CIp-valueMean 95% CI p-value
LowerUpper LowerUpper
Lipid metabolism
Triglyceride (mmol/L)
Baseline
Exposure
1.87
1.76
1.68
1.58
2.06
1.94
1.69
1.81
1.48
1.65
1.91
1.970.39120.3862
LDL-cholesterol (mmol/L)
Baseline
Exposure
3.01
2.93
2.88
2.81
3.14
3.05
3.14
3.09
3.05
2.99
3.24
3.19 0.36090.4478
Total cholesterol (mmol/L)
Baseline
Exposure
5.25
5.14
5.10
4.99
5.40
5.28
5.34
5.31
5.21
5.19
5.46
5.430.2871 0.7509
Kidney function
Urea nitrogen (mmol/L)
Baseline
Exposure
5.63
5.92
5.29
5.50
5.97
6.34
5.75
6.03
5.49
5.71
6.00
6.34 0.29690.1743
Creatinine (μmol/L)
Baseline
Exposure
70.00
72.31
66.57
68.66
73.44
75.95
75.58
78.20
72.04
74.11
79.13
82.30 0.3645 0.3416
Potassium (mmol/L)
Baseline
Exposure
4.40
4.47
4.34
4.41
4.47
4.54
4.32
4.36
4.27
4.31
4.36
4.41 0.11610.2339
p value: baseline vs exposure. CI denotes confidence interval. The mean values of all parameters showed no significant change between baseline and during the
exposure period.
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monotherapy. The results also suggest that olmesartan
monotherapy may have a more beneficial effect on TG
metabolism than candesartan monotherapy. Stratified
analysis showed the same outcome in patients with dia-
betes or hyperlipidemia as that in the overall population,
with a significant reduction of serum TG level in olme-
sartan users in comparison with candesartan users.
These results suggest a more beneficial effect of olme-
sartan monotherapy on TG metabolism than candesar-
tan monotherapy in patients with diabetes or
hyperlipidemia.
The lipid-lowering property of ARB is possibly due to
numerous different mechanisms. It is well known that
some ARBs modulate PPAR-g, which regulates lipid
metabolism [5,6]. It is more likely that some ARBs such
as telmisartan can activate PPAR-g, which partially
reduces TG and LDL-C levels. Additionally, an experi-
mental study showed that dyslipidemia may activate
angiotensin II endothelial injury and lipid peroxidation
by an AT1receptor-mediated mechanism, suggesting an
interaction between the renin-angiotensin-aldosterone
system and lipid metabolism [21]. Some clinical studies
have shown a close relationship between AT1receptor
density and plasma LDL-C, and an association of the
use of statins to lower cholesterol with AT1receptor
down-regulation [22,23]. It is possible that differences in
PPAR-g activation or AT1blockage cause the differences
in the lipid-lowering effect across different ARBs,
Table 3 Changes in adjusted laboratory test values during exposure period from baseline
Laboratory tests Olmesartan (n = 168) Candesartan (n = 266)p value
Mean 95% CIMean 95% CI
LowerUpperLower Upper
Lipid metabolism
Δ Triglyceride (mmol/L)
Δ LDL-cholesterol (mmol/L)
Δ Total cholesterol (mmol/L)
Renal function
Δ Urea nitrogen (mmol/L)
Δ Creatinine (μmol/L)
Δ Potassium (mmol/L)
-0.080
-0.085
-0.091
-0.185
-0.146
-0.168
0.024
-0.023
-0.015
0.132
-0.065
-0.039
0.025
-0.112
-0.106
0.239
-0.017
0.028
0.0087*
0.6094
0.3248
0.381
2.378
0.078
0.181
1.264
0.035
0.582
3.492
0.122
0.242
2.608
0.042
0.072
1.397
0.009
0.412
3.828
0.076
0.3059
0.7989
0.1933
Δ indicates the mean change in laboratory test value during the exposure period from baseline. CI denotes confidence interval. *: p < 0.05 (candesartan vs
olmesartan)
Table 4 Changes in adjusted laboratory test values during exposure period from baseline in patients with diabetes
mellitus or hyperlipidemia
Category Laboratory testsOlmesartan Candesartan
Mean95% CIMean 95% CI p value
Lower Upper LowerUpper
Diabetes mellitusLipid metabolism
Δ Triglyceride (mmol/L)
Δ LDL-cholesterol (mmol/L)
Δ Total cholesterol (mmol/L)
Renal function
Δ Urea nitrogen (mmol/L)
Δ Creatinine (μmol/L)
Δ Potassium (mmol/L)
-0.096
-0.117
-0.163
-0.194
-0.183
-0.246
0.003
-0.051
-0.080
0.108
-0.101
-0.089
-0.022
-0.160
-0.172
0.237
-0.041
-0.005
0.0228*
0.7241
0.2313
0.220
2.298
0.047
0.018
1.132
-0.001
0.422
3.456
0.096
0.251
3.209
0.060
0.019
1.618
0.017
0.483
4.791
0.104
0.8514
0.4025
0.7
HyperlipidemiaLipid metabolism
Δ Triglyceride (mmol/L)
Δ LDL-cholesterol (mmol/L)
Δ Total cholesterol (mmol/L)
Renal function
Δ Urea nitrogen (mmol/L)
Δ Creatinine (μmol/L)
Δ Potassium (mmol/L)
-0.079
-0.108
-0.111
-0.203
-0.177
-0.196
0.044
-0.038
-0.026
0.106
-0.087
-0.060
-0.019
-0.139
-0.135
0.231
-0.036
0.014
0.0498*
0.6414
0.3877
0.401
2.157
0.029
0.174
0.857
-0.015
0.629
3.448
0.073
0.231
2.661
0.049
0.034
1.308
0.012
0.428
4.005
0.086
0.2755
0.6173
0.5099
Δ indicates the mean change in laboratory test value during the exposure period from baseline. CI denotes confidence interval. *: p < 0.05 (candesartan vs
olmesartan)
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partially resulting in the significant difference in reduc-
tion of serum TG level between olmesartan users and
candesartan users in our study. PPAR-g activation
occurs at therapeutic dosages only with telmisartan,
which is the strongest modulator of PPAR-g, but cannot
be achieved with other ARBs at therapeutic dosages [5].
Therefore, the effects of olmesartan and candesartan on
lipid metabolism via PPAR-g activation may be very
small at therapeutic dosages. Supporting this, our study
showed no significant change of serum LDL-C, TC, and
TG levels from baseline to the end of the exposure per-
iod in both olmesartan and candesartan users. Also, sev-
eral clinical studies showed similar results with
administration of candesartan, suggesting no effect on
lipid metabolism in patients with mild hypertension or/
and type 2 diabetes [24-27]. On the other hand, only a
few studies have examined the effect of olmesartan on
lipid metabolism. Fliser et al showed no significant
changes of HDL-C, LDL-C, TC and TG levels after 6
weeks of olmesartan administration to patients with
essential hypertension and microinflammation [13]. Our
results, in combination with a previous study, suggest a
lack of obvious evidence of an unfavorable influence of
olmesartan on lipid metabolism. Therefore, the influence
of olmesartan monotherapy on lipid metabolism may be
small and may not be of clinical concern, the same as
with candesartan monotherapy.
Clinical trials have shown that ARBs have renoprotec-
tive effects in diabetes and can slow the progression of
microalbuminuria [3,28,29]. Although ARBs have a sig-
nificant antiproteinuric effect, there may be concern
about complications, including increased serum creati-
nine level and hyperkalemia. In the CHARM (Candesar-
tan in Heart failure-Assessment of Reduction in
Mortality and Morbidity) study, the risk of hyperkalemia
increased with addition of candesartan [30]. In the
CHARM-Added trial and CHARM-Overall trial, more
patients discontinued candesartan than placebo because
of adverse effects, particularly hypotension, increased
serum creatinine and hyperkalemia [2,31]. In this study,
serum urea nitrogen and creatinine levels tended to
increase from baseline, but were not significant in both
olmesartan and candesartan users. Also, we showed no
significant change of potassium level in both olmesartan
and candesartan users. Our study, showing no clinically
significant aggravation of renal function, suggests that
olmesartan or candesartan monotherapy may be safely
used for patients with hypertension. The reason for this
discrepancy between our study and those trials may be
variations in study design and cofounding variables. In
the CHARM-Added trial and CHARM-Overall trial, the
candesartan group included patients with ACEI treat-
ment. Although combination therapy with an ARB and
an ACEI has greater improvement with regard to target
organ damage, especially heart failure and proteinuria
[32], it may be associated with complications including
worsening of renal function and increased serum potas-
sium level. Therefore, when prescribing an ARB, regular
checks of serum potassium and creatinine levels should
be performed, especially when combined with an ACEI.
Our study has some limitations. First, the retrospective
and non-randomized nature of the design involved
inherent issues of selection bias and confounding. We
used rigorous statistical methods to balance potential
confounding variables between olmesartan and cande-
sartan users, including IPTW adjustment. However,
their ability to control for differences was limited to
variables that were available or measurable. Further-
more, the possibility that the findings of comparison of
baseline and exposure period in each treatment group
may be confounded by other variables should be consid-
ered when interpreting the results. Second, we did not
fix the daily dosage in both olmesartan and candesartan
users, because the achievement of blood pressure goal
requires various doses of an agent across different indi-
viduals or even in the same individual in clinical prac-
tice. This study was not designed to assess the effects of
olmesartan and candesartan at each dosage, because it is
difficult to determine whether or not pharmacodynamics
are dose-dependent in clinical settings. However, the
findings of our study, using a sophisticated statistical
method in a real-world setting, are reliable and informa-
tive for clinicians.
Conclusion
In this study, we observed a more beneficial effect on
lipid metabolism, a reduction of serum TG, with olme-
sartan monotherapy than with candesartan monother-
apy. In addition, we observed no clinically significant
changes of serum TG, TC, LDL-C, urea nitrogen, creati-
nine, and potassium levels during olmesartan or cande-
sartan treatment from baseline. These results suggest
that the influence of olmesartan or candesartan mono-
therapy on lipid metabolism and renal function is small,
and that they can be safely used for patients with
hypertension.
Acknowledgements
This work was supported in part by Tempstaff Co., Ltd. (Tokyo, Japan).
Author details
1Division of Genomic Epidemiology and Clinical Trials, Advanced Medical
Research Center, Nihon University School of Medicine, 30-1 Oyaguchi-
Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.2Division of Clinical Trial
Management, Advanced Medical Research Center, Nihon University School
of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
3Division of Pharmacology, Department of Biomedical Sciences, Nihon
University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo
173-8610, Japan.4Division of Laboratory Medicine, Department of Pathology
and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchi-
Nishida et al. Cardiovascular Diabetology 2011, 10:74
http://www.cardiab.com/content/10/1/74
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Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.5Division of General
Medicine, Department of Medicine, Nihon University School of Medicine,
Tokyo, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Authors’ contributions
YN and YT conceived the study and participated in its design. YN performed
the statistical analyses. YN and YT drafted the manuscript. TN, MS and SA
interpreted the data. All authors have read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 25 May 2011 Accepted: 10 August 2011
Published: 10 August 2011
References
1. Takai S, Kirimura K, Jin D, Muramatsu M, Yoshikawa K, Mino Y, Miyazaki M:
Significance of angiotensin II receptor blocker lipophilicities and their
protective effect against vascular remodeling. Hypertens Res 2005,
28:593-600.
2. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL,
Olofsson B, Ostergren J, Yusuf S, Pocock S, CHARM Investigators and
Committees: Effects of candesartan on mortality and morbidity in
patients with chronic heart failure: the CHARM-Overall programme.
Lancet 2003, 362:759-766.
3. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S,
Arner P, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria
Study Group: The effect of irbesartan on the development of diabetic
nephropathy in patients with type 2 diabetes. N Engl J Med 2001,
345:870-878.
4. Ritz E, Schmieder RE, Pollock CA: Renal protection in diabetes: lessons
from ONTARGET. Cardiovasc Diabetol 2010, 9:60.
5. Munger MA: Use of angiotensin receptor blockers in cardiovascular
protection: current evidence and future directions. P T 2011, 36:22-40.
6. Marshall TG, Lee RE, Marshall FE: Common angiotensin receptor blockers
may directly modulate the immune system via VDR, PPAR and CCR2b.
Theor Biol Med Model 2006, 3:1.
7. Kitamura N, Takahashi Y, Yamadate S, Asai S: Angiotensin II receptor
blockers decreased blood glucose levels: a longitudinal survey using
data from electronic medical records. Cardiovasc Diabetol 2007, 6:26.
8. Devabhaktuni M, Bangalore S: Fixed combination of amlodipine and
atorvastatin in cardiovascular risk management: patient perspectives.
Vasc Health Risk Manag 2009, 5:377-387.
9. Kyvelou SM, Vyssoulis GP, Karpanou EA, Adamopoulos DN, Zervoudaki AI,
Pietri PG, Stefanadis CI: Effects of antihypertensive treatment with
angiotensin II receptor blockers on lipid profile: an open multi-drug
comparison trial. Hellenic J Cardiol 2006, 47:21-28.
10. Nishida Y, Takahashi Y, Nakayama T, Soma M, Kitamura N, Asai S: Effect of
candesartan monotherapy on lipid metabolism in patients with
hypertension: a retrospective longitudinal survey using data from
electronic medical records. Cardiovasc Diabetol 2010, 9:38.
11. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, Mimran A,
Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G: ROADMAP Trial
Investigators: Olmesartan for the delay or prevention of
microalbuminuria in type 2 diabetes. N Engl J Med 2011, 364:907-917.
12. Stumpe KO, Agabiti-Rosei E, Zielinski T, Schremmer D, Scholze J, Laeis P,
Schwandt P, Ludwig M, MORE study investigators: Carotid intima-media
thickness and plaque volume changes following 2-year angiotensin II-
receptor blockade. The Multicentre Olmesartan atherosclerosis
Regression Evaluation (MORE) study. Ther Adv Cardiovasc Dis 2007,
1:97-106.
13. Fliser D, Buchholz K, Haller H, EUropean Trial on Olmesartan and Pravastatin
in Inflammation and Atherosclerosis (EUTOPIA) Investigators:
Antiinflammatory effects of angiotensin II subtype 1 receptor blockade
in hypertensive patients with microinflammation. Circulation 2004,
110:1103-1107.
14.de Vinuesa SG, Goicoechea M, Kanter J, Puerta M, Cachofeiro V, Lahera V,
Gomez-Campdera F, Luno J: Insulin resistance, inflammatory biomarkers,
and adipokines in patients with chronic kidney disease: Effects of
angiotensin II blockade. J Am Soc Nephrol 2006, 17:S206-S212.
15. Fogari R, Derosa G, Zoppi A, Rinaldi A, Preti P, Lazzari P, Mugellini A: Effects
of manidipine/delapril versus olmesartan/hydrochlorothiazide
combination therapy in elderly hypertensive patients with type 2
diabetes mellitus. Hypertens Res 2008, 31:43-50.
Takahashi Y, Nishida Y, Nakayama T, Asai S: Adverse effect profile of
trichlormethiazide: a retrospective observational study. Cardiovasc
Diabetol 2011, 10:45.
D’Agostino R: Tutorial on biostatistics: Propensity score methods for bias
reduction in the comparison of a treatment to a non-randomized
control group. Stat Med 1998, 17:2265-2281.
Leslie S, Thiebaud P: Using propensity score to adjust for treatment
selection bias. SAS Global forum 2007 paper [http://www2.sas.com/
proceedings/forum2007/184-2007.pdf], 184-2007.
Rosenbaum PR, Rubin DB: The central role of the propensity score in
observational studies for causal effects. Biometrika 1983, 70:41-55.
Robins JM, Hernán MA, Brumback B: Marginal structural models and
causal inference in epidemiology. Epidemiology 2000, 11:550-560.
Keidar S, Kaplan M, Hoffman A, Aviram M: Angiotensin II stimulates
macrophage-mediated oxidation of low density lipoproteins.
Atherosclerosis 1995, 115:201-215.
Nickenig G, Jung O, Strehlow K, Zolk O, Linz W, Schölkens BA, Böhm M:
Hypercholesterolemia is associated with enhanced angiotensin AT1-
receptor expression. Am J Physiol 1997, 272:H2701-H2707.
Nickenig G, Bäumer AT, Temur Y, Kebben D, Jockenhövel F, Böhm M:
Statin-sensitive dysregulated AT1 receptor function and density in
hypercholesterolemic men. Circulation 1999, 100:2131-2134.
Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N,
Yoshida D, Shimamoto K: Blockade of the renin-angiotensin system
increases adiponectin concentrations in patients with essential
hypertension. Hypertension 2003, 42:76-81.
Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Koh Y, Shin EK: Distinct vascular
and metabolic effects of different classes of anti-hypertensive drugs. Int
J Cardiol 2010, 140:73-81.
Trenkwalder P, Dahl K, Lehtovirta M, Mulder H: Antihypertensive treatment
with candesartan cilexetil does not affect glucose homeostasis or serum
lipid profile in patients with mild hypertension and type II diabetes.
Blood Press 1998, 7:170-175.
Derosa G, Cicero AF, Ciccarelli L, Fogari R: A randomized, double-blind,
controlled, parallel-group comparison of perindopril and candesartan in
hypertensive patients with type 2 diabetes mellitus. Clin Ther 2003,
25:1006-1021.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH,
Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators:
Effects of losartan on renal and cardiovascular outcomes in patients
with type 2 diabetes and nephropathy. N Engl J Med 2001, 345:861-869.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E,
Atkins RC, Rohde R, Raz I, Collaborative Study Group: Renoprotective effect
of the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med 2001, 345:851-860.
Desai AS, Swedberg K, McMurray JJ, Granger CB, Yusuf S, Young JB,
Dunlap ME, Solomon SD, Hainer JW, Olofsson B, Michelson EL, Pfeffer MA,
CHARM Program Investigators: Incidence and predictors of hyperkalemia
in patients with heart failure: an analysis of the CHARM Program. J Am
Coll Cardiol 2007, 50:1959-1966.
Young JB, Dunlap ME, Pfeffer MA, Probstfield JL, Cohen-Solal A, Dietz R,
Granger CB, Hradec J, Kuch J, McKelvie RS, McMurray JJ, Michelson EL,
Olofsson B, Ostergren J, Held P, Solomon SD, Yusuf S, Swedberg K,
Candesartan in Heart failure Assessment of Reduction in Mortality and
morbidity (CHARM) Investigators and Committees: Mortality and morbidity
reduction with candesartan in patients with chronic heart failure and
left ventricular systolic dysfunction: results of the CHARM low-left
ventricular ejection fraction trials. Circulation 2004, 110:2618-2626.
Bomback AS, Toto R: Dual blockade of the renin-angiotensin-aldosterone
system: beyond the ACE inhibitor and angiotensin-II receptor blocker
combination. Am J Hypertens 2009, 22:1032-1040.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
doi:10.1186/1475-2840-10-74
Cite this article as: Nishida et al.: Comparative effect of olmesartan and
candesartan on lipid metabolism and renal function in patients with
hypertension: a retrospective observational study. Cardiovascular
Diabetology 2011 10:74.
Nishida et al. Cardiovascular Diabetology 2011, 10:74
http://www.cardiab.com/content/10/1/74
Page 7 of 7