http://informahealthcare.

com/ceh
ISSN: 1064-1963 (print), 1525-6006 (electronic)

Clin Exp Hypertens, 2014; 36(4): 251–257

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2013.810228

ORIGINAL ARTICLE

A comparative study on the effectiveness of losartan/

hydrochlorothiazide and telmisartan/hydrochlorothiazide
in patients with hypertension
Toshihiro Hamada1*, Masanari Kuwabara2*, Arisa Watanabe1, Einosuke Mizuta3, Akira Ohtahara3, Hiroki Omodani4,
Masashi Watanabe5, Hiroki Nakamura6, Yutaka Hirota7, Satoshi Miyazaki8, Masahiko Kato9, Kazuhide Ogino10,
Hiroki Kosaka11, Ninomiya Haruaki12, Shin-ichi Taniguchi1, Kazuhiro Yamamoto9, Hiroshi Kotake13, and
Ichiro Hisatome2
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14

1
Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Japan, 2Division of Regenerative Medicine and Therapeutics,
Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan, 3Department of
Cardiovascular Medicine, Sanin Rosai Hospital, Yonago, Japan, 4Division of Cardiovasucular Medicine, Omodani Clinic, Yonago, Japan,
5
Division of Cardiovasucular Medicine, Watanabe Clinic, Sakaiminato, Japan, 6Nakamura Clinic, Hoki, Tottori, Japan, 7Tomimasu Surgery and
Primary Care Clinic, Yonago, Japan, 8Division of Cardiology, Nojima Hospital, Kurayoshi, Japan, 9Division of Molecular Medicine and Therapeutics,
Tottori University Faculty of Medicine, Yonago, Japan, 10Center for Clinical Residency Program, Tottori University Hospital, Yonago, Japan,
11
Division of Internal Medicine, Tottori Red Cross Hospital, Tottori, Japan, 12Department of Biological Regulation, Tottori University Faculty
of Medicine, Yonago, Japan, and 13Division of Cardiovascular Medicine, Kotake Clinic, Yonago, Japan
For personal use only.

Abstract Keywords
Purpose: Long-term effects of a low-dose hydrochlorothiazide (HCTZ) with losartan (LOS) on uric HOMA-R, hydrochlorothiazide, losartan,
acid (UA) metabolism as well as glucose metabolism have been studied in hypertensive serum uric acid, telmisartan
patients in comparison with those of a low-dose HCTZ with telmisartan (TEL).
Method: Fifty-nine hypertensive patients were allocated to a combination therapy with either History
losartan (50 mg/day)/HCTZ (12.5 mg/day) (LOS + HCTZ group: n ¼ 37) or telmisartan (40 mg/
day)/HCTZ (12.5 mg/day) (TEL + HCTZ group: n ¼ 22), respectively. Before and 1 year after the Received 27 January 2013
treatment, blood pressure and biochemical parameters of blood and urine were evaluated. Revised 25 April 2013
Results: Both systolic and diastolic blood pressures significantly decreased in two groups, Accepted 16 May 2013
without any statistical differences among them. LOS + HCTZ caused no changes in the serum Published online 17 July 2013
UA level or the ratio of UA clearance to creatinine clearance (CUA/Ccr), whereas TEL + HCTZ
significantly increased the serum UA level and reduced CUA/Ccr. LOS + HCTZ did not influence
CUA/Ccr in patients with their serum UA below 5.4 mg/dl, while LOS + HCTZ significantly
increased CUA/Ccr in patients with their serum UA above 5.5 mg/dl. TEL + HCTZ significantly
reduced CUA/Ccr in patients with their serum UA below and above 5.4 mg/dl to increase serum
UA level significantly. Neither combination therapies caused any changes in fasting plasma
glucose, HbA1c and HOMA-R. In patients with their serum UA level above 5.4 mg/dl, TEL + HCTZ
increased HOMA-R, whereas LOS + HCTZ did not.
Conclusions: LOS + HCTZ did not influence UA metabolism as well as glucose metabolism, likely
because of inhibitory action of losartan on URAT1, although TEL + HCTZ were accompanied
with impairment of the UA metabolism and glucose metabolism.

Introduction together with first-line drugs to achieve satisfactory blood

pressure (BP) control (1). Several combinations of hydro-
In order to prevent cerebral, cardiovascular and renal diseases,
chlorothiazide (HCTZ) together with the angiotensin II
guidelines for hypertension treatment recommend strict
receptor blockers (ARBs) such as losartan (LOS), telmisartan
control of blood pressure. Despite the treatment with first-
(TEL), valsartan or candesartan are expected to be effective
line drugs for hypertensive treatment, hypertensive patients
and safe, since ARBs can augment the BP lowering action of
have not achieved the recommended goal of blood pressure
HCTZ and suppress its adverse actions such as hyperuricemia
in Japan. The Japanese Society of Hypertension (JSH)
and impairment of glucose tolerance (2).
recommends the administration of diuretics at low-doses
Among various ARBs, LOS is known to reduce the
serum uric acid (UA) level by inhibiting urate transporter 1
*T. Hamada and M. Kuwabara equally contributed to this study.
(URAT1) (3). TEL is suggested to function as a partial
Correspondence: Dr. Toshihiro Hamada, Tottori University Faculty of agonist of peroxisome proliferator-activated receptor-g
Medicine, Department of Regional Medicine, 86 Nishicho, Yonago
6838503, Japan. E-mail: thammer@chukai.ne.jp (PPAR-g) in addition to its activity as an inhibitor of
 252 T. Hamada et al. Clin Exp Hypertens, 2014; 36(4): 251–257

URAT1 (4). Previously, we demonstrated that a combination Statistical analysis

of LOS at the daily dosage of 50 mg with HCTZ at 12.5 mg
Data were expressed as mean  standard deviation. All data
decreased the serum UA level and increased UA excretion,
were analyzed with SPSS software version 18.0 (SPSS,
while TEL at 40 mg with HCTZ at 12.5 mg increased the
Chicago, IL). The baseline characteristics of the patients were
serum UA level. These effects were observed in a short period
compared using the chi-square test or unpaired Student-t test.
of their administration of two months (5), suggesting LOS
Within-treatment changes from baseline were analyzed using
prevented thiazide diuretics-induced hyperuricemia during
paired Student-t test and between-treatment differences
this short period of administration.
using unpaired Student-t test. According to the Shapiro–
The purpose of the present study was to evaluate long-term
Wilk statistic, the Wilcoxon signed rank test was applied
effects of a combination of LOS at 50 mg and HCTZ at
to evaluate between-treatment differences of HOMA-R.
12.5 mg (LOS + HCTZ) on blood pressure and UA metabol-
Two-sided values of p50.05 were considered statistically
ism as well as glucose metabolism in hypertensive patients.
significant.
These effects were evaluated in comparison with a combin-
ation of TEL at 40 mg and HCTZ at 12.5 mg (TEL + HCTZ). Results
Material and methods Baseline characteristics
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14

Study subjects Figure 1 shows the flow of patients throughout the study.
A total of 67 patients met the entry criteria and were
This study was designed as a 12-month prospective, random-
randomly assigned to the two treatment groups. One patient
ized open-labeled parallel-group, multicenter trial (13 cen-
of them was lost to follow up. Seven patients were excluded
ters). The entry period was from January 1 to December 31,
because of protocol violations including gouty arthritis and
2010. The consecutive hypertensive patients (aged above
physician’s judgment (dizziness and erythema).
35 years) were treated either with candesartan (8 mg/day),
Thus, 37 patients (age; 70.3  11.4 years old) allocated
valsartan (80 mg) olmesartan (20 mg) monotherapy, or cal-
to a combination therapy with LOS 50 mg/day and HCTZ
cium channel blockers in combination with one of those
12.5 mg/day (LOS + HCTZ group, male: 14 cases, female:
ARBs. The patients, who had not reached BP goal (sitting
23 cases) and 22 patients (69.7  12.8 years old) allocated to
BP levels were either systolic BP  140 mmHg or diastolic
a combination therapy with TEL 40 mg/day and HCTZ
For personal use only.

BP  90 mmHg) over 1 month with antihypertensive therapy

12.5 mg/day (TEL + HCTZ group, male: 12 cases, female:
without diuretics, provided written informed consent to
10 cases) were used for the efficacy analysis. There were no
participate in this study.
significant differences between the two groups in duration
Exclusion criteria included secondary hypertension, malig-
of hypertension, incidence of complication of diabetes,
nant hypertension or uncontrolled hypertension, uncontrolled
hyperlipidemia, chronic kidney disease and cerebral stroke
diabetes mellitus (HbA1c  6.5), a history of gout, urolithia-
and the number of smokers, whereas the prevalence of alcohol
sis, serum creatinine levels more than 2 mg/dl, hyperkalemia,
intake was significantly higher in LOS + HCTZ group
and liver damage. The patients who were not decided to be
and prevalence of heart disease was significantly higher
eligible for participation from physician’s medical standpoint
in TEL + HCTZ group (Table 1). While all patients were
were also excluded.
previously treated with one or more antihypertensive agents
The Institutional Review Board the Tottori University
on an outpatient basis, there was not any significant difference
Faculty of Medicine and the Sanin Rosai Hospital approved
of prevalence of ARB involving candesartan, valsartan,
this study and written informed consent was obtained from
olmesartan and TEL among two groups. None of them had
each patient. The privacy of patients was protected according
a past history of gout or urolithiasis or had been treated with
to the Declaration of Helsinki.
UA lowering agents, non-steroidal anti-inflammatory drugs,
Study design hypoglycemic drugs, or fibrates. Table 2 showed the baseline
characteristics of both the LOS + HCTZ and TEL + HCTZ
After the baseline evaluation, using sealed envelope method,
patients were randomly assign to undergo a 1-year treatment
with either a combination of LOS at daily dosage of 50 mg 67 patients randomized
and HCTZ 12.5 mg (LOS + HCTZ) or TEL 40 mg and HCTZ
12.5 mg without a wash-out period (TEL + HCTZ). Every
day at 7:00 AM, the patients received orally their allocated 41 received 26 received
medicines. At 9:00 AM, in a sitting posture after rest, LOS 50mg+ HCTZ 12.5mg TEL 40mg+ HCTZ 12.5mg
blood pressure measurement, blood sampling, and urine
sampling were performed before and after treatment at 1, 6 1 lost to follow up
and 12 months.
41 safety analysis 25 safety analysis
The primary endpoint of this study was changes in blood
pressure and serum UA levels. Secondary endpoint included 4 protocol violation 3 protocol violation
changes in urinary UA excretion estimated by the ratio of
UA clearance to creatinine clearance (CUA/Ccr) and changes 37 efficacy analysis 22 efficacy analysis
in the glucose metabolic index such as fasting plasma glucose
(FPG), HbA1c, insulin and HOMA-R. Figure 1. The flow of patients.
 DOI: 10.3109/10641963.2013.810228 ARBs and hydrochlorothiazide in hypertensive patients 253
Table 1. Patients demographics.

LOS/HCTZ TEL/HCTZ
Total (n ¼ 59) group (n ¼ 37) group (n ¼ 22) p Value
Age (years) 70.1  11.8 70.3  114 69.7  12.8 NS
Sex (Male, %) 44.1 37.8 54.5 NS
BMI (kgm2) 23.4  2.5 23.1  2.5 23.9  2.5 NS
Smoking (%) 10.2 8.1 13.6 NS
Drinking (%) 28.8 24.3 0.0 0.012
Duration of hypertension (%)
51 year 6.8 8.8 4.8 NS
1 year and 55 years 16.9 17.6 19.0
5years and 510 years 32.2 26.5 47.6
10 years 35.6 44.1 28.6
Unknown 8.5 2.9 0.0
Complications (%)
History of diseases 61.0 59.5 63.6 NS
Diabetes 6.8 5.4 9.1 NS
Hyperlipidemia 30.5 29.7 31.8 NS
Chronic kidney disease 25.4 27.0 22.7 NS
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14

Stroke 11.9 13.5 9.1 NS

Heart disease 15.3 8.1 27.3 0.048
Previous antihypertensive medication (%)
Monotherapy 28.8 35.1 18.2 NS
Combination therapy 71.2 64.9 81.8 NS
Previous ARB (%)
Candesartan 39.0 45.9 27.3 NS
Valsartan 50.8 40.5 68.2
Telmisartan 1.7 0.0 4.5
Olmesartan 1.7 2.7 0.0
Not specified 6.8 10.8 0.0
Concomitant drugs (%)
Lipid lowering drugs 27.1 24.3 31.8 NS
For personal use only.

Antidiabetic drugs 3.4 2.7 4.5 NS

p Values; chi-square test, or unpaired t-test.

Table 2. Baseline characteristics.

LOS/HCTZ TEL/HCTZ
n group n group p Value
Systric BP, mmHg 37 158.9  14.5 22 159.2  13.1 NS
Diastolic BP, mmHg 37 87.6  9.0 22 88.7  16.2 NS
Pulse rate, bpm 35 70.1  8.5 21 71.3  10.3 NS
Serum uric acid, mg/dL 37 5.5  1.3 21 5.4  1.2 NS
Racio of uric acid clearance to creatinine clearance, % 35 0.55  0.17 20 0.62  0.18 NS
HbA1c, % 32 5.3  0.5 18 5.2  0.4 NS
Fasting blood glucose, mg/dL 35 98.5  19.8 21 100.1  17.2 NS
Fasting insulin level, mU/mL 30 9.3  9.7 16 10.4  14.3 NS
HOMA-R 29 2.5  2.8 16 2.9  5.1 NS
Total cholesterol, mg/dL 37 193.6  36.4 21 198.1  40.1 NS
Triglicerides, mg/dL 37 132.6  81.6 22 147.5  76.5 NS
HDL cholesterol, mg/dL 37 62.7  17.8 22 58.4  18.1 NS
eGFR, mL/min/1.73m2 32 68.3  16.3 21 75.5  18.9 NS
Serum creatinine, mg/dL 37 0.77  0.25 22 0.73  0.16 NS
Serum potassium, mEq/L 37 4.2  0.4 22 4.3  0.4 NS
Serum sodium, mEq/L 37 140.8  2.2 22 140.6  1.2 NS

p Value; unpaired-t test.

groups. There was not any significant difference between
two groups.
Changes in blood pressure, heart rate, serum UA and
potassium level in response to the treatment with
LOS + HCTZ or TEL + HCTZ
Figure 2 shows the effects of LOS + HCTZ and TEL + HCTZ
on the systolic and diastolic pressures in the hypertensive
subjects. Both agents significantly decreased both systolic
and diastolic pressures during 12 months. Neither agent
caused any changes in the heart rate.
Figure 3 shows the effects of LOS + HCTZ and
TEL + HCTZ on the serum UA level. TEL + HCTZ signifi-
cantly increased the serum UA level at 1, 6 and 12 months,
whereas LOS + HCTZ had no effect.
At 12 months, neither agent caused any changes in serum
potassium levels (from 4.2  0.4 mEq/l to 4.2  0.4 mEq/l in
 254 T. Hamada et al. Clin Exp Hypertens, 2014; 36(4): 251–257
Figure 2. Changes in blood pressure. (mmHg)
Ordinate indicates blood pressure, abscissa 200
indicates period of treatment. Closed circles:
LOS + HCTZ, closed triangles: 180
TEL + HCTZ.
160
∗ ∗ ∗
140
∗ ∗ ∗
120

100
∗ ∗ ∗
80
∗
∗ ∗
60
LOS + HCTZ SBP
40 TLM + HCTZ SBP
LOS + HCTZ DBP
20 TLM + HCTZ DBP
0
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14

0M 1M 6M 12M
∗: p<0.05 vs. 0M by paired t-test

Mean serum UA CUA/Ccr(%)

16.0

14.0

∗ ∗ 12.0
∗

10.0
For personal use only.

8.0
∗ ∗
6.0

4.0

LOS+HCTZ
2.0
TLM+HCTZ
0.0
0M 1M 6M 12M

∗:P<0.05, paired-t-test vs. 0M ∗:P<0.05 vs.0M paired t-test

Figure 3. Changes in serum UA. Serum UA in patients treated with Figure 4. Changes in CUA/Ccr. CUA/Ccr in patients treated with
LOS + HCTZ (closed circles) or TEL + HCTZ (closed triangles). LOS + HCTZ (closed circles) or TEL + HCTZ (closed triangles).
Ordinate indicates the serum UA level, abscissa indicates period of Ordinate indicates CUA/Ccr, abscissa indicates the period of treatment.
treatment. *p50.05 significance versus 0 month. *p50.05 significance versus 0 month.

the LOS + HCTZ group, 4.3  0.4 mEq/l to 4.1  0.5 mEq/l
in the TEL + HCTZ group).
Changes in UA metabolism in response to the
treatment with LOS + HCTZ or TEL + HCTZ
To study the effects of either treatment on the urinary UA
excretion, CUA/Ccr was measured at certain periods.
As shown in Figure 4, the CUA/Ccr was constant in the
LOS + HCTZ group before and after the 12 months treatment.
CUA/Ccr was significantly decreased in the TEL + HCTZ
group after the 12 months treatment. Thus, TEL + HCTZ
significantly reduced CUA/Ccr to increase the serum UA,
whereas LOS + HCTZ caused no effect on CUA/Ccr or the
serum UA level.
Changes in UA metabolism in response to the
treatment with LOS + HCTZ or TEL + HCTZ in
patients with the serum UA levels above or
below the average values
Since the uricosuric action of LOS is prominent in hyperten-
sive patients with hyperuricemia (6), the favorable action of
LOS + HCTZ might be more obviously seen in patients with
high serum UA levels. Given the average value of serum UA
level of 5.4 mg/dl, the subjects were separated into two groups
with the serum UA levels above or below the average values,
and the data set were re-analyzed. As shown in Figure 5a
and c, LOS + HCTZ did not influence the serum UA level
during treatment, whereas TEL + HCTZ significantly
increased it in both groups. The effects of LOS + HCTZ and
TEL + HCTZ on CUA/Ccr in patients with their serum UA
 DOI: 10.3109/10641963.2013.810228 ARBs and hydrochlorothiazide in hypertensive patients 255
Figure 5. Changes in UA metabolism after serum UA>5.4mg/dl
treatment in patients with their serum UA
(a) 10 (b) 14
below and above 5.4 mg/dl. (a) Serum UA in
9
patients treated with LOS + HCTZ (closed ∗ 12
circles) or TEL + HCTZ (closed triangles) in 8

serum UA (mg/dl)
patients with their serum UA above 5.4 mg/ 7 10

CUA/Ccr(%)
dl. Ordinate indicates the serum UA level, 6 8
abscissa indicates period of treatment. 5
*p50.05 significance versus 0 month. 6
4 ∗
(b) Changes in CUA/Ccr after treatment with
3 4
LOS + HCTZ (closed circles) or
TEL + HCTZ (closed triangles) in patients 2
2
with their serum UA above 5.4 mg/dl. 1
*p50.05 significance versus 0 month. 0 0
(c) Serum UA in patients treated with Pre 12M 0M 12M
LOS+HCTZ
LOS + HCTZ (closed circles) or
TEL + HCTZ (closed triangles) in patients serum UA<5.4mg/dl TEL+HCTZ
with their serum UA below 5.4 mg/dl. (c) 7 (d) 16
Ordinate indicates the serum UA level,
6 14
abscissa indicates period of treatment. ∗
serum UA (mg/dl)
*p50.05 significance versus 0 month. 12
5
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14

CUA/Ccr(%)
(d) Changes in CUA/Ccr after treatment with 10
LOS + HCTZ (closed circles) or 4 8
TEL + HCTZ (closed triangles) in patients 3 6 ∗
with their serum UA below 5.4 mg/dl. 4
*p50.05 significance versus 0 month. 2
2
1
0
0 −2
Pre 12M 0M 12M
∗ p<0.05, paired t-test vs. 0M
For personal use only.

levels above or below 5.4 mg/dl were shown in Figure 5b and 16

d. TEL + HCTZ decreased CUA/Ccr 12 months after treat- 14
ment in patients with both serum UA groups regardless of UA 12
levels, while LOS + HCTZ did not influence CUA/Ccr.
10
HOMA-R

Changes in HOMA-R in response to the treatment with 8 LOS+HCTZ

LOS + HCTZ or TEL + HCTZ in patients with their serum
UA higher than 5.4 mg/dl
Recently, hyperuricemia has been reported to correlate with
the impaired glucose tolerance, since it could elicit insulin
resistance by activating URAT1 in adipocytes to cause
oxidative stress (7). We evaluated the correlation between
changes in serum UA levels and laboratory parameters
related to the glucose metabolism. As shown in supplemental
Figures 1 and 2, the serum UA level significantly correlated
with the values of HbA1c and FPG indicating that
hyperuricemia could relate to impaired glucose metabolism,
There was no significant difference in the values of FPG,
HbA1c, insulin level and HOMA-R between the TEL +
HCTZ and LOS + HCTZ groups before and after the treat-
ment. However, in hypertensive patients with their serum UA
levels above 5.4 mg/dl, HOMA-R was significantly increased
at 12 months after the treatment with TEL + HCTZ, but not
by LOS + HCTZ as shown in Figure 6.
Discussion
In the present study, we found that LOS + HCTZ and
TEL + HCTZ significantly decreased both systolic and dia-
stolic pressures in hypertensive patients. LOS + HCTZ did not
increase the serum UA level or CUA/Ccr but TEL + HCTZ
significantly increased the serum UA level and reduced
‡
6
TEL+HCTZ
4
2
0
-2
Pre 12M
‡ P<0.05 Wilcoxon signed-rank test vs. 0M
Figure 6. Changes in HOMA-R after treatment in patients with their
serum UA above 5.4 mg/dl. HOMA-R in patients treated with
LOS + HCTZ (closed circles) or TEL + HCTZ (closed triangles) in
patients with their serum UA above 5.4 mg/dl. Ordinate indicates
HOMA-R, abscissa indicates period of treatment. zp50.05 significance
versus 0 month.
CUA/Ccr during the treatment period of 1 year. The main
players in thiazide diuretics-induced hyperuricemia are the
renin-angiotensin system (RAS) and URAT1, an apical urate/
anion exchanger that reabsorbs urate in the proximal tubules.
A reduction of the total plasma volume and accelerated
sodium excretion could activate the RAS. This in turn leads to
contraction of glomerular efferent arterioles, resulting in a
reduction of blood flow in the renal medulla and eventual
augmentation of urate reabsorption by URAT1 (8). The
intensified RAS activity as well as hyper-osmolality causes
over-expression of URAT1. It is therefore desirable to select
 256 T. Hamada et al.
an antihypertensive agent drug that can suppress both
RAS and URAT1 to treat hypertensive patients in combin-
ation with thiazide diuretics. The ARBs can be pharmaco-
logically divided into two categories based on their actions
on UA metabolism; one is represented by LOS and TEL,
which inhibit URAT1, and the other is represented by
candesartan, valsartan and olmesartan, which do not have
such an action (9–11). It has been reported that both LOS and
TEL could block URAT1 in in-vitro studies using heterol-
ogous expression in oocytes. We previously reported the short
term effects of a combination of LOS and HCTZ in
comparison with TEL and HCTZ (5). We found that LOS,
but not TEL, counteracted the HCTZ-induced elevation of
serum UA levels through its inhibitory action on URAT1
during 2 months. It has been indicated that LOS but not
TEL had a uricosuric action through inhibition of URAT1 to
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14
cancel HCTZ-induced elevation of serum UA. This report was
consistent with the present results with both LOS + HCTZ
and TEL + HCTZ during the long term of their administration
for 1 year. Hosoya et al. reported that LOS + HCTZ did
not increase the serum UA level at 6 months after switching
from prior ARBs, which was consistent with our findings
(12). The present findings that LOS + HCTZ did not increase
the serum UA level were also confirmed in the hypertensive
patients with serum UA levels above 5.4 mg/dl, excluding
adverse effects of LOS + HCTZ on UA metabolism.
Many studies indicated that hyperuricemia is an independ-
For personal use only.
ent risk factor for gout as well as cardiovascular disease
and renal failure in hypertensive patients. Therefore, the
guideline recommends that elevation of serum UA should be
avoided in the treatment of hypertensive patients. It has been
recently reported that antihypertensive agents caused gout
in hypertensive patients, which involved diuretics, b-blockers,
ACE inhibitors and ARBs. Strikingly, the combination of
diuretics with either b-blockers or ACE inhibitors signifi-
cantly increased the risk of gout (13). This suggested that the
combination of ARB with HCTZ may cause gout. However,
the present study indicated that LOS + HCTZ might be free
from such a risk because of cancelation of HCTZ-induced
elevation of serum UA levels, which might be consistent with
the notion that LOS decreases the risk of gout.
The most prominent finding is that in hypertensive patients
with serum UA levels above 5.4 mg/dl, LOS + HCTZ did not
influence HOMA-R. Thiazide antihypertensive diuretics
are less expensive and exert relatively favorable antihyper-
tensive effects, however, they cause hyperuricemia as well as
impaired glucose metabolism. Interestingly, in the present
study, the serum UA levels significantly correlated with the
values of FPG and HbA1c, suggesting the involvement of
serum UA in the development of insulin resistance. Roncal-
Jimenez et al. reported that hyperuricemia caused insulin
resistance via activation of URAT1 expressed in adipocytes
(14). Inokuchi et al. reported that benzbromarone, a potent
URAT1 inhibitor, increased the serum level of adiponectin
in hyperuricemic patients with a concomitant reduction of the
serum UA levels, while allopurinol, a xanthine oxidase
inhibitor, decreased the serum UA level but did not increase
adiponectin (15). Recently, Ogino et al. reported that
benzbromarone reduced the serum level of UA, TNF a and
HOMA-R in hyperuricemia patients with chronic heart
Clin Exp Hypertens, 2014; 36(4): 251–257
failure (16). These reports indicated that a URAT1 inhibitor
may suppress the insulin resistance in hyperuricemia patients
by normalizing adipocytokine levels. In the present study,
LOS + HCTZ did not influence the HOMA-R in hypertensive
patients with elevated serum UA levels, which may support
the above notion. On the other hand, TEL + HCTZ worsened
the HOMA-R in the present study, although among the ARBs,
TEL is reported to have an action as PPAR1-g stimulant to
improve glucose metabolism (4). This notion may support
that hyperuricemia could induced the insulin resistance via
activation of URAT1. Taken together, LOS could cancel the
HCTZ-induced elevation of both serum UA and impaired
glucose metabolism by its inhibitory action on URAT1.
According to Zillich et al., it has been supposed that
treatment of thiazide-induced hypokalemia might reverse
glucose intolerance (17). In the present study, averaged
changes in serum potassium levels were 0  0.4 mEq/L in
LOS + HCTZ group and 0.1  0.5 mEq/L in TEL/HCTZ
group. No significant association between within-treatment
changes in serum potassium and those in fasting plasma
glucose was postulated (data not shown).
The limitations of this study include small study popula-
tion and differences in the patient demographics between
two treatment groups probably because of sealed envelope
method. Change in weight of each patient was not monitored
during treatment. Renal clearance for UA and creatinine were
not determined before and after each treatment.
In summary, LOS + HCTZ did not influence UA metab-
olism as well as glucose metabolism, likely because of
inhibitory action of losartan on URAT1. On the other hand,
TEL + HCTZ were accompanied with impairment of the UA
metabolism and glucose metabolism.
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of the article.
References
1. Ogihara T, Kikuchi K, Matsuoka H, et al. Japanese Society of
Hypertension Committee: The Japanese Society of Hypertension
Guidelines for the Management of Hypertension (JSH 2009).
Hypertens Res 2009;32:3–107.
2. Tsuchihashi T. Combination therapy of ARB with diuretics in
Japanese hypertensive patients. Nihon Rinsho 2009;67:1439–44.
3. Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action
of losartan via the inhibition of urate transporter 1 (URAT 1) in
hypertensive patients. Am J Hypertens 2008;21:1157–62.
4. Minami J, Furukata S, Ishimitsu T, Matsuoka H. Comparison
of therapies between fixed-dose telmisartan/hydrochlorothiazide
and losartan/hydrochlorothiazide in patients with mild to moderate
hypertension. Int Heart J 2009;50:85–93.
5. Hamada T, Mizuta E, Kondo T, et al. Effects of a low-dose
antihypertensive diuretic in combination with losartan, telmisartan,
or candesartan on serum urate levels in hypertensive patients.
Arzneimittelforschung 2010;60:71–5.
6. Kita T, Yokota N, Ichiki Y, et al. One-year effectiveness and safety
of open-label losartan/hydrochlorothiazide combination therapy
in Japanese patients with hypertension uncontrolled with ARBs or
ACE inhibitors. Hypertens Res 2010;33:320–5.
7. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects
of the classic antioxidant uric acid in adipocytes: NADPH oxidase-
mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol
2007;293:C584–96.
 DOI: 10.3109/10641963.2013.810228
8. Reaven GM. The kidney: an unwilling accomplice in syndrome X.
Am J Kidney Dis 1997;30:928–31.
9. Iwanaga T, Sato M, Maeda T, et al. Concentration-dependent mode
of interaction of angiotensin II receptor blockers with uric acid
transporter. J Pharmacol Exp Ther 2007;320:211–17.
10. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular
identification of a renal urate anion exchanger that regulates
blood urate levels. Nature 2002;417:447–52.
11. Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action
of losartan via the inhibition of Urate Transporter 1 (URAT1)
in Hypertensive Patients. Am J Hypertens 2008;21:1157–62.
12. Hosoya T, Kuriyama S, Yoshizawa T, et al. Effects of combined
antihypertensive therapy with losartan/hydrochlorothiazide on uric
acid metabolism. Intern Med 2012;51:2509–14.
13. Choi HK, Soriano LC, Zhang Y, Rodrı́guez LA.
Antihypertensive drugs and risk of incident gout among patients
Clin Exp Hypertens Downloaded from informahealthcare.com by University of Maastricht on 06/24/14
For personal use only.
ARBs and hydrochlorothiazide in hypertensive patients 257
with hypertension: population based case-control study. Br Med J
2012;344:d8190.
14. Roncal-Jimenez CA, Lanaspa MA, Rivard CJ, et al. Sucrose
induces fatty liver and pancreatic inflammation in male breeder
rats independent of excess energy intake. Metabolism 2011;60:
1259–70.
15. Inokuchi T, Tsutsumi Z, Takahashi S, et al. Effects of benzbromar-
one and allopurinol on adiponectin in vivo and in vitro.
Horm Metab Res 2009;41:327–32.
16. Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment
with benzbromarone in patients with heart failure: a double-blind
placebo-controlled crossover preliminary study. Circ Heart Fail
2010;3:73–81.
17. Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and
the development of diabetes: a quantitative review. Hypertension
2006;48:219–24.