AJH 2006; 19:208 –213
Therapeutics
Effect of Losartan Versus Candesartan
on Uric Acid, Renal Function, and
Fibrinogen in Patients With Hypertension
and Hyperuricemia Associated With Diuretics
Brian L. Rayner, Yvonne A. Trinder, Donette Baines,
Sedick Isaacs, and Lionel H. Opie
Background: Hyperuricemia may counter benefits of
blood pressure (BP) reduction, although this is controver-
sial.
Methods: We examined the effects of candesartan and
losartan on uric acid, creatinine, and fibrinogen. Patients with
hypertension and serum uric acid ⱖ0.42 mmol/L (7 mg/dL)
associated with diuretics were randomized to receive losartan
50 to 100 mg or candesartan 8 to 16 mg for 24 weeks. At
randomization and after 24 weeks, systolic and diastolic BP,
serum uric acid, creatinine, and fibrinogen were measured.
Results: A total of 59 patients were entered into the
study (30 in the losartan and 29 in the candesartan group).
Mean systolic and diastolic BP were reduced in the can-
desartan group, from 156 mm Hg at baseline to 132 mm
Hg at 24 weeks, and from 90.9 to 80.8 mm Hg respec-
tively, P ⬍ .0001), and in the losartan group from 150.3 to
132 mm Hg and from 89.6 to 77.6 respectively, P ⬍
0001). Overall mean values of fibrinogen levels were
H
yperuricemia is common in patients with essential
hypertension.1 Diuretics are the preferred first-line
therapy for uncomplicated essential hyperten-
sion,2 but may cause hyperuricemia or exacerbate pre-
existing hyperuricemia.3,4 Untreated hyperuricemia may
predispose to gout, leading to poor patient compliance or
withdrawal of diuretic therapy. However, the effect of
long-term hyperuricemia on cardiac and renal outcomes
remains controversial. Several studies have shown that
hyperuricemia is a risk factor for the development of
cardiovascular disease.5–7 This has not been confirmed by
other large studies,8,9 and there is no published evidence to
Received January 6, 2005. First decision August 24, 2005. Accepted
August 24, 2005.
From the Divisions of Hypertension (BLR, YAT, DB, LHO) and
Medical Informatics (SI), Groote Schuur Hospital, University of Cape
Town, Cape Town, South Africa.
0895-7061/06/$30.00
doi:10.1016/j.amjhyper.2005.08.005
again reduced from 4.39 g/L at baseline to 4.01 g/L at 24
weeks (P ⬍ .02). Mean values of serum uric acid in the
losartan and candesartan groups wre similar at baseline
(0.44 and 0.46 mmol/L, respectively), but they were lower
in the losartan group after 24 weeks (0.39 and 0.48
mmol/L, P ⫽ .01). Twelve patients (44%) in the cande-
sartan group had a 10% increase in serum creatinine
compared with four patients (14.2%) in the losartan group
(P ⬍ .02).
Conclusions: Candesartan and losartan lowered BP,
but only losartan reduced uric acid. The lowering of fi-
brinogen in both groups may explain the reduction in
stroke with angiotensin receptor blockers. The effect of
persistent hyperuricemia on renal function requires further
study. Am J Hypertens 2006;19:208 –213 © 2006 Amer-
ican Journal of Hypertension, Ltd.
Key Words: Losartan, candesartan, hyperuricemia, renal
function, fibrinogen.
support the view that lowering uric acid improves cardio-
vascular outcomes. Reyes and Leary have also argued that
thiazide-induced hyperuricemia could provide one expla-
nation of the apparent benefit of diuretics over other
classes of antihypertensive agents in lowering cardiovas-
cular risk because uric acid may function as a potent
antioxidant.10 More recent evidence suggests that hyper-
uricemia may lead to proteinuria and declining renal func-
tion in animal models, which may be modified by lowering
uric acid.11 An elevated uric acid predicts renal insufficiency
in individuals with normal renal function,12 progression of
IgA nephropathy,13,14 and type 2 diabetic nephropathy.15 The
This study was supported by a grant from the Merck University
program.
Address correspondence and reprint requests to Dr. B.L. Rayner, E13
Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa;
e-mail: rayner@curie.uct.ac.za
© 2006 by the American Journal of Hypertension, Ltd.
Published by Elsevier Inc.
AJH–February 2006 –VOL. 19, NO. 2
possible detrimental effects of hyperuricemia and the pos-
sible beneficial effects of diuretic-induced increases in
serum uric acid have recently been discussed.16,17
Hypertension is associated with increased fibrinogen.
Prospective studies have shown that fibrinogen is an in-
dependent marker for future cardiovascular events,18 in-
cluding ischemic stroke19; but no data have been published
on the effect of uric acid on fibrinogen.
Angiotensin receptor blockers (ARB) are highly specific
antagonists of the angiotensin II type 1 (AT1) receptor; and
they effectively treat hypertension, particularly in combi-
nation with diuretics. Losartan is the only ARB that is uri-
cosuric, which is independent of AT1 receptor blockade.20
The reduction in uric acid may be as much as 25%.4
There are no clear guidelines in the literature in regard
to continuation of diuretic therapy in patients who develop
asymptomatic hyperuricemia. In the Systolic Hypertension
in the Elderly Program (SHEP) the benefits of chlorthalidone
were nullified in subjects whose serum uric acid increased by
⬎1 mg/dL during treatment.21 In the Losartan Intervention
for Endpoint reduction in hypertension (LIFE) study, in
which losartan was shown to be superior to atenolol for
preventing cardiovascular events, a recent subanalysis
demonstrated that 29% of the benefits could be attributed
to the ability of losartan to lower uric acid.22 On the other
hand, in the Antihypertensive and Lipid-Lowering Treat-
ment to Prevent Heart Attack Trial (ALLHAT), chlortha-
lidone, which is known to raise serum uric acid, was
associated with a lower risk for stroke, heart failure, and
coronary revascularization than was lisinopril.23 To reach
target blood pressure (BP), combinations are often needed,
including diuretics with an ARB. To date there have been
no studies comparing the uricosuric effects of losartan
versus another ARB on renal function and fibrinogen in
patients with hypertension and hyperuricemia associated with
diuretic therapy.
In this study we tested our hypotheses that losartan,
compared with candesartan, would lower serum uric acid
in hypertensive patients with hyperuricemia associated with
diuretics, and produce a reduction of fibrinogen (a marker of
future cardiovascular events).
Methods
This was an open-label, randomized, controlled, two–
parallel group study with blinded endpoints. Adult patients
were eligible for the study if they were receiving thiazide
or either thiazide-like or loop diuretics, had uncontrolled
mild to moderate essential hypertension, had systolic
blood pressure (SBP) between 140 and 180 mm or dia-
stolic blood pressure (DBP) between 90 and 110 mm Hg,
and had uric acid ⱖ0.42 mmol/L (7 mg/dL). The 0.42
mmol level was chosen, as this is the upper limit of normal
of serum uric acid used by our laboratory and others.24
The dose of diuretics was required to be stable for the past
12 weeks before study entry, and women of childbearing
potential were required to be using an effective form of
HYPERTENSION AND HYPERURICEMIA 209
FIG. 1. Design of trial comparing the effects of losartan versus
candesartan on uric acid, renal function, and fibrinogen in patients
with hypertension and hyperuricemia associated with diuretics.
contraception. Exclusion criteria were as follows: second-
ary, severe, or malignant hypertension; poorly controlled
diabetes mellitus; compelling indications for an angioten-
sin-converting enzyme (ACE) inhibitor use; regular use of
steroids, nonsteroidal anti-inflammatory drugs, allopuri-
nol, or colchicine; class III or IV heart failure according to
the New York Heart Association criteria; recent myocar-
dial infarction; coronary revascularization in the last 6
months; unstable angina or significant cardiac arrhythmia;
stroke or transient ischemic attack in the past 6 months;
acute or chronic liver disease with aspartate aminotrans-
ferase or alanine aminotransferase twice the upper limit of
normal; serum creatinine ⬎200 ␮mol/L; and known hy-
persensitivity or contra-indication to losartan or candesar-
tan. The University of Cape Town Research Ethics
Committee approved the study.
After informed consent, eligible patients underwent a
2-week run in period (Fig. 1) before randomization. All
patients received standard dietary advice regarding so-
dium, fat, and carbohydrate intake, which was reinforced
at each visit. Therapy with ACE inhibitors was withdrawn.
Patients were then randomized to either losartan 50 mg or
candesartan 8 mg daily. Medication could be up-titrated to
losartan 100 mg and candesartan 16 mg daily respectively
if BP remained ⬎140/90 mm Hg at 6 weeks. After 12
weeks, if BP remained uncontrolled and losartan and can-
desartan had been up-titrated, open-label therapy (exclud-
ing an ACE inhibitor or ARB) could be used. Each patient
was required to continue taking a constant dose of diuret-
ics for the duration of the study.
Blood pressure was measured at each visit using a
mercury spyghmomanometer according to standard guide-
lines.2 This was done in the sitting position after a 5-min
rest with the arm supported at heart level. The mean of last
two stable readings was recorded. Blood was taken for
serum uric acid, creatinine, and fibrinogen at randomiza-
tion and at week 24. Urinary sodium excretion was not
measured.
The primary outcome of the study was the difference in
210 HYPERTENSION AND HYPERURICEMIA
Table 1. Mean baseline demographics of study subjects
Parameter Losartan (SD)
Number 30
Men (%) 40
Systolic BP (mm Hg) 151 (8.4)
Diastolic BP (mm Hg) 89.2 (8.4)
Creatinine (␮mol/L) 88.5 (56–123)†
Prior antihypertension 2.7
BP ⫽ blood pressure.
* Student t test; † Median and range; ‡ Mann-Whitney test.
serum uric acid between the candesartan and losartan groups
at week 24. The sample size was estimated at n ⫽ 24 in each
group, taking a 20% difference at week 24, with ␣ ⫽ 0.05
and a power of 80%. Secondary outcomes were the dif-
ferences in BP, fibrinogen, and creatinine between the
groups. Results of the study were analyzed by the Student t
and Mann-Whitney tests for baseline demographics and the
Fisher exact test for nonparametric data. Changes in BP,
serum uric acid, and fibrinogen were evaluated for differ-
ences over time and between the groups by analysis of
variance for repeated measurements, and the differences in
mean fibrinogen and serum uric acid at week 24 were
analyzed by the Student t test. The numbers of patients in
each group with a 10% increase in serum creatinine were
analyzed using the Fisher exact test (two-tailed). The level
of significance was set at P ⬍ .05.
Results
A total of 59 patients were entered into the study (30 in the
losartan and 29 in the candesartan group). Patients were well
matched at randomization, with no significant differences in
mean baseline demographics (Table 1). The number of pa-
tients with underlying diabetes (28% v 33.3%, P ⫽ .63),
previous cardiovascular events (17.3% v 23.3%, P ⫽ .51),
and prior use of ACE inhibitors (62% v 60%, P ⫽ .87) was
similar in the candesartan and losartan groups respec-
tively. Two patients, both in the losartan group, had a
history of gout. A total of 55 patients successfully com-
pleted the 24-week study. Four patients did not complete
the study: one in each group was lost to follow-up, one in
the candesartan group was withdrawn because of hypoten-
sion at week 6, and one in the losartan group was with-
drawn at 18 weeks because of noncompliance. The type of
diuretics received by each group was very similar and is
shown in Table 2. No patient developed gout, and there
were no other serious adverse events.
The differences over time (weeks 0 and 24) and be-
tween the groups were evaluated by analysis of variance
for repeated measurements. In the overall study (both
groups combined), the mean systolic BP, diastolic BP, and
fibrinogen levels decreased (Table 3), without change in
mean potassium between randomization and week 24.
There were no differences between the losartan and can-
AJH–February 2006 –VOL. 19, NO. 2
Candesartan (SD) P value*
29
41 0.91
157 (16.7) 0.07
90.5 (7.840) 0.57
95 (63–155)† 0.56‡
2.8 0.87
desartan groups in mean systolic and diastolic BP, potas-
sium, and fibrinogen at week 24 (Table 3). Only the serum
uric acid decreased in the losartan group at week 24, which
was significantly different from the values noted with
candesartan (P ⫽ .01). In the losartan and candesartan
groups, four patients (14.2%) and 12 patients (44%) ex-
perienced 10% increases in serum creatinine at week 24
(P ⫽ .02, Fisher exact test, two-tailed) respectively. Be-
cause of the effect of renal function on uric acid, we used
creatinine as a covariate in the analysis of repeated mea-
surements, and the power of the study to detect a 10%
change in creatinine was 54%.
The differences between the groups in the serum uric acid
and fibrinogen at 24 weeks was also analyzed by the Student
t test. There was no difference in fibrinogen in the losartan
and candesartan groups (4.12 v 3.9 g/L, P ⫽ .29); however,
the serum uric acid was significantly lower in the losartan
group (0.39 v 0.48 mmol/L, P ⬍ .008). The number of
patients that went below the threshold of 0.42 mmol/L in the
losartan and candesartan groups was 20 v 8 patients, and the
number remaining above the threshold were 8 v 19 patients
respectively (P ⬍ .003, Fisher exact test).
Discussion
In this study losartan and candesartan reduced both SBP
and DBP. The drugs were well tolerated. There was only
one serious adverse event in the entire study.
As anticipated, uric acid levels were significantly re-
duced by losartan (⫺0.05 mmol/L), but not candesartan.
These differences were not likely caused by differences in
serum potassium (Table 3), or sodium intake, as all pa-
tients received the same dietary advice. However, it is
Table 2. Dose and type of diuretics used by study
subjects
Diuretic Losartan Candesartan
Hydrochlorothiazide
(12.5–25 mg) 26 26
Indapamide (2.5 mg) 2 0
Furosemide
(40–160 mg) 2 3
AJH–February 2006 –VOL. 19, NO. 2 HYPERTENSION AND HYPERURICEMIA 211

Table 3. Change in mean blood pressure (BP), uric acid, potassium, and fibrinogen from week 0 compared with week 24 in the overall study and, in the
important to note that 24-h urinary sodium was not mea-

P value*
C vs L

.02‡
sured. The differences in renal function could have been a

.19
.71
⬍.01
.19
.41
confounder. In the losartan group the uric acid was re-
duced with unchanged creatinine levels, whereas in the
candesartan group uric acid was unchanged with a slight
increase in creatinine. This would argue against renal func-

0.48 (0.02)

3.9 (0.14)
Week 24

132 (2.1)
80.8 (1.7)
tion causing the changes in uric acid.

12 (44)
(SD)

4.19
Srinivas et al.16 and Reyes and Leary17 have debated
the importance of increases in serum uric acid. Briefly
C (n ⴝ 25)

there are two opposing viewpoints. On the one hand, uric

acid is considered to be a powerful anti-oxidant and di-
uretic-induced hyperuricemia may protect against future
0.46 (0.01)

4.38 (0.18)
156 (2.7)
90.9 (1.8)
Week 0

cardiovascular events, and on the other hand it may cause

(SD)

4.27

— adverse cardiovascular events and progressive renal dete-

rioration. In this study we were unable to show either bene-
ficial or deleterious effects of persistent hyperuricemia on
fibrinogen as a marker of future cardiovascular events;
however, there was a small but significant decline in renal
0.39 (0.02)

4.12 (0.14)

4 (14.2)
Week 24

132 (2.2)
77.6 (1.7)

function in the candesartan group.

(SD)

4.02

Of interest is the reduction of fibrinogen seen with both

candesartan and losartan, which does not occur with all
L (n ⴝ 27)

antihypertensive drugs.25–28 In general, inhibitors of the

renin–angiotensin system tend to reduce fibrinogen levels.
It is not known whether reducing fibrinogen levels decreases
0.44 (0.01)

4.49 (0.18)
150.3 (2.7)
89.6 (1.8)

cardiovascular events. Previous studies have suggested that

Week 0
(SD)

4.23

fibrinogen is a powerful predictor of cardiovascular events,

—

particularly ischemic stroke.19 Thus our findings may

partly explain the reduction of stroke associated with can-
desartan noted in the Study on COgnition and Prognosis in
the Elderly (SCOPE),29 with losartan in the LIFE study,30
P value*†

and with eprosartan in the Morbidity and Mortality After

⬍.001
⬍.001

⬍.001

Stroke, Eprosartan Compared with Nitrendipine for Sec-

.21
.16

* ANOVA for repeated measurements; † Number (%); ‡ Fisher exact test, two-tailed.

ondary Prevention (MOSES) study.31

In regard to the important question of the long-term
effect of hyperuricemia on renal function, significantly
more patients in the candesartan group had a ⬎10% decline
Overall (n ⴝ 55)

(10.1)

(0.09)
(0.57)
(0.72)
(8.9)

in serum creatinine. The systolic BP in the candesartan group

Week 24

16 (29)
(SD)

was slightly but not significantly higher; however, the

achieved BP in each group was very similar. Our results
132.1
79.1
0.43
4.23
4.01

would be in agreement with recent work done by Kang et

al.11 The induction of hyperuricemia in rats was associated
with increasing proteinuria, hypertension, and declining
candesartan (C) and losartan (L) groups

(0.07)
(0.51)
(0.95)

renal function. Lowering uric acid with allopurinol pre-

(9.1)
(9.1)
Week 0

vented these changes.

(SD)

In human beings, the relationship between hyperurice-

—
153.9
89.8
0.45
4.13
4.39

mia and progressive loss of renal function has not been

established; however, there are several lines of emerging
evidence to support this concept. Uric acid predicts renal
insufficiency in individuals with normal renal function,12
Diastolic BP (mm Hg)
Systolic BP (mm Hg)

progression of IgA nephropathy,13,14 and type 2 diabetic

Potassium (mmol/L)
Uric acid (mmol/L)

nephropathy.15 In a recent article in the Journal, Hawkins

Fibrinogen (g/L)
10% increase in

and Houston reported an association with population-wide

creatinine†

diuretic use and end-stage renal failure; however, they

Parameter

were unable to establish whether this was a precipitating

factor or an epiphenomenon, and they were also unable to
establish an underlying mechanism.32 In the ALLHAT
study there was no change in glomerular filtration rate in
212 HYPERTENSION AND HYPERURICEMIA
the chlorthalidone group compared with the effect ob-
served with amlodipine or lisinopril32; and in the LIFE
study the use of losartan was not associated with an improve-
ment in renal function as compared with atenolol, which
does not influence uric acid.22,30
There are several important limitations of the study,
particularly related to changes in creatinine. First, this is a
small study with a short observation period, and the study
was underpowered to detect changes in creatinine after
using covariate analysis. Second, the changes in uric acid
associated with losartan were small. Third, the use of
creatinine as a marker of renal function has several limi-
tations, and the changes in creatinine were small. Finally,
in the candesartan group, the baseline serum creatinine
was higher (95 v 88.5 ␮mol/L) and there was greater
reduction in systolic BP. The changes in creatinine in the
candesartan compared with the losartan group may have
been caused by underlying impairment of renal autoregu-
lation, resulting in a greater risk for renal impairment at
reduced renal perfusion pressure.
In conclusion, both candesartan and losartan lowered
BP, but only losartan lowered uric acid. The reduction of
fibrinogen with both candesartan and fibrinogen may in
part explain the reduction in stroke seen in the MOSES,
LIFE, and SCOPE studies. The long-term effect of persis-
tent hyperuricemia on renal function requires further study.
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