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Hypertension Research
https://doi.org/10.1038/s41440-023-01273-3
REVIEW ARTICLE
Current topic in Hypertension
Update in uric acid, hypertension, and cardiovascular diseases
Masanari Kuwabara1●Takahide Kodama1●Ryusuke Ae2●Mehmet Kanbay3●Ana Andres-Hernando4●
Claudio Borghi5●Ichiro Hisatome6●Miguel A. Lanaspa4
Received: 5 December 2022 / Revised: 18 February 2023 / Accepted: 12 March 2023
© The Author(s), under exclusive licence to The Japanese Society of Hypertension 2023
Abstract
A direct relationship between serum uric acid levels and hypertension, cardiovascular, renal and metabolic diseases has been
reported in many basic and epidemiological studies. Among these, high blood pression is one of the most common features
associated with hyperuricemia. In this regard, several small-scale interventional studies have demonstrated a significant
reduction in blood pressure in hypertensive or prehypertensive patients on uric acid-lowering drugs. These observation or
intervention studies have led to affirm that there is a causal relationship between uric acid and hypertension. While the
clinical association between uric acid and high blood pressure is notable, no clear conclusion has yet been reached as to
whether lowering uric acid is beneficial to prevent cardiovascular and renal metabolic diseases. Recently, several prospective
randomized controlled intervention trials using allopurinol and other uric acid-lowering drugs have been reported, and the
results from these trials were almost negative, suggesting that the correlation between hyperuricemia and cardiovascular
disease has no causality. However, it is important to note that in some of these recent studies there were high dropout
rates and an important fraction of participants were not hyperuricemic. Therefore, we should carry caution in interpreting
the results of these studies. This review article presents the results of recent clinical trials using uric acid-lowering
drugs, focusing on hypertension and cardiovascular and renal metabolic diseases, and discusses the future of uric acid
therapy.
Keywords Uric acid ●Hypertension ●Cardiovascular renal metabolic diseases ●Causality ●Risk factor
Background
The “Japanese guideline for the management of hyperur-
icemia and gout”defines hyperuricemia as a serum uric acid
level exceeding 7 mg/dL [1,2]. The reason for this
definition is that serum uric acid levels up to 7 mg/dL can
exist in human blood without becoming supersaturated and
crystallizing due to the presence of uric acid-binding pro-
teins, even though the physiological solubility of uric acid is
6.4 mg/dL. Importantly, serum uric acid levels differ largely
between men and women due to the hypouricemic proper-
ties of female hormones. Because of this, hyperuricemia is
internationally defined as a serum uric acid level of 6.0 mg/
dL or larger in women [3,4]. However, circulating uric acid
levels substantially increase after menopause, and therefore,
it should be noted that aging is a strong confounding factor
in hyperuricemia, especially in women [5]. Some studies
showed increased risk of cardiometabolic diseases begins at
approximately 5 mg/dL in men or 4 mg/dL in women [6,7].
Elevated uric acid is the consequence of increased uric
acid production or decreased excretion (Fig. 1). Unlike most
mammals, uric acid is the final product of purine degrada-
tion in humans and therefore, excessive or chronic purine
intake increases serum uric acid levels. Consistently, con-
sumption of purine-rich foods like seafood, shellfish, alco-
holic beverages like beer and some meats are not
*Masanari Kuwabara
kuwamasa728@gmail.com
1Department of Cardiology, Toranomon Hospital, Tokyo, Japan
2Division of Public Health, Center for Community Medicine, Jichi
Medical University, Tochigi, Japan
3Division of Nephrology, Department of Medicine, Koc University
School of Medicine, Istanbul, Turkey
4Division of Endocrinology, Metabolism and Diabetes, School of
Medicine, University of Colorado Denver, Aurora, CO, USA
5Department of Medical and Surgical Sciences, University of
Bologna, Bologna, Italy
6Department of Cardiology, Yonago Medical Center,
Yonago, Torrori, Japan
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recommended in individuals with gout or hyperuricemia.
Moreover, besides its dietary source, a high production of
uric acid occurs when adenosine triphosphate (ATP), a
human energy source, is metabolized. The metabolism of
ATP leads to the accumulation of its monophosphate form
adenosine monophosphate (AMP), which enters the purine
degradation pathway via deamination through AMP dea-
minase [8]. Because of this, besides the consumption of
purines, foods that cause acute and significant ATP deple-
tion like alcoholic beverages, fructose and sugar containing
foods and umami-rich products elevate plasma uric acid
levels post-prandially.
Xanthine oxidase (XO) catalyzes the last step in the
purine degradation pathway by converting hypoxanthine to
xanthine and uric acid. Therefore, drugs that inhibit XO like
allopurinol and febuxostat decrease uric acid production and
subsequently plasma uric acid levels, which are considered
more effective for overproduction type of hyperuricemia.
On the other hand, the kidneys are responsible for 2/3 of
total uric acid excretion while the intestinal tract is
responsible for the remaining 1/3 via specific transporters
like URAT1, SLC2A9 (GLUT9), or ABCG2 [9,10].
Because of this, uricosuric drugs that promote uric acid
excretion like benzbromarone, probenecid, and dotinurad
which inhibit these specific transporters are considered
more effective for under-secretion type hyperuricemia
associated with decreased uric acid excretion in conditions
like dehydration or impaired renal function.
The mechanism whereby uric acid causes
hypertension, cardiovascular and renal
metabolic diseases
For decades, uric acid was considered just a mere waste
product necessary for nitrogen excretion in humans and its
plasma levels just a reflection of renal function. However,
the concept of uric acid being just an inert neutral meta-
bolite has been noteworthy challenged and numerous basic
and epidemiological studies and some interventional studies
have identified a causal role for uric acid in metabolic
dysfunction and a risk factor in cardiovascular and renal
disease [11,12]. The proposed interplay between hyperur-
icemia and arteriosclerosis, hypertension, chronic kidney
disease, and cardiovascular disease is summarized in Fig. 2
[5,11–14]. The production of uric acid via XO generates
reactive oxygen species like superoxide. Also, uric acid
although it has antioxidant properties in serum, intracellu-
larly it acts as a prooxidant molecule activating a specific
catalytic subunit of nicotinamide-adenine dinucleotide
phosphate (NADPH) oxidase, NOX4 [15]. Ultimately,
reactive oxygen species and NOX4 cause mitochondrial
dysfunction and reduced glucose and fatty acid oxidation.
In the endothelium, uric acid diminishes nitric oxide
availability, a vasodilator, resulting in vascular endothelial
damage and vascular dysfunction thus contributing to the
high blood pressure [16]. Another deleterious effect if uric
acid is via urate crystals, which in turn induce inflammation
M. Kuwabara et al.
Graphical Abstract
leading to not only to gout and gouty kidneys but also
arteriosclerosis. In addition, it has also been pointed out that
the process of increased production of uric acid is caused by
ATP degradation, and the ATP depletion may coexist with
hyperuricemia and affect various diseases.
The relationship between hyperuricemia
and hypertension
Besides gender and diet, other risk factors associated with
hyperuricemia include obesity, diabetes, metabolic syn-
drome, and some medications [5]. Obesity and metabolic
syndrome are often associated with hyperinsulinemia.
Hyperinsulinemia induces sodium reabsorption and increa-
ses uric acid reabsorption by urate transporters (URAT1)
[17], which could contribute to increased blood pressure.
Therefore, when managing the patients with hypertension
and hyperuricemia, life-style modification is the primary
treatment for the patients including weight loss, restricted
excess calories, reducing purine-rich foods, such as meat
and seafood, and restricted intake of alcohol and fructose.
Figure 3shows the summary of the associated factors of
uric acid and the difficulty to show the causality between
uric acid and cardiovascular disease. We should take care of
tips and pit-falls in uric acid clinical research [18]. Many
studies have demonstrated a positive relationship between
uric acid and hypertension, but it is important to consider
the influence of these confounding factors when conducting
uric acid research. For example, we showed in a cross-
sectional study using health examination data that the pre-
valence of hypertension increased by approximately 20%
for each 1 mg/dL increase in serum uric acid levels in a
population not taking antihypertensive or uric acid-lowering
medications [19]. Furthermore, in a cohort study in which
participants were followed for 5 years, we concluded that
hyperuricemia is an independent risk factor for the pro-
gression from prehypertension (systolic blood pressure of
130–139 mmHg/ diastolic blood pressure of 80-89 mmHg)
to hypertension [20]. Similarly, in the highest prediction
model of high blood pressure in young aged 12–13 years
followed up for an average of 8.6 years, uric acid was one
of several important predictive components of high blood
pressure [21]. Intervention studies using blood pressure as
the primary endpoint with uric acid-lowering drugs have
shown significant positive results. For example, a rando-
mized, placebo-controlled, crossover study of 30 newly
Fig. 2 Mechanisms between hyperuricemia and arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease. (Cited Figure 11
on the article [11]). ATP, adenosine triphosphate
Fig. 1 The mechanism of hyperuricemia (elevated uric acid)
Update in uric acid, hypertension, and cardiovascular diseases
diagnosed hypertensive adolescents, allopurinol reduced
blood pressure by lowering systemic vascular resistance and
plasma renin activity compared with placebo [20]. In another
randomized, controlled, three-arm trial with placebo, allo-
purinol, and probenecid, both types of uric acid-lowering
therapy reduced systolic and diastolic blood pressure in 11- to
17-year-olds [22]. In addition to the effects of XO inhibitors
and urate excretion inhibitors on blood pressure, a sub-
analysis of two randomized controlled trials using pegloti-
case, a circulating uric acid-degrading enzyme, showed a
significant reduction in mean arterial pressure, systolic pres-
sure, and diastolic pressure from baseline to 6 months in the
pegloticase group responders whose uric acid levels were
maintained less than 6 mg/dL [23].
On the other hand, while the results from interventional
studies in newly diagnosed hypertensive patients and parti-
cularly in youth and young adults are promising, results from
adults and older population trials are more challenging.
Because of this ambivalence, there is still much debate as to
whether hyperuricemia is an independent factor for hyper-
tension on its own. As an example, the FEATHER study
(Febuxostat Versus Placebo Randomized Controlled Trial
Regarding Reduced Renal Function in Patients with Hyper-
uricemia Complicated by Chronic Kidney Disease Stage 3), a
multicenter, placebo-controlled, double-blind, randomized
study, examined the effect on blood pressure by febuxostat.
Although there was a reduction in blood pressure in the
febuxostat group, there was no significant difference com-
pared with the placebo [24]. To address the issue of con-
founding factors for uric acid, we conducted a study of
generally healthy subjects, excluding patients who were
overweight/obese, hypertensive, diabetic, dyslipidemic, had
chronic kidney disease, or had previously been treated for
gout or hyperuricemia. The 5-year retrospective cohort study
has shown that even isolated asymptomatic hyperuricemia is
a risk for developing hypertension [3].
The PRIZE (Program of Vascular Evaluation Under Uric
Acid Control by the Xanthine Oxidase Inhibitor Febuxostat:
Multicenter, Randomized, Controlled) study showed that
febuxostat did not delay the progression of carotid athero-
sclerosis in patients with asymptomatic hyperuricemia [25].
In contrast, the additional febuxostat treatment in patients
with asymptomatic hyperuricemia for 24 months might
potentially have preventable effects on the impaired diastolic
dysfunction in the sub-analysis of the PRIZE study [26].
These reports suggested the potential direct antioxidant
effects of the treatment as reflected in serum uric acid levels
as well as its xanthine-oxidase-lowering properties in tissue
[27]. Whether the preferential use of xanthine oxidase inhi-
bitors becomes a new therapeutic strategy for preventing
cardiovascular disease in patients with asymptomatic hyper-
uricemia awaits further high-quality trials [28].
Several meta-analyses have shown a relationship
between hyperuricemia and hypertension and between uric
acid medications and blood pressure [29,30]. Allopurinol
has been shown to reduce systolic and diastolic blood
pressure by 3.3 mmHg and 1.3 mmHg, respectively [29].
Taken together, these results show that focusing uric acid-
lowering drugs for hyperuricemia is likely to decrease blood
pressure by reducing systemic vascular resistance and
plasma renin activity, among other effects.
The relationship between hyperuricemia
and renal disease
A biopsy-based study showed positive relationship between
uric acid and renal arteriolar hyalinosis and wall thickening,
which suggest that hyperuricemia is related to renal arter-
iolar damage in patients with chronic kidney disease (CKD)
[31]. The relationship between uric acid and kidney disease
is discussed in the 2012 “Guidelines for CKD”issued by
the International Kidney Disease: Improving Global Out-
come (KDIGO) [32]. Although the guidelines indicate the
importance of management of hyperuricemia in CKD, the
evidence for using uric acid-lowering agents for renal pro-
tection in CKD is insufficient and not recommended [32]. In
2020, the results of two randomized controlled trials of
allopurinol for hyperuricemia were reported [33,34]. Both
in the PERL (Preventing Early Renal Loss in Diabetes) trial
[33] and the CKD-FIX (Controlled Trial of Slowing of
Kidney Disease Progression from the Inhibition of Xanthine
Oxidase) [34], uric acid-lowering treatment with allopurinol
did not slow the decline in eGFR compared with placebo
controls. However, it is important to note that in both of the
Fig. 3 Summary of the associated factors of uric acid and the difficulty
to show the causality between uric acid and cardiovascular disease.
*Food includes purine-rich foods like seafood, shellfish, and some
meats, fructose and sugar containing food like snacks, and umami-rich
products. **Drink includes alcoholic beverages like beer, and fructose
and sugar containing beverages like juice. Gray background shows
congenital or non-interventional factors. Yellow background shows
mostly acquired diseases and preventable (except for genetic or some
acquired diseases). Purple background shows lifestyle associated fac-
tors, which can be improved by lifestyle modification
M. Kuwabara et al.
PERL and the CKD-FIX studies included a large number of
normouricemic participants. In this regard, it is important to
note that normouricemia is not associated with the pro-
gression of CKD and therefore lowering uric acid in nor-
mouricemic patients should not be included in clinical trials
to test the effect of hyperuricemia in CKD. Also, to note.
data from participants who dropped out of the study was
still included in the analysis even though the drug was
discontinued before the completion of the trial. In any case,
the results presented in the CKD-FIX and PERL studies
coincided with previous reports from the FEATHER study
conducted in Japan [24], which showed that febuxostat
treatment was not significantly effective in preventing renal
dysfunction in the setting of adequate CKD treatment.
However, a report from India showed that six months of
febuxostat treatment reduced renal dysfunction compared to
placebo [35], indicating that the renoprotective effects of
uric acid-lowering drugs may be sufficient for patients with
inadequately treated CKD. Further, the “Multicenter Ran-
domized Controlled Trial of the Effect of Febuxostat Pre-
vention of CerebroCardio-Renal Vascular Events in
Hyperuricemic Patients: FREED”showed a significant
reduction in renal dysfunction including proteinuria in the
febuxostat use group [35,36]. Taken together, while these
results suggest that in discriminant use of uric acid-lowering
drugs in subjects with CKD is likely not indicated, in
subjects who have CKD with proteinuria or progressive
kidney functional deterioration, that trials should still be
performed, especially in subjects who are hyperuricemic or
have gout. Still, they may be effective in treating inade-
quately treated CKD by decreasing proteinuria.
The relationship between hyperuricemia
and cardiovascular diseases
A subanalysis of the Japanese Coronary Artery Disease
Study (J-CAD) demonstrated significantly more cere-
brovascular events at three years in the group with higher
serum uric acid levels [37]. Moreover, a recent cohort study
showed that hyperuricemia was associated with more than
50% increased hazard ratio of major adverse cardiovascular
events in patients with chronic coronary syndrome after
percutaneous coronary intervention [38]. Also, Noman et al.
reported in 2010 in a randomized, placebo-controlled,
crossover trial that high-dose oral allopurinol (600 mg/day)
was effective in improving symptoms during exertion of
angina pectoris [39]. These studies suggests the positive
relationship between uric acid and cardiovascular diseases.
The CARES (Cardiovascular Safety of Febuxostat and
Allopurinol in Patients with Gout and Cardiovascular
Morbidities) trial compared the xanthine oxidase inhibitor
febuxostat with allopurinol in the United States to evaluate
the safety of febuxostat for cerebrovascular disease events,
primarily in patients with cerebrovascular disease and gout
[40,41]. The results showed that the secondary endpoint of
all-cause mortality and cardiovascular death was higher
with febuxostat. However, a post-hoc analysis of the
CARES trial revealed more deaths in the drug dis-
continuation group, suggesting a possible effect of xanthine
oxidase inhibitor withdrawal syndrome [42]. Subsequently,
in 2020, the FAST trial (febuxostat versus allopurinol
streamlined trial) in patients with gout in the United
Kingdom and Denmark was reported [43]. In the patient
group of the FAST trial, which had a low dropout rate, there
was no difference in cardiovascular events or death between
allopurinol and febuxostat; with a significant reduction in
all-cause mortality in the febuxostat group [43].
The relationship between uric acid-lowering drugs and
cardiovascular disease is considered to be a situation that
has yet to be answered definitively. The results of the ALL-
HEART, a large-scale, prospective, randomized controlled
trial, examining whether allopurinol can prevent cere-
brocardiovascular disease in ischemic heart disease patients
aged 60 years or older with no history of gout, have recently
been reported [44]. The results showed that allopurinol was
not effective in preventing cerebrocardiovascular disease.
However, similar to the PERL and the CKD-FIX studies for
CKD, the ALL-HEART should be noted that the study
subjects’baseline serum uric acid levels were 0.34 mmol/L
(5.7 mg/dL). So even though allopurinol effectively lowered
serum uric acid levels in these normouricamic patients (to as
low as 0.18 mmol/L (3.0 mg/dL)) the study was not
designed to test the effect of lowering uric acid for hyper-
uricemia in cerebrocardiovascular disease. Moreover, the
high dropout rate of 57.4% in the allopurinol group should
be interpreted with caution. Allopurinol and other uric acid-
lowering drugs are designed to prevent and treat gout and
hyperuricemia, so their effectiveness is likely limited in
patients who do not have gout or hyperuricemia as nor-
mouricemia is not a risk factor for cardiovascular disease. In
fact, a retrospective cohort study in the United Kingdom
showed that in elderly patients with hypertension, the
allopurinol group had lower stroke and cardiovascular dis-
ease rates [45]. In order to answer the question of whether
uric acid-lowering drugs reduce cardiovascular events,
further high-quality intervention studies in hypertensive
patients with hyperuricemia are required. It should also be
noted that ALL-HEART excludes patients with gout.
Similar to the more promising results obtained with uric
acid-lowering drugs in newly diagnosed hypertensive
patients and young adult, a study reported cerebrovascular
events are more common within 120 days of gout onset,
especially within 60 days [45]. It is possible that uric acid-
lowering therapy is more beneficial in reducing cere-
brovascular events in newly diagnosed patients with gout.
Update in uric acid, hypertension, and cardiovascular diseases
The relationship between gout and cerebrocardiovascular
events is becoming more evident, and prevention of cere-
brocardiovascular disease in gout patients is also considered
important [46]. The results of the ALL-HEART suggest that
allopurinol is ineffective in preventing cardiovascular dis-
ease, at least in older patients without a history of gout or
hyperuricemia, but it is appropriate to treat hyperuricemia to
prevent the onset of gout in patients with a history of gout
attacks or ongoing hyperuricemia.
Recently, imaging modalities have identified mono-
sodium urate deposits in both the aorta and coronary
arteries, especially in areas of atherosclerotic plaque, of
individuals with gout. One study used dual-energy com-
puted tomography to demonstrate that vascular mono-
sodium urate deposits was found in approximately 85% of
subjects with gout compared with a rate of 15% in controls
and were associated with higher coronary calcium score
[47]. Another study also showed that gout patients had
significantly higher volume of monosodium urate deposits
within the aorta compared to controls [48]. These studies
suggest a potentially direct role of urate crystal deposition
with atherosclerotic disease. Based on these findings, fur-
ther high-quality clinical studies with cardiovascular disease
as an outcome for patients with hyperuricemia or gout are
needed.
In regards with uric acid and heart failure, there are
currently no recommendations for hyperuricemia treatment
for heart failure in Japanese or Western guidelines. Several
previous observational studies have also reported that
hyperuricemia is a prognostic determinant of heart failure
[49–51]. In the JCARE-CARD study, 56% of the 1,869
heart failure patients had hyperuricemia (serum uric acid
levels ≥7.0 mg/dL) [49], suggested that heart failure
patients are more likely to have hyperuricemia. In a cohort
study of 4912 Framingham II patients in the United States,
the high serum uric acid group (6.3-13.7 mg/dL) had a
sixfold higher incidence of heart failure and confounding
[52]. Epidemiological studies have shown that hyperur-
icemia is a prognostic factor for heart failure. However, the
efficacy of uric acid-lowering therapy in heart failure
patients with hyperuricemia has not been determined.
Although several retrospective cohort studies have shown
the effectiveness of oral treatment with allopurinol or
febuxostat in heart failure patients [53–55], most pro-
spective studies have been negative. The OPT-CHF, an
intervention trial with oxypurinol in heart failure patients
with New York Heart Association (NYHA) cardiac function
classification III-IV, showed no improvement in clinical
symptoms, total mortality, cardiovascular death, hospitali-
zation, or heart failure hospitalization [56]. However, a sub-
analysis of the OPT-CHF showed a trend toward reduction in
all-cause mortality, cardiovascular death, and improvement
in clinical symptoms in the highest hyperuricemic group
with serum uric acid levels of 9.5 mg/dL or higher [56].
Based on the results of this study, the EXACT-HF, a
prospective, placebo-controlled, double-blind, multicenter
intervention trial, was conducted with targeting 600 mg of
allopurinol per day in patients with symptomatic severe heart
failure with a left ejection fraction of 40% or less and a
serum uric acid level of 9.5 mg/dL or higher. The results of
EXACT-HF showed a significant reduction in serum uric
acid levels in the allopurinol group, but no significant dif-
ferences in clinical symptoms, all-cause mortality, rehospi-
talization, 6-minute walk test, or left ventricular ejection
fraction at 24 weeks [57]. A crossover study comparing
benzbromarone and placebo in heart failure patients with
hyperuricemia also demonstrated a reduction in serum uric
acid levels with benzbromarone but no improvement in car-
diac function [58]. Currently, the prognostic value of uric
acid-lowering drugs for heart failure patients with hyperur-
icemia is almost negative, but some reports show efficacy.
Although the number of cases is small, there are reports that
allopurinol reduced myocardial oxygen consumption and
improved myocardial energy efficiency in idiopathic dilated
cardiomyopathy [59], that it caused a decrease in BNP in
heart failure patients [60], and that oxypurinol improved left
ventricular mass ejection fraction in heart failure patients
[61]. There is also a report that febuxostat significantly
improved left ventricular ejection fraction and prognosis
compared to allopurinol in hyperuricemic heart failure
patients with serum uric acid levels > 8 mg/dl and an average
left ventricular ejection fraction of 37% [54]. Consistent with
the FAST results described above, febuxostat may be effec-
tive in heart failure patients with hyperuricemia.
The results of the ongoing LEAF-CHF study, a multi-
center randomized controlled trial of the effect of febuxostat
in chronic heart failure patients with hyperuricemia, are
awaited [62].
The relationship between uric acid and atrial
fibrillation
The association between hyperuricemia and atrial fibrilla-
tion (AF) is well known [63,64]. The first report regarding
a positive relationship between serum uric acid and atrial
fibrillation (AF) was published in 2010 [65], although the
study was involving only 45 cases of paroxysmal AF and 41
cases of permanent AF. Many studies have since been
published showing that the relationship between hyperur-
icemia and AF becomes clear. A meta-analysis with a total
of 31 studies with 504,958 participants showed that high
serum uric acid levels was significantly associated with the
incidence of AF (relative risk, 1.92) as the results from
M. Kuwabara et al.
8 cohort studies and serum uric acid levels elevated in
patients with AF as the results from 29 studies [66]. The
meta-analysis study also showed that the serum uric acid
levels in persistent AF were significantly higher compared
with that in paroxysmal AF and new-onset AF [66]. From
Japan, a cross-sectional study of 325,771 patients under-
going regular physical examinations showed that serum uric
acid levels were independent of other cardiovascular risk
factors for AF in both men and women [67]. Besides,
another cross-sectional study showed that hyperuricemia is
an independent competing risk factor for AF even in a
general healthy population without any comorbidity
(hypertension, diabetes, dyslipidemia, chronic kidney dis-
ease, and hyperuricemia or gout) [68].
Hyperuricemia might contribute to AF by either a direct
or indirect mechanism [69]. Hyperuricemia is associated
with hypertension, diabetes, metabolic syndrome, and
CKD, which are considered as risks for AF. Hyperuricemia
could also indirectly affect the provocation of AF via other
risk factors. In addition, uric acid might directly influence
AF from both inflammation-induced effects and
inflammation-independent effects. Urate crystal induces
inflammation by activation of the NACHT, LRR and PYD
domains-containing protein 3 (NLRP3) inflammasome in
the macrophage [70]. In addition, soluble uric acid can enter
cells via the urate transporter. Activation of Kv1.5 channel
is one of the main factors for provocation and recurrence of
AF. The accumulation of intracellular uric acid via activa-
tion of urate transporters enhances Kv1.5 protein expression
to shorten the atrial potential duration [71], which con-
tributes to the reentry circuit for AF. There are some
experimental findings that support a role for uric acid in AF
[70], but there is little clinical evidence showing that uric
acid-lowering therapy could prevent AF provocation. The
FREED showed that febuxostat did not decrease the inci-
dence of AF, which is one of the primary composite end-
points [36]. We need further large-scale clinical studies to
check whether uric acid-lowering therapy for patients with
hyperuricemia or gout can prevent new onset of AF.
Mendelian randomization study
Mendelian randomization analyses have shown that genes
responsible for hyperuricemia are not independent risk
factors for hypertension, ischemic heart disease, type 2
diabetes, cerebrovascular disease, or heart failure [72–74].
These results suggest that genetic predisposition encoding
uric acid transporters is not directly a risk for hypertension
or heart disease. On the other hand, some studies showed a
positive relationship between the xanthine oxidoreductase
gene and blood pressure, which suggests the role of xan-
thine oxidoreductase and oxidative stress in blood pressure
[75,76]. Another report showed that serum uric acid levels
and the genetic risk score for uric acid concentration based
on eight uric acid-regulating single nucleotide polymorph-
isms were both associated with cardiovascular death and
sudden cardiac death [77]. Moreover, D. Gill et al. recently
showed that Mendelian randomization using data from UK
Biobank and clinical trial data supports an effect of higher
serum uric acid levels on increasing blood pressure, which
may mediate a consequent impact on cardiovascular disease
risk [78]. Uric acid levels are regulated by both the gene
expression of urate-transporter and xanthine oxidoreductase
involved in its production and accumulation. Importantly,
while most studies of the urate-transporter gene are negative,
most studies exploring gene regulation of xanthine oxidor-
eductase have been positive. In addition, serum uric acid
levels are also strongly influenced by lifestyle factors such as
purine intake in the diet, alcohol and fructose in fluid intake,
and exercise. Dietary habits have rapidly changed in the last
100 years, and these acquired factors strongly affect cardio-
vascular diseases [79]. Hyperuricemia may be influence by
acquired factors, including diet and lifestyle, rather than the
genetic background. Therefore, we should take caution in
considering genetic predisposition alone.
Treatment for hyperuricemia
Traditionally, asymptomatic hyperuricemia who were not
suffered from gout.is not a condition to be treated clinically.
However, the “Japanese guideline for the management of
hyperuricemia and gout”recommended the therapeutic
intervention in hyperuricemic patients with serum uric acid
levels of 8.0 mg/dl or higher and comorbidities such as
hypertension, considering the prevention of gout attacks and
gout nodules [1,2]. For hyperuricemic patients without any
comorbidities, therapeutic intervention is recommended at
serum uric acid levels of 9.0 mg/dl or higher [1,2]. Prior to
pharmacotherapy, water intake of more than 2 litter per day
and dietary therapy including reduction of purine intake,
alcohol and fructose intake, as well as lifestyle modification
such as reduction of salt intake, weight loss, and exercise
habits are recommended. Of course, paying attention the
amount of water intake to patients with heart failure or other
underlying diseases is needed. If hyperuricemia persists
even after lifestyle modification, uric acid-lowering drug
therapy is then recommended.
When treating hypertensive patients with hyperuricemia,
it is required to select an antihypertensive drug that is
unlikely to affect serum uric acid levels adversely. This is
particularly relevant as some antihypertensive drugs
increase serum uric acid levels including thiazides and beta-
blockers. Hyperuricemia is also a common complication in
patients with salt-sensitive hypertension. Calcium channel
Update in uric acid, hypertension, and cardiovascular diseases
Table 1 Trials of uric acid-lowering drugs with the outcome of (A) blood pressure, (B) cardiovascular disease, and (C) heart failure
Authors or
study name
Year Design Patients Sample size Target drug and periods Comparison Outcome Results
(A) Blood pressure
Feig et al.
[20]
2008 Randomized, double-
blind, placebo-
controlled,
crossover trial
Adolescents with stage 1
essential hypertension
and serum uric acid > or
=6 mg/dL mg/dL (11-
17 years)
30 15:15
crossover
Allopurinol 200 mg
twice daily for 4 weeks
Placebo Blood pressure Positive
Soletsky et al.
[22]
2012 Randomized, double-
blinded, placebo-
controlled trial
obese adolescents with
prehypertension
(11–17 years)
56
19 placebo,
19 allopurinol,
18 probenecid
allopurinol 100 mg
twice daily, probenecid
250 mg twice daily for
1 week, then
allopurinol 200 mg
twice daily, probenecid
500 mg twice daily for
7 weeks
Placebo Blood pressure Positive
Higgins et al.
[82]
2014 Randomized, double-
blind, placebo-
controlled study
Patients aged over 18
years with recent
ischemic stroke or TIA
(mean age 67.8 years)
69
34 allopurinol,
35 placebo
Allopurinol 300 mg
daily for 1-year
Placebo brachial and central blood
pressure carotid intima-media
thickness progression
Positive
Positive
Segal et al.
[83]
2015 Randomized, double-
blind, placebo-
controlled study
African Americans with
Stage 1 hypertension
without clinical renal
disease (18-65 years)
110
56 allopurinol,
54 placebo
Allopurinol (300 mg/
day) plus
chlorthalidone for
8 weeks
Placebo plus
chlorthalidone
Blood pressure Negative
(Tendency)
(−3.4 vs.
0.8 mmHg,
p=0.059)
Johnson et al.
[23]
2019 Post hoc analysis used
results from two
6-month randomized
clinical trials
subjects were treated
with 8 mg pegloticase
every 2 or 4 weeks (q2w
or q4w) or placebo
212
85 8 mg q2w,
84 8 mg q4w,
43 Placebo
Pegloticase 8 mg every
2 or 4 weeks (q2w or
q4w) for 6 months
Placebo Blood pressure changes in
estimated glomerular
filtration rate
Positive
Negative
PRIZE [25] 2020 Randomized, open-
label, blinded-endpoint
clinical
Adults with both
asymptomatic
hyperuricemia
(SUA > 7.0 mg/dL) and
maximum IMT of the
common carotid
artery > _1.1 mm
400
207 febuxostat,
193 control
Febuxostat 10 mg daily
for 1month, 20 mg
daily for 1 month, then
40 mg daily (febuxostat
could be increased to
60 mg daily)
Control (Lifestyle
modification)
maximum IMT of the common
carotid artery
Blood pressure
Negative
Negative
M. Kuwabara et al.
Table 1 (continued)
Authors or
study name
Year Design Patients Sample size Target drug and periods Comparison Outcome Results
(B) Cardiovascular disease
Noman et al.
[39]
2010 Randomized, placebo
controlled
crossover trial
Patients with stable
chronic angina pectoris
(for at least 2 months)
(aged 18–85 years)
60
28 allopurinol,
32 placebo
Allopurinol 600 mg
per day for 6 weeks
Placebo Time to ST depression and
exercise time
Positive
Goicoechea
et al. [84]
2010 Single-blind,
randomized,
controlled trial
Patients with estimated
GFR (eGFR) <60 ml/min
(mean age
71.4–72.1 years)
113
57 allopurinol,
56 control
Allopurinol administered
a dose of 100 mg/d.
Mean follow-up time of
23.4 +/- 7.8 months
Control Cardiovascular events Positive
Goicoechea
et al. [85]
2015 Single-blind,
randomized,
controlled trial
(same as above)
Patients with estimated
GFR (eGFR) <60 ml/min
(mean age
71.4–72.1 years)
113
57 allopurinol,
56 control
long-term follow-up
(median 84 months)
Control Cardiovascular events Positive
FREED [36] 2019 Randomized, open-
label, blinded-
endpoint study
Elderly patients aged 65
years or older with
hyperuricemia (serum
uric acid >7.0
to < _9.0 mg/dL) who
had one or more risks for
cerebral, cardiovascular,
or renal disease
1070
537
febuxostat,
533 non-
febuxostat
Febuxostat 10 mg/day for
4 weeks, 20 mg/day for
8 weeks, then 40 mg/day
for 36 months
The median follow-up
35.5 months
Allopurinol (100 mg)
allowed
The median follow-up
35.1 months
composite endpoint: death and
cerebral, cardiovascular, renal
disease, cardiac failure,
arteriosclerotic disease, and
new atrial fibrillation
Positive
(Mostly from
renal
impairment)
CARES [41] 2018 Randomized, double-
blind,
noninferiority trial
Patients with gout and a
history of major
cardiovascular disease: a
myocardial infarction,
hospitalization for
unstable angina, stroke,
hospitalization for
transient ischemic attack,
peripheral vascular
disease, or diabetes
mellitus with evidence of
microvascular or
macrovascular disease.
6190
3098
febuxostat,
3092
allopurinol
Febuxostat 40 mg
once daily
If SUA > 6.0 mg/dL at the
week 2 visit, the dose was
increased to 80 mg
once daily
The median follow-up
32 months (maximum,
85 months).
Allopurinol 300 mg
once daily, which was
increased in 100-mg
increments monthly
until the
SUA < 6.0 mg/dL or
600 mg once daily
Composite endpoint of
cardiovascular death, nonfatal
myocardial infarction, nonfatal
stroke, or urgent
revascularization for unstable
angina (Primary endpoint)
All-cause mortality and
cardiovascular mortality
(Secondary endpoint)
Non-inferiority
Higher with
febuxostat
Update in uric acid, hypertension, and cardiovascular diseases
Table 1 (continued)
Authors or
study name
Year Design Patients Sample size Target drug and periods Comparison Outcome Results
FAST 2020 Randomised, open-
label, blinded-
endpoint, non-
inferiority trial
Patients with gout
already receiving
allopurinol, and had at
least one additional
cardiovascular risk
factor. (60 years or older)
6128
3063
febuxostat,
3065
allopurinol
Febuxostat 80 mg daily
for the first 2 weeks after
randomisation. After
2 weeks, if SUA not
controlled, the febuxostat
dose was increased to
120 mg daily.
Median follow-up time
was 1467 days (IQR
1029-2052) and median
on-treatment follow-up
was 1324 days
Allopurinol maximum
licensed dose (900 mg/
day) or maximum
tolerated dose of
allopurinol.
Composite endpoint of
hospitalisation for non-fatal
myocardial infarction or
biomarker-positive acute
coronary syndrome; non-fatal
stroke; or
cardiovascular death.
Non-inferiority
ALL-HEART
[44]
2022 Randomised, open-
label, blinded-
endpoint trial
Patients aged 60 years or
older with ischemic heart
disease but no history of
gout (mean age
72.0 years)
5721
2853
allopurinol,
2868 control
(usual care)
Allopurinol up-titrated to
a dose of 600 mg daily
(300 mg daily in
participants with moderate
renal impairment at
baseline)
Control (Usual care) Composite cardiovascular
endpoint of non-fatal
myocardial infarction, non-
fatal stroke, or
cardiovascular death.
Negative
(C) Heart failure
OPT-CHF
[56]
2008 Randomised, double-
blind, placebo-
controlled study
Patients with New York
Heart Association
functional class III to IV
heart failure due to
systolic dysfunction
receiving optimal
medical therapy
405 Oxypurinol 600 mg/day
Efficacy at 24 weeks was
assessed
Placebo composite clinical end point
that classified subject’s clinical
status based on death,
hospitalization, emergency
department visit or emergent
clinic visit for worsening heart
failure at week 24
Negative
Positive in the
sub-analysis for
the patients with
SUA > _
9.5 mg/dL
EXACT-HF
[57]
2015 Randomised, double-
blind, placebo-
controlled study
Patients with
symptomatic heart
failure, left ventricular
ejection fraction ≤40%,
and serum uric acid
levels ≥9.5 mg/dL mean
age 63 years
(52–74 years)
253
128
allopurinol
125 placebo
Allopurinol 300 mg once
daily for 1 week, and if
tolerated, increased to
600 mg daily.
Placebo Composite clinical endpoint
that classified a subject’s
clinical status at 12 and
24 weeks.
Negative
M. Kuwabara et al.
blockers have little effect on uric acid metabolism and are
relatively safe to use. When angiotensin II receptor blockers
(ARBs) are used, losartan and irbesartan are recommended
because they lower serum uric acid levels. In this regard, the
combination of losartan and a Ca channel blocker has been
reported to reduce the risk of developing gout [80]. Serum
uric acid levels should be strongly considered in the choice
of antihypertensive medication. Still, beta-blockers and
diuretics are often necessary for patients with heart failure,
which often increases serum uric acid levels. In the coming
heart failure pandemic, the number of patients with heart
failure and hyperuricemia will increase. At this time, there
is little evidence that uric acid-lowering drugs improve
prognosis in patients with heart failure complicated by
hyperuricemia, like the results of EXACT-HF [57]. How-
ever, in such cases, the administration of uric acid-lowering
drugs should be considered when the serum uric acid level
remains above 8.0 mg/dl, and the target serum uric acid
level should be 6.0 mg/dl or lower for the purpose to pre-
vent gout [1,2]. This recommendation is supported by the
recent study that showed that appropriate control of serum
uric acid levels of 5–6 mg/dL was less than a half of risk of
gout than untreated hyperuricemic subjects whose serum
uric acid levels was more than 8.0 mg/dL [81].
Summary
Hyperuricemia is an apparent cause of gout, increasing
adverse cerebrovascular events. From the viewpoint of gout
prevention, lowering uric acid for patients with hyperur-
icemia could be considered appropriate. A direct relation-
ship between hyperuricemia and metabolic diseases such as
hypertension, kidney disease, cardiovascular disease, and
heart failure has been established for many years. However,
except for gout and hypertension, recent interventional
randomized-controlled trials have not been able to conclude
a positive effect between lowering uric acid levels and the
progression of cardiovascular and renal disease. Table 1
summarized the clinical trials of uric acid-lowering drug
with the outcome of blood pressure, cardiovascular disease,
and heart failure. To note, the conclusions of these studies
not recommending lowering uric acid in cardiovascular and
renal disease seem premature as they included a high per-
centage of normouricemic patients and had a high drop-out
rate and drug discontinuation. Therefore, high-quality
clinical trials that take into account patient backgrounds
and other factors are required to determine whether uric
acid-lowering drugs can prevent each disease in the future.
Acknowledgements We thank Richard Johnson (Division of Renal
Diseases and Hypertension, School of Medicine, University of Col-
orado Denver, CO, USA) for his advice of this review article.
Compliance with ethical standards
Conflict of interest Dr Kuwabara reports a research grant from JSPS
KAKENHI (Grant Number 20K17168 and 23K07493), Okinaka
Memorial Institute for Medical Research, and Toranomon Hospital.
The remaining authors have nothing to disclose.
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Update in uric acid, hypertension, and cardiovascular diseases
