Drugs

https://doi.org/10.1007/s40265-019-01081-5

REVIEW ARTICLE

Cardiovascular Disease in Gout and the Protective Effect of Treatments

Including Urate‑Lowering Therapy
Manik K. Gupta1 · Jasvinder A. Singh2 

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign
copyright protection 2019

Abstract
Cardiovascular disease affects more than 90 million Americans. Recent studies support an increased cardiovascular disease
risk in inflammatory conditions, such as gout. Increased serum urate levels, or hyperuricemia, are a precursor to gout. Data
from meta-analyses have shown hyperuricemia to be linked to hypertension and coronary heart disease. Similarly, gout has
been associated with an increased risk of myocardial infarction, cerebrovascular accidents, and death from cardiovascular
disease in randomized clinical trials. Urate-lowering therapy reduces serum urate and may decrease systemic inflammation,
generation of oxidative species, and reverses endothelial dysfunction through hyperuricemia-dependent or hyperuricemia-
independent pathways. Cardioprotective benefits of allopurinol, a first-line agent for the treatment of gout, have been dem-
onstrated to potentially prevent myocardial infarction, stroke, atrial fibrillation, and other cardiovascular diseases in observa-
tional studies in select populations. Randomized controlled trials (RCTs) have also examined the role of newer urate-lowering
therapies, such as febuxostat and lesinurad, and their risk of cardiovascular-specific mortality in comparison to allopurinol.
A large post-marketing study of febuxostat vs. allopurinol showed higher all-cause and cardiovascular-specific mortality in
the febuxostat group than in the allopurinol group; a major study limitation was that large numbers of patients were lost to
follow-up or discontinued treatment. RCTs are required to assess the comparative effectiveness of urate-lowering therapies,
validate findings of observational studies, and to determine which subgroup populations of gout are most likely to benefit
from appropriate long-term urate-lowering therapy. This review examines the data for increased cardiovascular disease in
gout and potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, oxidative stress)
and the effect of urate-lowering therapy on cardiovascular disease.

Key Points 

Patients with a diagnosis of gout have a higher risk of

cardiovascular disease (CVD).
Treatment of patients with gout with urate-lowering
therapy may delay the onset of CVD.
Studies have demonstrated anti-inflammatory agents
used for the treatment for gout likely decrease the inci-
dence of CVD, even in general populations.

* Jasvinder A. Singh
jasvinder.md@gmail.com
1 Introduction
1
Wayne State University School of Medicine, Detroit, MI,
USA
Cardiovascular disease (CVD) affects more than 90 million
2
Department of Medicine, University of Alabama School Americans and by 2030, nearly one of every two adults liv-
of Medicine, 510 20th Street South, Faculty Office Tower
ing in USA is expected to be affected by CVD [1]. While
805B, Birmingham, AL 35294, USA

Vol.:(0123456789)

traditional cardiovascular (CV) risk factors such as hyperten-
sion, smoking, diabetes mellitus, age, obesity, and dyslipi-
demia [2] are strongly associated with CVD, inflammation
has emerged as a risk factor for the development of early cor-
onary artery disease, and possibly acute CV events, such as
myocardial infarction (MI). Evidence supports an increased
CVD risk in inflammatory conditions, such as gout [3–5].
Gout is the most common inflammatory arthritis in adults
worldwide [6]. Recent data from the National Health and
Nutrition Examination Survey (NHANES) demonstrate
rising trends in the incidence and prevalence of gout [7].
Increased serum urate (SU) levels, or hyperuricemia, are a
precursor to gout. Urate-lowering therapy (ULT) reduces
SU. Urate-lowering therapy may decrease systemic inflam-
mation, generation of oxidative species, and reverse
endothelial dysfunction through hyperuricemia-dependent or
hyperuricemia-independent pathways. This review examines
the data for increased CVD in gout and the potential under-
lying mechanisms (including hyperuricemia, inflammation,
endothelial dysfunction, oxidative stress) and the effect of
ULT on CVD.
2 Role of Hyperuricemia in Cardiovascular
Disease
2.1 Hypertension
Hyperuricemia, or increased SU, is a potential risk factor
for hypertension, a leading cause of CVD [8] (Table 1).
Increased SU preceded primary hypertension and correlated
with elevated blood pressure in children and adults [9, 10].
Sanchez-Lozada et al. used a rat model of hyperuricemia
to demonstrate the pathophysiologic mechanisms by which
increased SU levels cause changes in renal morphology [11].
Oxonic acid, a uricase inhibitor, was administered to rats
to induce hyperuricemia, who were also fed a low-sodium
diet to further potentiate hyperuricemia. The control group
was given only a low-sodium diet. A third group of rats
was given allopurinol in addition to oxonic acid and a low-
sodium diet. Blood pressure and SU levels were monitored
at 2 and 5 weeks after the start of the infusion of oxonic acid.
Compared with the controls, hyperuricemia and hyperten-
sion were present in the experimental group given oxonic
acid and a low-sodium diet, secondary to hypertrophic
vascular remodeling. Hyperuricemia, glomerular hyperten-
sion, and hypertension were prevented in the group receiv-
ing allopurinol, in whom the glomerular afferent arteriolar
thickening was prevented [11].
Two separate systematic reviews and meta-analyses dem-
onstrated the association of hyperuricemia and hyperten-
sion. Grayson et al. examined 18 prospective cohort studies
encompassing 55,607 patients. There was a 41% increased
M. K. Gupta, J. A. Singh
risk of hypertension [relative risk (RR), 1.41, 95% confi-
dence interval (CI) 1.23–1.58] in subjects with hyperurice-
mia when compared with those who did not have hyper-
uricemia. A dose-dependent relationship between SU levels
and hypertension was also seen. For every 1-mg/dL increase
in SU, there was a 13% increase in risk of hypertension.
In this systematic review, hyperuricemia was defined as an
average SU level of 6.2 mg/dL and greater [12].
Wang et al. reviewed 25 studies and included 97,824
subjects in a more recent meta-analysis and confirmed that
hyperuricemia was associated with a higher risk of hyperten-
sion by 48% (RR 1.48, 95% CI 1.33–1.65). For every 1-mg/
dL increase in SU, the risk for hypertension increased by
15% (RR 1.15, 95% CI 1.06–1.26) [13].
2.2 Cardiovascular Disease and Cardiovascular
Mortality
In a meta-analysis of 402,997 adults with hyperuricemia
(26 studies; several adjusted for potential confounding var-
iables), Kim et al. found a 9% increase in coronary heart
disease (CHD) incidence (RR 1.09, 95% CI 1.03–1.16)
and a 13% increase in CHD mortality (RR 1.13, 95% CI
1.01–1.30) in people with hyperuricemia compared with
people with normouricemia. Compared with normour-
icemia, women with hyperuricemia had a 67% increased
risk of CHD mortality (RR 1.67, 95% CI 1.30–2.04),
while men with hyperuricemia did not (RR 1.09, 95%
CI 0.98–1.19). Each 1-mg/dL increase in SU conferred
a 12% increase in CHD mortality overall (RR 1.12, 95%
CI 1.05–1.19) [14]. Traditional risk factors for CHD were
adjusted in most studies included in this analysis.
As a part of the Systolic Hypertension in the Elderly
Program, Franse et al. studied the role of elevated SU and
incident CV events in subjects with hypertension rand-
omized to either diuretic treatment or placebo and fol-
lowed for 5 years [15]. The primary CV outcome of inter-
est was stroke; secondary outcomes were incident MI,
CHD, and all-cause mortality. In total, 4327 patients who
were 60 years or older were initially treated with placebo
or given chlorthalidone to reduce systolic blood pressure
to a goal of < 160 mmHg or at least a 20-mmHg reduction
in systolic blood pressure. In the active treatment group,
there was no increase in the risk of stroke or any CV event
when compared to placebo after adjusting for appropriate
risk factors [15]. The decrease in blood pressure second-
ary to treatment with a diuretic may have offset the risk of
increased CV events due to increased SU.
Other studies have also demonstrated the association
between hyperuricemia and the development of CVD.
Santos et al. found white men with elevated SU and no
symptoms of CHD had a far greater risk of accumulating
coronary artery calcium than those with normal SU [16].
Treatment of Cardiovascular Disease in Gout
A cross-sectional population-based study from NHANES
data demonstrated an association between increased SU
and CV events, defined as CVD mortality and ischemic
heart disease mortality in both black and white, male and
female individuals. For each 59-µmol/L (equivalent to
1-mg/dL) increase in SU, a 21% increase in the risk (haz-
ard ratio (HR) 1.21, 95% CI 1.11–1.34) of CV mortality
was noted in this population [17].
Not all data, however, have shown a clear association
between SU and an increased risk of CVD. In an anal-
ysis of the Framingham heart study that included 6763
patients, there was no greater adjusted (for risk factors
and confounders) incidence of CHD, CVD-specific mor-
tality, or all-cause mortality based on the SU levels. This
prospective study showed that the association between SU
and cardiac outcomes was eliminated after adjusting for
diuretic use, indicating that diuretic use was the covari-
ate responsible for the noted association of SU with CV
outcomes (i.e., confounder) [18]. In NHANES, by com-
parison, the effect of diuretics on SU and its association
with mortality was only seen in a small subset of male
individuals. This difference is likely explained by the dif-
ference in the race/ethnicity of included subjects in both
studies. While the Framingham study consists of mainly
white Americans, NHANES is representative of the popu-
lation of USA. Unadjusted CVD mortality and all-cause
mortality rates were higher in the NHANES population,
but this could be explained by the slightly older population
in the NHANES study group. Owing to the inclusion of a
representative US population in NHANES, the results of
this cross-sectional study have greater external validity,
i.e., are more generalizable than the Framingham study,
which has higher internal validity but limited generaliz-
ability as a cohort study.
3 Clinical Evidence of Association of Gout
with Cardiovascular Disease
Gout is associated with an increased risk of MI, cerebro-
vascular accidents, and death from CVD. In a secondary
analysis of a large prospective randomized controlled trial
(RCT), Krishnan et al. found the presence of gout to confer
a greater risk of acute MI in their study of 12,866 men (OR
1.26, 95% CI 1.14–1.40), independent of hyperuricemia. The
Multiple Risk Factor Intervention Trial randomized men into
an interventional program aimed at smoking cessation and
reducing serum cholesterol and blood pressure vs. usual care
as determined by their personal physician. 10.5% of men
with a diagnosis of gout vs. 8.4% of men without gout expe-
rienced an MI during the same follow-up period. Men with
hyperuricemia and gout had a 30% increased risk (HR 1.30,
95% CI 1.04–1.61) of death from any CVD after adjusting
for traditional CV risk factors [4]. Another population-based
study found women with gout to have an increased risk for
acute MI. Women with gout were 39% more susceptible to
MI (RR 1.39, 95% CI 1.20–1.61) than those with no gout.
Adjusted risk ratios showed women with gout were at a
higher risk of acute MI than men with gout [19]. These find-
ings were similar to a more recent study by Clarson et al. that
found women with gout to be at a greater risk for all vascular
disease in comparison to men (HR, 1.25 vs. 1.06) [20].
These studies that show a clear association between gout
and CVD raise the question: is gout a cardiac risk equiva-
lent for CVD similar to diabetes mellitus (DM) or hyper-
tension? A study of insurance claims data of US Medicare
beneficiaries showed that patients with a diagnosis of gout
and no DM had a decreased risk of MI (HR 0.81, 95% CI
0.76–0.87), but a similar risk of stroke (HR 1.02, 95% CI
0.95–1.10), in comparison to patients with DM and no gout,
suggesting that gout is not a cardiac risk equivalent for MI,
but is a cardiac risk equivalent for stroke. In this cohort,
subjects with gout and DM had a 35% (HR 1.35, 95% CI
1.25–1.47) increased risk of MI and a 42% (HR 1.42, 95%
CI 1.29–1.56) increased risk of stroke when compared with
those with only DM after adjusting for confounding vari-
ables. This finding suggested that a diagnosis of gout confers
an increased risk of MI and stroke, in addition to DM [21].
While a diagnosis of hyperuricemia or gout confers a greater
risk of CVD, there is insufficient evidence to identify gout
as an equivalent risk factor for CVD similar to smoking and
diabetes. Because it is known that gout patients have higher
incidence of CVD, aggressive screening and treatment of
gout patients should occur routinely in primary care settings.
This has the potential to effectively improve cardiovascular
outcomes for patients with gout (Table 1).
4 Pathogenic Explanation
for Cardiovascular Disease in Gout
Increased SU is also associated with increased levels of
C-reactive protein (CRP), tumor necrosis factor, and other
systemic markers of inflammation, such as interleukin-1
(IL-1), which in turn lead to a greater risk of adverse CV
outcomes [5, 22]. Inflammation results in increased oxida-
tive stress. In turn, oxidative stress is linked to atherogen-
esis through the production of reactive oxidative species
in endothelial cells and activation of the enzyme, xanthine
oxidase, which further propagates the production of harm-
ful free radicals [23]. The free radicals lead to increased
oxidization of low-density lipoproteins [24, 25] in inflam-
matory conditions, such as gout, and have been associated
with CVD [23, 26].
Previous studies linked systemic inflammatory conditions
such as lupus and rheumatoid arthritis to incident CVD [27],

Table 1  Summary of studies examining the association of serum urate (SU) with hypertension
Study Type of study Population
Sanchez-Lozada et al. [11] Animal Experimental study in
which rats were given oxonic
acid and a low-sodium diet to
induce hyperuricemia compared
to control rats given low-sodium
diet only
Feig et al. [10] Observational 125 consecutive children newly
diagnosed with primary hyper-
tension
Grayson et al. [12] Meta-analysis 18 prospective cohort studies
encompassing 55,607 subjects
Wang et al. [13] Meta-analysis 25 cohort and case–control studies
encompassing 97,824 subjects
BP blood pressure, CI confidence interval, RR relative risk
Outcomes
Glomerular hemodynamics after
inducing hyperuricemia
Development of hypertension; sys- Elevated SU found in 89% of
tolic and diastolic blood pressure subjects with primary hyperten-
The association between hyper-
uricemia and hypertension
The association between hyper-
uricemia and hypertension
Main findings Limitations
Hyperuricemia and hypertension Animal study
seen in experimental group given
oxonic acid and low-sodium diet
Findings not generalizable to adults,
observational study design
sion Strong correlation between
SU and systolic BP (r = 0.8,
p < 0.001)
41% (RR, 1.41, 95% CI 1.23–1.58) Primarily included prospective
increased risk of hypertension in cohort studies, variable number of
subjects with hyperuricemia vs. cofounding factors in each study,
those who did not have hyper- and a significant heterogeneity
uricemia between studies reviewed
Hyperuricemia was associated with Significant heterogeneity between
a higher risk of hypertension included studies, particularly in the
(RR, 1.48, 95% CI 1.33–1.65) baseline demographics of subjects
and the definition of hyperurice-
mia
M. K. Gupta, J. A. Singh
Treatment of Cardiovascular Disease in Gout
which bear similarity to gout with regards to chronic inflam-
mation. Mouse models with antibody-induced arthritis were
shown to develop cardiac remodeling, impaired contractility,
and diastolic dysfunction secondary to chronic inflamma-
tion and oxidative stress [28]. Use of IL-1 inhibitors has
proven to be efficacious in the resolution of rheumatoid
arthritis symptoms and has led to a functional improvement
in patients with known CVD through the reduction in oxida-
tive stress [29].
Targeting systemic markers of inflammation as well as
proatherogenic factors has been shown to decrease the risk
of CV events [5, 30], including the Canakinumab Antiin-
flammatory Thrombosis Outcome Study (CANTOS, see
Sect. 6 for details) [5]. Several underlying mechanisms of
CVD have been hypothesized in gout including hyperurice-
mia-associated endothelial dysfunction through impaired
nitric oxide-mediated vasodilation [31–33], increased oxi-
dized low-density lipoproteins [24, 25], dyslipidemia [34],
and/or acute and chronic inflammation [5, 22] (Fig.  1).
Each of these factors may contribute to atherosclerosis and
endothelial damage increasing the incidence of CV events.
The endothelial damage and dysfunction may be a patho-
genic explanation for an increased incidence of acute vas-
cular events associated with hyperuricemia. Association of
gout with metabolic syndrome and its components, which
are established risk factors for CVD, may also contribute
Fig. 1  Pathogenic explanation for an increased risk of cardiovascular disease in gout. LDL low-density lipoprotein (reproduced from Singh [27],
with permission from BMJ Publishing Group Ltd)
to an increased risk of CV [35]. In a representative sample
of the population of USA, Choi et al. utilized data from
NHANES-III and found a three-fold higher prevalence of
metabolic syndrome in people with gout (n = 223) compared
with those without gout (n = 8584), > 60% vs. 25% [35].
While the strength of this cross-sectional study is the large
sample size, it had an important limitation of misclassifica-
tion of disease because the authors used survey data from
the NHANES database, not validated by a physician [35].
5 Urate‑Lowering Therapy and its
Association with Lowering
of Cardiovascular Risk
The 2012 American College of Rheumatology gout treat-
ment guideline recommends a target SU of ≤ 6 mg/dL as a
goal for the management of gout, and a target SU of < 5 mg/
dL in people with tophaceous gout [36]. Therapies to lower
SU, ULTs, can be divided into two categories uricostatic and
uricosuric drugs [37]. The uricostatic agents, allopurinol and
febuxostat, are inhibitors of xanthine oxidase, a key enzyme
involved in the degradation of purines. Xanthine oxidase
inhibitors are the first-line therapy for the management of
gout and symptomatic hyperuricemia [36, 38]. Allopurinol
is cost effective and is efficacious as first-line therapy for the

Table 2  Summary of studies detailing the effect of lowering serum urate with allopurinol on cardiovascular disease (CVD)
Study Type of study Population
White et al. [45]/CARES RCT​ 6190 patients with a his-
tory of gout and CV events
randomized to receive either
febuxostat or allopurinol
with median follow-up of
32 months
Singh [44] Cohort Sample of new allopurinol
users (n = 28,488) among a
random sample of Medicare
beneficiaries from 2006 to
2012
Singh [46] Cohort Sample of new allopurinol
users (n = 28,488) among a
random sample of Medicare
beneficiaries from 2006 to
2012
Singh [47] Cohort Sample of new allopurinol
users (n = 9244) among a
random sample of Medicare
beneficiaries from 2006 to
2012
Singh [48] Cohort Sample of new allopurinol
users (n = 26,985) among a
random sample of Medicare
beneficiaries from 2006 to
2012
Kok et al. [49] Population-based cohort 2483 subjects taking allopurinol
matched with a group of 2483
participants not taking allopu-
rinol, followed for a median
of 5.25 years to evaluate for
CV outcomes
de Abajo et al. [50] Case–control 3171 cases of acute MI com-
pared with 18,525 controls to
assess risk of MI in allopuri-
nol users
Grimaldi-Bensouda et al. [51] Case–control 2277 cases of MI matched with
4849 controls
AF atrial fibrillation, BMI body mass index, BP blood pressure, CHD coronary heart disease, CI confidence interval, CRP C-reactive protein, CV cardiovascular, HF heart failure, HR hazard
ratio, MI myocardial infarction, OR odds ratio, PAD peripheral arterial disease, RCT​randomized controlled trial
CVD outcomes
CV death, non-fatal MI, non-
fatal stroke, or revasculariza-
tion for unstable angina
First incidence of MI after
initiation of allopurinol
First incidence of stroke after
initiation of allopurinol
First incidence of atrial fibrilla- 17% decreased risk (HR 0.83,
tion after initiating allopu-
rinol
First incidence of PAD after
initiating allopurinol
CV hospitalization: stroke, MI,
HF, CHD
Non-fatal acute MI
First-time MI
Main findings Limitations
All-cause and CV-specific Attrition bias owing to a large
mortality higher in the number of patients lost to
febuxostat group than in the follow-up or who discontinued
allopurinol group; HR for treatment; lack of placebo
all-cause mortality, 1.22, 95% control
CI 1.01–1.47, HR for CV-
specific mortality, 1.34, 95%
CI 1.03–1.73
15% decreased risk (HR, 0.85, Study design: not a RCT, results
95% CI 0.77–0.95) of incident generalizable for a US elderly
MI vs. those who did not take population only; residual
allopurinol confounding
9% decreased risk of incident
stroke (HR 0.91, 95% CI
0.83–0.99) vs. those who did
not take allopurinol
95% CI 0.74–0.93) of incident
AF vs. those who did not take
allopurinol
12% decreased risk (HR 0.88,
95% CI 0.81–0.95) of incident
PAD vs. those who did not
take allopurinol
Patients with gout receiving Residual confounding due to
allopurinol HR of CV event, smoking status, BMI, alcohol
1.25, 95% CI 1.1–1.41 use, and BP
Overall OR of MI 0.52, 95% CI No inclusion of fatal MI cases;
0.33–83 residual confounding
Higher dose and prolonged
duration of use associated
with decreased risk of MI
OR of MI with allopurinol use No inclusion of fatal MI cases;
0.80 (95% CI 0.59–0.99) residual confounding
M. K. Gupta, J. A. Singh
Treatment of Cardiovascular Disease in Gout
management of gout [39]. The uricosuric drugs, probenecid
and lesinurad, prevent the reabsorption of uric acid in the
renal tubule that can provide additional urate lowering [40].
A list of studies assessing the effect of ULT on CVD
outcomes is summarized in Table 2.
The use of allopurinol to lower SU reversed the effects
of decreased levels of nitric oxide on the endothelium
thus decreasing endothelial damage in smaller RCTs with
human subjects [41]. Xanthine oxidase inhibition with
allopurinol also decreased flow-mediated vasodilation, a
sign of improvement in the vascular endothelial function
[42]. Allopurinol use was also associated with a reduction
in blood pressure [43] and a decreased risk of incident MI
in adults aged 65 years or older [44].
Febuxostat is a newer XO inhibitor that is metabolized in
the liver in contrast to allopurinol. It is more expensive than
allopurinol and is usually used clinically as a second-line
agent, in patients who have allopurinol-associated adverse
events, or do not achieve target SU on therapeutic doses
[39]. The CONFIRMS study demonstrated greater urate-
lowering ability of therapeutic doses of febuxostat when
compared with low-dose allopurinol [52]. RCTs have been
conducted to study the rate of CV events in patients taking
febuxostat vs. allopurinol [45, 53]. In a phase III RCT, sev-
eral major CV adverse events occurred with febuxostat [39].
As a condition of approval for febuxostat by the US Food
and Drug Administration, a large-scale, industry-sponsored
post-marketing surveillance study was performed to deter-
mine if a causal relationship existed between febuxostat use
and adverse CV events. More than 6000 subjects with gout
and known CVD, defined as history of MI, stroke, periph-
eral vascular disease, diabetes with micro- or macrovascular
disease, or hospitalization for transient ischemic attack, were
enrolled [45]. Patients were assigned to randomly receive
either once-daily dosing of febuxostat or allopurinol. Sub-
jects were followed for a median of 32 months. Major CV
events (primary outcome) were similar between both groups.
Febuxostat use was associated with a 49% (HR 1.49, 95%
CI 1.01–2.22) higher risk of CV-specific mortality in com-
parison to allopurinol. A major limitation of this study was
that nearly 50% of subjects discontinued treatment and did
not follow up. The percentage of patients lost to follow-up
was similar in both groups.
Notwithstanding the study’s limitations, one interpreta-
tion of this study is that allopurinol may be more cardiopro-
tective than febuxostat or that febuxostat use in gout is asso-
ciated with an increased CV risk. Without the knowledge
of actual CV risk attributable to hyperuricemia and gout,
it is difficult to know the baseline CV risk in subjects with
gout. Therefore, it cannot be determined whether allopurinol
is beneficial for CVD, or febuxostat is harmful, or if both
allopurinol and febuxostat are potentially cardioprotective,
but allopurinol is significantly more cardioprotective than
febuxostat. Current evidence (as summarized in this arti-
cle) supports the first two explanations rather than the last
explanation. This issue remains unsolved at present. Care-
fully designed observational studies, mechanistic studies,
and RCTs in the near future can address these questions.
Since the availability of febuxostat, one new oral ULT
is now available for the treatment of gout. Lesinurad is a
selective uric acid reabsorption inhibitor commonly used
in combination with allopurinol/febuxostat for treating
hyperuricemia in gout. In an RCT, Saag et al. demonstrated
that the use of 200- and 400-mg doses of lesinurad with
allopurinol led to a > 50% reduction in SU (p < 0.0001),
while allopurinol alone caused a 28% reduction in SU after
6 months [40]. The rate of adverse CV events in this phase
III efficacy trial was similar with allopurinol and lesinurad
in comparison to allopurinol alone. Arhalofenate, a urico-
suric drug that behaves similarly to lesinurad in preventing
reabsorption of uric acid in the proximal tubule (but not yet
approved for clinical use), was effective in decreasing gout
flares and lowering SU when compared with allopurinol
[54]. Further RCTs are required to determine if adverse CV
events are lowered with arhalofenate. However, traditional,
placebo-controlled, phase III efficacy RCTs, performed for
obtaining efficacy estimates, are not powered to examine CV
harms or benefits with these new and emerging therapies.
Pharmaco-epidemiological or phase IV studies can further
our understanding of CV effects of these new ULTs.
Singh et al. examined the effectiveness of allopurinol for
the risk of MI [44], stroke [46], peripheral arterial disease
(PAD) [48], and atrial fibrillation (AF) [47] in the Medicare
population. Multivariable models demonstrated that allopu-
rinol was associated with a 15% decreased risk (HR 0.85,
95% CI 0.77–0.95) of incident MI, defined as first-time MI
after beginning allopurinol. Compared with those who did
not take allopurinol, subjects who used allopurinol for more
than half a year and up to 2 years had a 24% decreased risk
of MI (HR 0.76, 95% CI 0.68–0.85), while those who used
allopurinol for more than 2 years had a 28% decreased risk of
incident MI (HR 0.72, 95% CI 0.60–0.87) [44], supporting
the notion that allopurinol may be cardioprotective. Similar
findings were seen for incident stroke, defined as first-time
stroke after initiation of allopurinol, in Medicare recipients.
Allopurinol use was associated with a 9% decreased risk
of stroke (HR 0.91, 95% CI 0.83–0.99). Longer duration
of allopurinol use was associated with a greater risk reduc-
tion in stroke. Compared with non-users, those who took
allopurinol for more than 2 years had a 21% decreased risk
(HR 0.79, 95% CI 0.65–0.96) of stroke vs. those who used
allopurinol for more than half a year but less than 2 years
who had a 12% decreased risk of stroke (HR 0.88, 95% CI
0.78–0.99) after adjusting for potential cofounders [46]. In
the Medicare population, a 17% decreased risk (HR 0.83,
95% CI 0.74–0.93) of incident AF, defined as first-time AF

after the initiation of allopurinol, was observed in patients
taking allopurinol vs. non-users of the drug. In adjusted
analyses, prolonged use of allopurinol (> 2 years) was asso-
ciated with a 35% decreased risk of incident AF (HR 0.65,
95% CI 0.52–0.82), while use of allopurinol for more than
6 months but less than 2 years was associated with a 15%
decreased risk of incident AF (HR 0.85, 95% CI 0.73–0.99)
in comparison to those who did not take allopurinol [47].
The risk of incident PAD, defined as first-time PAD after
initiation of allopurinol, was decreased by 12% (HR 0.88,
95% CI 0.81–0.95) in comparison to those not taking allopu-
rinol. Longer duration of allopurinol use was associated
with a decreased risk of incident PAD (181 days to 2 years,
HR 0.88, 95% CI 0.79–0.97; > 2 years, HR 0.75, 95% CI
0.63–0.89) [48].
These observational studies assessing a 5% random sam-
ple of Medicare claims demonstrated the cardioprotective
effects of allopurinol in a large representative sample of
elderly US patients. Confirmation of these findings in a simi-
lar sample of older populations in an independent sample is
needed. Further RCTs are needed to evaluate if long-term
use (> 2 years) decreases the risk of incident MI, stroke,
AF, and PAD.
Not all data show strong evidence for ULT in improv-
ing endothelial function. In a double-blinded randomized
placebo study of 149 patients, Borgi et al. demonstrated no
significant difference in endothelium-dependent vasodilation
in groups treated with probenecid, allopurinol, or placebo
despite decreased SU levels after 8 weeks of ULT in treat-
ment arms [55]. The subjects in this study were either over-
weight or obese, which implies that while the study results
can be generalized to this group, it cannot be generalized
to the entire population. Additionally, it is likely that cer-
tain metabolic factors play a role in endothelial-mediated
vasodilation.
Moreover, research suggests that more aggressive dosing
of ULT is required to treat gout and hyperuricemia [56].
Data from NHANES 2007–2010 showed that almost half of
adult Americans receiving ULT had SU ≥ 6 mg/dL, which
falls short of the American College of Rheumatology gout
treatment guideline that recommends a SU target of < 6 mg/
dL for ULT. Whether appropriate ULT treatment of gout can
also improve CV outcomes in people with gout remains to be
seen. This hypothesis testing requires a large cohort study or
RCT with a treat-to-SU-target vs. a non-targeted approach.
M. K. Gupta, J. A. Singh
6 Does Treating Gout with Urate‑Lowering
Therapy or Anti‑Inflammatory Agents
Improve Cardiovascular Disease
Outcomes?
Zhang et al. studied the efficacy of febuxostat vs. allopurinol
in patients aged 65 years and older with gout. The primary
outcome of interest was the occurrence of incident stroke or
MI. The authors matched 24,900 users of febuxostat with
74,700 patients taking allopurinol. Incidence rates of MI or
stroke were similar in both groups. The risk of MI or stroke
in the febuxostat group differed by 2% (HR 1.02, 95% CI
0.95–1.10) vs. the allopurinol group, which was not statisti-
cally significant [57].
Crittenden et al. examined the association of the use of
colchicine for MI in patients with gout in a cross-sectional
study that compared 576 subjects taking colchicine to 712
patients with no colchicine use. Compared with those who
did not take colchicine, subjects taking colchicine had
decreased CRP levels (2.5 vs. 3.4 mg/dL; p = 0.24), and a
lower prevalence of MI (crude rates, 1.2% vs. 2.6%; p = 0.03)
but no difference in all-cause mortality (crude rates, 3.9% vs.
5.1%; p = 0.18). Key study limitations were cross-sectional
design, limited power, and residual confounding [58].
A summary of studies examining the effect of anti-inflam-
matory drugs on CVD mortality is presented in Table 3.
In CANTOS, Ridker et al. studied the efficacy of the IL-1
monoclonal antibody, canakinumab, for the treatment of ath-
erosclerotic disease. CANTOS compared the effect of IL-1
inhibition with canakinumab or placebo in 10,061 patients
with a previous history of MI and elevated CRP levels [5].
Subjects were randomized to receive placebo or 50-mg, 150-
mg, or 300-mg doses of the study drug every 3 months for
a mean follow-up of more than 48 months [5]. The primary
outcome of interest was non-fatal MI, non-fatal stroke, or
CV death with a median follow-up of 3.7 years. The most
marked effect was seen in the subjects receiving 150-mg
doses of the IL-1 inhibitor. Compared with placebo, use of
150 mg of canakinumab was associated with a 15% reduc-
tion in non-fatal MI, stroke, or CV-specific death (odds ratio
0.85, 95% CI 0.74–0.98, p = 0.021), indicating the role of
inflammation in the recurrence of CV events and ameliora-
tion of this risk with an effective reduction in inflamma-
tion. Subjects in the treatment arm reported higher rates of
infection than those in the placebo group. While the study
demonstrates a reduced risk of recurrent MI and a decrease
in CV mortality, the increased risk of fatal infections is a
cause for concern [5]. Further understanding of the effect of
IL-1 inhibition on atherosclerosis is needed.
Treatment of Cardiovascular Disease in Gout

7 Management of Asymptomatic

Low power; residual confounding; cross-

Hyperuricemia

subjects with low CRP, high risk of

Results not generalizable as many
Asymptomatic hyperuricemia is defined as a SU ≥ 7.0 mg/
dL with an absence of gouty attacks. Japanese researchers

infection were excluded

reported an increased incidence of CKD and cardiometa-
bolic conditions in Japanese cohorts with asymptomatic

sectional analysis
hyperuricemia [59, 60]. The current guideline from the
Japanese Society of Gout and Nucleic Acid Metabolism
Limitations

noted weak evidence to support the treatment of asympto-

matic hyperuricemia [61]. Clinically, asymptomatic hyper-
uricemia is frequently treated with ULT in Japan. Vinik
et al. examined studies performed in USA and Europe and
(p = 0.18) than those in the no colchi-
decreased CRP levels (p = 0.24), and
150 mg/3 months canakinumab vs.

found no evidence to recommend treatment to lower SU

stroke, or CV death, 37% decrease

lower prevalence of MI (p = 0.03),

in CRP (p < 0.001) in those given

lower rates of all-cause mortality

levels in asymptomatic hyperuricemia [62]. However, in

Colchicine group had an overall
15% reduction in non-fatal MI,

a study that used Markov modeling to establish an asso-

ciation between SU and the risk of CVD, evidence for the
treatment of asymptomatic hyperuricemia was found [63].
Akkineni et al. found that the use of allopurinol was most
effective in decreasing vascular events in asymptomatic men
Main findings

CI confidence interval, CRP C-reactive protein, HR hazard ratio, MI myocardial infarction, RCT​randomized controlled trial
cine group

with SU > 7.0 mg/dL and in asymptomatic women with SU

placebo

> 5.0 mg/dL [63]. This indicates that double-blinded RCTs

are required to determine if ULT should be recommended
Table 3  Summary of studies detailing the effect of anti-inflammatory therapy on cardiovascular (CV) mortality

for people with asymptomatic hyperuricemia.

Non-fatal MI, non-
fatal stroke, CV

Diagnosis of MI

8 Conclusion
Outcomes

death

Gout is a debilitating disease affecting many elderly patients.

Control of SU can be achieved with aggressive appropri-
10,061 patients with a previous history

into two groups, colchicine (n = 576)

ate use of ULT. Associated comorbidities (which are also

of MI who either received canaki-

Cross-sectional 1288 patients with gout categorized

numab or placebo with a median

proatherogenic factors) and oxidative stress that worsen gout

symptoms can also contribute to the pathogenesis of CVD.
and no colchicine (n = 712)

Chronic and recurrent acute inflammation and associated

follow-up of 3.7 years

processes in gout also contribute to CVD risk. Recent lit-

erature indicates that anti-inflammatory agents may decrease
CVD in the general population and potentially in people
with chronic inflammatory conditions. Cardioprotective
Population

benefits of treating gout with allopurinol include a potential

reduction in the risk of MI, stroke, atrial fibrillation, and
other CVDs in observational studies in select populations.
Observational studies have shown that a longer duration
Type of study

of ULT use (2 years of longer) may be needed to decrease

CVD-specific morbidity. However, RCTs are required to
Ridker et al. [5]/CANTOS RCT​

validate findings of observational studies and to determine

which subgroup populations of gout are most likely to ben-
efit from appropriate long-term urate lowering with ULTs.
Crittenden et al. [58]

Care providers should commence treatment quickly once a

diagnosis of gout is conferred because the important role of
inflammation in cardiac disease has become clear in the last
two decades. Well-designed RCTs are needed to test these
hypotheses generated from observational studies.
Study

Compliance with Ethical Standards  15. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW,
Conflict of interest Jasvinder A. Singh has received consultant fees
from Crealta/Horizon, Fidia, UBM LLC, Medscape, WebMD, the Na-
16. Santos RD, Nasir K, Orakzai R, Meneghelo RS, Carvalho JA,
tional Institutes of Health, and the American College of Rheumatol-
ogy. He owns stock options in Amarin Pharmaceuticals and Viking
Therapeutics. He is a member of the executive of OMERACT, an or-
ganization that develops outcome measures in rheumatology and re-
ceives arms-length funding from 36 companies. Jasvinder A. Singh is
17. Fang J, Alderman MH. Serum uric acid and cardiovascular mor-
also a member of the Veterans Affairs Rheumatology Field Advisory
Committee and is the editor and the Director of the UAB Cochrane
Musculoskeletal Group Satellite Center on Network Meta-analysis.
Manik K. Gupta has no conflicts of interest that are directly relevant to
18. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid
the content of this article.
Funding  No sources of funding were received for the preparation of
19. De Vera MA, Rahman MM, Bhole V, Kopec JA, Choi HK. Inde-
this review.
20. Clarson LE, Hider SL, Belcher J, Heneghan C, Roddy E, Mallen
References
1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R,
et al. Heart disease and stroke statistics-2017 update: a report from
the American Heart Association. Circulation. 2017;135:e146–603.
2. Dawber TR, Moore FE, Mann GV. Coronary heart disease in
the Framingham study. Am J Public Health Nations Health.
1957;47:4–24.
3. Choi HK, Curhan G. Independent impact of gout on mortality and
risk for coronary heart disease. Circulation. 2007;116:894–900.
4. Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and
the risk of acute myocardial infarction. Arthritis Rheumatol.
2006;54:2688–96.
5. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH,
Ballantyne C, et al. Antiinflammatory therapy with canakinumab
for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.
6. Bardin T, Richette P. Impact of comorbidities on gout and hyperu-
ricaemia: an update on prevalence and treatment options. BMC
Med. 2017;15:123.
7. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyper-
uricemia in the US general population: the National Health and
Nutrition Examination Survey 2007–2008. Arthritis Rheumatol.
2011;63:3136–41.
8. Breckenridge A. Hypertension and hyperuricaemia. Lancet.
1966;1:15–8.
9. Tykarski A. Evaluation of renal handling of uric acid in essential
hypertension: hyperuricemia related to decreased urate secretion.
Nephron. 1991;59:364–8.
10. Feig DI, Johnson RJ. Hyperuricemia in childhood primary hyper-
tension. Hypertension. 2003;42:247–52.
11. Sanchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco
M, Santamaria J, et al. Mild hyperuricemia induces glomeru-
lar hypertension in normal rats. Am J Physiol Renal Physiol.
2002;283:F1105–10.
12. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and
incident hypertension: a systematic review and meta-analysis.
Arthritis Care Res (Hoboken). 2011;63:102–10.
13. Wang J, Qin T, Chen J, Li Y, Wang L, Huang H, et al. Hyper-
uricemia and risk of incident hypertension: a systematic
review and meta-analysis of observational studies. PLoS One.
2014;9:e114259.
14. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert
DA. Hyperuricemia and coronary heart disease: a system-
atic review and meta-analysis. Arthritis Care Res (Hoboken).
2010;62:170–80.
M. K. Gupta, J. A. Singh
et al. Serum uric acid, diuretic treatment and risk of cardiovas-
cular events in the Systolic Hypertension in the Elderly Program
(SHEP). J Hypertens. 2000;18:1149–54.
Blumenthal RS. Relation of uric acid levels to presence of coro-
nary artery calcium detected by electron beam tomography in men
free of symptomatic myocardial ischemia with versus without the
metabolic syndrome. Am J Cardiol. 2007;99:42–5.
tality the NHANES I epidemiologic follow-up study, 1971–1992.
National Health and Nutrition Examination Survey. JAMA.
2000;283:2404–10.
and risk for cardiovascular disease and death: the Framingham
Heart Study. Ann Intern Med. 1999;131:7–13.
pendent impact of gout on the risk of acute myocardial infarction
among elderly women: a population-based study. Ann Rheum Dis.
2010;69:1162–4.
CD. Increased risk of vascular disease associated with gout: a
retrospective, matched cohort study in the UK clinical practice
research datalink. Ann Rheum Dis. 2015;74:642–7.
21. Singh JA, Ramachandaran R, Yu S, Yang S, Xie F, Yun H, et al.
Is gout a risk equivalent to diabetes for stroke and myocardial
infarction? A retrospective claims database study. Arthritis Res
Ther. 2017;19:228.
22. Jalal DI, Jablonski KL, McFann K, Chonchol MB, Seals DR.
Vascular endothelial function is not related to serum uric acid
in healthy adults. Am J Hypertens. 2012;25:407–13.
23. Kotur-Stevuljevic J, Memon L, Stefanovic A, Spasic S, Spaso-
jevic-Kalimanovska V, Bogavac-Stanojevic N, et al. Correla-
tion of oxidative stress parameters and inflammatory markers in
coronary artery disease patients. Clin Biochem. 2007;40:181–7.
24. Tsutsumi Z, Moriwaki Y, Takahashi S, Ka T, Yamamoto T.
Oxidized low-density lipoprotein autoantibodies in patients with
primary gout: effect of urate-lowering therapy. Clin Chim Acta.
2004;339:117–22.
25. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ.
Cardiovascular benefits and diabetes risks of statin therapy in
primary prevention: an analysis from the JUPITER trial. Lancet.
2012;380:565–71.
26. Nakajima T, Origuchi N, Matsunaga T, Kawai S, Hokari S,
Nakamura H, et al. Localization of oxidized HDL in atheroma-
tous plaques and oxidized HDL binding sites on human aortic
endothelial cells. Ann Clin Biochem. 2000;37(Pt 2):179–86.
27. Singh JA. When gout goes to the heart: does gout equal a cardio-
vascular disease risk factor? Ann Rheum Dis. 2015;74:631–4.
28. Pironti G, Bersellini-Farinotti A, Agalave NM, Sandor K, Fer-
nandez-Zafra T, Jurczak A, et al. Cardiomyopathy, oxidative
stress and impaired contractility in a rheumatoid arthritis mouse
model. Heart. 2018;104(24):2026–34.
29. Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I,
Andreadou I, Kaplanoglou T, et  al. Inhibition of interleu-
kin-1 by anakinra improves vascular and left ventricular
function in patients with rheumatoid arthritis. Circulation.
2008;117:2662–9.
30. Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco
P, Pedersen TR, et al. Very low levels of atherogenic lipopro-
teins and the risk for cardiovascular events: a meta-analysis of
statin trials. J Am Coll Cardiol. 2014;64:485–94.
31. Gavin AR, Struthers AD. Hyperuricemia and adverse outcomes
in cardiovascular disease: potential for therapeutic intervention.
Am J Cardiovasc Drugs. 2003;3:309–14.
Treatment of Cardiovascular Disease in Gout
32. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu
W, et al. Hyperuricemia induces endothelial dysfunction. Kid-
ney Int. 2005;67:1739–42.
33. Choi YJ, Yoon Y, Lee KY, Hien TT, Kang KW, Kim KC, et al.
Uric acid induces endothelial dysfunction by vascular insulin
resistance associated with the impairment of nitric oxide syn-
thesis. FASEB J. 2014;28:3197–204.
34. Hopps E, Noto D, Caimi G, Averna MR. A novel component
of the metabolic syndrome: the oxidative stress. Nutr Metab
Cardiovasc Dis. 2010;20:72–7.
35. Choi HK, Ford ES, Li C, Curhan G. Prevalence of the meta-
bolic syndrome in patients with gout: the Third National
Health and Nutrition Examination Survey. Arthritis Rheumatol.
2007;57:109–15.
36. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi
T, et al. 2012 American College of Rheumatology guidelines
for management of gout. Part 1: systematic nonpharmacologic
and pharmacologic therapeutic approaches to hyperuricemia.
Arthritis Care Res (Hoboken). 2012;64:1431–46.
37. Bove M, Cicero AF, Veronesi M, Borghi C. An evidence-based
review on urate-lowering treatments: implications for optimal
treatment of chronic hyperuricemia. Vasc Health Risk Manag.
2017;13:23–8.
38. Sautner J. Diagnosis and management of gout in Austria: survey
of current practice considering the EULAR recommendations.
Z Rheumatol. 2014;73:836–42.
39. Stamp LK, Chapman PT. Urate-lowering therapy: current options
and future prospects for elderly patients with gout. Drugs Aging.
2014;31:777–86.
40. Saag KG, Fitz-Patrick D, Kopicko J, Fung M, Bhakta N, Adler
S, et al. Lesinurad combined with allopurinol: a randomized,
double-blind, placebo-controlled study in gout patients with an
inadequate response to standard-of-care allopurinol (a US-based
study). Arthritis Rheumatol. 2017;69:203–12.
41. Melendez-Ramirez G, Perez-Mendez O, Lopez-Osorio C, Kuri-
Alfaro J, Espinola-Zavaleta N. Effect of the treatment with allopu-
rinol on the endothelial function in patients with hyperuricemia.
Endocr Res. 2012;37:1–6.
42. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk.
N Engl J Med. 2008;359:1811–21.
43. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood
pressure of adolescents with newly diagnosed essential hyperten-
sion: a randomized trial. JAMA. 2008;300:924–32.
44. Singh JA, Yu S. Allopurinol reduces the risk of myocardial infarc-
tion (MI) in the elderly: a study of Medicare claims. Arthritis Res
Ther. 2016;18:209.
45. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whel-
ton A, et al. Cardiovascular safety of febuxostat or allopurinol in
patients with gout. N Engl J Med. 2018;378:1200–10.
46. Singh JA, Yu S. Allopurinol and the risk of stroke in older adults
receiving medicare. BMC Neurol. 2016;16:164.
47. Singh JA, Yu S. Allopurinol and the risk of atrial fibrillation
in the elderly: a study using Medicare data. Ann Rheum Dis.
2017;76:72–8.
48. Singh JA, Cleveland J. Allopurinol and the risk of incident periph-
eral arterial disease in the elderly: a US Medicare claims data
study. Rheumatology (Oxford). 2018;57:451–61.
49. Kok VC, Horng JT, Chang WS, Hong YF, Chang TH. Allopu-
rinol therapy in gout patients does not associate with beneficial
cardiovascular outcomes: a population-based matched-cohort
study. PLoS One. 2014;9:e99102.
50. de Abajo FJ, Gil MJ, Rodriguez A, Garcia-Poza P, Alvarez A, Bry-
ant V, et al. Allopurinol use and risk of non-fatal acute myocardial
infarction. Heart. 2015;101:679–85.
51. Grimaldi-Bensouda L, Alperovitch A, Aubrun E, Danchin N,
Rossignol M, Abenhaim L, et al. Impact of allopurinol on risk of
myocardial infarction. Ann Rheum Dis. 2015;74:836–42.
52. Becker MA, Schumacher HR, Espinoza LR, Wells AF, Mac-
Donald P, Lloyd E, et al. The urate-lowering efficacy and safety
of febuxostat in the treatment of the hyperuricemia of gout: the
CONFIRMS trial. Arthritis Res Ther. 2010;12:R63.
53. MacDonald TM, Ford I, Nuki G, Mackenzie IS, De Caterina R,
Findlay E, et al. Protocol of the Febuxostat versus Allopurinol
Streamlined Trial (FAST): a large prospective, randomised, open,
blinded endpoint study comparing the cardiovascular safety of
allopurinol and febuxostat in the management of symptomatic
hyperuricaemia. BMJ Open. 2014;4:e005354.
54. Poiley J, Steinberg AS, Choi YJ, Davis CS, Martin RL,
McWherter CA, et al. A randomized, double-blind, active- and
placebo-controlled efficacy and safety study of arhalofenate
for reducing flare in patients with gout. Arthritis Rheumatol.
2016;68:2027–34.
55. Borgi L, McMullan C, Wohlhueter A, Curhan GC, Fisher ND,
Forman JP. Effect of uric acid-lowering agents on endothelial
function: a randomized, double-blind, placebo-controlled trial.
Hypertension. 2017;69:243–8.
56. Juraschek SP, Kovell LC, Miller ER 3rd, Gelber AC. Gout, urate-
lowering therapy, and uric acid levels among adults in the United
States. Arthritis Care Res (Hoboken). 2015;67:588–92.
57. Zhang M, Solomon DH, Desai RJ, Kang EH, Liu J, Neogi T,
et al. Assessment of cardiovascular risk in older patients with
gout initiating febuxostat versus allopurinol. Circulation.
2018;138(11):1116–26.
58. Crittenden DB, Lehmann RA, Schneck L, Keenan RT, Shah B,
Greenberg JD, et al. Colchicine use is associated with decreased
prevalence of myocardial infarction in patients with gout. J Rheu-
matol. 2012;39:1458–64.
59. Kawashima M, Wada K, Ohta H, Terawaki H, Aizawa Y. Associa-
tion between asymptomatic hyperuricemia and new-onset chronic
kidney disease in Japanese male workers: a long-term retrospec-
tive cohort study. BMC Nephrol. 2011;12:31.
60. Kuwabara M, Niwa K, Hisatome I, Nakagawa T, Roncal-Jimenez
CA, Andres-Hernando A, et al. Asymptomatic hyperuricemia
without comorbidities predicts cardiometabolic diseases: five-
year Japanese cohort study. Hypertension. 2017;69:1036–44.
61. Yamanaka H, Metabolism TG. Essence of the revised guideline
for the management of hyperuricemia and gout. Jpn Med Assoc
J. 2012;55:324–9.
62. Vinik O, Wechalekar MD, Falzon L, Buchbinder R, van der Heijde
DM, Bombardier C. Treatment of asymptomatic hyperuricemia
for the prevention of gouty arthritis, renal disease, and cardiovas-
cular events: a systematic literature review. J Rheumatol Suppl.
2014;92:70–4.
63. Akkineni R, Tapp S, Tosteson AN, Lee A, Miller KL, Choi HK,
et al. Treatment of asymptomatic hyperuricemia and prevention
of vascular disease: a decision analytic approach. J Rheumatol.
2014;41:739–48.