Hyperuricaemia: prevalence and association with mortality in an elderly Finnish population

Abstract

Objective
To establish the prevalence of hyperuricaemia in an elderly Finnish cohort and to assess its association with comorbidities and mortality.

Design
Prospective cohort study.

Setting
Good Ageing in Lahti Region study, Finland 2002–2012 (mortality data analysed until 2018).

Participants
2673 participants (mean age 64 years; 47% men).

Primary and secondary outcome measures
Prevalence of hyperuricaemia in the study population was detected. Associations between hyperuricaemia and mortality were assessed using multivariable adjusted Cox proportional hazards models.

Methods
Data from a prospective, population-based study of elderly people (52–76 years) in the Lahti region, Finland, were used. Information on serum uric acid (SUA) levels as well as several other laboratory variables, comorbidities, lifestyle habits and socioeconomic factors was collected, and the association between SUA level and mortality in a 15-year follow-up period was analysed.

Results
Of 2673 elderly Finnish persons included in the study 1197 (48%) were hyperuricaemic. Hyperuricaemia was extremely prevalent in men (60%). There was an association between elevated SUA and mortality which remained after adjustment for potential confounding factors (age, gender, education, smoking status, body mass index, hypertension and dyslipidaemia). The adjusted HR for all-cause mortality among clearly hyperuricaemic individuals with SUA≥420 µmol/L compared with normouricaemic individuals (SUA<360 µmol/L) was 1.32 (95% CI 1.05 to 1.60) in women and 1.29 (95% CI 1.05 to 1.60) in men. In slightly hyperuricaemic individuals (SUA 360–420 µmol/L) the corresponding HRs were 1.03 (95% CI 0.78 to 1.35) and 1.11 (95% CI 0.89 to 1.39).

Conclusions
Hyperuricaemia is very prevalent in the elderly Finnish population and is independently associated with increased mortality.

Full text

1
TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
Open access
Hyperuricaemia: prevalence and
association with mortality in an elderly
Finnish population
Janis Timsans ,1,2 Jenni Emilia Kauppi,3,4 Anne Mirjam Kerola,4,5
Tiina Maarit Lehto,6 Hannu Kautiainen,4,7 Markku Jaakko Kauppi1,4
To cite: TimsansJ,
KauppiJE, KerolaAM,
etal. Hyperuricaemia:
prevalence and association
with mortality in an elderly
Finnish population. BMJ Open
2023;13:e072110. doi:10.1136/
bmjopen-2023-072110
►Prepublication history for
this paper is available online.
To view these les, please visit
the journal online (http://dx.doi.
org/10.1136/bmjopen-2023-
072110).
Received 04 February 2023
Accepted 17 April 2023
1Department of Rheumatology,
Päijät- Häme Central Hospital,
Lahti, Finland
2Centre for Rheumatic Diseases,
Tampere University Hospital,
Tampere, Finland
3Unit of Physiatry and
Rehabilitation Medicine, Päijät-
Häme Central Hospital, Lahti,
Finland
4University of Helsinki, Helsinki,
Finland
5Inammation Center, Helsinki
University Central Hospital,
Helsinki, Finland
6Department of Clinical
Chemistry, Fimlab Laboratoriot
Oy, Lahti, Finland
7Folkhälsan Research Center,
Helsinki, Finland
Correspondence to
Dr Janis Timsans;
janis. timsans@ gmail. com
Original research
© Author(s) (or their
employer(s)) 2023. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
BMJ.
ABSTRACT
Objective To establish the prevalence of hyperuricaemia
in an elderly Finnish cohort and to assess its association
with comorbidities and mortality.
Design Prospective cohort study.
Setting Good Ageing in Lahti Region study, Finland 2002–
2012 (mortality data analysed until 2018).
Participants 2673 participants (mean age 64 years; 47%
men).
Primary and secondary outcome measures Prevalence
of hyperuricaemia in the study population was detected.
Associations between hyperuricaemia and mortality were
assessed using multivariable adjusted Cox proportional
hazards models.
Methods Data from a prospective, population- based
study of elderly people (52–76 years) in the Lahti region,
Finland, were used. Information on serum uric acid (SUA)
levels as well as several other laboratory variables,
comorbidities, lifestyle habits and socioeconomic factors
was collected, and the association between SUA level and
mortality in a 15- year follow- up period was analysed.
Results Of 2673 elderly Finnish persons included in the
study 1197 (48%) were hyperuricaemic. Hyperuricaemia
was extremely prevalent in men (60%). There was an
association between elevated SUA and mortality which
remained after adjustment for potential confounding
factors (age, gender, education, smoking status, body
mass index, hypertension and dyslipidaemia). The adjusted
HR for all- cause mortality among clearly hyperuricaemic
individuals with SUA≥420 µmol/L compared with
normouricaemic individuals (SUA<360 µmol/L) was 1.32
(95% CI 1.05 to 1.60) in women and 1.29 (95% CI 1.05 to
1.60) in men. In slightly hyperuricaemic individuals (SUA
360–420 µmol/L) the corresponding HRs were 1.03 (95%
CI 0.78 to 1.35) and 1.11 (95% CI 0.89 to 1.39).
Conclusions Hyperuricaemia is very prevalent in the
elderly Finnish population and is independently associated
with increased mortality.
INTRODUCTION
A high uric acid level in blood (hyperuri-
caemia) is common and affects as much as
20%–25% of the general population.1 The
serum uric acid (SUA) level used to define
hyperuricaemia varies somewhat in different
studies, but the most widely used threshold is
360 µmol/L (approximately 6 mg/dL), which
is the precipitation threshold of monosodium
urate in the peripheral joints. The prevalence
of hyperuricaemia differs across geographical
areas2 and has increased significantly in the
recent decades, particularly in developed,
high- income countries.2–6
High SUA levels have been identified as an
independent risk factor for all- cause mortality
as well as for cardiovascular, renal and respira-
tory mortality.7–16 Several studies indicate that
the association between SUA and mortality is
U shaped, suggesting that extremely low SUA
levels are unfavourable, as well.9–13 The cut- off
point for high SUA associated with mortality
varies rather widely—from 238 µmol/L (4
mg/dL) to 506 µmol/L (8.5 mg/dL) and it
tends to be higher in men than in women.
A significant number of the studies have
been done in Asian populations and to our
knowledge there have been only a few studies
done in northern Europe on the association
STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒The study is population based and includes a large
number of hyperuricaemic elderly individuals.
⇒Abundant information available on many covariables
made it possible to adjust the main nding of our
study—the association of hyperuricaemia with all-
cause and cardiovascular mortality—for confound-
ing factors and the nding was not affected after the
adjustment.
⇒The long follow- up period of 15 years enabled to
detect that mortality of patients with hyperuricaemia
starts to signicantly rise in comparison to patients
with normouricaemia after the 7th year of follow- up
in women and after the 11th in men.
⇒The most ill and disabled persons of the age groups
studied were probably under- represented due to
lower response rate to the invitations.
⇒Even though we know that a history of urate-
lowering therapy was rare during the active follow-
up period (years 2002–2012), we have only limited
information on the diagnoses of gout in the study
population.

2TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
Open access
between hyperuricaemia and mortality and the evidence
for causality is still insufficient.17–19
There is insufficient evidence in favour for pharmaco-
logical urate- lowering treatment (ULT) for patients with
hyperuricaemia who have not had gout attacks. Indeed,
in current guidelines pharmacological ULT is generally
not suggested.20–22
We conducted a population- based study in a senior
population of the Lahti region in Finland to establish the
prevalence of elevated SUA levels and the association—
if any—between hyperuricaemia and mortality over a
follow- up period of 15 years.
SUBJECTS, MATERIALS AND METHODS
Study population
The data for this research were retrieved from the
Good Ageing in Lahti Region (GOAL) study. GOAL is
a prospective, population- based study of elderly people
that started with baseline visits in 2002. Follow- up visits
were conducted in 2005, 2008 and 2012. Mortality
data are available up until the end of 2018. Three age
cohorts (52–76 years) were included—individuals born
in 1926–1930, 1936–1940 and 1946–1950. A total of 4272
subjects from the catchment area of the Päijät- Häme
Central Hospital (located in Lahti) were invited and 2815
(66%) responded to the invitation. The SUA level of
the study subjects was measured at baseline and at each
follow- up visit. The data on the study subjects included
socioeconomic status, psychosocial background, educa-
tion, income, lifestyle habits (smoking, alcohol consump-
tion, exercise), previously diagnosed medical conditions
(hypertension, diabetes, coronary heart disease, stroke,
cancer) and hospitalisation 12 months prior to the base-
line visit. The blood pressure (BP) of the study subjects
was measured at baseline three times and the average
was documented. Height and weight of the study subjects
were measured and the body mass index (BMI) calcu-
lated. The waist circumference was measured at a level
mid- way between the lowest rib and the iliac crest. In
addition to the SUA, the following laboratory tests were
made from the blood samples taken on each visit: creat-
inine, cystatin C, blood glucose, total cholesterol, low-
density lipoprotein cholesterol, high- density lipoprotein
cholesterol, triglycerides, C- reactive protein (CRP), high-
sensitivity CRP (hsCRP) and 25- hydroxyvitamin D. The
use of medication was also documented.
Data on mortality were provided by Statistics Finland.
Causes of death were classified according to the Inter-
national Statistical Classification of Diseases and Related
Health Problems, 10th Revision. The follow- up of each
subject started at the time of the first study visit (February
to August 2002) and ended on 31 December 2018.
Uric acid
We present the demographics and the mortality in three
SUA groups (<360, 360–419 and ≥420 µmol/L). The cut-
off point of 360 µmol/L (approximately 6 mg/dL) was
chosen because it is a precipitation threshold of monoso-
dium urate in the peripheral joints and it is used as a defi-
nition of hyperuricaemia in numerous sources.23–25 Other
sources use cut- off point of 420 µmol/L (approximately 6
mg/dL) to define hyperuricaemia26 27 and some use cut-
off point of 360 µmol/L in women and 420 µmol/L in
men.28 29 We decided to investigate the associations with
mortality separately in group with SUA of ≥420 µmol/L
(clearly hyperuricaemic individuals) and group with SUA
of 360–419 µmol/L (slightly hyperuricaemic individ-
uals) to detect if slight hyperuricaemia poses a risk for
mortality and does differ from the risk associated with
clear hyperuricaemia.
Statistical methods
Data are presented as means with SD or as counts (n) with
percentages (%). Statistical significances for the unad-
justed hypothesis of linearity across categories of the SUA
levels were evaluated by using the Cochran–Armitage test,
analysis of variance or logistic models with an appropriate
contrast. In the case of violation of the assumptions (eg,
non- normality), a bootstrap type of test was used. The
Kaplan- Meier method was applied to estimate all- cause
mortality and the log- rank test was used to test the trend
of the mortality function across three SUA levels.
Cox proportional hazards regression was used to esti-
mate the adjusted HRs and their 95% CIs. Age, gender,
education, current smoking, BMI, hypertension and
dyslipidaemia were used as covariates in these models.
The proportional hazards assumption was evaluated
by Schoenfeld residuals and log- log plots. A possible
non- linear relationship between mortality and SUA
was assessed by using 4- knot restricted cubic spline Cox
regression models. The length of the distribution of knots
was located at the 5th, 35th, 65th and 95th percentiles;
knot locations are based on Harrell’s recommended
percentiles.30 The ratio of observed to expected number
of deaths (ie, the standardised mortality ratio, SMR)
for all- cause deaths was calculated using subject- years
methods with 95% CIs. The expected number of deaths
was calculated on the basis of gender, age and calendar
period- specific mortality rates in the Finnish population
(Official Statistics of Finland). The normality of the distri-
bution of variables was evaluated graphically and by using
the Shapiro- Wilk W test. Stata V.17.0 (StataCorp, College
Station, Texas, USA) was used for the statistical analyses.
The study followed the guidelines of the Declaration
of Helsinki. All participants gave their written informed
consent prior to data collection.
Patient and public involvement
Patients and/or the public were not involved in the
design, or conduct, or reporting, or dissemination plans
of this research.
RESULTS
Of the 2815 individuals who responded to the invitation,
the SUA level was available from 2673 (1404 women, 1269

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TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
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men (47%)) representing 95% of all invited. If these
data were lacking at the baseline visit, the individual was
excluded from the study. The mean age of the partici-
pants was 64 years (range 52–76 years). The baseline
characteristics of the study subjects by SUA levels (<360,
360–419 and ≥420 µmol/L) are presented in table 1.
We found hyperuricaemia to be very prevalent in the
study population. SUA ≥360 µmol/L at the baseline visit
was present in 436 (31%, 95% CI 29% to 33%) of the
female subjects and 761 (60%, 95% CI 57% to 63%) of
the male subjects, p<0.001. The mean (SD) SUA level
of the whole study group was 357 µmol/L (86); in the
female population it was 330 (78) and in the male popu-
lation 387 (86). The distribution of urate levels in women
and men is shown in figure 1.
Adjusted HRs (adjusted for age, gender, education,
current smoking status, BMI, hypertension (systolic BP
≥140 mm Hg or diastolic BP ≥90 mm Hg) or antihyper-
tensive medication) and dyslipidaemia (total cholesterol
≥5.0 mmol/L or medication for lipid disorders) for all-
cause mortality and cardiovascular mortality are shown in
table 2. Also, the median age at mortality and time from
enrolment in the study to death in both men and women
are presented in table 2. Figure 2 demonstrates the
cumulative all- cause mortality by SUA levels during the
follow- up period. The change in the adjusted mortality
HRs by SUA level is shown in figure 3. The SMRs by SUA
level groups are presented in table 3.
DISCUSSION
The present study is one of the few studies that report the
prevalence of hyperuricaemia in the elderly population
of a Nordic country. It shows that elevated plasma urate
levels are very prevalent in the ageing Finnish population
and is, in general, consistent with previous studies.3 31–33 In
the current study population the rate of hyperuricaemia
appeared to be even higher than in other developed
countries and it could be explained by the fact that the
population of our study included only elderly persons.
The most important finding is the identification of
hyperuricaemia as an independent risk factor for all-
cause mortality and cardiovascular mortality. The higher
unadjusted mortality in the hyperuricaemic population is
easily explained by well- known confounding risk factors
for cardiovascular diseases and mortality. Importantly,
however, the mortality of hyperuricaemic individuals
in the present study remained statistically significantly
higher than of normouricaemic individuals after adjust-
ment for age, gender, education, smoking, BMI, hyper-
tension and dyslipidaemia.
The pathophysiology of the association between hyper-
uricaemia and cardiovascular disease and premature
death is unknown. Some possible mechanisms have been
proposed. Uric acid has both pro- oxidative and antiox-
idative properties, and the pro- oxidative properties are
thought to be linked to cardiovascular disease.34 Another
mechanism contributing to cardiovascular disease and
mortality might be chronic low- level inflammation
induced by high levels of intracellular uric acid, which
is known to promote the expression of inflammatory
markers.35 In our study, we found a statistically significant
association between elevated levels of the well- known
inflammatory marker hsCRP and hyperuricaemia in both
genders. A similar association has been demonstrated in a
handful of Chinese studies36–38 and in a Nepalese study,39
but has not previously been unequivocally demon-
strated in Western populations. High level of hsCRP is
a predictor of myocardial infarction, stroke, peripheral
arterial disease and sudden cardiac death in healthy indi-
viduals without a history of cardiovascular disease and
of recurrent events and death in patients with acute or
stable coronary syndromes.40
Hyperuricaemia is linked with insulin resistance and
diabetes and this might partially explain the association
between high SUA levels and mortality (both cardio-
vascular and all cause).41 Hyperinsulinaemia caused by
insulin resistance might be the driver of a process of
rising urate levels, since high levels of insulin in the blood
enhance the activity and protein expression of urate
transporter 1 (URAT1). This, in turn, leads to reabsorp-
tion of uric acid in the renal proximal tubules increasing
urate levels in the serum.42
Also, hyperuricaemia- induced endothelial dysfunction
and endoplasmic reticulum stress may increase cardiovas-
cular morbidity.43
Similar findings of hyperuricaemia- associated mortality
increases have been reported in several studies in other
populations.7–14 This raises a need for discussing the poten-
tial usefulness of treating hyperuricaemia also in asymp-
tomatic individuals (ie, individuals with no urate crystal
deposition disorder).44–46 There is already quite strong
evidence that ULT in patients with gout improves cardio-
vascular outcomes.47–49 The evidence favouring benefits
of ULT in asymptomatic individuals has, however, thus far
been generally regarded as inconclusive and guidelines,
at least in Western countries, do not recommend ULT in
such cases. In a recent large randomised controlled trial of
allopurinol therapy in elderly asymptomatic patients with
hyperuricaemia with ischaemic heart disease, the rates of
cardiovascular events and cardiovascular mortality were
similar in the group treated with allopurinol and in the
usual care group.50 The guidelines published by the Polish
Society of Hypertension, however, recommend striving
for serum urate levels of 5.0 mg/dL (approximately 300
µmol/L) or less in all patients with hypertension with
high cardiovascular risk.51 Treatment of asymptomatic
hyperuricaemia has been advised in the Japanese guide-
lines for over a decade, and a recommendation to treat
asymptomatic SUA of ≥9.0 mg/dL without complication
or asymptomatic SUA of ≥8.0 mg/dL with complication
(kidney disease, cardiovascular disease, diabetes mellitus,
metabolic syndrome) has been included also in the most
recent version of the Japanese guidelines.27
Some remarks are in order before ULT for asymp-
tomatic patients with hyperuricaemia is initiated. The

4TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
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Table 1 Baseline characteristics of the study subjects according to SUA levels (μmol/L)
Women Men
<360
n=968
360–419
n=255
≥420
n=181 P value*
<360
n=508
360–419
n=345
≥420
n=416 P value*
Demographics
Age, years, n (%) 0.001 0.024
52–57 345 (36) 87 (34) 43 (24) 177 (35) 85 (25) 121 (29)
62–67 345 (36) 89 (35) 66 (36) 179 (35) 148 (43) 147 (35)
72–77 278 (29) 79 (31) 72 (40) 152 (30) 112 (32) 148 (36)
Education years, mean
(SD)
9.7 (3.3) 9.4 (3.4) 8.7 (2.9) <0.001 9.4 (3.4) 9.3 (3.3) 9.6 (3.4) 0.30
Retired, n (%) 591 (61) 160 (63) 129 (71) 0.015 311 (61) 230 (67) 282 (68) 0.082
Cohabiting, n (%) 617 (64) 154 (60) 103 (57) 0.062 423 (83) 280 (81) 326 (78) 0.059
Health behaviours
Current smokers, n (%) 113 (12) 31 (12) 23 (13) 0.68 127 (25) 73 (21) 71 (17) 0.003
AUDIT score C8, n (%) 2.2 (1.9) 2.4 (2.1) 2.5 (2.3) 0.30 4.0 (2.6) 4.5 (2.5) 4.5 (2.8) 0.009
LTPA, n (%) <0.001 0.060
Low 192 (20) 51 (20) 60 (33) 144 (29) 88 (26) 129 (32)
Moderate 407 (43) 114 (46) 71 (39) 198 (40) 138 (40) 178 (44)
High 353 (37) 84 (34) 49 (27) 157 (31) 116 (34) 98 (24)
Clinical
Body mass index 27.1 (4.6) 29.6 (4.7) 31.5 (5.9) <0.001 26.5 (3.7) 27.5 (3.5) 29.0 (4.3) <0.001
Waist 89.1 (12.3) 95.7 (12.1) 100.7 (12.4) <0.001 96.6 (10.5) 99.7 (9.6) 103.9 (11.3) <0.001
Fasting glucose
(mmol/L), mean (SD)
5.46 (1.20) 5.63 (1.17) 5.99 (1.25) <0.001 5.94 (1.66) 5.84 (0.98) 6.10 (1.42) <0.001
Total cholesterol
(mmol/L), mean (SD)
5.88 (1.03) 5.90 (1.04) 5.88 (1.20) 0.92 5.63 (1.11) 5.58 (1.07) 5.65 (1.16) 0.79
HDL cholesterol
(mmol/L), mean (SD)
1.70 (0.46) 1.55 (0.41) 1.46 (0.41) <0.001 1.42 (0.39) 1.36 (0.35) 1.30 (0.36) <0.001
LDL cholesterol
(mmol/L), mean (SD)
3.57 (0.93) 3.57 (0.95) 3.53 (1.05) 0.70 3.58 (0.97) 3.53 (0.96) 3.52 (1.03) 0.34
Triglycerides (mmol/L),
mean (SD)
1.33 (0.63) 1.69 (0.84) 1.95 (1.14) <0.001 1.40 (0.75) 1.54 (0.81) 1.93 (1.83) <0.001
hsCRP 2.39 (4.77) 2.99 (3.23) 4.06 (4.94) <0.001 3.03 (6.91) 2.28 (3.30) 3.40 (6.03) <0.001
Blood pressure, mean (SD)
Systolic 145 (20) 146 (19) 150 (19) 0.002 145 (19) 145 (18) 149 (19) 0.003
Diastolic 84 (9) 86 (9) 86 (9) 0.001 87 (10) 88 (10) 88 (10) 0.031
Comorbidities
DM 45 (5) 16 (6) 16 (9) 0.019 45 (9) 26 (8) 42 (10) 0.55
Hypertension 302 (31) 103 (40) 97 (54) <0.001 118 (23) 119 (34) 179 (43) <0.001
CVD 60 (6) 20 (8) 19 (10) 0.033 48 (9) 45 (13) 67 (16) 0.002
Respiratory diseases 87 (9) 17 (7) 21 (12) 0.59 21 (4) 19 (6) 35 (8) 0.007
Mental health disorders 66 (7) 15 (6) 6 (3) 0.080 23 (5) 16 (5) 17 (4) 0.76
Cancer 34 (4) 13 (5) 6 (3) 0.74 27 (5) 14 (4) 19 (5) 0.57
Neurological disorders 39 (4) 7 (3) 7 (4) 0.65 24 (5) 22 (6) 28 (7) 0.19
Musculoskeletal
disorders
360 (37) 102 (40) 68 (38) 0.69 153 (30) 104 (30) 151 (36) 0.051
Medication
Urate lowering† 21 (2) 10 (4) 26 (14) <0.001 16 (3) 17 (5) 102 (25) <0.001
Antidiabetic‡ 35 (4) 12 (5) 13 (7) 0.031 37 (7) 22 (6) 32 (8) 0.84
Continued

5
TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
Open access
evidence for ULT reducing mortality and cardiovascular
morbidity is scarce, and some studies have not distin-
guished between patients with gout and asymptomatic
patients with hyperuricaemia. The results of the studies
have been somewhat inconsistent. A SUA threshold for
initiating ULT has not been established.
In our study, we found hyperuricaemia (defined as
SUA ≥360 µmol/L) to be very prevalent and treating all
patients with hyperuricaemia would mean prescribing
urate- lowering medication for 60% of the elderly male
population and to almost one- third of the elderly female
population. It would be irrational to recommend ULT to
such a substantial part of the elderly population and the
risks of it would very likely outweigh any benefits due to
adverse events. Although urate- lowering drugs are gener-
ally well tolerated, rare severe adverse events do occur
and the number of them would markedly increase if there
would be a surge of patients using ULT.
A higher threshold for considering ULT in asymptom-
atic patients would be more reasonable. In our study,
mortality was considerably higher in the clearly hyperuri-
caemic group (SUA ≥420 µmol/L) and that SUA level or
probably even a higher one (as recommended in the Japa-
nese guidelines) may be a feasible threshold for consid-
ering ULT for asymptomatic patients. A further uncertain
issue is the target of treatment in asymptomatic hyper-
uricaemia. In patients with gout, we strive to lower the
SUA level below 360 µmol/L, which is the precipitation
threshold of uric acid in peripheral joints. In asymptom-
atic patients with hyperuricaemia it might be reasonable
to accept slight hyperuricaemia (SUA 360–420 µmol/L),
but in cases of higher SUA values it might be prudent
to consider ULT, if the patient has other risk factors for
cardiovascular diseases.
More studies are clearly necessary to provide us with
conclusive evidence on the importance of uric acid as an
independent risk factor for all- cause mortality and cardio-
vascular mortality and on the usefulness of ULT in asymp-
tomatic patients with hyperuricaemia.
Our study has several important strengths. It is popu-
lation based and includes a large number of elderly
individuals. In this population, the prevalence of hyper-
uricaemia is high. There was an abundance of infor-
mation available on lifestyle factors, comorbidities and
laboratory parameters of each study subject and this
made it possible to adjust the results for many potential
confounding factors. The main finding—that is, that
hyperuricaemia is associated with mortality—was not
affected after adjustments for confounding factors. Thus,
hyperuricaemia was demonstrated to be an independent
risk factor for mortality. Another substantial strength of
our study is the long follow- up period of 15 years. We
Women Men
<360
n=968
360–419
n=255
≥420
n=181 P value*
<360
n=508
360–419
n=345
≥420
n=416 P value*
Antihypertensive‡ 241 (25) 95 (37) 97 (54) <0.001 100 (20) 104 (30) 159 (38) <0.001
CVD‡ 100 (10) 31 (12) 40 (22) <0.001 59 (12) 59 (17) 95 (23) <0.001
Lipid lowering‡ 126 (13) 44 (17) 27 (15) 0.22 60 (12) 77 (22) 94 (23) <0.001
Psychiatric‡ 56 (6) 11 (4) 4 (2) 0.036 16 (3) 8 (2) 9 (2) 0.34
*P for linearity
†Number of patients with a history of a urate- lowering drug purchase in the active follow- up period of the study (years 2002–2012).
‡Number of patients who used medication at baseline.
AUDIT, Alcohol Use Disorders Identication Test; CVD, cardiovascular disease; DM, diabetes mellitus; HDL, high- density lipoprotein;
hsCRP, high- sensitivity C- reactive protein; LDL, low- density lipoprotein; LTPA, leisure- time physical activity, graded as low (exercise less
than once a week), moderate (from one to two times a week) or high (at least three times a week); SUA, serum uric acid.
Table 1 Continued
Figure 1 The distribution of urate levels (µmol/L) in women
and men. The distributions are based on the kernel estimate.
SUA, serum uric acid.

6TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
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identified the difference in mortality between hyperuri-
caemic and normouricaemic elderly subjects, and found
that mortality increases most substantially after the 7th
year of follow- up in women and after the 11th year in
men. Thus, a long follow- up time is needed to evaluate
the mortality risks associated with hyperuricaemia.
There are some limitations in our study. First, invita-
tions were sent to a randomly selected cohort of subjects
of defined age groups in the Lahti region, and although
the participation rate was quite good (66%), there was
still a substantial proportion of persons who did not
respond, and thus the study might not represent the
entire population of this age equally. It would be reason-
able to assume that the most ill and disabled persons were
less likely to respond to the invitation, possibly leading
to under- representation of that group. The invitees were
instructed to visit a local study centre. Data were not
collected from inpatients in hospitals or from homes for
the aged.
The fact that our series does not include the most ill
population probably attenuates the findings. The invitees
who did not take part in the study would probably have
higher mortality rates and SUA levels than the average
population of this study. This is reflected by the finding
Table 2 Adjusted HRs for all- cause and cardiovascular mortality
All cause
CVD
All CVD IHD CeVD
Women, n 381 153 63 33
Age at mortality, years, median (IQR) 81 (76, 86) 83 (79, 87) 83 (79, 87) 82 (77, 87)
Time to mortality*, years, median (IQR) 11 (8, 14) 11 (8, 14) 11 (7, 15) 11 (7, 14)
Adjusted HR (95% CI)†
SUA <360 µmol/L 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
SUA 360–419 µmol/L 1.03 (0.78 to 1.35) 0.79 (0.50 to 1.25) 1.37 (0.72 to 2.61) 0.25 (0.06 to 1.08)
SUA ≥420 µmol/L 1.32 (1.01 to 1.74) 1.31 (0.87 to 1.99) 1.96 (1.05 to 3.65) 0.82 (0.30 to 2.22)
P for trend 0.045 0.56 0.039 0.17
Men, n 506 221 138 33
Age at mortality, years, median (IQR) 80 (74, 84) 80 (76, 85) 79 (74, 84) 82 (79, 87)
Time to mortality*, years, median (IQR) 10 (6, 14) 10 (7, 14) 11 (6, 13) 10 (7, 14)
Adjusted HR (95% CI)†
SUA <360 µmol/L 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 1.00 (Reference)
SUA 360–419 µmol/L 1.11 (0.89 to 1.39) 1.18 (0.83 to 1.67) 1.23 (0.79 to 1.91) 1.53 (0.65 to 3.60)
SUA ≥420 µmol/L 1.29 (1.05 to 1.60) 1.41 (1.01 to 1.95) 1.49 (0.99 to 2.45) 1.12 (0.47 to 2.66)
P for trend 0.018 0.040 0.042 0.97
*Time from enrolment in the study to death.
†Adjusted for age, gender, education, smoking status, body mass index (BMI), hypertension and dyslipidaemia.
CeVD, cerebrovascular disease; CVD, cardiovascular disease; IHD, ischaemic heart disease; SUA, serum uric acid.
Figure 2 All- cause mortality in men and women during the
15- year follow- up period. SUA, serum uric acid.
Figure 3 The change in adjusted HR according to serum
uric acid (SUA) level.

7
TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
Open access
that people with high SUA levels did have a significantly
increased mortality risk compared with those with normal
SUA levels, but still their mortality risk was on the level of
the general population of similar age.
Second, we have only limited information on the diag-
noses of gout in this population. We know, however, that a
history of ULT was rare during the active follow- up period
(years 2002–2012), but we do not have this information
about the second part of the follow- up (2013–2018) and
we do not have exact information on the doses and dura-
tion of the urate- lowering drugs in those who used them.
CONCLUSIONS
In this large population- based cohort study we found
hyperuricaemia to be very prevalent in the elderly Finnish
population. There is an independent association between
hyperuricaemia and all- cause mortality and cardiovas-
cular mortality. The findings imply that reducing the SUA
levels in persons with no history of gout attacks might be
beneficial from a cardiovascular perspective and reduce
mortality. Meticulous further research is required to
shed light on the effectiveness of interventions to reduce
serum urate levels and to maintain a scientific discussion
on the subject is important, since the outcome of more
information may carry substantial health benefits.
Acknowledgements We thank all the participants in the GOAL project.
Contributors All authors (JT, JEK, AMK, TML, HK and MJK) were involved in critical
review of the manuscript. JT, HK and MJK designed and conceived the study. JT,
JEK, AMK, TML, HK and MJK contributed substantially to interpretation of data. HK
conducted the statistical analyses. JT conducted the drafting of the manuscript.
JT, JEK, AMK, TML, HK and MJK reviewed the manuscript, tables and gures
and contributed in writing to the interpretation and discussion of data. JT is the
guarantor of the study. The study was supervised by MJK.
Funding The authors have not declared a specic grant for this research from any
funding agency in the public, commercial or not- for- prot sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not applicable.
Ethics approval This study involves human participants and was approved in
2002 by the Ethics Committee of Päijät- Häme Central Hospital, Lahti, Finland (ID
number: PHSP 2/2002/Q11 § 87). Participants gave informed consent to participate
in the study before taking part.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See:http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iD
JanisTimsans http://orcid.org/0000-0002-0858-0412
REFERENCES
1 Li L, Zhang Y, Zeng C. Update on the epidemiology, genetics,
and therapeutic options of hyperuricemia. Am J Transl Res
2020;12:3167–81.
2 Roman YM, Daniel K. The Daniel K. inouye College of pharmacy
scripts: perspectives on the epidemiology of gout and hyperuricemia.
Hawaii J Med Public Health 2019;78:71–6.
3 Kumar A. U. A, Browne LD, Li X, etal. Temporal trends in
hyperuricaemia in the Irish health system from 2006- 2014: a cohort
study. PLoS ONE 2018;13:e0198197.
4 Wallace KL, Riedel AA, Joseph- Ridge N, etal. Increasing prevalence
of gout and hyperuricemia over 10 years among older adults in a
managed care population. J Rheumatol 2004;31:1582–7.
5 Trirò G, Morabito P, Cavagna L, etal. Epidemiology of gout and
hyperuricaemia in Italy during the years 2005–2009: a nationwide
population- based study. Ann Rheum Dis 2013;72:694–700.
6 Chen- Xu M, Yokose C, Rai SK, etal. Contemporary prevalence of
gout and hyperuricemia in the United States and decadal trends: the
National health and nutrition examination survey, 2007- 2016. Arthritis
Rheumatol 2019;71:991–9.
7 Juraschek SP, Tunstall- Pedoe H, Woodward M. Serum uric acid and
the risk of mortality during 23 years follow- up in the Scottish heart
health extended cohort study. Atherosclerosis 2014;233:623–9.
8 Kikuchi A, Kawamoto R, Ninomiya D, etal. Hyperuricemia is
associated with all- cause mortality among males and females:
ndings from a study on Japanese community- dwelling individuals.
Metabol Open 2022;14:100186.
9 Hu L, Hu G, Xu BP, etal. U- Shaped association of serum uric acid
with all- cause and cause- specic mortality in US adults: a cohort
study. J Clin Endocrinol Metab 2020;105:dgz068.
10 Cho SK, Chang Y, Kim I, etal. U- Shaped association between
serum uric acid level and risk of mortality: a cohort study. Arthritis
Rheumatol 2018;70:1122–32.
11 Tseng W- C, Chen Y- T, Ou S- M, etal. U- shaped association between
serum uric acid levels with cardiovascular and all- cause mortality
in the elderly: the role of malnourishment. J Am Heart Assoc
2018;7:e007523.
12 Kim K, Go S, Son HE, etal. Association between serum uric acid
level and ESRD or death in a Korean population. J Korean Med Sci
2020;35:e254.
13 Cang Y, Xu S, Zhang J, etal. Serum uric acid revealed a U- shaped
relationship with all- cause mortality and cardiovascular mortality in
high atherosclerosis risk patients: the assure study. Front Cardiovasc
Med 2021;8:641513.
14 Virdis A, Masi S, Casiglia E, etal. Identication of the uric acid
thresholds predicting an increased total and cardiovascular mortality
over 20 years. Hypertension 2020;75:302–8.
15 Masulli M, D’Elia L, Angeli F, etal. Serum uric acid levels threshold
for mortality in diabetic individuals: the uric acid right for heart health
(URRAH) project. Nutr Metab Cardiovasc Dis 2022;32:1245–52.
16 Ungar A, Rivasi G, Di Bari M, etal. The association of uric acid with
mortality modies at old age: data from the uric acid right for heart
health (urrah) study. J Hypertens 2022;40:704–11.
17 Niskanen LK, Laaksonen DE, Nyyssönen K, etal. Uric acid level as a
risk factor for cardiovascular and all- cause mortality in middle- aged
men: a prospective cohort study. Arch Intern Med 2004;164:1546–51.
Table 3 Standardised mortality ratios in study subjects
according to SUA levels (μmol/L)
Standardised mortality
ratio (SMR)
Women
SUA <360 µmol/L 0,74 (0.65 to 0.84)
SUA 360–419 µmol/L 0.83 (0.65 to 1.05)
SUA ≥420 µmol/L 1.10 (0.87 to 1.39)
P for trend 0.007
Men
SUA <360 µmol/L 0.69 (0.59 to 0.80)
SUA 360–419 µmol/L 0.74 (0.62 to 0.87)
SUA ≥420 µmol/L 0.87 (0.75 to 1.00)
P for trend 0.026
SUA, serum uric acid.

8TimsansJ, etal. BMJ Open 2023;13:e072110. doi:10.1136/bmjopen-2023-072110
Open access
18 Reunanen A, Takkunen H, Knekt P, etal. Hyperuricemia as a
risk factor for cardiovascular mortality. Acta Med Scand Suppl
1982;668:49–59.
19 Bengtsson C, Lapidus L, Stendahl C, etal. Hyperuricaemia and risk
of cardiovascular disease and overall death. A 12- year follow- up
of participants in the population study of women in Gothenburg,
Sweden. Acta Med Scand 1988;224:549–55.
20 FitzGerald JD, Dalbeth N, Mikuls T, etal. 2020 American College of
Rheumatology guideline for the management of gout. Arthritis Care
Res (Hoboken) 2020;72:744–60.
21 Hui M, Carr A, Cameron S, etal. The British Society for rheumatology
guideline for the management of gout. Rheumatology (Oxford)
2017;56:1246.
22 Pascart T, Latourte A, Flipo R- M, etal. 2020 recommendations from
the French Society of rheumatology for the management of gout:
urate- lowering therapy. Joint Bone Spine 2020;87:395–404.
23 Bardin T, Richette P. Denition of hyperuricemia and gouty
conditions. Curr Opin Rheumatol 2014;26:186–91.
24 Desideri G, Castaldo G, Lombardi A, etal. Is it time to revise the
normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci
2014;18:1295–306.
25 Bardin T. Hyperuricemia starts at 360 micromoles (6 mg/dl). Joint
Bone Spine 2015;82:141–3.
26 Guo Y, Huang H, Chen Y, etal. Association between circulating
cystatin C and hyperuricemia: a cross- sectional study. Clin
Rheumatol 2022;41:2143–51.
27 Hisatome I, Ichida K, Mineo I, etal. Japanese Society of gout
and uric & nucleic acids 2019 guidelines for management
of hyperuricemia and gout. Gout and Uric & Nucleic Acids
2020;44:sp1–sp- 40.
28 Yang Y, Zhou W, Wang Y, etal. Gender- Specic association between
uric acid level and chronic kidney disease in the elderly health
checkup population in China. Ren Fail 2019;41:197–203.
29 Akashi N, Kuwabara M, Matoba T, etal. Hyperuricemia predicts
increased cardiovascular events in patients with chronic coronary
syndrome after percutaneous coronary intervention: a nationwide
cohort study from Japan. Front Cardiovasc Med 2022;9:1062894.
30 Harrell FE. Regression modeling strategies: with applications to linear
models, logistic regression, and survival analysis. New York, NY:
Springer- Verlag, 2001.
31 Winder M, Owczarek AJ, Mossakowska M, etal. Prevalence of
hyperuricemia and the use of allopurinol in older poles- results from
a population- based polsenior study. Int J Environ Res Public Health
2021;18:387.
32 Burke BT, Köttgen A, Law A, etal. Physical function, hyperuricemia,
and gout in older adults. Arthritis Care Res (Hoboken)
2015;67:1730–8.
33 Guasch- Ferré M, Bulló M, Babio N, etal. Mediterranean diet and risk
of hyperuricemia in elderly participants at high cardiovascular risk. J
Gerontol A Biol Sci Med Sci 2013;68:1263–70.
34 Kang D- H, Ha S- K. Uric acid puzzle: dual role as anti- oxidantand
pro- oxidant. Electrolyte Blood Press 2014;12:1–6.
35 Kimura Y, Tsukui D, Kono H. Uric acid in inammation and the
pathogenesis of atherosclerosis. Int J Mol Sci 2021;22:12394.
36 Liu XZ, Tian YJ, Fan J, etal. Inverted J- shaped association of high-
sensitivity C- reactive protein with the levels of serum uric acid: cross-
sectional and longitudinal analyses. J Inamm Res 2022;15:341–4.
37 Dai H- X, Zhao Z- Y, Xia Y, etal. Higher levels of high- sensitivity
C- reactive protein is positively associated with the incidence of
hyperuricemia in Chinese population: a report from the China
health and retirement longitudinal study. Mediators Inamm
2020;2020:3854982.
38 Yang T, Ding X, Wang Y- L, etal. Association between high- sensitivity
C- reactive protein and hyperuricemia. Rheumatol Int 2016;36:561–6.
39 Sah SK, Khatiwada S, Pandey S, etal. Association of high- sensitivity
C- reactive protein and uric acid with the metabolic syndrome
components. Springerplus 2016;5:269.
40 Bassuk SS, Rifai N, Ridker PM. High- Sensitivity C- reactive protein:
clinical importance. Curr Probl Cardiol 2004;29:439–93.
41 Rathmann W, Funkhouser E, Dyer AR, etal. Relations of
hyperuricemia with the various components of the insulin resistance
syndrome in young black and white adults: the cardia study.
Coronary artery risk development in young adults. Ann Epidemiol
1998;8:250–61.
42 Toyoki D, Shibata S, Kuribayashi- Okuma E, etal. Insulin stimulates
uric acid reabsorption via regulating urate transporter 1 and ATP-
binding cassette subfamily G member 2. Am J Physiol Renal Physiol
2017;313:F826–34.
43 Yu W, Cheng J- D. Uric acid and cardiovascular disease: an update
from molecular mechanism to clinical perspective. Front Pharmacol
2020;11:582680.
44 Petreski T, Ekart R, Hojs R, etal. Hyperuricemia, the heart, and the
kidneys- to treat or not to treat? Ren Fail 2020;42:978–86.
45 Chalès G. How should we manage asymptomatic hyperuricemia?
Joint Bone Spine 2019;86:437–43.
46 Yip K, Cohen RE, Pillinger MH. Asymptomatic hyperuricemia: is it
really asymptomatic? Curr Opin Rheumatol 2020;32:71–9.
47 Szwejkowski BR, Gandy SJ, Rekhraj S, etal. Allopurinol reduces left
ventricular mass in patients with type 2 diabetes and left ventricular
hypertrophy. J Am Coll Cardiol 2013;62:2284–93.
48 Rekhraj S, Gandy SJ, Szwejkowski BR, etal. High- Dose allopurinol
reduces left ventricular mass in patients with ischemic heart disease.
J Am Coll Cardiol 2013;61:926–32.
49 Chen J- H, Lan J- L, Cheng C- F, etal. Effect of urate- lowering therapy
on the risk of cardiovascular disease and all- cause mortality in
patients with gout: a case- matched cohort study. J Rheumatol
2015;42:1694–701.
50 Mackenzie IS, Hawkey CJ, Ford I, etal. Allopurinol versus usual
care in UK patients with ischaemic heart disease (ALL- HEART): a
multicentre, prospective, randomised, open- label, blinded- endpoint
trial. Lancet 2022;400:1195–205.
51 Tykarski A, Filipiak KJ, Januszewicz A, etal. Zasady postępowania W
nadcişnieniu tętniczym—2019 ROK. Nadciśnienie Tętnicze w Praktyce
2019;5:1–86.