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Reviews in Cardiovascular Medicine  2021, Vol. 22 Issue (3): 991-1001     DOI: 10.31083/j.rcm2203108
Special Issue: Diet, nutrients and cardiovascular disease prevention
Original Research Previous articles | Next articles
The association between serum uric acid levels and 10-year cardiovascular disease incidence: results from the ATTICA prospective study
Niki Katsiki1, Matina Kouvari2, Demosthenes B Panagiotakos2, *(), Claudio Borghi3, Christina Chrysohoou4, Dimitri P Mikhailidis5, Christos Pitsavos4
1First Department of Internal Medicine, Diabetes Center, Division of Endocrinology and Metabolism, AHEPA University Hospital, 54621 Thessaloniki, Greece
2Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece
3Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
4First Cardiology Clinic, School of Medicine, University of Athens, 15772 Athens, Greece
5Department of Clinical Biochemistry, Royal Free Hospital campus, University College London Medical School, University College London (UCL), NW3 2QG London, UK
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Abstract:

Limited data suggests possible gender-specific association between serum uric acid (SUA) and cardiovascular disease (CVD) incidence. The aim of the present analysis was to evaluate the association between SUA levels and 10-year CVD incidence (2002–2012) in the ATTICA study participants. Overall, 1687 apparently healthy volunteers, with SUA measurements, residing in the greater metropolitan Athens area (Greece), were included. Multivariable Cox-regression models were used to estimate the hazard ratios for SUA in relation to 10-year CVD incidence. Receiver operating curve analysis was conducted to detect optimal SUA cut-off values. Participants in the 2nd and 3rd SUA tertile had 29 and 73% higher 10-year CVD incidence compared with those in the 1st tertile (p < 0.001). In gender-specific analysis, only in women SUA was independently associated with CVD incidence; women in the 3rd SUA tertile had 79% greater 10-year CVD event risk compared to their 1st tertile counterparts. Obese in the 3rd SUA tertile had 2-times higher CVD incidence compared to those in the 1st tertile. Similar findings were observed in metabolically healthy (vs. unhealthy) and metabolically healthy obese. SUA thresholds best predicting 10-year CVD incidence was 5.05 and 4.15 mg/dL (0.30 and 0.25 mmol/L) in men and women, respectively. In conclusion, increased SUA levels were independently related to 10-year CVD event rate in women, obese and metabolically healthy individuals. SUA could predict 10-year CVD incidence even at low levels. Further studies are warranted to identify SUA cut-off values that may improve the detection of individuals at higher CVD risk in clinical practice.

Key words:  Serum uric acid      Cardiovascular disease      ATTICA study      Gender      Metabolic health status     
Submitted:  01 June 2021      Revised:  24 June 2021      Accepted:  29 July 2021      Published:  24 September 2021     
Fund: HCS2002/Hellenic Cardiology Society;HAS2003/Hellenic Atherosclerosis Society
*Corresponding Author(s):  Demosthenes B Panagiotakos     E-mail:  dbpanag@hua.gr

Cite this article: 

Niki Katsiki, Matina Kouvari, Demosthenes B Panagiotakos, Claudio Borghi, Christina Chrysohoou, Dimitri P Mikhailidis, Christos Pitsavos. The association between serum uric acid levels and 10-year cardiovascular disease incidence: results from the ATTICA prospective study. Reviews in Cardiovascular Medicine, 2021, 22(3): 991-1001.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm2203108     OR     https://rcm.imrpress.com/EN/Y2021/V22/I3/991

Table 1.  Baseline sociodemographic, clinical, anthropometric, biochemical and lifestyle characteristics of men and women from the ATTICA study according to serum uric acid tertiles (n = 1687).
Baseline characteristics Gender-specific SUA tertiles
Men 1st tertile 2nd tertile 3rd tertile p-value
n 248 286 291
SUA, mg/dL 3.71 (0.55) 4.81 (0.27) 6.35 (0.89) <0.001
Age, years 44 (13) 42 (11) 46 (13) <0.001
Body mass index, kg/m2 26.5 (3.6) 26.8 (3.2) 28.5 (4.4) <0.001
Waist circumference, cm 94 (12) 97 (12) 100 (12) <0.001
Obesity, % 16 14 29 <0.001
Physical activity, % 49 39 40 0.37
Metabolically unhealthy status, % 36 47 66 <0.001
Current smoking, % 46 50 44 0.21
History of hypertension, % 37 32 42 0.02
Antihypertensive treatment, % 20 27 25 0.12
History of diabetes mellitus, % 8 5 9 0.05
Antidiabetic treatment, % 3 3 4 0.27
HOMA-IR 3.57 (2.63) 3.27 (1.85) 3.53 (2.31) 0.13
History of hypercholesterolemia, % 33 41 45 <0.001
Hypolipidemic treatment, % 20 31 32 <0.001
LDL-C, mg/dL 108 (33) 117 (35) 129 (36) <0.001
CRP, mg/L 1.58 (1.97) 1.90 (2.24) 2.38 (2.48) <0.001
Alanine transaminase, U/L 22 (10) 21 (8) 29 (18) 0.004
Aspartate transaminase, U/L 27 (13) 26 (8) 28 (13) 0.53
eGFR, mL/min/1.73 m2 113 (24) 113 (24) 116 (29) 0.16
Family CVD history, % 22 26 30 0.12
Women 1st tertile 2nd tertile 3rd tertile p-value
n 252 317 293
SUA, mg/dL 2.46 (0.38) 3.38 (0.24) 4.48 (0.97) <0.001
Age, years 39 (12) 42 (13) 48 (18) <0.001
Body mass index, kg/m2 23.1 (3.8) 24.8 (4.5) 27.3 (5.1) <0.001
Waist circumference, cm 76 (10) 81 (13) 89 (14) <0.001
Obesity, % 6 15 27 <0.001
Physical activity, % 41 37 41 0.01
Metabolically unhealthy status, % 57 57 77 <0.001
Current smoking, % 43 37 38 0.18
History of hypertension, % 15 19 33 <0.001
Antihypertensive treatment, % 9 8 19 <0.001
History of diabetes mellitus, % 2 4 9 <0.001
Antidiabetic treatment, % 1 1 3 0.07
HOMA-IR 2.52 (1.12) 2.70 (1.86) 2.87 (1.51) 0.008
History of hypercholesterolemia, % 28 36 52 <0.001
Hypolipidemic treatment, % 17 18 27 <0.001
LDL-C, mg/dL 119 (35) 121 (34) 133 (40) <0.001
C-Reactive Protein, mg/L 1.19 (1.81) 1.99 (2.59) 2.68 (2.96) <0.001
Alanine transaminase, U/L 16 (6) 18 (9) 20 (13) 0.001
Aspartate transaminase, U/L 23 (13) 23 (9) 25 (11) 0.30
eGFR, mL/min/1.73 m2 99 (15) 100 (23) 104 (26) 0.12
Family CVD history, % 35 27 26 0.05
Data are presented as mean ± standard deviation (SD) or median (Interquartile Range) if normality was not met. p-values were obtained using one-way ANOVA for the normally distributed variables (age, body mass index), Kruskal Wallis test for the rest quantitative variables and chi-squared test for categorical variables.
Abbreviations: SUA, serum uric acid; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; HOMA-IR, homeostatic model assessment of insulin resistance.
Table 2.  Unadjusted 10-year cardiovascular disease incidence rate in men and women from the ATTICA study according to gender-specific serum uric acid tertiles.
Statistical metrics Overall sample Gender-specific SUA tertiles p-value
1st tertile 2nd tertile 3rd tertile
Men, n/cases 825/157 248/42 286/46 291/69 0.04
CVD incidence rate per 100 participants 19.0 16.9 16.1 23.7
Women, n/cases 862/96 252/20 317/30 293/46 0.008
CVD incidence rate per 100 participants 11.1 7.9 9.5 15.7
Overall, n/cases 1687/253 500/62 603/76 584/115 <0.001
CVD incidence rate per 100 participants 15.0 12.4 12.6 19.7
Man-to-woman CVD incidence rate ratio 1.72 2.13 1.69 1.50
p-values were obtained using chi-squared test.
Abbreviations: CVD, cardiovascular disease; SUA, serum uric acid.
Table 3.  Nested Cox-regression analysis models to evaluate the association of serum uric acid with 10-year cardiovascular disease incidence (n = 1687).
Variables included in the model Model 1 Model 2 Model 3 Model 4 Model 5 Model 6
HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)
SUA tertiles
1st Ref Ref Ref Ref Ref Ref
2nd 1.29 (1.19, 1.40) 1.16 (1.07, 1.26) 1.12 (1.03, 1.21) 1.09 (1.00, 1.18) 1.05 (0.96, 1.15) 1.02 (0.95, 1.07)
3rd 1.73 (1.23, 2.42) 1.55 (1.11, 2.18) 1.51 (1.09, 2.11) 1.47 (1.05, 2.08) 1.42 (1.01, 1.99) 1.39 (0.98, 1.95)
Age, per 1 year - 1.08 (1.07, 1.09) 1.08 (1.06, 1.09) 1.07 (1.05, 1.09) 1.07 (1.05, 1.09) 1.07 (1.05, 1.09)
Male gender - 1.86 (1.41, 2.46) 1.82 (1.36, 2.45) 1.81 (1.17, 2.76) 1.66 (1.07, 2.61) 1.66 (1.07, 2.61)
Years of school, per 1 year - - 0.96 (0.92, 0.99) 0.97 (0.92, 1.02) 0.95 (0.90, 1.01) 0.95 (0.90, 1.01)
MedDietScore (range 0–55), per 1/55 - - 0.98 (0.96, 0.99) 0.98 (0.94, 0.99) 0.97 (0.94, 1.01) 0.97 (0.94, 1.01)
Alcohol consumption, yes vs. no - - 0.90 (0.75, 1.10) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11)
Physical activity, yes vs. no - - 0.94 (0.70, 1.25) 1.32 (0.88, 1.98) 1.43 (0.94, 2.17) 1.43 (0.94, 2.17)
Current smoking, yes vs. no - - 1.27 (0.94, 1.71) 1.50 (1.00, 2.28) 1.45 (0.94, 2.23) 1.45 (0.94, 2.23)
LDL-C, per 1 mg/dL - - - 1.01 (1.00, 1.03) 1.00 (0.99, 1.01) 1.00 (0.99, 1.01)
Family history of CVD, yes vs. no - - - 1.37 (0.90, 2.08) 1.39 (0.89, 2.17) 1.39 (0.89, 2.17)
ALT, per 1 U/L - - - 1.01 (0.98, 1.04) 1.00 (0.97, 1.04) 1.00 (0.97, 1.04)
AST, per 1 U/L - - - 0.99 (0.95, 1.02) 0.98 (0.94, 1.01) 0.98 (0.94, 1.01)
Waist circumference, per 1 cm - - - 1.00 (0.98, 1.02) 1.00 (0.98, 1.02) 1.00 (0.98, 1.02)
HOMA-IR, per 1 unit - - - 1.06 (0.98, 1.16) 1.06 (0.98, 1.16) 1.06 (0.98, 1.16)
CRP, per 1 mg/L - - - 1.06 (0.98, 1.15) 1.06 (0.98, 1.15) 1.06 (0.98, 1.15)
eGFR, per mL/min/1.73 m2 - - - 0.99 (0.98, 1.01) 0.99 (0.98, 1.01) 0.99 (0.98, 1.01)
Obesity, yes vs. no - - - - 1.65 (1.00, 2.92) 1.61 (0.89, 2.52)
Metabolic health status, healthy vs. unhealthy - - - - - 0.43 (0.17, 0.99)
HRs and their corresponding 95% CIs were obtained from Cox regression analysis. Bold indicates statistically significant outcomes, i.e., p < 0.05.
Abbreviations: SUA, serum uric acid; ALT, alanine transaminase; AST, aspartate transaminase; CVD, cardiovascular disease; CI, confidence interval; CRP, C-Reactive Protein; eGFR, estimated glomerular filtration rate; HR, Hazard ratio; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; LDL-C, low density lipoprotein cholesterol.
Table 4.  Nested Cox-regression analysis models to evaluate the dose-response association of serum uric acid with 10-year cardiovascular disease incidence (n = 1687).
Variables included in the model Model 1 Model 2 Model 3 Model 4 Model 5 Model 6
HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)
SUA per 1 mg/dL 1.27 (1.16, 1.39) 1.14 (1.09, 1.25) 1.12 (1.06, 1.21) 1.10 (1.04, 1.18) 1.06 (0.99, 1.12) 1.04 (0.97, 1.10)
Age, per 1 year - 1.09 (1.06, 1.11) 1.09 (1.07, 1.12) 1.09 (1.07, 1.12) 1.09 (1.07, 1.12) 1.09 (1.07, 1.12)
Male gender - 1.87 (1.40, 2.45) 1.83 (1.35, 2.46) 1.83 (1.35, 2.46) 1.66 (1.07, 2.61) 1.65 (1.08, 2.60)
Years of school, per 1 year - - 0.96 (0.92, 0.99) 0.97 (0.92, 1.02) 0.95 (0.90, 1.01) 0.95 (0.90, 1.01)
MedDietScore (range 0–55), per 1/55 - - 0.98 (0.96, 0.99) 0.98 (0.94, 0.99) 0.97 (0.94, 1.01) 0.97 (0.94, 1.01)
Alcohol consumption, yes vs. no - - 0.90 (0.75, 1.10) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11)
Physical activity, yes vs. no - - 0.94 (0.70, 1.25) 1.32 (0.88, 1.98) 1.43 (0.94, 2.17) 1.43 (0.94, 2.17)
Current smoking, yes vs. no - - 1.27 (0.94, 1.71) 1.50 (1.00, 2.28) 1.45 (0.94, 2.23) 1.45 (0.94, 2.23)
LDL-C, per 1 mg/dL - - - 1.01 (1.00, 1.03) 1.00 (0.99, 1.01) 1.00 (0.99, 1.01)
Family history of CVD, yes vs. no - - - 1.37 (0.90, 2.08) 1.39 (0.89, 2.17) 1.39 (0.89, 2.17)
ALT, per 1 U/L - - - 1.01 (0.98, 1.04) 1.00 (0.97, 1.04) 1.00 (0.97, 1.04)
AST, per 1 U/L - - - 0.99 (0.95, 1.02) 0.98 (0.94, 1.01) 0.98 (0.94, 1.01)
Waist circumference, per 1 cm - - - 1.00 (0.98, 1.02) 1.00 (0.98, 1.02) 1.00 (0.98, 1.02)
HOMA-IR, per 1 unit - - - 1.06 (0.98, 1.16) 1.06 (0.98, 1.16) 1.06 (0.98, 1.16)
CRP, per 1 mg/L - - - 1.06 (0.98, 1.15) 1.07 (0.99, 1.15) 1.07 (0.99, 1.15)
eGFR, per mL/min/1.73 m2 - - - 0.99 (0.98, 1.01) 0.99 (0.98, 1.01) 0.99 (0.98, 1.01)
Obesity, yes vs. no - - - - 1.64 (1.01, 2.90) 1.60 (0.88, 2.50)
Metabolic health status, healthy vs. unhealthy - - - - - 0.42 (0.19, 0.99)
HRs and their corresponding 95% CIs were obtained from Cox regression analysis. Bold indicates statistically significant outcomes, i.e., p < 0.05.
Abbreviations: SUA, serum uric acid; ALT, alanine transaminase; AST, aspartate transaminase; CVD, cardiovascular disease; CI, confidence interval; CRP, C-Reactive Protein; eGFR, estimated glomerular filtration rate; HR, Hazard ratio; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; LDL-C, low density lipoprotein cholesterol.
Table 5.  Gender-based sensitivity analyses to evaluate the association of serum uric acid with 10-year cardiovascular disease incidence (n = 1687).
Men Women
N, cases 825/157 862/96 Models adjusted for
HR (95% CI) HR (95% CI)
Model with SUA as continuous variable Crude model
per 1 mg/dL 1.11 (0.97, 1.27) 1.34 (1.13, 1.58)
Model with SUA tertiles
1st Ref Ref
2nd 0.94 (0.59, 1.48) 1.21 (0.67, 2.19)
3rd 1.52 (1.10, 2.33) 2.16 (1.24, 3.76)
Model with SUA as continuous variable Model 1: Age, years of school,
per 1 mg/dL 0.99 (0.87, 1.14) 1.20 (1.02, 1.77) MedDietScore, alcohol consumption
Model with SUA tertiles physical activity, current smoking
1st Ref Ref
2nd 0.85 (0.52, 1.31) 1.09 (0.60, 1.97)
3rd 1.35 (0.98, 2.09) 1.94 (1.11, 3.38)
Model with SUA as continuous variable Model 2: Model 1 plus LDL-C,
per 1 mg/dL 0.95 (0.48, 1.24) 1.01 (0.55, 1.85) family history of CVD, ALT, AST,
Model with SUA tertiles waist circumference, HOMA-IR,
1st Ref Ref CRP, eGFR, menopause status
2nd 0.82 (0.51, 1.30) 1.04 (0.57, 1.94) (only in women)
3rd 1.27 (0.97, 2.05) 1.85 (1.05, 3.29)
Model with SUA as continuous variable Model 3: Model 2 plus obesity
per 1 mg/dL 0.93 (0.47, 1.21) 0.98 (0.53, 1.81)
Model with SUA tertiles
1st Ref Ref
2nd 0.78 (0.48, 1.24) 1.01 (0.55, 1.85)
3rd 1.21 (0.93, 1.96) 1.79 (1.04, 3.17)
Model with SUA as continuous variable Model 4: Model 3 plus metabolic health status
per 1 mg/dL 0.89 (0.45, 1.16) 0.94 (0.50, 1.73)
Model with SUA tertiles
1st Ref Ref
2nd 0.76 (0.47, 1.21) 0.98 (0.53, 1.81)
3rd 1.18 (0.91, 1.92) 1.75 (0.97, 3.01)
HRs and their corresponding 95% CIs were obtained from Cox regression analysis. Bold indicates statistically significant outcomes, i.e., p < 0.05.
Abbreviations: SUA, serum uric acid; ALT, alanine transaminase; AST, aspartate transaminase; CVD, cardiovascular disease; CI, confidence interval; CRP, C-Reactive Protein; eGFR, estimated glomerular filtration rate; HR, Hazard ratio; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; LDL-C, low density lipoprotein cholesterol.
Table 6.  Multi-adjusted sensitivity analysis to evaluate the association between serum uric acid and 10-year cardiovascular disease incidence according to A. obesity, B. metabolic health and C. combined obesity- and metabolic health-status in men and women participants of the ATTICA study (n = 1687).
1st tertile of SUA 2nd tertile of SUA 3rd tertile of SUA
Stratified by HR (95% CI) HR (95% CI) HR (95% CI)
A. Obesity status
Non obese Ref 0.95 (0.57, 2.10) 1.47 (0.86, 2.90)
Obese Ref 1.06 (0.67, 1.91) 1.89 (1.10, 3.20)
Obesity status * SUA: p for interaction = 0.02
B. Metabolic health status
Metabolically Healthy Ref 1.12 (0.97, 1.87) 2.10 (1.15, 3.23)
Metabolically unhealthy Ref 0.91 (0.62, 2.02) 1.36 (0.81, 2.79)
Metabolic status * SUA: p for interaction = 0.04
C. Combined obesity- and metabolic health- status
MHN Ref 1.09 (0.91, 1.69) 1.95 (1.12, 3.10)
MHO Ref 1.09 (0.82, 1.89) 1.99 (1.13, 3.21)
MUN Ref 0.93 (0.59, 2.06) 1.41 (0.83, 2.82)
MUO Ref 1.10 (0.63, 1.95) 1.59 (0.95, 3.01)
Combined obesity and metabolic status * SUA: p for interaction = 0.02
HRs and their corresponding 95% CIs were obtained from Cox regression analysis adjusted for age, (gender), body mass index, physical activity, current smoking, MedDietScore, (history of hypertension, diabetes and hypercholesterolemia, in case A) and family history of cardiovascular disease. Metabolically healthy status was defined as the absence of hypertension, dyslipidemia and diabetes at baseline. Bold indicates statistically significant outcomes, i.e., p < 0.05.
Abbreviations: SUA, serum uric acid; MHN, metabolically healthy non-obese; MHO, metabolically healthy obese; MUN, metabolically unhealthy non-obese; MUO, metabolically unhealthy obese.
Fig. 1.   Receiver operating characteristic curve to evaluate the predictive capacity of serum uric acid on 10-year cardiovascular disease incidence through the area under the curve (AUC) and the corresponding 95% confidence intervals (95% CI) in male and female participants of the ATTICA study (n = 1687).

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