Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study

Abstract

High serum uric acid (SUA) and triglyceride (TG) levels might promote high-cardiovascular risk phenotypes across the cardiometabolic spectrum. However, SUA predictive power in the presence of normal and high TG levels has never been investigated. We included 8124 patients from the URic acid Right for heArt Health (URRAH) study cohort who were followed for over 20 years and had no established cardiovascular disease or uncontrolled metabolic disease. All-cause mortality (ACM) and cardiovascular mortality (CVM) were explored by the Kaplan-Meier estimator and Cox multivariable regression, adopting recently defined SUA cut-offs for ACM (≥4.7 mg/dL) and CVM (≥5.6 mg/dL). Exploratory analysis across cardiometabolic subgroups and a sensitivity analysis using SUA/serum creatinine were performed as validation. SUA predicted ACM (HR 1.25 [1.12-1.40], p < 0.001) and CVM (1.31 [1.11-1.74], p < 0.001) in the whole study population, and according to TG strata: ACM in normotriglyceridemia (HR 1.26 [1.12-1.43], p < 0.001) and hypertriglyceridemia (1.31 [1.02-1.68], p = 0.033), and CVM in normotriglyceridemia (HR 1.46 [1.23-1.73], p < 0.001) and hypertriglyceridemia (HR 1.31 [0.99-1.64], p = 0.060). Exploratory and sensitivity analyses confirmed our findings, suggesting a substantial role of SUA in normotriglyceridemia and hypertriglyceridemia. In conclusion, we report that SUA can predict ACM and CVM in cardiometabolic patients without established cardiovascular disease, independent of TG levels.

Keywords: cardiometabolic; cardiovascular; hypertriglyceridemia; mortality; risk prediction; serum uric acid; triglycerides.

Figure 1

Flowchart of the study population selection from the national regional-based dataset. CV: cardiovascular. SBP: systolic blood pressure. DBP: diastolic blood pressure. URRAH: URic acid Right for heArt Health.

Figure 2

Relationship between uric acid and triglyceride levels. Serum uric acid and triglyceride levels are correlated (p ≤ 0.001, St.β 0.26, r = 0.332). Triglyceride levels (mg/dL) are log-transformed. Spearman coefficient was used to assess correlation. p < 0.05 was deemed statistically significant. TG: triglycerides. SUA: serum uric acid.

Figure 3

Kaplan–Meier survival analysis across triglycerides strata. Kaplan–Meier curves for SUA cut-offs in normotriglyceridemia for all-cause mortality (A) and cardiovascular mortality (C) and KM curves for SUA cut-offs in hypertriglyceridemia for all-cause mortality (B) and cardiovascular mortality (D). SUA < 4.7 mg/dL (for all-cause mortality) or <5.6 mg/dL (for cardiovascular mortality): green lines; SUA ≥ 4.7 mg/dL (for all-cause mortality) or ≤5.6 mg/dL (for cardiovascular mortality): orange lines. Log-rank test was used to compare the curves. p < 0.05 was deemed statistically significant. nTG: normotriglyceridemia. hTG: hypertriglyceridemia. SUA: serum uric acid.

Figure 4

Trends for all-cause mortality (A) and cardiovascular mortality (B) across the cardiometabolic spectrum in patients with normotriglyceridemia (light blue dots and lines) vs. hypertriglyceridemia (red dots and lines) adopting SUA ≥ 4.7 mg/dL and SUA ≥ 5.6 mg/dL as cut-offs for all-cause mortality and cardiovascular mortality, respectively. The analysis was not run on people with obesity and type diabetes and no other comorbidities due to the small sample size of the subgroup (n = 18). Data in undersized groups (n < 50) are reported for completeness in Supplementary Tables S1 and S2. CI: confidence interval. DM: patients with diabetes and no other comorbidities. HR: hazard ratio. HT: patients with hypertension and no other comorbidities. HT + DM: patients with hypertension and diabetes and no other comorbidities. Ob: patients with obesity and no other comorbidities. Ob + HT: patients with obesity and hypertension and no other comorbidities. Ob + HT + DM: patients with obesity, hypertension, and diabetes, and no other comorbidities.

Figure 5

Kaplan–Meier survival analysis across triglycerides strata adopting SUA/serum creatinine cut-off. Kaplan–Meier curves for SUA cut-offs (SUA/creatinine ≤ 5.35: green lines; SUA/creatinine > 5.35: orange lines) in normotriglyceridemia for all-cause mortality (A) and cardiovascular mortality (C) and KM curves for SUA cut-offs in hypertriglyceridemia for all-cause mortality (B) and cardiovascular mortality (D). Log-rank test was used to compare the curves. p < 0.05 was deemed statistically significant. Cr: serum creatinine; nTG: normotriglyceridemia. hTG: hypertriglyceridemia. SUA: serum uric acid.