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.

Expert consensus for the diagnosis and treatment of patients with hyperuricemia and high cardiovascular risk: 2023 update

“…This association held true when stratifying according to triglyceride (TG) levels: ACM predictions in individuals with normal TG levels and hypertriglyceridemia and CVM predictions in those with normal TG levels and hypertriglyceridemia. Therefore, the study reveals that sUA can anticipate ACM and CVM among individuals with cardiometabolic profiles without established CVD, independently of TG levels [ 21 ].…”

The Results of the URRAH (Uric Acid Right for Heart Health) Project: A Focus on Hyperuricemia in Relation to Cardiovascular and Kidney Disease and its Role in Metabolic Dysregulation

“…The risk of CV mortality is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol. [ 42 ] Serum uric acid predicts all-cause and cardiovascular mortality independently of hypertriglyceridemia in cardiometabolic patients without established CV disease N = 8124 Age = 58.8 ± 16.1 years Triglycerides = 104 (76–145) mg/dl eGFR = 85 ± 20 mL/min/1.73m 2 SUA levels = 5.0 ± 1.4 mg/dl 73% of patients with AH SUA can predict all-cause mortality and CV mortality in cardiometabolic patients without established cardiovascular disease, independent of triglycerides levels [ 43 ] The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk N = 9589 Age = 58 ± 15 years 45% of patients were males 73% of patients with AH 53% of patients with diagnosis of metabolic syndrome Increasing SUA levels are associated with a higher CV mortality risk irrespective of the presence of metabolic syndrome: a cardiovascular SUA threshold may improve risk stratification The URRAH population cohort included patients attending hypertension clinics, as well as subjects recruited in prospective observational cohort studies with a follow-up period of at least 20 years AH arterial hypertension, CV cardiovascular, CKD chronic kidney disease, DM diabetes mellitus, eGFR estimated glomerular filtration rate, HDL high-density lipoprotein, LDL low-density lipoprotein, LVH left ventricular hypertrophy, LVMI left ventricular mass index, sCr serum creatinine, SUA serum uric acid …”

“…Similar results were seen in a subpopulation (n = 8124) with different degrees of cardiometabolic damage (patients with obesity, arterial hypertension, T2D, either alone or combined) but without established cardiovascular disease (subjects with previous CV events, history of heart failure, systolic/diastolic blood pressure > 240/149 mmHg, fasting blood glucose > 350 mg/dl, or serum creatinine > 4 mg/dL were excluded). A total of 8,124 patients were included in the final analysis : HR 1.25, (95% CI 1.12–1.40) for ACM and 1.31 (95% CI 1.11–1.74) for CV mortality [ 42 ]. The association with CV mortality was also examined in a sub-cohort of patients selected based on the data availability for the metabolic syndrome (MS) parameters (n = 9589; n = 5100 met MS criteria), confirming that SUA ≥ 5.6 mg/dL was strongly associated with CV death: HR 1.79 (95% CI 1.15–2.79).…”

Purine Metabolism Dysfunctions: Experimental Methods of Detection and Diagnostic Potential

“…In cardiovascular disorders, SUA levels are also associated with the clinical severity of the diseases. Cumulative evidence from the URRAH project (as well as from other huge epidemiological studies) supports the role of SUA as an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infarction, stroke, and heart failure [ 11 , 94 ].…”