Overview
Understanding how serum uric acid (SUA) relates to cardiovascular outcomes in older adults is crucial given the high prevalence of hyperuricemia in this population. A population-based prospective analysis using the Berlin Initiative Study (BIS) cohort provides new insights. The study followed community-dwelling adults aged 70 and older to examine whether baseline and time-updated SUA levels predict major adverse cardiovascular events (MACE) and all-cause mortality.
Study Population and Design
The BIS recruited 2,069 individuals in 2009, all drawn from statutory health insurance beneficiaries in Berlin who were at least 70 years old. Exclusion criteria included the need for nursing care and dialysis or kidney transplantation at baseline. Researchers linked BIS data with individual healthcare claims and tracked participants until an outcome occurred, the end of follow-up in 2021, or a defined cut-off after the last SUA assessment.
Crucially, SUA was measured using a standardized enzymatic colorimetric method. SUA values were updated at each biennial visit, and missing values were addressed with a last observation carried forward approach. This time-varying exposure definition allowed participants to contribute person-time to multiple SUA categories over the study period.
What Were the Outcomes?
Two primary outcomes were evaluated:
– MACE: a composite of non-fatal stroke, non-fatal myocardial infarction (MI), and cardiovascular death.
– All-cause mortality.
Outcome adjudication integrated self-reports validated by hospital records and death certificates, with cardiovascular death confirmed by two independent physicians when possible.
Exposure and Covariates
SUA tertiles defined baseline exposure as follows: Tertile 1 (lower SUA, 1.68–5.16 mg/dl), Tertile 2 (intermediate SUA, 5.17–6.48 mg/dl), and Tertile 3 (higher SUA, 6.49–13.00 mg/dl). The analysis used time-varying SUA to reflect real-world fluctuations. Covariates spanned sociodemographic factors, lifestyle, renal function (eGFR BIS2 and ACR), comorbidities (hypertension, diabetes, hyperlipidemia, prior MI/stroke, heart failure, peripheral vascular disease), and use of uric acid–related medications (though these were not confounders in the final models).
Statistical Approach
The team employed Cox proportional hazards models with time-fixed covariates and SUA as a time-varying exposure. Both crude and adjusted hazard ratios (HRs) with 95% confidence intervals were reported, comparing lower vs. intermediate and higher vs. intermediate SUA levels. Proportional hazard assumptions were checked using Schoenfeld residuals.
Secondary analyses explored potential effect modification by diabetes status, age groups (70–<80 vs. ≥80), and sex. Sensitivity analyses included time-dependent adjustments for kidney function (eGFR, ACR) and marginal structural models to address time-dependent confounding. Post-hoc analyses redefined SUA exposure using standard reference ranges and used directed acyclic graphs for covariate selection.
Main Findings
Across 2,058 BIS participants, mean age was about 80 years, and roughly half were female. The principal finding was that higher SUA levels were associated with an increased risk of all-cause mortality, particularly among those aged 70–<80 years. However, higher SUA did not meaningfully elevate the risk of MACE after accounting for time-dependent confounding. Notably, when time-dependent kidney function was incorporated through advanced methods, the association between higher SUA and all-cause mortality largely disappeared, suggesting that kidney function and related factors may mediate or confound this relationship.
Interpretation and Clinical Implications
The BIS analysis challenges the notion that SUA is a straightforward predictor of cardiovascular events in very old adults. While an initially apparent link between high SUA and all-cause mortality faded with more rigorous, time-aware analyses, the results underscore the complexity of SUA’s role in aging populations. The findings align with randomized trials that question the benefit of lowering SUA in asymptomatic individuals and with KDIGO guidance against routine SUA-lowering therapy in CKD patients without symptoms.
For clinicians, this study suggests that treating SUA to prevent cardiovascular events in asymptomatic older adults may not be warranted. A broader focus on kidney health, functional status, physical activity, and comorbidity management remains essential in this age group.
Strengths, Limitations, and Future Directions
Strengths include a population-based cohort design, longitudinal SUA measurements, comprehensive outcome adjudication, and rigorous confounding control, including time-dependent factors. Limitations involve potential residual confounding and exposure misclassification in earlier studies; while this analysis mitigates these issues, unmeasured factors (e.g., gout symptoms) could still influence results. Future research should explore non-linear SUA associations, possible subgroup differences, and mechanistic pathways linking kidney function, uric acid, and mortality in aging populations.
Bottom Line
Among older adults, higher SUA levels were linked to a higher risk of all-cause mortality in preliminary analyses, but this association did not persist when time-dependent confounding was accounted for. SUA alone should not be targeted to reduce cardiovascular risk in asymptomatic elderly individuals; emphasis should be on holistic, individualized care.
