Overview: What the BIS study examined
Recent findings from a population-based prospective cohort in Berlin raise important questions about serum uric acid (SUA) and its role in cardiovascular risk among older adults. Using data from the Berlin Initiative Study (BIS), researchers followed 2,058 community-dwelling seniors (average age about 80) to explore whether SUA levels predict major adverse cardiovascular events (MACE) or death. The study uniquely employed a time‑varying exposure definition, updating SUA measurements at each biennial visit to reduce exposure misclassification common in long-term studies.
How SUA was categorized and measured
Uric acid was quantified with a standardized enzymatic colorimetric method. Participants were grouped into tertiles defined by baseline SUA distribution: lower SUA (1.68–5.16 mg/dl), intermediate SUA (5.17–6.48 mg/dl), and higher SUA (6.49–13.00 mg/dl). Exposures could change over time as SUA values were updated across follow-up visits. When data were missing, a last observation carried forward approach was used, with a specific rule for consecutive missing values.
Outcomes: MACE and all-cause mortality
The primary outcomes were MACE — a composite of non-fatal stroke, non-fatal myocardial infarction (MI), and cardiovascular death — and all-cause mortality. Case validation drew on self-reports, hospital records, death certificates, and expert adjudication for cardiovascular deaths. These robust outcome definitions aimed to ensure reliable assessment of SUA’s impact on clinically meaningful endpoints.
Key results: No clear SUA–MACE link; possible all-cause mortality signal
Compared with the reference intermediate SUA level, the study found:
- Lower SUA levels: no significant association with MACE (adjusted hazard ratio [HR] ~1.16; 95% CI 0.88–1.54) or all-cause mortality (HR ~1.06; 95% CI 0.86–1.31).
- Higher SUA levels: no significant association with MACE (adjusted HR ~1.11; 95% CI 0.85–1.45) but a higher risk of all-cause mortality (adjusted HR ~1.26; 95% CI 1.03–1.53) in primary analyses.
Importantly, when time-dependent confounding was addressed in sensitivity analyses (e.g., using marginal structural models with time-varying eGFR and albumin-to-creatinine ratio), the association between higher SUA and all-cause mortality diminished and became non-significant. This suggests that kidney function and kidney damage markers may mediate or confound the observed relationship.
Secondary analyses: Does age, diabetes, or sex matter?
Secondary analyses explored potential effect modification. Differential effects emerged by age: the link between higher SUA and all-cause mortality was more pronounced in younger seniors (70–<80 years) than in octogenarians, though interaction results were modest. Stratification by sex or diabetes status did not yield strong, consistent modifications for either MACE or all-cause mortality. Overall, no robust modifications were detected across these subgroups in relation to MACE risk.
Interpretation: What does this mean for clinicians and patients?
The BIS study adds to a nuanced picture of SUA in older adults. In this older population, higher SUA did not translate into a higher risk of MACE after accounting for time-varying kidney function and damage. A transient association with all-cause mortality in some analyses faded under more rigorous methods, arguing against SUA lowering alone as a strategy to reduce cardiovascular events in asymptomatic older adults.
These findings align with several randomized trials and KDIGO guidance that question the benefit of lowering SUA in the absence of symptoms. Given the high prevalence of hyperuricemia in older adults and potential medication-related harms, routine SUA‑lowering therapy without clear clinical indications may not be warranted.
Strengths and limitations
Strengths include a large, population-based cohort with time-varying SUA exposure, comprehensive covariate adjustment, and rigorous outcome adjudication. Limitations include residual confounding inherent to observational designs and the absence of data on symptomatic gout status for all participants, though reported use of SUA-lowering drugs was relatively low at baseline.
Bottom line for practice
Among older adults in this Berlin cohort, SUA levels were not associated with MACE. A higher SUA–all-cause mortality signal observed in some analyses disappeared when time-dependent confounding was properly accounted for. Clinicians should focus on cardiovascular risk prevention using established factors rather than pursuing SUA normalization in asymptomatic, older patients.
About the study and data origin
The Berlin Initiative Study (BIS) followed community-dwelling seniors starting in 2009 to investigate chronic kidney disease, linking health data with claims and adjudicated outcomes. The current analysis applied time-varying SUA exposure, a robust approach for a biomarker known to fluctuate with age and kidney function.
