Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies

Abstract

Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels. Design Umbrella review. Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references. Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes. Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10-6, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies. Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

Fructose metabolism and metabolic disease

“…A substantial body of work suggests that increased uric acid levels may independently regulate important aspects of metabolism and contribute to cardiometabolic risk (79)(80)(81)(82)(83). However, Mendelian randomization studies do not strongly support a causal role for circulating uric acid in mediating cardiometabolic disease (84). The association between uric acid levels and cardiometabolic risk may be indirect and may reflect activation of distinct fructoseregulated processes that contribute both to uric acid production and cardiometabolic risk.…”

Serum uric acid as a metabolic regulator of endothelial function in heart failure

“…In contrast, in recent meta-analysis lowering SUA levels under treatment did not predict improved surrogate clinical outcomes in HF [30]. Moreover, there was not convincing evidence regarding associations of SUA levels with increased risk of HF and other disease at higher risk of HF and HF mortality [31].…”

A Changing Landscape of Gout: Comorbidity Matters

“…Second, does the increased prevalence of comorbidities in incident gout patients imply a pathogenic link between these conditions? A recent metaanalysis summarizing studies investigating the association between urate levels and comorbidities concluded that a causal role of urate levels linked to comorbidities such as diabetes, hypertension, metabolic syndrome, and renal diseases has not been demonstrated by Mendelian randomization study (which eliminates confounding using genetic tools) with sufficient evidence, despite a strong support from epidemiological studies 17 . Third, should gout patients with comorbidities be managed differently from those with "primary" gout?…”