Serum urate change among gout patients treated with sodium-glucose cotransporter type 2 inhibitors vs. sulfonylurea: A comparative effectiveness analysis.

OBJECTIVE: To investigate the serum urate (SU) change among gout patients initiating SGLT2i, and to compare with sulfonylurea, the second-most widely used glucose-lowering medication after metformin. METHODS: We conducted a cohort study of patients with gout and baseline SU >6 mg/dL who had SU measured within 90 days before and after SGLT2i or sulfonylurea initiation. Using multivariable linear regression, we compared SU change among SGLT2i initiators between those with and without diabetes and then compared SU change between SGLT2i and sulfonylurea. RESULTS: We identified 28 patients with gout initiating SGLT2i (including 16 with diabetes) and 28 patients initiating sulfonylurea (all with diabetes). Among SGLT2i initiators, the mean within-group SU change was -1.8 (95 % CI, -2.4 to -1.1) mg/dL, including -1.2 (-1.8 to -0.6) mg/dL and -2.5 (-3.6 to -1.3) mg/dL among patients with and without diabetes, respectively, with an adjusted difference between those with and without diabetes of -1.4 (-2.4 to -0.5) mg/dL. The SU did not change after initiating sulfonylurea (+0.3 [-0.3 to 1.0] mg/dL). The adjusted SU change difference between SGLT2i vs. sulfonylurea initiation was -1.8 (-2.7 to -0.9) mg/dL in all patients. The SU reduction persisted regardless of urate-lowering therapy or diuretic use and the presence of diabetes, chronic kidney disease, or heart failure. CONCLUSION: Among patients with gout, SGLT2i was associated with a notable reduction in SU compared with sulfonylurea, with a larger reduction among patients without diabetes. With their proven cardiovascular-kidney-metabolic benefits, adding SGLT2i to current gout management could provide streamlined benefits for gout and its comorbidities.

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin.

Importance: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits. Objective: To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy. Design, Setting, and Participants: This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022. Exposures: Initiation of SGLT2i vs sulfonylurea. Main Outcomes and Measures: The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023. Results: Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting. Conclusions: In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to be required to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

Frequently Encountered Artifacts in the Application of Dual-Energy Computed Tomography to Cardiovascular Imaging for Urate Crystals in Gout: A Matched-Control Study.

OBJECTIVE: There is surging interest in using dual-energy computed tomography (DECT) to identify cardiovascular monosodium urate (MSU) deposits in patients with gout. We sought to examine the prevalence and characterization of cardiovascular DECT artifacts using non-electrocardiogram (EKG)-gated DECT pulmonary angiograms. METHODS: We retrospectively reviewed non-EKG-gated DECT pulmonary angiograms performed on patients with and without gout at a single academic center. We noted the presence and locations of vascular green colorization using the default postprocessing two-material decomposition algorithm for MSU. The high- and low-energy grayscale images and advanced DECT measurements were used to determine whether they were true findings or artifacts. We classified artifacts into five categories: streak, contrast medium mixing, misregistration due to motion, foreign body, and noise. RESULTS: Our study included CT scans from 48 patients with gout and 48 age- and sex-matched controls. The majority of patients were male with a mean age of 67 years. Two independent observers attributed all areas of vascular green colorization to artifacts. The most common types of artifacts were streak (56% vs 57% between patients and controls, respectively) and contrast medium mixing (51% vs 65%, respectively). Whereas some of the default DECT measurements of cardiovascular green colorization were consistent with values reported for subcutaneous tophi, advanced DECT measurements were not consistent with that of tophi. CONCLUSION: Artifacts that could be misconstrued as cardiovascular MSU deposits were commonly identified in patients with and without gout on non-EKG-gated DECT pulmonary angiograms. These artifacts can inform future vascular DECT studies on patients with gout to minimize false-positive findings.

Serum Urate and Recurrent Gout.

Importance: Approximately 12 million adults in the US have a history of gout, but whether serum urate levels can help predict recurrence is unclear. Objective: To assess associations of a single serum urate measurement with subsequent risk of acute gout flares and subsequent risk of hospitalizations for gout among patients in the UK with a history of gout. Design, Setting, and Participants: This retrospective study included patients with a history of gout identified from the UK between 2006 and 2010 who were followed up through Primary Care Linked Data medical record linkage until 2017 and through the Hospital Episode Statistics database until 2020. Exposures: Serum urate levels at enrollment. Main Outcome and Measure: Rate of recurrent acute gout, ascertained by hospitalization, outpatient, and prescription/procedure records, and adjusted rate ratios using negative binomial regressions. Results: Among 3613 patients with gout (mean age, 60 years; 3104 [86%] men), 1773 gout flares occurred over a mean follow-up of 8.3 years. Of these, 1679 acute gout flares (95%) occurred in people with baseline serum urate greater than or equal to 6 mg/dL and 1731 (98%) occurred in people with baseline serum urate greater than or equal to 5 mg/dL. Rates of acute gout flares per 1000 person-years were 10.6 for participants with baseline urate levels less than 6 mg/dL, 40.1 for levels of 6.0 to 6.9 mg/dL, 82.0 for levels of 7.0 to 7.9 mg/dL, 101.3 for levels of 8.0 to 8.9 mg/dL, 125.3 for urate levels of 9.0 to 9.9 mg/dL, and 132.8 for levels greater than or equal to 10 mg/dL. Rate ratio of flares were 1.0, 3.37, 6.93, 8.67, 10.81, and 11.42, respectively, over 10 years (1.61 [1.54-1.68] per mg/dL). Rates of hospitalization per 1000 person-years during follow-up were 0.18 for those with baseline serum urate less than 6 mg/dL, 0.97 for serum urate of 6.0 to 6.9 mg/dL, 1.8 for serum urate of 7.0 to 7.9 mg/dL, 2.2 for serum urate of 8.0 to 8.9 mg/dL, 6.7 for serum urate of 9.0 to 9.9 mg/dL, and 9.7 for serum urate greater than or equal to 10 mg/dL. Rate ratios of hospitalization for gout, adjusting for age, sex, and race were 1.0, 4.70, 8.94, 10.37, 33.92, and 45.29, respectively (1.87 [1.57-2.23] per mg/dL). Conclusions and Relevance: In this retrospective study of patients with a history of gout, serum urate levels at baseline were associated with the risk of subsequent gout flares and rates of hospitalization for recurrent gout. These findings support using a baseline serum urate level to assess risk of recurrent gout over nearly 10 years of follow-up.

Unclosing Premature Mortality Gap Among Patients With Gout in the US General Population, Independent of Serum Urate and Atherosclerotic Cardiovascular Risk Factors.

OBJECTIVE: Gout flares are followed by transient major cardiovascular (CV) risk, implicating the role of inflammation; the aim of this study was to determine whether premature mortality rates in patients with gout and CV risk are independent of serum urate (SU) and atherosclerotic CV disease (ASCVD) risk factors. METHODS: Using serial US nationwide prospective cohorts, we evaluated the independent association of prevalent gout with all-cause and CV mortality, adjusting for SU, ASCVD risk factors, comorbidities, medications, and kidney function and compared mortality rates between the early (1988-1994 baseline) and late cohorts (2007-2016 baseline). We replicated late cohort findings among patients with gout in a nationwide UK cohort (2006-2010 baseline). RESULTS: Adjusted hazard ratios (HRs) for mortality rates in patients with prevalent gout were similar in early and late US cohorts (1.20 [1.03-1.40] and 1.19 [1.04-1.37], respectively); HRs with further adjustment for SU were 1.19 (1.02-1.38) and 1.19 (1.03-1.37), respectively. Adjusted HR among patients with gout from the UK late cohort was 1.61 (1.47-1.75); these associations were larger among women (P = 0.04) and prominent among Black individuals. Adjusted HR for CV mortality rates in the late US cohort was 1.39 (1.09-1.78); those for circulatory, CV, and coronary heart disease deaths among UK patients with incident gout were 1.48 (1.24-1.76), 1.49 (1.20-1.85), and 1.59 (1.26-1.99), respectively. CONCLUSIONS: Patients with gout experience a persistent mortality gap in all-cause and CV deaths, even adjusting for SU and ASCVD risk factors, supporting a role for gout-specific pathways (eg, flare inflammation). These findings suggest gaps in current care, particularly in women and possibly among Black patients.

Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations : A General Population Cohort Study.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) decrease serum urate levels, but whether this translates into prevention of recurrent flares among patients with gout and gout-primary emergency department (ED) visits or hospitalizations is unknown. OBJECTIVE: To compare gout flares and cardiovascular events among patients with gout initiating SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP-4is), another second-line glucose-lowering agent not associated with serum urate levels or cardiovascular risk. DESIGN: Propensity score-matched, new-user cohort study. SETTING: General population database from 1 January 2014 to 30 June 2022. PARTICIPANTS: Patients with gout and type 2 diabetes. MEASUREMENTS: The primary outcome was recurrent gout flare counts ascertained by ED, hospitalization, outpatient, and medication dispensing records. Secondary outcomes included myocardial infarction and stroke; genital infection (positive control) and osteoarthritis encounter (negative control) were also assessed. Poisson and Cox proportional hazards regressions were used with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). RESULTS: After propensity score matching, the flare rate was lower among SGLT2i initiators than DPP-4i initiators (52.4 and 79.7 events per 1000 person-years, respectively), with a rate ratio (RR) of 0.66 (95% CI, 0.57 to 0.75) and a rate difference (RD) of -27.4 (CI, -36.0 to -18.7) per 1000 person-years. The corresponding RR and RD for gout-primary ED visits and hospitalizations were 0.52 (CI, 0.32 to 0.84) and -3.4 (CI, -5.8 to -0.9) per 1000 person-years, respectively. The corresponding hazard ratio (HR) and RD for myocardial infarction were 0.69 (CI, 0.54 to 0.88) and -7.6 (CI, -12.4 to -2.8) per 1000 person-years; the HR for stroke was 0.81 (CI, 0.62 to 1.05). Those who initiated SGLT2is showed higher risk for genital infection (HR, 2.15 [CI, 1.39 to 3.30]) and no altered risk for osteoarthritis encounter (HR, 1.07 [CI, 0.95 to 1.20]). Results were similar when propensity score overlap weighting was applied. LIMITATION: Participants had concurrent type 2 diabetes. CONCLUSION: Among patients with gout, SGLT2is may reduce recurrent flares and gout-primary ED visits and hospitalizations and may provide cardiovascular benefits. PRIMARY FUNDING SOURCE: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Prediagnostic Glycoprotein Acetyl Levels and Incident and Recurrent Flare Risk Accounting for Serum Urate Levels: A Population-Based, Prospective Study and Mendelian Randomization Analysis.

OBJECTIVE: To prospectively investigate population-based metabolomics for incident gout and reproduce the findings for recurrent flares, accounting for serum urate. METHODS: We conducted a prediagnostic metabolome-wide analysis among 105,615 UK Biobank participants with nuclear magnetic resonance metabolomic profiling data (168 total metabolites) from baseline blood samples collected 2006-2010 in those without history of gout. We calculated hazard ratios (HRs) for incident gout, adjusted for gout risk factors, excluding and including serum urate levels, overall and according to fasting duration before sample collection. Potential causal effects were tested with 2-sample Mendelian randomization. Poisson regression was used to calculate rate ratios (RRs) for the association with recurrent flares among incident gout cases. RESULTS: Correcting for multiple testing, 88 metabolites were associated with risk of incident gout (N = 1,303 cases) before serum urate adjustment, including glutamine and glycine (inversely), and lipids, branched-chain amino acids, and most prominently, glycoprotein acetyls (GlycA; P = 9.17 × 10-32 ). Only GlycA remained associated with incident gout following urate adjustment (HR 1.52 [95% confidence interval (95% CI) 1.22-1.88] between extreme quintiles); the HR increased progressively with fasting duration before sample collection, reaching 4.01 (95% CI 1.36-11.82) for ≥8 hours of fasting. Corresponding HRs per SD change in GlycA levels were 1.10 (95% CI 1.04-1.17) overall and 1.54 (95% CI 1.21-1.96) for ≥8 hours of fasting. GlycA levels were also associated with recurrent gout flares among incident gout cases (RR 1.90 [95% CI 1.27-2.85] between extreme quintiles) with larger associations with fasting. Mendelian randomization corroborated a potential causal role for GlycA on gout risk. CONCLUSION: This prospective, population-based study implicates GlycA, a stable long-term biomarker reflecting neutrophil overactivity, in incident and recurrent gout flares (central manifestation from neutrophilic synovitis) beyond serum urate.

Trends in Prevalence of Gout Among US Asian Adults, 2011-2018.

Importance: Gout disparities among Black individuals in the US have recently been explained by socioclinical factors; however, no information is available among Asian individuals living in Western countries, despite their disproportionately worsening metabolic health. Objective: To determine the prevalence of gout and serum urate concentrations according to race and ethnicity and to explore the association of social determinants of health and clinical factors. Design, Setting, and Participants: This is a population-based, cross-sectional analysis. Data from a nationally representative sample of US adults were obtained from the National Health and Nutrition Examination Survey (NHANES) (2011-2018) in which Asian race data were collected (primary). Data from the UK Biobank (2006-2021) were used for replication of the Asian vs White differences. Data analysis was performed from December 2021 to September 2022. Main Outcomes and Measures: Race-specific gout prevalence and serum urate levels. Results: A total of 22 621 participants from NHANES (2011-2018) were included in the analysis (mean [SD] age, 49.8 [17.8] years; 10 948 male participants [48.4%]). In 2017 to 2018, gout affected 12.1 million US individuals, with its crude prevalence increasing from 3.6% (95% CI, 2.8%-4.5%) in 2011 to 2012 to 5.1% (95% CI, 4.2%-5.9%) in 2017 to 2018 (P for trend = .03); this trend was no longer significant after age adjustment (P for trend = .06) or excluding Asian individuals (P for trend = .11). During the same period, age- and sex-adjusted prevalence among Asian Americans doubled from 3.3% (95% CI, 2.1%-4.5%) to 6.6% (95% CI, 4.4%-8.8%) (P for trend = .007) to numerically exceed all other racial and ethnic groups in 2017 to 2018, with age- and sex-adjusted odds ratio (ORs) of 1.61 (95% CI, 1.03-2.51) and a socioclinical factor-adjusted multivariable OR of 2.62 (95% CI, 1.59-4.33) for Asian vs White individuals. The latest age- and sex-adjusted gout prevalence among US individuals aged 65 years and older was 10.0% among White individuals and 14.8% among Asian individuals (including 23.6% of Asian men). Serum urate concentrations also increased between 2011 and 2018 among US Asian individuals (P for trend = .009). The Asian vs White disparity was also present in the UK Biobank. Conclusions and Relevance: The findings of this study suggest that the prevalence of gout among Asian individuals numerically surpassed that for all other racial and ethnic groups in 2017 to 2018. This Asian vs White disparity did not appear to be associated with socioclinical factors.

Interactions Between Genetic Risk and Diet Influencing Risk of Incident Female Gout: Discovery and Replication Analysis of Four Prospective Cohorts.

OBJECTIVE: To examine whether the cross-sectional gene-diet interaction for prevalent hyperuricemia among women translates prospectively to risk of incident female gout. METHODS: We analyzed the interaction between genetic predisposition and adherence to a healthy dietary pattern (i.e., Dietary Approaches to Stop Hypertension [DASH] score) on risk of incident female gout in 18,244 women from Nurses' Health Study (NHS; discovery) and 136,786 women from 3 additional prospective female cohorts from the US and UK (replication). Genetic risk score (GRS) was calculated from 114 urate-associated loci. RESULTS: In the NHS and replication cohorts, association between diet and gout risk was larger and stronger among women with higher genetic risk. In all cohorts combined, compared to women with an unhealthy DASH score (less than the mean score), multivariable relative risk (RR) for incident gout among women with a healthy DASH score (greater than/equal to the mean score) was 0.67 (95% confidence interval [95% CI] 0.60-0.76) among higher GRS (greater than/equal to the mean score) and 0.91 (0.78-1.05) among lower GRS (P for multiplicative interaction = 0.001); multivariable RR for higher versus lower GRS was 2.03 (95% CI 1.80-2.29) and 1.50 (95% CI 1.31-1.71) among unhealthy and healthy DASH score groups, respectively. Additive interaction was also significant, in both the discovery and replication cohorts (P < 0.001), with 51% of the excess risk attributable to the additive gene-diet interaction in all cohorts combined. CONCLUSION: The deleterious effect of genetic predisposition on risk of incident female gout was more pronounced among women with unhealthy diets, with nearly half the excess risk attributable to this gene-diet interaction. These data elucidate the important synergy of genetics and diet for female gout development.

Nationwide racial/ethnic disparities in US emergency department visits and hospitalizations for gout.

OBJECTIVES: Gout prevalence is reportedly ∼20% higher in US Black adults than Whites, but racial differences in emergency department (ED) visits and hospitalizations for gout are unknown. We evaluated the latest US national utilization datasets according to racial/ethnic groups. METHODS: Using 2019 US National Emergency Department Sample and National Inpatient Sample databases, we compared racial/ethnic differences in annual population rates of ED visits and hospitalizations for gout (primary discharge diagnosis) per 100 000 US adults (using 2019 age- and sex-specific US census data). We also examined rates of ED visits and hospitalizations for gout among all US ED visits/hospitalizations and mean costs for each gout encounter. RESULTS: Compared with White patients, the per capita age- and sex-adjusted rate ratio (RR) of gout primary ED visits for Black patients was 5.01 (95% CI 4.96, 5.06), for Asian patients 1.29 (1.26, 1.31) and for Hispanic patients 1.12 (1.10, 1.13). RRs for gout primary hospitalizations were 4.07 (95% CI 3.90, 4.24), 1.46 (1.34, 1.58) and 1.06 (0.99, 1.13), respectively. Corresponding RRs among total US hospitalizations were 3.17 (95% CI 2.86, 3.50), 3.23 (2.71, 3.85) and 1.43 (1.21, 1.68) and among total ED visits were 2.66 (95% CI, 2.50, 2.82), 3.28 (2.64, 4.08), and 1.14 (1.05, 1.24), respectively. RRs were largest among Black women. Costs for ED visits and hospitalizations experienced by race/ethnicity showed similar disparities. CONCLUSIONS: These first nationwide data found a substantial excess in both gout primary ED visits and hospitalizations experienced by all underserved racial/ethnic groups, particularly by Black women, revealing an urgent need for improved care to eliminate inequities in gout outcomes.

Racial and Sex Disparities in Gout Prevalence Among US Adults.

Importance: Emerging data suggest gout and hyperuricemia may now be more frequent among Black adults in the US than White adults, especially Black women. However, national-level, sex-specific general population data on racial differences in gout prevalence and potential socioclinical risk factors are lacking. Objective: To identify sex-specific factors driving disparities between Black and White adults in contemporary gout prevalence in the US general population. Design, Setting, and Participants: This cross-sectional analysis used nationally representative, decadal survey data from successive cycles of the National Health and Nutrition Examination Survey from 2007 to 2016. Data were analyzed from November 1, 2019, through May 31, 2021. Participants included US adults self-reporting Black or White race. Exposures: Self-reported race, excess body mass index, chronic kidney disease (CKD; defined as estimated glomerular filtration rate <60 mL/min/1.73 m2, according to latest equations without race coefficient), poverty, poor-quality diet, low educational level, alcohol consumption, and diuretic use. Main Outcomes and Measures: Race- and sex-specific prevalence of physician- or clinician-diagnosed gout and hyperuricemia and their differences before and after adjusting for potential socioclinical risk factors. Results: A total of 18 693 participants were included in the analysis, consisting of 3304 Black women (mean [SD] age, 44.8 [0.4] years), 6195 White women (mean [SD] age, 49.8 [0.3] years), 3085 Black men (mean [SD] age, 43.6 [0.5] years]), and 6109 White men (mean [SD] age, 48.2 [0.3] years). Age-standardized prevalence of gout was 3.5% (95% CI, 2.7%-4.3%) in Black women and 2.0% (95% CI, 1.5%-2.5%) in White women (age-adjusted odds ratio [OR], 1.81 [95% CI, 1.29-2.53]); prevalence was 7.0% (95% CI, 6.2%-7.9%) in Black men and 5.4% (95% CI, 4.7%-6.2%) in White men (age-adjusted OR, 1.26 [95% CI, 1.02-1.55]). These associations attenuated after adjusting for poverty, diet, body mass index, and CKD among women and for diet and CKD among men but became null after adjusting for all risk factors (ORs, 1.05 [95% CI, 0.67-1.65] among women and 1.05 [95% CI, 0.80-1.35] among men). Hyperuricemia end point findings were similar. Conclusions and Relevance: In this nationally representative race- and sex-specific cross-sectional study of US adults, gout was more prevalent in adults self-reporting Black race during a recent 10-year period compared with their White counterparts. These racial differences may be explained by sex-specific differences in diet and social determinants of health and clinical factors. Culturally informed efforts focusing on these factors could reduce current gout-related disparities.

Adherence to 2020 to 2025 Dietary Guidelines for Americans and the Risk of New-Onset Female Gout.

IMPORTANCE: Female-specific gout data are scarce despite perceived differences from males in its risk factors and disproportionate worsening in disease and comorbidity burden globally. The 2020 to 2025 Dietary Guidelines for Americans recommend multiple healthy eating patterns for prevention of cardiovascular-metabolic outcomes, which may also be relevant to the prevention of female gout. OBJECTIVE: To examine the associations of dietary scores for the latest guideline-based healthy eating patterns with risk of incident female gout. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 80 039 US women in the Nurses' Health Study followed up through questionnaires every 2 years starting from 1984. Participants had no history of gout at baseline, and the study used questionnaire responses through 2018. Statistical analyses were performed over September 2020 to August 2021. EXPOSURES: Four healthy eating patterns: Dietary Approaches to Stop Hypertension (DASH), Alternate Mediterranean Diet Score, Alternative Healthy Eating Index (AHEI), and Prudent, plus Western (unhealthy) for comparison, with scores derived from validated food frequency questionnaires. MAIN OUTCOMES AND MEASURES: Incident, physician-diagnosed female-specific gout. RESULTS: During 34 years of follow-up, we documented 3890 cases of incident female gout. Compared with the least-adherent quintile, women most adherent to healthy diets had significantly lower risk of incident gout, with multivariable-adjusted hazard ratios (HRs) 0.68 (95% CI, 0.61-0.76) (DASH), 0.88 (95% CI, 0.80-0.98) (Mediterranean), 0.79 (95% CI, 0.71-0.89) (AHEI), and 0.75 (95% CI, 0.73-0.90) (Prudent); all P for trend ≤.009. Conversely, women with highest-quintile Western diet score had 49% higher risk of gout (HR, 1.49; 95% CI, 1.33-1.68], P <.001). When combined, the most DASH-diet adherent women with normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) had a 68% lower risk of gout compared with the least adherent women with overweight or obese BMI; the corresponding risk reduction was 65% combining high DASH diet adherence with no diuretic use. CONCLUSIONS AND RELEVANCE: These large-scale, long-term prospective cohort findings extend the pleotropic benefits of the 2020 to 2025 Dietary Guidelines for Americans to female gout prevention, with multiple healthy diets that can be adapted to individual food traditions, preferences, and comorbidities.

Identifying Potential Classification Criteria for Calcium Pyrophosphate Deposition Disease: Item Generation and Item Reduction.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first 2 phases of a 4-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35-member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item-rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item-rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

Excess comorbidities in gout: the causal paradigm and pleiotropic approaches to care.

Gout is a common hyperuricaemic metabolic condition that leads to painful inflammatory arthritis and a high comorbidity burden, especially cardiometabolic-renal (CMR) conditions, including hypertension, myocardial infarction, stroke, obesity, hyperlipidaemia, type 2 diabetes mellitus and chronic kidney disease. Substantial advances have been made in our understanding of the excess CMR burden in gout, ranging from pathogenesis underlying excess CMR comorbidities, inferring causal relationships from Mendelian randomization studies, and potentially discovering urate crystals in coronary arteries using advanced imaging, to clinical trials and observational studies. Despite many studies finding an independent association between blood urate levels and risk of incident CMR events, Mendelian randomization studies have largely found that serum urate is not causal for CMR end points or intermediate risk factors or outcomes (such as kidney function, adiposity, metabolic syndrome, glycaemic traits or blood lipid concentrations). Although limited, randomized controlled trials to date in adults without gout support this conclusion. If imaging studies suggesting that monosodium urate crystals are deposited in coronary plaques in patients with gout are confirmed, it is possible that these crystals might have a role in the inflammatory pathogenesis of increased cardiovascular risk in patients with gout; removing monosodium urate crystals or blocking the inflammatory pathway could reduce this excess risk. Accordingly, data for CMR outcomes with these urate-lowering or anti-inflammatory therapies in patients with gout are needed. In the meantime, highly pleiotropic CMR and urate-lowering benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors and key lifestyle measures could play an important role in comorbidity care, in conjunction with effective gout care based on target serum urate concentrations according to the latest guidelines.

Impact of adiposity on risk of female gout among those genetically predisposed: sex-specific prospective cohort study findings over >32 years.

OBJECTIVES: To evaluate the joint (combined) association of excess adiposity and genetic predisposition with the risk of incident female gout, and compare to their male counterparts; and determine the proportion attributable to body mass index (BMI) only, genetic risk score (GRS) only, and to their interaction. METHODS: We prospectively investigated potential gene-BMI interactions in 18 244 women from the Nurses' Health Study and compared with 10 888 men from the Health Professionals Follow-Up Study. GRS for hyperuricaemia was derived from 114 common urate-associated single nucleotide polymorphisms. RESULTS: Multivariable relative risk (RR) for female gout was 1.49 (95% CI 1.42 to 1.56) per 5 kg/m2 increment of BMI and 1.43 (1.35 to 1.52) per SD increment in the GRS. For their joint association of BMI and GRS, RR was 2.18 (2.03 to 2.36), more than the sum of each individual factor, indicating significant interaction on an additive scale (p for interaction <0.001). The attributable proportions of joint effect for female gout were 42% (37% to 46%) to adiposity, 37% (32% to 42%) to genetic predisposition and 22% (16% to 28%) to their interaction. Additive interaction among men was smaller although still significant (p interaction 0.002, p for heterogeneity 0.04 between women and men), and attributable proportion of joint effect was 14% (6% to 22%). CONCLUSIONS: While excess adiposity and genetic predisposition both are strongly associated with a higher risk of gout, the excess risk of both combined was higher than the sum of each, particularly among women.

Dietary and Lifestyle-Centered Approach in Gout Care and Prevention.

PURPOSE OF REVIEW: We aim to provide a comprehensive review of the available literature to inform dietary recommendations for patients with gout and hyperuricemia that have the potential to simultaneously lower serum urate and reduce gout morbidity while addressing gout's cardiometabolic comorbidities holistically. RECENT FINDINGS: The global burden of gout is rising worldwide, particularly in developed nations as well as in women. Patients with gout are often recommended to follow a low-purine (i.e., low-protein) diet to avoid purine-loading. However, such an approach may lead to increased consumption of unhealthy carbohydrates and fats, which in turn contributes to metabolic syndrome and subsequently raises serum urate levels and leads to adverse cardiovascular outcomes. On the other hand, several well-established diets for cardiometabolic health, such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets, in combination with weight loss for those who are overweight or obese, also have beneficial effects on relevant gout endpoints. It is important to recognize not only the direct effect of diet on hyperuricemia and gout, but its mediated effect through obesity and insulin resistance. Thus, several preeminent healthy dietary patterns that have proven benefits in cardiometabolic health have the power to holistically address not only gout morbidity but also its associated comorbidities that lead to premature mortality among patients with gout.

Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization.

OBJECTIVE: Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequelae); however, whether they are causally related has long been debated. We undertook this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses. METHODS: We used genome-wide association data (n = 288,649 for serum urate [SU] concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2-sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual-level, electronic medical record-linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single-sample MR analysis. RESULTS: Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg/dl per log-unit increase in fasting insulin [95% confidence interval (95% CI) 0.15, 0.58]; P = 0.001). This persisted in outlier-corrected (ß = 0.56 mg/dl [95% CI 0.45, 0.67]) and multivariable MR analyses adjusted for BMI (ß = 0.69 mg/dl [95% CI 0.53, 0.85]) (P < 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (P < 0.001). Findings for gout risk were bidirectionally consistent with those for SU level. CONCLUSION: These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.

Effects of Dietary Patterns on Serum Urate: Results From a Randomized Trial of the Effects of Diet on Hypertension.

OBJECTIVE: To determine whether the Dietary Approaches to Stop Hypertension (DASH) diet or an alternative, simplified diet, emphasizing high-fiber fruits and vegetables (the FV diet), lowers serum urate levels. METHODS: We conducted a secondary study of the DASH feeding study, a 3-arm, parallel-design, randomized trial of 459 adults with systolic blood pressure (BP) of <160 mm Hg and diastolic BP of 80-95 mm Hg, who were not receiving BP medications. Participants were randomized to receive 8 weeks of monitored feeding and ate 1 of 3 diets: 1) a typical American diet (control), 2) the FV diet, a diet rich in fruits and vegetables but otherwise similar to the control diet, or 3) the DASH diet, which was rich in fruits, vegetables, and low-fat dairy products, and reduced in fat, saturated fat, and cholesterol. Body weight was kept constant throughout the study. Serum urate levels were measured at baseline and after 8 weeks of feeding. RESULTS: For the 327 participants with available specimens (mean ± SD age 45.4 ± 11.0 years, 47% women, 50% African American), the mean ± SD baseline serum urate level was 5.7 ± 1.5 mg/dl. Compared to the control diet, the FV diet reduced the mean serum urate level by 0.17 mg/dl (95% confidence interval [95% CI] -0.34, 0.00; P = 0.051) and the DASH diet reduced the mean serum urate level by 0.25 mg/dl (95% CI -0.43, -0.08; P = 0.004). These effects increased with increasing baseline serum urate levels (<5, 5-5.9, 6-6.9, 7-7.9, and ≥8 mg/dl) for those receiving the DASH diet (a reduction of 0.08, 0.12, 0.42, 0.44, and 0.73 mg/dl, respectively; P for trend = 0.04), but not for those receiving the FV diet. CONCLUSION: Our findings indicate that the DASH diet reduces serum urate levels, particularly among those with hyperuricemia. These findings support the growing need for a dedicated trial to test the DASH diet among patients with hyperuricemia and gout.

The role of diet in hyperuricemia and gout.

PURPOSE OF REVIEW: Although gout's cardinal feature is inflammatory arthritis, it is closely associated with insulin resistance and considered a manifestation of the metabolic syndrome. As such, both gout and hyperuricemia are often associated with major cardiometabolic and renal comorbidities that drive the persistently elevated premature mortality rates among gout patients. To that end, conventional low-purine (i.e., low-protein) dietary advice given to many patients with gout warrant reconsideration. RECENT FINDINGS: Recent research suggests that several healthy diets, such as the Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diets, in combination with weight loss for those who are overweight or obese, can drastically improve cardiometabolic risk factors and outcomes. By treating gout as a part of the metabolic syndrome and shifting our dietary recommendations to these healthy dietary patterns, the beneficial effects on gout endpoints should naturally follow for the majority of typical gout cases, mediated through changes in insulin resistance. SUMMARY: Dietary recommendations for the management of hyperuricemia and gout should be approached holistically, taking into consideration its associated cardiometabolic comorbidities. Several healthy dietary patterns, many with similar themes, can be tailored to suit comorbidity profiles and personal preferences.