Non-interventional weight changes are associated with alterations in uric acid levels

doi:10.21203/rs.3.rs-3339380/v1

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Non-interventional weight changes are associated with alterations in uric acid levels

https://doi.org/10.21203/rs.3.rs-3339380/v1

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Background

uric acid is an emerging cardiovascular risk factor. Obesity is associated with higher serum UA.

Objective

we aimed to assess whether non-interventional weight changes affect serum UA.

Design

a retrospective analysis of subjects referred to annual medical screening. Body mass index (BMI) and uric acid were measured annually.

Participants

19,193 patients were divided to five groups according to the change in BMI between visits (large reduction, moderate reduction, unchanged, moderate increase, and large increase).

Main Measure

the primary outcome was the change in uric acid levels between visits.

Key Results

uric acid levels were progressively lower or higher as BMI decreased or increased, respectively. The proportion of patients with at least 10% rise in uric acid progressively increased with the relative increase in BMI, while the proportion of patients with at least 10% decrease in uric acid decreased with the relative increase in BMI.

Conclusions

even modest non interventional weight changes are associated with serum uric acid.

Overweight and obesity are associated with increased risk for cardiovascular (CV) related morbidity such as hypertension (HTN), type 2 diabetes mellitus (DM), ischemic heart disease (IHD), dyslipidemia and chronic kidney disease (CKD)^1–7. Increased serum uric acid (UA) is associated with higher BMI, augmented glucose intolerance, elevated blood pressure, dyslipidemia and atherosclerotic CV disease (CVD)^8–12. Overweight and obesity predispose to increased urate production and decrease in UA renal clearance, and thereby associated with hyperuricemia^13,14. It has been previously demonstrated that among patients with overweight and obesity, intentional weight loss correlates with reduction in serum UA¹⁵. However, data regarding non-interventional weight gain or loss and changes in UA levels are scarce. As serum UA in an emerging CV risk factor^16,17, unraveling a relationship between non-interventional weight changes and serum UA levels may shed further light on CV risk stratification with a specific focus on prevention and treatment of hyperuricemia. Here we aimed to assess the association between non-interventional weight changes and alterations in serum UA in a large cohort of ambulatory subjects.

Study population

The Chaim Sheba Medical Center Institute for Medical Screening performs approximately 10,000 annual examinations, A computerized database, to which all data are recorded, was established in 2000. As previously described¹⁸, all subjects enrolled are asymptomatic men and women examined annually at the Chaim Sheba Medical Center Institute for Medical Screening between the years 2000 and 2020. The annual examination includes filling a standard questionnaire regarding demographic characteristics, a complete medical history, lifestyle and health-related habits, and any unusual medical events which occurred since the previous visit. Height and weight for all participants, wearing light clothing without shoes, were measured and recorded at each encounter. Participants underwent a thorough physical examination. The body mass index (BMI) was calculated as weight in Kg divided by the squared height in meters. No weight loss intervention program was applied and all weight changes were subject-driven. Lab tests including serum UA levels were drawn by a trained nurse following at least 8 hours of fasting.

The study was approved by the Chaim Sheba medical center institutional ethical Helsinki board, and all the methods were performed in accordance with the relevant guidelines and regulations. Data were recorded anonymously. Due to the retrospective nature of the study, the need of informed consent was waived by the Chaim Sheba medical center institutional ethical Helsinki board.

Inclusion and exclusion criteria

The complete database included 21,111 individuals with 2 consecutive annual clinic visits. Individuals were excluded if height, weight or serum uric acid levels records were missing, or if they had extreme BMI values (less than 15 kg/m² or more than 50 kg/m²) or extreme serum UA levels (less than 1 mg/dl or more than 15 mg/dl). After patients' exclusion, the final study cohort comprised 19,193 participants.

Definitions and outcome

Participants were divided according to the percent change in BMI between the first and second visits: BMI reduction of more than 5% ("large reduction"), BMI reduction between 2.5% and 5% ("moderate reduction"), BMI reduction of < 2.5% or elevation of < 2.5% ("unchanged"), BMI elevation between 2.5% and 5% ("moderate increase"), and BMI elevation of more than 5% ("large increase").

The primary outcome was the change in serum UA levels between the first and second visit.

Statistical analysis

Trends in characteristics for categorical variables were assessed using chi-square test. Logistic regression, presented as a forest plot, was calculated to assess the relationship between baseline characteristics and increase of at least 10 percent in serum UA levels in the second visit. Subset analysis was performed for gender and baseline BMI. All analyses were performed using R software (R Development Core Team, version 4.1.0)¹⁹. A 2-sided p-value < .05 was used for statistical significance.

The final analysis included 19,193 patients. Baseline demographic and clinical characteristics according to the pre-specified groups of BMI change are presented in Table 1. Patients in the "large increase" group were younger and more likely to be females compared to other BMI change groups (Table 1). No statistically significant difference in other CV risk factors between the pre-specified groups was observed (Table 1).

Table 2 depicts BMI and serum UA levels for visit 1 and visit 2, across all pre-specified groups. Overall, mean baseline BMI was 26 Kg/m² and there was no significant change in mean BMI between visits for the entire study population. 20.8% of patients reduced their BMI by at least 2.5% and 23.3% increased their BMI by more than 2.5% (Table 2). 9.3% of the patients reduced their BMI by at least 5% and 9.2% of patients increased their BMI by at least 5% (Table 2). Overall, for the entire study population, mean baseline serum UA was 5.5 mg/dL, and it did not change significantly on the second visit (Table 2). Patients in the pre-specified "large reduction" group had an absolute mean UA decrease of 0.21 mg/dL on the second visit, with a mean percent decrease of 2.7% (Table 2, Fig. 1). Patients in the pre-specified “large increase” group had an absolute mean UA increase of 0.19 mg/dL, with a mean percent increase of 4.6% (Table 2, Fig. 1). Patients in pre-specified "moderate reduction" group had an absolute mean UA decrease of 0.04 mg/dL on the second visit, with a mean percent decrease of 0.24% (Table 2, Fig. 1). Patients in the pre-specified “moderate increase” group had an absolute mean increase of 0.12 mg/dL, with a mean percent increase of 3% (Table 2, Fig. 1).

The proportion of patients with at least 10% rise in serum UA progressively increased with the relative change in BMI (17.3%, 20.8%, 23.4%, 27.5%, and 33.1% for "large reduction”, “moderate reduction”, “unchanged”, “moderate increase”, and “large increase” groups, respectively (p < .01)). Similarly, the proportion of patients with at least 10% decrease in UA progressively decreased with the relative change in BMI (31.2%, 22%, 17.6%, 15.2% and 14.2% for "large reduction”, “moderate reduction”, “unchanged”, “moderate increase”, and “large increase”, respectively (p < .01)) (Fig. 2).

Compared to the “unchanged” group, the odds ratio for UA increase of at least 10% was 0.66, 0.84, 1.25 and 1.59 for "large reduction” (p < .001), “moderate reduction” (p = .014), “moderate increase” (p < .001), and “large increase” (p < .001) groups (Fig. 3). Male gender and HTN were significantly associated with increased OR for an at least 10% increase in UA levels (Fig. 3). Subgroup analyses by gender, baseline BMI and HTN showed similar results (data not shown).

In this study, we demonstrate a significant correlation between non-interventional weight changes and alterations in serum UA levels. UA was progressively lower or higher as BMI decreased or increased, respectively. The proportion of patients with at least 10% rise in UA progressively increased with the relative increase in BMI, while the proportion of patients with at least 10% decrease in UA decreased with the relative increase in BMI. Additionally, we found that male gender and HTN were associated with significant UA elevation.

Obesity and overweight are established CV risk factors and are associated with increase prevalence of dyslipidemia, DM, HTN, and atherosclerotic CV-related morbidity and mortality^20–23. Weight changes may have significant clinical consequences; Weight gain itself is associated with increased prevalence of cardio-metabolic risk factors such as high triglycerides, impaired fasting glucose and reduced HDL cholesterol²⁴, while achieving and maintaining a lower body weight reduces CV risk among overweight and obese patients²⁵, with some of the benefit preserved even after weight regain²⁶. Notably, we have previously shown that even modest non-intervention weight changes are associated with blood pressure alterations¹⁸, thus supporting the notion that weight and CV risk factors are closely related.

Hyperuricemia is associated with oxidative stress, endothelial dysfunction and increased oxidation of LDL, contributing to the development of atherosclerosis and its complications²⁷. Several studies have previously demonstrated an association between serum UA and prevalence of CKD, CV diseases and the metabolic syndrome^28–30. In addition, serum UA variability has also been found to be associated with the development of coronary heart disease and all-cause mortality³¹, and an association was also established between serum UA, even without frank hyperuricemia, and CV-related mortality as well as all-cause mortality³². Moreover, lowering serum UA into the normal range was found to be associated with reduction in all-cause mortality and CV-related death³³.

The association between obesity and serum UA has been previously explored. Obesity poses a high risk for hyperuricemia, partially attributed to overproduction of UA in adipose tissue, as well as decreased urinary urate excretion and clearance³⁴. To date, most studies have focused either on the association between baseline BMI and serum UA, or on interventional weight changes and UA, mostly among overweight and obese patients^13,35–38. Some suggest that the association between BMI and UA is mediated by hyperinsulinemia or insulin resistance³⁹; Evidently, lower body weight has been shown to be associated with lower prevalence of hyperuricemia³⁶, and recently a significant correlation was observed between decrease in fat mass and lower UA among normal-weight Korean individuals⁴⁰. Contrary to previous studies, our study included subjects with a wide spectrum of BMI, and all weight changes were non-interventional.

Notably, in regression analysis we found that apart from weight gain, male sex and hypertension were also associated with an at least 10% increase in SUA. The association of SUA elevation with weight gain and other traditional CV risk factors ⁴¹ highlights the a potential role for minor non-interventional weight changes in CV risk stratification.

Our study has several limitations; first, this is a retrospective study, therefore causality between BMI alterations and UA could not be established. In addition, data regarding the method for any weight changes obtained is not available. Nevertheless, our large cohort has the potential to mitigate the impact of these caveats.

In conclusion, we show that non-interventional weight alterations, even when modest, are associated with a significant change in UA levels.

Acknowledgements

Funding: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Prior presentation: this manuscript was presented as an abstract in the European congress of internal medicine (ECIM), 15-18 March, 2023

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by SW and EM. The first draft of the manuscript was written by SW and GS. Statistical analysis was performed by SW. all authors commented on previous versions of the manuscript, read and approved the final manuscript.

Conflicts of interest

The authors declare no competing interests.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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No competing interests reported.

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Non-interventional weight changes are associated with alterations in uric acid levels

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Abstract

Figures

Introduction

Methods

Study population

Inclusion and exclusion criteria

Definitions and outcome

Statistical analysis

Results

Discussion

Declarations

References

Tables

Additional Declarations

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