Obesity is associated with higher prevalence of gastroesophageal reflux disease and reflux related complications: A global healthcare database study

Prior studies have demonstrated that obesity may be associated with the development of gastroesophageal reflux disease (GERD) and GERD‐related complications. However, such association has never been assessed in a global‐wide real‐world patient population.

has increased significantly in the past three decades in parallel with the increased population with obesity. 3[6][7][8][9] Obesity could result in many esophagogastric anatomy and physiology changes that increase the risk of developing GERD.
Studies showed that patients with obesity demonstrated a higher intra-gastric pressure, 10 slower esophageal transit time, 11,12 higher esophageal acid exposure, 13 and higher incidence of defective lower esophageal sphincter, 14 which all may attribute to the development of GERD and its complications.
Barrett's esophagus and esophageal adenocarcinoma are GERD complications.The current hypothesis suggests a stepwise process, starting with the onset of GERD, leading to the development of BE, and eventually resulting in esophageal adenocarcinoma. 15However, while there is strong evidence linking obesity to GERD, the evidence linking obesity to BE is limited. 16Moreover, the increase in the incidence of esophageal adenocarcinoma is much higher than the increase in the prevalence of obesity. 17,18This raises questions about the role of obesity in the development of esophageal cancer and highlights the need for further valid data to accurately assess the proposed association between obesity, gastroesophageal reflux disease, Barrett's esophagus, and esophageal cancer in a large-scale multicenter electronic health records network study.
In this study, we utilized a global healthcare database to address such knowledge gap.Our primary aim was to determine whether obesity is associated with increased odds of developing GERD or GERD-related complications, including erosive esophagitis, Barrett's esophagus, and esophageal cancer.Our secondary aim was to further explore if such association is more pronounced in specific sex and race subgroups.

| Study design and data collection/patient population
A multicenter electronic health records network study was performed using TriNetX electronic health records network, which involves 123 million de-identified electronic medical records from 100 healthcare organizations (HCOs) across 14 countries.The HCOs are a mixture of academic medical centers, specialty physician practices, and community hospitals.Demographics, diagnoses (using codes from ICD-10), laboratory, medications, and procedures data were available for analysis.As a federated network, research studies using the TriNetX research network were exempted from getting ethical approvals since no patient-identifiable information was received.

| Cohorts
A real-time search was conducted on January 29th, 2023 on TriNetX platform.Using the TriNetX user interface, cohorts can be created based on inclusion and exclusion criteria, matched for confounding variables with a built-in propensity score-matching algorithm, and compared for outcomes of interest over specified time periods (Figure 1).
The index event was defined as the first-time patient's body mass index (BMI) had been recorded.The study included adult patients aged 18-to 80-year-old at the time of the index event.The cohort with obesity was defined as patients with BMI of more than 30 kg/ m 2 , while the cohort without obesity with BMI of less than 30 kg/m 2 .
We excluded patients who had eosinophilic esophagitis, achalasia, esophageal cancer, stomach cancer, or any major abdominal surgeries that occurred before or up to 1 month after the index event.

| Covariates
To avoid the confounder effect, we identified a set of established or suspected risk factors that could predict the odds of GERD and GERD-related complications from article review, which included age, gender, 19 ethnicity and race, 20 diabetes mellitus, 21 nicotine dependence, 22 and alcohol use disorder. 19Above variants were considered as relevant covariates and used for propensity score matching between the cohorts with and without obesity.To avoid overadjustment bias, other comorbidities were not matched, however were satisfactorily similar after matching for above relevant covariates (Table 1).
F I G U R E 1 Flow diagram of data search and results.

Key points
• This is the first multicenter electronic health record network study that demonstrated a strong relationship between obesity and a higher prevalence of GERD, erosivec esophagitis, Barrett's esophagus and esophageal adenocarcinoma.

| Outcomes/secondary analyses
The primary outcomes of the study were incidence of GERD, erosive esophagitis, and GERD-related complications including Barrett's esophagus, Barrett's esophagus with dysplasia, esophageal cancer starting 1 day after the index event.Secondary outcomes included the incidence of upper endoscopy (EGD) and usage of proton pump inhibitors (PPI) like pantoprazole, omeprazole, esomeprazole, lansoprazole, or rabeprazole.We further investigated whether GERD and GERD-related complications were affected by gender and race/ethnicity.The incidence of outcomes was estimated separately into female versus male subgroups, Caucasian versus non-Caucasian subgroups, and Hispanic versus non-Hispanic subgroups.

| Statistical analysis
Mean and standard deviation were calculated for continuous variables, and proportion and percentage were calculated for dichotomous and categorical variables.We performed propensity score matching to control for baseline differences in demographics and comorbidities between the two cohorts using relevant covariates (See the Covariates section and Table 1).Logistic regression was used to generate propensity scores for each patient in both cohorts.
The propensity score matching algorithm is provided by the TriNetX network as a built-in feature, which is implemented using a greedy nearest neighbor matching approach.The quality of matching was subsequently evaluated.A standardized mean difference of less than 0.1 for variables was adopted as the criterion to consider the cohorts were well-matched (see Table 1).Finally, difference in clinical outcome between the two cohorts was assessed using odds ratio (OR) with 95% confidence interval (CI).An a priori defined 2-sided alpha of <0.05 was used for statistical significance.propensity-score matching (standardized mean difference <0.1) was achieved for all comparisons and baseline characteristics.

| Comparison of GERD and GERD-related complications
In the group with obesity, patients had a significantly higher prevalence of GERD (30% vs. 24%, OR 1.35, 95% CI 1.34-1.36)compared to the group without obesity (Figure 2).The same was true for erosive esophagitis (OR 1.07, 95% CI

| Gender differences
There were 61.7% and 60.8% of female patients included in groups with and without obesity, respectively.To further investigate whether the association between obesity and GERD/GERD-related complication were the same among the different genders, subgroup analysis was performed to assess for outcomes in the female and male groups separately (Figure 3).In females, the risk difference and OR of GERD between patients with and without obesity were higher compared to the male population (female vs. male: OR 1.46, 95% CI 1.44-1.47 vs. OR 1.19, 95% CI 1.18-1.20).Similarly, the OR of erosive esophagitis between the groups with and without obesity was higher in the female population (female vs. male: OR 1.16, 95% CI 1.14-1.18vs. OR 0.95, 95%CI 0.93-0.97).The odd ratios of Barrett's esophagus and BE with dysplasia between groups with and without obesity were similar for both sexes.Interestingly, there was no significant difference in the prevalence of esophageal cancer between groups with and without obesity in female patients (OR 1.18, 95% CI 0.92-1.52).In contrast, the difference was much more significant in the male group (OR 1.45, 95% CI 1.22-1.72).

| Ethnic differences
Studies suggested a stronger association between obesity and GERD in the white population than in individuals of other ethnicities.Thus, we further analyzed the difference of the prevalence of GERD and GERD-related complications between groups with and without obesity in the Caucasian and non-Caucasian populations (Figure 4).In the Caucasian population, the patients with obesity had a significantly higher prevalence of GERD (31% vs. 25%, OR Notably, the prevalence of GERD-related complications showed no statistical significance between the groups with and without obesity in non-Caucasian patients.

| DISCUSS ION
Our study is the first multicenter electronic health records network study to assess for association between obesity, GERD and GERDrelated complications.From the propensity-matched cohorts, including 2,356,548 patients, we concluded that obesity with BMI >30 was associated with a higher prevalence of GERD, GERD esophagitis, Barrett's esophagus, and esophageal cancer.Interestingly, we also identified the strength of the association varied among different gender and race, which provides further information in understanding the pathophysiology by which obesity leads to GERD and GERD-related complications.
The association between obesity and GERD has been described in other studies with smaller samples.A case-control study from Norway in 2003, which included 3113 GERD and 39,872 non-GERD patients, revealed a positive association between higher BMI and GERD.The study showed that any increase in BMI was associated with an increase in the risk of GERD, even among individuals whose BMI was within the normal range. 4A cohort study comprising 10,545 women in US, further elucidated that even moderate weight gain among persons of normal weight might cause or exacerbate GERD symptoms. 5A meta-analysis has concluded that patients with BMI >30 have an approximately twofold increased risk of GERD compared with patients with normal BMI. 6There was a similar association reported for obesity and erosive esophagitis, which is a complication in patients with chronic GERD.8][9] On the other hand, weight loss with diet modification has been shown to associate with decreased esophageal acid exposure, fewer GERD symptoms, and GERD esophagitis. 8,23terestingly, our study showed that the associations of BMI with GERD and erosive esophagitis were stronger in women with obesity than in men with obesity, which was in concordance with prior study. 4,24This difference has been attributed to increased estrogen levels in women, supported by a study that revealed hormone replacement therapy with estrogen as an independent risk factor for reflux symptoms. 25Furthermore, studies showed that the association of BMI and GERD/esophagitis was stronger in Caucasians than in other ethnicities, [26][27][28] which were validated in our cohort as well.
Barrett's esophagus refers to metaplasia in which the normal squamous cell epithelium of the distal esophagus is replaced by specialized columnar epithelium. 1 This condition is usually a consequence of long standing GERD and is a well-established risk factor for esophageal adenocarcinoma. 18Our study consisted of some other studies that showed a higher prevalence of BE in patients with higher BMI. 29,30However, there were studies indicating only weak and inconsistent links between BMI and Barrett's esophagus, but instead, strong and consistent associations of Barrett's esophagus with anthropometric measures of abdominal adiposity, [31][32][33][34] which left the conclusion controversial.Moreover, there was no established data showing the difference in the association between BMI and Barrett esophagus between the sexes or races.Our study was the first one to identify that the association between obesity and BE was significantly stronger in women than in men and in Caucasian than non-Caucasian populations.The underline pathophysiologic mechanism of how gender and race affect the development of BE in patients with obesity still requires further investigation.

F I G U R E 4
Comparison of associations between GERD/GERD-related complications and obesity between Caucasian and Non-Caucasian populations.
The incidence of esophageal cancer had been increased in the past decades, and this has been associated with the increased prevalence of GERD, BE, and obesity. 18There were robust data showing the positive association between higher BMI and higher prevalence of esophageal cancer. 35,36It worth mentioned that prior meta-analysis reviewed similar associations between obesity and esophageal cancer in both sexes (males: OR, 2.4; 95% CI, 1.9-3.2;females: OR, 2.1; 95% CI, 1.4-3.2), 35while in our study the association was only significant in men, but not women.One theory to explain the discrepancy was the difference in body fat distribution between men and women.A prospective study by Steffen showed that among several anthropometric measures (including BMI, waist circumference, and waist: hip ratio) the risk of esophageal adenocarcinoma correlated most strongly with waist circumference. 37The predominantly abdominal adiposity in males and predominantly hip and thigh adiposity in women may explain the stronger association of BMI and esophageal cancer in men. 38r study was the first multicenter electronic health records network study, including more than one million patients in each cohort from across the globe.The larger sample size provides us with better power to identify the significance and review the stronger association between BE and obesity in women and the Caucasian population.Despite the strength, there are limitations to our study.
As an electronic health records network study with limited longitudinal follow-up data, it is difficult to establish a causal link between obesity and GERD or other GERD-related complications.Second, the initial and final average BMIs were not adequately propensitymatched, thus, the effects of weight loss or weight gain on the prevalence of GERD or GERD-related complications were unable to assess.Furthermore, Barrett's esophagus is an asymptomatic and chronic condition that requires EGD for detection.The prevalence of BE is highly affected by compliance with endoscopic surveillance, which is difficult to assess and ensure in an electronic health records network study.

| CON CLUS ION
In conclusion, our study found a strong link between obesity and a higher prevalence of GERD, erosive esophagitis, BE, and esophageal cancer.The correlation was particularly strong in women and Caucasian individuals.However, the relationship between obesity and esophageal cancer was even stronger in men, warranting further investigation into the male-specific mechanisms behind the development of esophageal adenocarcinoma.

1. 37 ,F I G U R E 3 | 5 of 7 XIE
95% CI 1.34-1.38)compared to the group without obesity.F I G U R E 2 Prevalence and ORs for GERD and GERD-related Complications in Cohorts with versus without Obesity.Comparison of associations between GERD/GERD-related complications and obesity between men and women.et al.A similar difference was revealed in the non-Caucasian population with lower risk difference and OR (27% vs. 23%, OR 1.27, 95% CI 1.25-1.28).The odd ratio of erosive esophagitis between patients with and without was also higher in Caucasian group (Caucasian vs. non-Caucasian: OR 1.07, 95%CI 1.04-1.10 vs. OR 1.00, 95%CI 0.94-1.04).The Caucasian group with obesity also showed a higher prevalence of all GERD-related complications compared to the Caucasian group without obesity: Barrett's esophagus (1.07, 1.04-1.10),BE with dysplasia (1.08, 1.01-1.16),esophageal cancer (1.38, 1.18-1.61).
Baseline characteristics of cohorts with and without obesity before and after propensity matching.
A total of 1,255,738 patients in the group with obesity and 2,098,861 patients in the group without obesity from 59 HCOs matched the query inclusion and exclusion criteria.After propensity score matching, 1,178,274 patients were included in each of the obesity and non-obesity groups, respectively.Table1summarizes the main demographic features and comorbidities of the cohorts with and without obesity.AdequateTA B L E 1Note: Variants with a standardized mean difference between cohort less than 0.1 are considered well matched.Abbreviation: Std diff, standardized mean difference.