Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Understanding patient journey in ulcerative colitis prior to biologic initiation: a 5-year exploration.

BACKGROUND: There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn's disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent. METHODS: UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients' treatment, disease progression and overall health care utilization prior to initiating biologic agents. RESULTS: Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased. CONCLUSIONS: Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.

Opioid Use in Patients With Inflammatory Bowel Disease.

Background: Data on opioid use in patients with inflammatory bowel disease and the relationship between disease, opioid use, and healthcare resource utilization are needed. Methods: This analysis of real-world data from IBM Watson Health Commercial Claims and Encounters Database included patients with the first claim of inflammatory bowel disease (IBD) between 2007 and 2014. Results: Opioid use was higher in patients with IBD than in the matched non-IBD cohort. Adjusted for age, gender, and Charlson Comorbidity Index score, inpatient and emergency room visits risk was higher in opioid users than non-users in both IBD cohorts. Conclusions: Opioid use could be a potential surrogate for inadequate disease control manifested by increased inpatient and emergency room visit risks. These results suggest a need exists for better disease management and the development of an outcomes measurement tool for IBD pain.

Prevalence of Chronic Metoclopramide Use and Associated Diagnoses in the US Pediatric Population.

OBJECTIVE: Metoclopramide is the only medication widely used to promote gastrointestinal motility in the USA. Despite its appreciable risk of central nervous system complications, it continues to be prescribed to children for chronic use. We sought to estimate the prevalence of chronic metoclopramide use among US children and identify the diagnoses that may have prompted this use. The US metoclopramide label lists only two indications in adults: symptomatic gastroesophageal reflux (GERD) and diabetic gastroparesis. The latter is rare in children so, in examining the indications likely to have prompted chronic metoclopramide use, we focused on GERD. METHODS: From two health services databases representing privately and publically insured children, respectively, we estimated the number of US children who used metoclopramide chronically and identified the diagnoses recorded at approximately the time when the chronic use began. We defined chronic use liberally as ≥ 35 days' supply, or conservatively as ≥ 130 days' supply in a 6-month period. For each chronic-use definition, insurance type, and age group, we estimated the proportion of children using metoclopramide chronically. We applied these proportions to US population estimates. RESULTS: Under the liberal and conservative definitions, respectively, 89,020 and 28,222 US children used metoclopramide chronically. CONCLUSION: In spite of its risk, substantial numbers of US children use metoclopramide chronically for symptoms suggestive of GERD.

Exploring the physiologic role of human gastroesophageal reflux by analyzing time-series data from 24-h gastric and esophageal pH recordings.

Our previous finding of a fractal pattern for gastric pH and esophageal pH plus the statistical association of sequential pH values for up to 2 h led to our hypothesis that the fractal pattern encodes information regarding gastric acidity and that depending on the value of gastric acidity, the esophagus can signal the stomach to alter gastric acidity by influencing gastric secretion of acid or bicarbonate. Under our hypothesis values of gastric pH should provide information regarding values of esophageal pH and vice versa. We used vector autoregression, a theory-free set of inter-related linear regressions used to measure relationships that can change over time, to analyze data from 24-h recordings of gastric pH and esophageal pH. We found that in pH records from normal subjects, as well as from subjects with gastroesophageal reflux disease alone and after treatment with a proton pump inhibitor, gastric pH values provided important information regarding subsequent values of esophageal pH and values of esophageal pH provided important information regarding subsequent values of gastric pH. The ability of gastric pH and esophageal pH to provide information regarding subsequent values of each other was reduced in subjects with gastroesophageal reflux disease compared to normal subjects. Our findings are consistent with the hypothesis that depending on the value of gastric acidity, the esophagus can signal the stomach to alter gastric acidity, and that this ability is impaired in subjects with gastroesophageal reflux disease.

Safety and efficacy of delayed release rabeprazole in 1- to 11-month-old infants with symptomatic GERD.

AIM: : The efficacy and safety of rabeprazole, a proton pump inhibitor, were studied in infants with gastroesophageal reflux disease (GERD). METHODS: Infants ages 1 to 11 months, with symptomatic GERD resistant to conservative therapy and/or previous exposure to acid-suppressive medications, were screened. After scoring >16 on a GERD symptom score (Infant Gastroesophageal Reflux Questionnaire-Revised [I-GERQ]), 344 infants were enrolled in a 1- to 3-week open-label (OL) phase and received rabeprazole 10 mg/day. Following caregiver-rated clinical improvement during the OL phase, patients were randomized to placebo, rabeprazole 5 mg, or rabeprazole 10 mg in the ensuing 5-week double-blind (DB) withdrawal phase. Primary endpoints evaluated from DB baseline to the end of the DB withdrawal phase included frequency of regurgitation, weight-for-age z score, and daily and weekly GERD symptom scores. RESULTS: Overall, 231 (86%) of the 268 randomized infants (placebo: 90; rabeprazole 5 mg: 90; rabeprazole 10 mg: 88) completed the study. Efficacy endpoints were similarly improved during the OL phase in all of the groups, and continued improving during the DB withdrawal phase with no difference between the placebo and combined rabeprazole groups. Mean decrease in frequency of regurgitation (-0.79 vs -1.20 times per day; P = 0.168), in I-GERQ-Revised scores (-3.6 [-25%] vs -3.9 points [-27%]; P = 0.960), in I-GERQ-Daily Diary scores (-1.87 [-19%] vs -1.85 [-19%]; P = 0.968), and increase in weight-for-age z scores (mean [standard deviation]: 0.11 [0.329] vs 0.14 [0.295]; P = 0.440) indicated equal improvement. Equal percentages (47%) reported adverse events in placebo and combined rabeprazole groups, with no new safety signals emerging. CONCLUSIONS: In those infants with GERD who improved with rabeprazole during the OL phase, improvements in symptoms and weight were similar in those who continued rabeprazole and those withdrawn to placebo during a 5-week DB phase.

Maintenance of efficacy and safety of rabeprazole in children with endoscopically proven GERD.

OBJECTIVE: The aim of the present study was to evaluate 24-week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). METHODS: Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12-week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing ≥ 15 kg (high-weight cohort) received 10 or 20 mg. RESULTS: Healing was maintained in 90% of children (100% [low-weight cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups (P = 0.026) during the maintenance phase, except the 10-mg dose group (low-weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score (P < 0.001); 95% of investigators and 92% of parent/caregivers rated "Good to Excellent" on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment-emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%). CONCLUSIONS: Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups.

Efficacy and safety of rabeprazole in children (1-11 years) with gastroesophageal reflux disease.

OBJECTIVE: Evaluate the efficacy and safety of rabeprazole in children, 1 to 11 years old, with endoscopically/histologically proven gastroesophageal reflux disease (GERD). METHODS: Children were randomized to 0.5- or 1.0-mg/kg rabeprazole granule formulation for 12 weeks. The dose was further determined by weight: children 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children ≥15 kg (high-weight cohort) received 10 or 20 mg. The primary endpoint was endoscopic/histologic healing at week 12 (defined as grade 0 on the Hetzel-Dent classification scale and/or grade 0 on the Histological Features of Reflux Esophagitis scale). RESULTS: Overall, 81% (87/108) achieved endoscopic/histologic healing at week 12 with higher healing in the low-weight cohort (82% [5-mg dose], 94% [10-mg dose]) compared with high-weight cohort (76% [10-mg dose], 78% [20-mg dose]). There was a significant (P < 0.001) decrease in the mean Total GERD Symptoms and Severity score from 19.7 points (baseline) to 8.6 points (week 12), with 26% fewer children reporting GERD symptoms at week 12. The average frequency of symptoms per child decreased from 7.7 (week 1) to 4.7 (week 12). The GERD Symptom Relief score showed that 71% of children felt better, 81% were rated "good to excellent" on the Global Treatment Satisfaction scale by the investigator; 77% were rated "good to excellent" on the Clinical Global Impressions-Improvement scale by the parent/caregiver. The most common (>10%) treatment-emergent adverse events included cough and vomiting (14% each), abdominal pain (12%), and diarrhea (11%). CONCLUSIONS: Rabeprazole was effective and safe in 1- to 11-year-old children with GERD.

Normal and proton pump inhibitor-mediated gastrin levels in infants 1 to 11 months old.

BACKGROUND: Scant data exist on the normal range of serum gastrin in infants. In phase I and III trials of rabeprazole in gastroesophageal reflux disease, we studied serum gastrin levels in infants 1 to 11 months old, and assessed normal ranges and the effect of acid-suppressive drugs. METHODS: Overall, 349 treatment-naïve or treatment-experienced (previously exposed to proton pump inhibitors and/or H2-receptor antagonists) infants with gastroesophageal reflux disease were screened for baseline serum gastrin. Repeat gastrin was monitored at early termination or end of study, allowing assessment of 1 to 8 week daily rabeprazole (5- or 10-mg) treatment on gastrin levels. RESULTS: Median (5%-95% range) baseline gastrin was 118 ng/L (39-315) in the treatment-naïve group (n = 251), driven mostly by high levels (121.5 [48-326] ng/L) in the 1- to <4-month-old subgroup. Treatment-experienced infants (n = 98) had elevated baseline gastrin levels (152 [48-487] ng/L; P = 0.0011) with no clear difference between previously proton pump inhibitor-exposed and H2-receptor antagonist-exposed groups. At the end of study, mean (standard deviation) levels were unchanged from baseline in infants withdrawn from rabeprazole to placebo (124 [94] ng/L), but elevated from baseline in those continuing treatment with 5-mg (245 [151] ng/L) and 10-mg (332 [222] ng/L) rabeprazole during the study. CONCLUSIONS: Gastrin levels in treatment-naïve infants were elevated through 8 months of age. Between 8 and 12 months of age, they declined so that the median level was within the upper limit of the normal adult range (<100 ng/L). Previous exposure to acid-suppressive medications and short-term exposure to rabeprazole significantly increased gastrin levels in infants younger than 1 year.

Time esophageal pH < 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors.

BACKGROUND: A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure. AIM: We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4. METHODS: We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion. RESULTS: The prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux. CONCLUSION: In GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period.

Efficacy of rabeprazole in the treatment of symptomatic gastroesophageal reflux disease.

The purpose of this study was to assess the rapidity of symptom relief and 4-week efficacy of rabeprazole 20 mg in patients with moderately severe nonerosive gastroesophageal reflux disease. Data were analyzed from 2 similarly designed, double-blind, placebo-controlled, multicenter, U.S. trials. After a 2-week placebo run-in period, patients (N = 261) were randomized to 4 weeks of rabeprazole 20 mg once daily or placebo. Patients kept symptom diaries and scored symptom severity. Median time to first 24-hour heartburn-free interval was 3.5 days for the rabeprazole group compared with 19.5 days for the placebo group (P < or = .0002). Complete heartburn relief at week 4 was 32% with rabeprazole and 3.8% with placebo (P < or = .001). Rabeprazole also significantly improved other GERD-associated symptoms (e.g., regurgitation, belching, early satiety) by week 4 compared with placebo (P < or = .05). Rabeprazole provides fast and potent relief from heartburn and other symptoms of nonerosive gastroesophageal reflux disease.

Reductions in symptom distress reported by patients with moderately severe, nonerosive gastroesophageal reflux disease treated with rabeprazole.

Gastroesophageal reflux disease (GERD) is characterized by heartburn and related symptoms that are distressing to patients and interfere with everyday functioning and well-being. A measure of symptom distress, the GERD Symptom Assessment Scale (GSAS), was included in two randomized, placebo-controlled trials of rabeprazole among patients with nonerosive GERD. The age (mean +/- SD) of the 223 patients was 43.5 +/- 11.9 years, and most were female (67%) and Caucasian (78%). Significantly greater reductions in symptom distress were observed among patients receiving rabeprazole 20 mg daily for 4 weeks relative to those receiving placebo (-0.62 vs -0.36, P < 0.0001). The magnitude of this treatment difference was comparable to the differences observed between levels of overall symptom improvement on the patient global rating (0.2 and 0.3 points; P < 0.0001). In conclusion, reducing symptom distress is an important goal of therapeutic interventions for GERD. Rabeprazole significantly reduced the distress associated with a broad range of GERD symptoms, and the magnitude of this effect was meaningful to patients.

Rabeprazole-based therapy in the management of symptomatic gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is associated with several symptoms, such as heartburn, belching, and regurgitation, which arise from esophageal exposure to gastric acid. Symptoms may occur in the absence of endoscopically observed esophageal mucosal damage and inflammation. These patients represent the majority of those who present with GERD symptoms. Although acid suppression therapy is a logical approach to relieving GERD symptoms, it has been thought to relieve symptoms less reliably in patients with endoscopically negative, or symptomatic GERD than in those with erosive GERD. Two multicenter, randomized, double-blind, placebo-controlled clinical trials were conducted in the United States to evaluate the efficacy of rabeprazole sodium 10 mg and 20 mg compared with placebo for the relief of heartburn and other symptoms associated with symptomatic GERD. Results from these studies indicated that rabeprazole 10 or 20 mg once daily relieved heartburn within the first 1 or 2 days of treatment and also had significant positive effects on other GERD symptoms, including regurgitation, belching, bloating, satiety, and nausea. Overall, these results suggest that rabeprazole may hold a significant therapeutic advantage in the treatment of heartburn and other symptoms associated with endoscopically negative GERD, particularly in the majority of patients who often are treated empirically without, or before, endoscopic evaluation.

Impact of proton pump inhibitor utilization patterns on gastroesophageal reflux disease-related costs.

OBJECTIVE: To determine proton pump inhibitor (PPI) treatment patterns and their effect on costs related to gastroesophageal reflux disease. METHODS: This study used claims data to identify continuously enrolled subjects diagnosed with gastroesophageal reflux disease (GERD) and newly treated with a PPI between Oct. 1, 1999 and March 31, 2000. Data were analyzed for 6 months following PPI initiation. Results were stratified by first PPI filled during the study period. Compliance (as measured by a medication-possession ratio), dosage escalation (> 25 percent of initial dose), and daily average consumption (DACON) were measured. Regression analysis was performed on GERD-related costs using treatment patterns, type of PPI drug, and compliance as independent variables of interest. RESULTS: Of 75,452 subjects, there were 51,232 (67.9 percent) lansoprazole, 22,829 (30.3 percent) omeprazole, and 1,391 (1.8 percent) rabeprazole subjects. The possession ratio was not significantly different by drug. Only 3.5 percent of rabeprazole subjects escalated versus 5.5 percent of omeprazole subjects and 9.3 percent of lansoprazole subjects (p = .0001). Among subjects with esophageal ulcer or hiatal hernia, rabeprazole users had a significantly lower final DACON (1.03) versus both lansoprazole (1.20) and omeprazole subjects (1.22, p = .0299). Subjects who were compliant with therapy (ratio > 0.80) had 43 percent higher GERD-related pharmacy costs and 33 percent higher GERD-related total costs (both p < .001). GERD-related medical costs were not significantly affected by compliance. Subjects who filled lansoprazole prescriptions had 9.4 percent higher GERD-related pharmacy costs versus rabeprazole subjects (p < .01). Omeprazole subjects had 12.5 percent higher GERD-related total costs versus rabeprazole subjects (p < .01), while lansoprazole subjects had 18 percent higher GERD-related total costs versus rabeprazole subjects (p < .001). CONCLUSIONS: Rabeprazole subjects had lower GERD-related costs, less escalation, and lower DACON (measured as number of tablets consumed per day), compared to lansoprazole and omeprazole subjects. Compliance was not significantly different between the drugs, nor did increased compliance decrease GERD-related costs.

Rabeprazole in nonerosive gastroesophageal reflux disease: a randomized placebo-controlled trial.

OBJECTIVES: Clinical results to date suggest that antisecretory therapy may be less effective in providing symptom relief for patients with nonerosive gastroesophageal reflux disease (GERD) than for patients with erosive disease. This study was carried out to assess the efficacy and rapidity of once-daily rabeprazole (10 mg or 20 mg) in relieving symptoms in endoscopically negative patients with moderately severe GERD symptoms and to evaluate the safety of these doses over 4 wk. METHODS: This placebo-controlled, double blind study enrolled 203 men and women with moderately severe symptoms of GERD. After a 2-wk, single-blind placebo run-in phase, patients were randomized to receive 10 mg or 20 mg of rabeprazole or placebo once daily for 4 wk. RESULTS: Rabeprazole rapidly and effectively relieved heartburn, with significant improvements on day 1 of dosing. It also improved most other GERD-related symptoms, including regurgitation, belching, bloating, early satiety, and nausea. Both rabeprazole doses were significantly superior to the placebo with respect to time to the first 24-h heartburn-free interval (2.5 and 4.5 days for 10 mg and 20 mg of rabeprazole, respectively, vs 21.5 days for the placebo) and first daytime or nighttime heartburn-free interval (1.5-3 days for rabeprazole groups vs 12.5-15 days for the placebo), as well as to percentage of time patients were heartburn-free and free of antacid use. Both rabeprazole doses were well tolerated. CONCLUSIONS: Based on these findings and prior studies, rabeprazole reliably relieves GI symptoms equally well in both nonerosive GERD and erosive GERD.

Quality of life in a US national sample of adults with diabetes and motility-related upper gastrointestinal symptoms.

Our objective was to describe the health-related quality of life (HRQoL) of individuals with diabetes with and without motility-related upper gastrointestinal symptoms compared to individuals without diabetes. A total of 483 individuals with diabetes and 422 age- and gender-matched nondiabetic controls were recruited from a prior US national health survey for a telephone interview on upper gastrointestinal symptoms. Individuals with diabetes self-reported a physician's diagnosis of diabetes and provided confirming information on clinical management measures. Subjects were asked about upper gastrointestinal symptoms in the month before interview using an instrument with demonstrated high reliability. HRQoL was measured using the SF-12 Health Survey. Individuals with diabetes reporting upper gastrointestinal symptoms scored significantly lower in HRQoL measures of physical health and mental health than either individuals with diabetes who did not report upper gastrointestinal symptoms or individuals without diabetes (P < 0.0001). Individuals with diabetes and no upper gastrointestinal symptoms had physical and mental health summary scores similar to those of individuals without diabetes. Early satiety was the strongest predictor (P < 0.0001) of differences in physical health scores between individuals with and without diabetes. Nausea was the strongest predictor (P < 0.0001) of differences in mental health scores between individuals with and without diabetes. In conclusion, this is the first US national survey to demonstrate that motility-related upper gastrointestinal symptoms are associated with a significantly lower quality of life in individuals with diabetes.