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: Annals of Internal Medicine: Vol 176, No 8

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.

Disparities in Guideline-Recommended Statin Use for Prevention of Atherosclerotic Cardiovascular Disease by Race, Ethnicity, and Gender: A Nationally Representative Cross-Sectional Analysis of Adults in the United States: Annals of Internal Medicine: Vol 176, No 8

Background: Although statins are a class I recommendation for prevention of atherosclerotic cardiovascular disease and its complications, their use is suboptimal. Differential underuse may mediate disparities in cardiovascular health for systematically marginalized persons. Objective: To estimate disparities in statin use by race–ethnicity–gender and to determine whether these potential disparities are explained by medical appropriateness of therapy and structural factors. Design: Cross-sectional analysis. Setting: National Health and Nutrition Examination Survey from 2015 to 2020. Participants: Persons eligible for statin therapy based on 2013 and 2018 American College of Cardiology/American Heart Association blood cholesterol guidelines. Measurements: The independent variable was race–ethnicity–gender. The outcome of interest was use of a statin. Using the Institute of Medicine framework for examining unequal treatment, we calculated adjusted prevalence ratios (aPRs) to estimate disparities in statin use adjusted for age, disease severity, access to health care, and socioeconomic status relative to non-Hispanic White men. Results: For primary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors among non-Hispanic Black men (aPR, 0.73 [95% CI, 0.59 to 0.88]) and non-Mexican Hispanic women (aPR, 0.74 [CI, 0.53 to 0.95]). For secondary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors for non-Hispanic Black men (aPR, 0.81 [CI, 0.64 to 0.97]), other/multiracial men (aPR, 0.58 [CI, 0.20 to 0.97]), Mexican American women (aPR, 0.36 [CI, 0.10 to 0.61]), non-Mexican Hispanic women (aPR, 0.57 [CI, 0.33 to 0.82), non-Hispanic White women (aPR, 0.69 [CI, 0.56 to 0.83]), and non-Hispanic Black women (aPR, 0.75 [CI, 0.57 to 0.92]). Limitation: Cross-sectional data; lack of geographic, language, or statin-dose data. Conclusion: Statin use disparities for several race–ethnicity–gender groups are not explained by measurable differences in medical appropriateness of therapy, access to health care, and socioeconomic status. These residual disparities may be partially mediated by unobserved processes that contribute to health inequity, including bias, stereotyping, and mistrust. Primary Funding Source: National Institutes of Health.

Association Between Vascular 18F-Fluorodeoxyglucose Uptake at Diagnosis and Change in Aortic Dimensions in Giant Cell Arteritis: A Cohort Study: Annals of Internal Medicine: Vol 176, No 10

Background: Previous studies have shown that patients with giant cell arteritis (GCA) who have vascular 18F-fluorodeoxyglucose (FDG) uptake at diagnosis are at increased risk for thoracic aortic complications. Objective: To measure the association between vascular FDG uptake at diagnosis and the change in aortic dimensions. Design: Prospective cohort study. Setting: University Hospitals Leuven. Patients: 106 patients with GCA and FDG positron emission tomography (PET) imaging 3 days or less after initiation of glucocorticoids. Measurements: Patients had PET and computed tomography (CT) imaging at diagnosis and CT imaging yearly for a maximum of 10 years. The PET scans were scored 0 to 3 in 7 vascular areas and summed to a total vascular score (TVS). The PET scan results were positive when FDG uptake was grade 2 or greater in any large vessel. The association between vascular FDG uptake and aortic dimensions was estimated by linear mixed-effects models with random intercept and slope. Results: When compared with patients with a negative PET scan result, those with a positive scan result had a greater increase in the diameter of the ascending aorta (difference in 5-year progression, 1.58 mm [95% CI, 0.41 to 2.74 mm]), the diameter of the descending aorta (1.32 mm [CI, 0.38 to 2.26 mm]), and the volume of the thoracic aorta (20.5 cm³ [CI, 4.5 to 36.5 cm³]). These thoracic aortic dimensions were also positively associated with TVS. Patients with a positive PET scan result had a higher risk for thoracic aortic aneurysms (adjusted hazard ratio, 10.21 [CI, 1.25 to 83.3]). Limitation: The lengthy inclusion and follow-up period resulted in missing data and the use of different PET machines. Conclusion: Higher TVS was associated with greater yearly increase in thoracic aortic dimensions. Performing PET imaging at diagnosis may help to estimate the risk for aortic aneurysm formation. Primary Funding Source: None.

How Would You Manage This Patient With Recurrent Diverticulitis?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 176, No 6

Acute diverticulitis, which refers to inflammation or infection, or both, of a colonic diverticulum, is a common medical condition that may occur repeatedly in some persons. It most often manifests with left-sided abdominal pain, which may be associated with low-grade fever and other gastrointestinal symptoms. Complications may include abscess, fistula formation, perforation, and bowel obstruction. The American College of Physicians recently published practice guidelines on the diagnosis and management of acute diverticulitis, the role of colonoscopy after resolution, and interventions to prevent recurrence of this condition. Among the recommendations were the use of abdominal computed tomography (CT) scanning in cases where there was diagnostic uncertainty, initial management of uncomplicated cases in the outpatient setting without antibiotics, referral for colonoscopy after an initial episode if not performed recently, and discussion of elective surgery to prevent recurrent disease in patients with complicated diverticulitis or frequent episodes of uncomplicated disease. Here, 2 gastroenterologists with expertise in acute diverticulitis debate CT scanning for diagnosis, antibiotics for treatment, colonoscopy to screen for underlying malignancy, and elective surgery to prevent recurrent disease.

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, −6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, −10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (−2.1 weeks [95% CI, −11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

National Trends in Alcohol Use, Metabolic Syndrome, and Liver Disease From 1999 to 2018

Achievement of Guideline-Recommended Targets in Diabetes Care in China: A Nationwide Cross-Sectional Study: Annals of Internal Medicine: Vol 176, No 8

Background: Nationwide achievement of guideline-recommended diabetes care targets has not been comprehensively assessed in China. Objective: To estimate the proportions of adults with diabetes achieving major clinical risk factor control, body mass index (BMI), lifestyle, and dietary targets specified in the Chinese diabetes guidelines. Design: Nationwide cross-sectional survey. Setting: China, 2015 to 2017. Participants: A national sample of 8401 adults with self-reported diabetes and a subset of 3531 with dietary data. Measurements: The assessed targets included 1) ABC targets (individualized hemoglobin A1c [HbA1c] target; blood pressure [BP] <130/80 mm Hg; and low-density lipoprotein cholesterol [LDL-C] level <2.6 or <1.8 mmol/L [<100 or <70 mg/dL], depending on the presence of atherosclerotic cardiovascular disease), 2) BMI below 24 kg/m2, 3) lifestyle targets (not currently smoking or drinking, guideline-recommended leisure time activity level, and sleep duration of 7 to 8 hours), and 4) dietary targets (50% to 65% of energy from carbohydrate, 15% to 20% from protein, 20% to 30% from fat, ≥14 g of fiber per 1000 kcal, and <2000 mg of sodium per day). Results: The proportion of adults with self-reported diabetes achieving each ABC target was 64.1% (95% CI, 61.4% to 66.8%) for HbA1c, 22.2% (CI, 20.2% to 24.1%) for BP, and 23.9% (CI, 21.9% to 25.9%) for LDL-C. The proportion achieving a BMI below 24 kg/m2 was 32.2% (CI, 30.3% to 34.2%). The proportion achieving each lifestyle target was 75.8% (CI, 73.9% to 77.7%) for smoking, 66.7% (CI, 64.4% to 69.1%) for drinking, 17.9% (CI, 15.8% to 20.1%) for leisure time activity, and 52.0% (CI, 49.6% to 54.3%) for sleep duration. The proportion achieving each dietary target was 39.1% (CI, 36.0% to 42.2%) for carbohydrate, 20.1% (CI, 16.9% to 23.3%) for protein, 20.5% (CI, 17.6% to 23.4%) for fat, 9.0% (CI, 7.0% to 10.9%) for sodium, and 2.5% (CI, 1.3% to 3.6%) for fiber. Only 4.4% (CI, 3.5% to 5.2%) of participants achieved all 3 ABC targets, 5.1% (CI, 4.3% to 6.0%) achieved all 4 lifestyle targets, and 4 participants achieved all 5 dietary targets. Limitations: Self-reported data and age of the data. Conclusion: Achievement of guideline-recommended diabetes care targets in Chinese adults with self-reported diabetes was exceedingly low. The findings highlight the need for immediate national health actions to improve diabetes care. Primary Funding Source: Shanghai Municipal Education Commission, National Key R&D Program of the People's Republic of China, and the National Health Commission of the People's Republic of China.

Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection: A Prospective Cohort Study: Annals of Internal Medicine: Vol 176, No 7

Background: The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. Objective: To evaluate the performance of Ag-RDTs for detection of SARS-CoV-2 among symptomatic and asymptomatic participants. Design: This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. Setting: Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. Participants: Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. Measurements: The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. Results: Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. Limitation: Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. Conclusion: The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours. Primary Funding Source: National Institutes of Health RADx Tech program.

Predicting Inflammatory Arthritis in At-Risk Persons: Development of Scores for Risk Stratification

Background: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis. Objective: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers. Design: Prospective observational cohort study. Setting: Single-center, Leeds, United Kingdom. Participants: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred. Measurements: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done. Results: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years. Limitations: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability. Conclusion: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials. Primary Funding Source: National Institute for Health and Care Research Leeds Biomedical Research Centre.

Decompression Illness in Divers With or Without Patent Foramen Ovale: A Cohort Study: Annals of Internal Medicine: Vol 176, No 7

Background: In previous studies, the prevalence of patent foramen ovale (PFO) has been reported to be higher in scuba divers who experienced decompression illness (DCI) than in those who did not. Objective: To assess the association between PFO and DCI in scuba divers. Design: Prospective cohort study. Setting: Tertiary cardiac center in South Korea. Participants: One hundred experienced divers from 13 diving organizations who did more than 50 dives per year. Measurements: Participants had transesophageal echocardiography with a saline bubble test to determine the presence of a PFO and were subsequently divided into high- and low-risk groups. They were followed using a self-reported questionnaire while blinded to their PFO status. All of the reported symptoms were adjudicated in a blinded manner. The primary end point of this study was PFO-related DCI. Logistic regression analysis was done to determine the odds ratio of PFO-related DCI. Results: Patent foramen ovale was seen in 68 divers (37 at high risk and 31 at low risk). Patent foramen ovale–related DCI occurred in 12 divers in the PFO group (non-PFO vs. high-risk PFO vs. low-risk PFO: 0 vs. 8.4 vs. 2.0 incidences per 10 000 person-dives; P = 0.001) during a mean follow-up of 28.7 months. Multivariable analysis showed that high-risk PFO was independently associated with an increased risk for PFO-related DCI (odds ratio, 9.34 [95% CI, 1.95 to 44.88]). Limitation: The sample size was insufficient to assess the association between low-risk PFO and DCI. Conclusion: High-risk PFO was associated with an increased risk for DCI in scuba divers. This finding indicates that divers with high-risk PFO are more susceptible to DCI than what has been previously reported and should consider either refraining from diving or adhering to a conservative diving protocol. Primary Funding Source: Sejong Medical Research Institute.