Ann Intern Med
· 2026 Jun · PMID 42372279
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BACKGROUND: Safety studies of the COVID-19 vaccine have identified some adverse events. Yet newer variant-updated formulations, along with increased hybrid immunity, may change these risks. Early-era safety data may not...BACKGROUND: Safety studies of the COVID-19 vaccine have identified some adverse events. Yet newer variant-updated formulations, along with increased hybrid immunity, may change these risks. Early-era safety data may not reflect experience with updated formulations in more immune-experienced populations. OBJECTIVE: To evaluate 90-day risks for adverse events after coadministration of COVID-19 and influenza vaccines compared with influenza vaccination alone, across bivalent, XBB-adapted, and KP-adapted COVID-19 vaccine periods. DESIGN: Target trial emulation using electronic health care data. SETTING: U.S. Department of Veterans Affairs. PARTICIPANTS: Participants receiving both COVID-19 and seasonal influenza vaccines ( = 705 124) and those receiving only an influenza vaccine ( = 1 813 205) between 1 September 2022 and 26 August 2025. INTERVENTION: Receipt of both COVID-19 and seasonal influenza vaccines versus receipt of only an influenza vaccine. MEASUREMENTS: 90-day risks for 46 prespecified individual adverse events grouped into 3 composite outcomes (tier 1, serious or life-threatening; tier 2, clinically significant; tier 3, less severe or self-limiting), using weighted discrete-time survival models. RESULTS: For all 3 composite outcomes, risks were similar between groups: tier 1 (risk ratio [RR], 1.03 [95% CI, 0.99 to 1.09]), tier 2 (RR, 0.99 [CI, 0.96 to 1.03]), and tier 3 (RR, 0.99 [CI, 0.96 to 1.02]). Of the 46 individual adverse events, 2 tier-3 risks had nominal statistical significance: syncope (RR, 1.09 [CI, 1.02 to 1.17]) and tinnitus (RR, 0.95 [CI, 0.92 to 0.99]); no risks were statistically significant after correcting for multiple comparisons. For all risks in tier 1 or tier 2, confidence bounds included 1.0 (no effect). In period-stratified analyses, neither composite (tier) nor individual event estimates supported differences in risks between groups. LIMITATION: Generalizability and potential unmeasured confounding. CONCLUSION: Same-day coadministration of COVID-19 and influenza vaccines was not associated with an increased risk for adverse events in 3 updated-formulation periods. These findings support the short-term safety of coadministration. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.
Arterburn D, Curtis LH, Toh S
… +12 more, Bradley MC, D'Alessio D, Duchovny N, Hines D, Narain K, Parekh A, Skinner A, Wee CC, Wong JB, Wright DR, Osganian SK, Hales C
Ann Intern Med
· 2026 Jun · PMID 42372278
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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity and diabetes management, with rapidly expanding indications and use among U.S. adults. Despite their promise, key questions remain about optim...Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity and diabetes management, with rapidly expanding indications and use among U.S. adults. Despite their promise, key questions remain about optimal treatment pathways, long-term safety, effectiveness across diverse populations, adherence, and economic impact. Real-world evidence (RWE) derived from electronic health records, claims, and other data sources could address these gaps, but unique challenges complicate its use, such as inconsistent insurance coverage, high discontinuation rates, medication shortages, compounded formulations, and off-label prescribing. To explore these issues, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop in May 2025 with experts from regulatory agencies, guideline committees, payers, and academia. Discussions focused on identifying knowledge gaps in GLP-1RA use, evaluating how RWE informs practice, assessing limitations of real-world data, and strategies to reduce bias in RWE. Presentations emphasized RWE's potential to complement randomized trials by capturing rare adverse events, long-term outcomes, and effectiveness in routine care. However, persistent challenges include data reliability, confounding, and incomplete capture of medication use and outcomes, particularly in pediatric and underserved populations. Coverage decisions remain heterogeneous across Medicare, Medicaid, and private payers and across time, underscoring the need for rigorous cost-benefit analyses. The workshop concluded that robust RWE is essential for developing value-based coverage policies and optimizing GLP-1RA use. Continued investment in high-quality data infrastructure and analytic methods will be critical to inform regulatory, clinical, and economic decisions as utilization expands.
Curtis LH, Arterburn D, Toh S
… +13 more, Guo J, Hernán MA, Iturralde E, Jastreboff A, Lewis KH, Lund JL, Maciejewski ML, McCoy RG, McTigue KM, Narain K, Wee CC, Osganian SK, Hales C
Ann Intern Med
· 2026 Jun · PMID 42372277
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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the clinical approach to managing obesity and type 2 diabetes. As approved indications have expanded, use of GLP-1RAs has increased rapidly in the United...Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the clinical approach to managing obesity and type 2 diabetes. As approved indications have expanded, use of GLP-1RAs has increased rapidly in the United States. Although randomized trials demonstrate strong efficacy, many questions remain about their optimal use in clinical practice. Real-world data (RWD) from electronic health records, registries, insurance claims, and other sources offer a promising avenue to address these questions. However, concerns about data quality, selection bias, and incomplete ascertainment of medication use and outcomes pose significant challenges to the validity of the resulting evidence. In May 2025, the National Institute of Diabetes and Digestive and Kidney Diseases convened experts from regulatory agencies, payer organizations, and academia to explore these challenges. This second of 2 synopsis articles on the workshop summarizes the discussion around the strengths and limitations of various RWD sources and methodological approaches to strengthen causal inference and generalizability. Presenters highlighted pragmatic clinical trials and target trial emulation as strategies to generate stronger real-world evidence (RWE) that is relevant to both clinical practice and policy. The workshop underscored that careful attention to study design, data limitations, and analytic approach is essential to yield RWE that informs clinicians, patients, payers, and policymakers.
Liu M, Cheng Z, Lu L
… +12 more, Cai H, Liu J, Liu J, Zheng Y, Wang S, Zhao J, Yang W, Xie T, Li Y, He A, Rodbard HW, Chen W
Ann Intern Med
· 2026 Jun · PMID 42372276
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BACKGROUND: Bofanglutide is a novel glucagon-like peptide-1 receptor agonist under development for type 2 diabetes mellitus (T2DM) and overweight and obesity. OBJECTIVE: To evaluate the efficacy and safety of bofanglutid...BACKGROUND: Bofanglutide is a novel glucagon-like peptide-1 receptor agonist under development for type 2 diabetes mellitus (T2DM) and overweight and obesity. OBJECTIVE: To evaluate the efficacy and safety of bofanglutide compared with semaglutide. DESIGN: Phase 2b, randomized, open-label, active-controlled trial. (ClinicalTrials.gov: NCT06256549). SETTING: Multicenter (37 sites in China). PARTICIPANTS: Adults with T2DM who were drug-naive or receiving stable oral antidiabetic drugs (glycated hemoglobin A [HbA], 7.0% to 11.0%). INTERVENTION: Participants were randomly assigned 1:1:1:1:1 to 1 of 5 treatment groups: bofanglutide titrated to targets of 12, 18, or 24 mg (biweekly [once every 2 weeks; Q2W]); bofanglutide titrated to 24 mg (once weekly [QW]); or semaglutide titrated to 1 mg QW. MEASUREMENTS: Change in HbA level from baseline to week 24 (primary end point), secondary efficacy end points, and safety. RESULTS: Overall, 272 participants were enrolled, with a mean age of 50.8 years, HbA level of 8.35%, and body mass index of 27.9 kg/m. At week 24, HbA level change from baseline was -1.87% (95% CI, -2.11% to -1.63%), -2.28% (CI, -2.54% to -2.03%), and -1.94% (CI, -2.19% to -1.69%) for bofanglutide 12, 18, 24 mg Q2W, respectively; -2.32% (CI, -2.57% to -2.06%) for bofanglutide 24 mg QW; and -1.60% (CI, -1.85% to -1.35%) for 1 mg of semaglutide QW. Corresponding treatment differences versus semaglutide were -0.27% (CI, -0.61% to -0.08%), -0.68% (CI, -1.04% to -0.33%), -0.34% (CI, -0.70% to 0.02%), and -0.72% (CI, -1.08% to -0.36%), respectively. Gastrointestinal adverse events (GIAEs) (mostly grade 1 or 2 in severity) occurred in 81.8% to 87.3% and 51.9% of participants in the bofanglutide and semaglutide groups, respectively. Hypoglycemia occurred in 0% to 3.8% versus 1.9%, with no severe hypoglycemia. LIMITATION: Open-label, short duration, only Chinese participants. CONCLUSION: Meaningful reductions in HbA levels were seen with bofanglutide in patients with T2DM; GIAEs were the most common and generally manageable. PRIMARY FUNDING SOURCE: Gan & Lee Pharmaceuticals.
Yu X, Zeidan L, Khabsa J
… +27 more, Petkovic J, Agoritsas T, Bou Akl I, Al-Ansary LA, Amer YS, Ben Brahem A, Chang S, Concannon T, Florez ID, Jameleddine M, Lytvyn L, Marušić A, McCaul M, Moja L, Naude C, Palm M, Pardo Pardo J, Saginur M, Thomas R, Tovey D, Ziganshina LE, Tugwell P, Welch V, Estill J, Bian Z, Chen Y, Akl EA
Ann Intern Med
· 2026 Jun · PMID 42372274
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BACKGROUND: As part of the development of practice guidelines, developers need to systematically engage relevant interest-holder groups. The Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist for rep...BACKGROUND: As part of the development of practice guidelines, developers need to systematically engage relevant interest-holder groups. The Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist for reporting practice guidelines lacks detailed guidance on how to report the engagement process. OBJECTIVE: To develop a standardized checklist for reporting interest-holder engagement in practice guidelines, named the RIGHT-MuSE checklist. DESIGN: The development process followed the methods recommended by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network, as well as lessons learned from the development of the RIGHT statement and its extensions. Key steps included developing the protocol, registering the project, establishing a working group, conducting background work, generating an initial list of items, conducting a consensus survey, holding panel discussions, and creating the final RIGHT-MuSE checklist and an accompanying explanation and elaboration document. SETTING: International collaboration. PARTICIPANTS: 25 panelists from various guideline development interest-holder groups. MEASUREMENTS: Consensus agreement on checklist items. RESULTS: The final RIGHT-MuSE checklist consists of 11 items covering the guidance used, methods of engagement, characteristics of interest-holders, evaluation of engagement, and management of conflicts of interest. The checklist is supplemented with a glossary of key terms and detailed explanations for each item to facilitate its use. LIMITATION: The RIGHT-MuSE checklist has not been evaluated in a broader context or widely applied in real-world guideline development processes. CONCLUSION: Guideline developers can use the RIGHT-MuSE checklist to comprehensively report on interest-holder engagement. PRIMARY FUNDING SOURCE: The Vincent and Lily Woo Foundation.
Feng X, Guida F, Guenoun A
… +18 more, Alcala K, Aldrich MC, Arslan AA, Cai Q, Zheng W, Chen C, Triplette M, Tinker LF, Patel AV, Liao LM, Sinha R, Rohan TE, Sesso HD, Zhang X, Visvanathan K, Wang Y, Johansson M, Robbins HA
Ann Intern Med
· 2026 Jun · PMID 42372272
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BACKGROUND: Racial and ethnic disparities are a concern in lung cancer screening. OBJECTIVE: To investigate the performance of risk prediction models to define screening eligibility across 4 U.S. racial and ethnic groups...BACKGROUND: Racial and ethnic disparities are a concern in lung cancer screening. OBJECTIVE: To investigate the performance of risk prediction models to define screening eligibility across 4 U.S. racial and ethnic groups. DESIGN: Cohort study. SETTING: United States, Lung Cancer Cohort Consortium. PARTICIPANTS: 641 830 participants aged 50 to 80 years with a smoking history from 12 U.S. cohorts, including 6390 Asian, 9781 Hispanic, 39 872 non-Hispanic Black, and 585 787 non-Hispanic White participants. MEASUREMENTS: Calibration and discrimination were quantified for 16 lung cancer prediction models. Then, screening-related metrics were calculated after applying model thresholds to select the same number of eligible participants as the 2021 criteria from the U.S. Preventive Services Task Force (USPSTF-2021). These included eligibility, sensitivity, and efficiency measured as estimated number needed to screen (NNS; the ratio between participants and lung cancer cases) for each strategy or prediction model in each racial and ethnic group. RESULTS: General patterns across the 16 models included substantial underestimation of lung cancer risk in non-Hispanic Black participants (expected-observed ratio < 0.75 for 11 of 16 models), lower discrimination in Asian participants than all other groups (13 of 16 models), and lower discrimination in non-Hispanic Black than non-Hispanic White participants (15 of 16 models). When a same-sized screening-eligible population as USPSTF-2021 (38.0%) was enforced, all risk-based strategies achieved better average estimated screening efficiency and reduced racial and ethnic differences in efficiency compared with USPSTF-2021. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 (PLCOm2012) and Life Years gained From Screening-Computed Tomography model (LYFS-CT) performed best (mean estimated NNS, 36.5 [SD, 8.8] and 40.1 [SD, 8.2], respectively). However, no strategy could simultaneously optimize eligibility, sensitivity, and efficiency while also reducing racial and ethnic differences. LIMITATION: Smaller sample for Asian and Hispanic participants. CONCLUSION: To optimize efficiency and minimize its variation across racial and ethnic groups, risk-based strategies were superior to USPSTF criteria. Further optimization of prediction models for the diverse U.S. population is needed. PRIMARY FUNDING SOURCE: U.S. National Cancer Institute, Lung Cancer Research Foundation, and Cancer Research UK.
Palsdottir T, Micoli C, Eklund M
… +9 more, Grönberg H, Jäderling F, Tilki D, Lin DW, Cooperberg MR, Eggener SE, Oeffinger KC, Nordström T, Vigneswaran HT
Ann Intern Med
· 2026 Jun · PMID 42330502
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BACKGROUND: Prostate-specific antigen (PSA) testing to screen for prostate cancer is controversial. An alternative approach, Stockholm3, combines PSA, plasma protein biomarkers, polygenic risk, and clinical factors into...BACKGROUND: Prostate-specific antigen (PSA) testing to screen for prostate cancer is controversial. An alternative approach, Stockholm3, combines PSA, plasma protein biomarkers, polygenic risk, and clinical factors into a multivariable risk score. OBJECTIVE: To compare detection of clinically significant prostate cancer (csPC) using PSA and Stockholm3 in a population-based screening with short-term follow-up. DESIGN: Secondary analysis of the baseline round of the prospective STHLM3-MRI (Prostate Cancer Screening Using a Combination of Risk-Prediction, MRI, and Targeted Prostate Biopsies) randomized screening trial in men aged 50 to 74 years who had PSA and Stockholm3 screening. Men with abnormal screening tests (PSA ≥3 ng/mL or Stockholm3 ≥11) were randomly assigned (2:3) to systematic biopsy or magnetic resonance imaging with systematic and targeted biopsies for lesions with a Prostate Imaging Reporting and Data System score of 3 or greater. Cancer diagnosed within 2 years was identified through linkage to the Swedish National Cancer Register; cancer after a negative baseline test was classified as false negative. (ClinicalTrials.gov: NCT03377881). SETTING: Stockholm region, Sweden, 2018 to 2020. PARTICIPANTS: Men aged 50 to 74 years who had PSA and Stockholm3 screening. INTERVENTION: Prostate-specific antigen and Stockholm3 tests at baseline. MEASUREMENTS: Clinically significant prostate cancer (grade group ≥2) within 2 years of baseline. RESULTS: Among 12 670 men, 443 (3.5%) were diagnosed with csPC. Decision curve analysis showed higher net benefit for Stockholm3 versus PSA across a range of decision thresholds for biopsy, indicating fewer unnecessary biopsies and fewer missed csPC cases. Stockholm3 (≥11) had a false-negative rate of 10% (43 of 443) and a false-positive rate of 11% (1289 of 12 227), whereas PSA (≥3 ng/mL) had a false-negative rate of 26% (116 of 443) and a false-positive rate of 10% (1203 of 12 227). Correspondingly, sensitivity was 90% (95% CI, 87% to 93%) for Stockholm3 and 74% (CI, 69% to 78%) for PSA, with similar specificity (89% vs. 90%). LIMITATIONS: Participation was approximately 25% of invited men; follow-up was limited to 2 years; and the cohort was predominantly Swedish or European, which may limit generalizability. CONCLUSION: In this screening cohort with short-term follow-up, Stockholm3 provided greater clinical net benefit than PSA for detecting csPC, driven by fewer false-negative results, although follow-up was limited to 2 years. PRIMARY FUNDING SOURCE: Swedish Research Council, Swedish Prostate Cancer Society, Stockholm Region, and the Swedish Cancer Society.
Crowley MJ, Lewinski AA, Yang Q
… +18 more, Hatch D, Palipana A, Bosworth HB, Kaufman BG, Chatterjee R, Pennington G, Matters D, Lee D, Urlichich D, Miller HN, German J, Sang S, Smith B, Kokosa S, Gregory P, Roberson CL, Canupp H, Shaw RJ
Ann Intern Med
· 2026 Jun · PMID 42330500
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BACKGROUND: Comprehensive telehealth is used effectively for treatment-resistant chronic diseases in certain integrated health systems but has seldom been implemented in systems that provide mainly fee-for-service (FFS)...BACKGROUND: Comprehensive telehealth is used effectively for treatment-resistant chronic diseases in certain integrated health systems but has seldom been implemented in systems that provide mainly fee-for-service (FFS) care. OBJECTIVE: To examine the effectiveness and implementation of comprehensive telehealth delivered in an FFS environment for patients with uncontrolled type 2 diabetes (T2D) and comorbid hypertension. DESIGN: Pragmatic, randomized, effectiveness-implementation trial. (ClinicalTrials.gov: NCT05120544). SETTING: 6 academic primary care or endocrinology clinics. PARTICIPANTS: Participants had both T2D with hemoglobin A (HbA) persistently at 8.0% or higher for at least 6 months and hypertension with at least 1 systolic blood pressure (BP) above 140 mm Hg or diastolic BP above 90 mm Hg in the past year. INTERVENTION: Two 12-month, mobile monitoring-enabled interventions: a self-monitoring control program and a nurse-delivered, comprehensive telehealth program incorporating self-management support and medication management. MEASUREMENTS: Primary (HbA) and secondary outcomes were evaluated at 12 months. Implementation analyses evaluated fidelity and barriers to intervention delivery. RESULTS: Participants were 64% female and 68% Black. The mean age was 54.5 years, mean HbA 9.8%, and mean BP 135/81 mm Hg. The estimated mean change in HbA from 0 to 12 months was -0.7 percentage points with self-monitoring and -1.1 percentage points with comprehensive telehealth; the estimated mean between-group difference in HbA change at 12 months was -0.4 percentage points (95% CI, -1.0 to 0.3 percentage points). Between-group differences in change in secondary outcomes did not reach statistical significance, except for diabetes self-care (0.4 [CI, 0.0 to 0.9], favoring comprehensive telehealth). The comprehensive program was delivered with suboptimal fidelity (median encounters per participant, 9; fidelity threshold, ≥12); analyses identified barriers to program delivery. LIMITATION: Generalizability to dissimilar populations and systems lacking telehealth infrastructure may be limited. CONCLUSION: Comprehensive telehealth did not substantially lower HbA relative to control in this study. Population factors, intervention and control program design, and barriers to FFS implementation of comprehensive telehealth may have contributed to these findings. PRIMARY FUNDING SOURCE: National Institute of Nursing Research and Duke Clinical & Translational Science Institute.
Cheung LC, Mao F, Rydzak G
… +4 more, Wentzensen N, Poitras NE, Lorey TS, Castle PE
Ann Intern Med
· 2026 Jun · PMID 42330497
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BACKGROUND: Cervical intraepithelial neoplasia (CIN) grade 2 (CIN 2) is an equivocal diagnosis of cervical precancer, and appropriate management continues to be debated. OBJECTIVE: To estimate the effect of immediate (by...BACKGROUND: Cervical intraepithelial neoplasia (CIN) grade 2 (CIN 2) is an equivocal diagnosis of cervical precancer, and appropriate management continues to be debated. OBJECTIVE: To estimate the effect of immediate (by 6 months) versus delayed (after 6 months or no) treatment of CIN 2. DESIGN: Observational emulation of a target trial of immediate versus delayed treatment, using inverse probability weighting (IPW) to adjust for baseline factors. SETTING: Routine cervical screening at Kaiser Permanente Northern California. PATIENTS: 12 012 women with CIN 2 found on initial biopsy from 2017 to 2023. INTERVENTION: Immediate treatment (excision by 6 months after initial CIN 2 without interim surveillance by screening or colposcopy) versus delayed treatment (continued surveillance by screening or colposcopy, regardless of subsequent excision timing, or excision ≥6 months after initial CIN 2). MEASUREMENTS: 3-year probability of potentially unnecessary excision (less severe than CIN 2 [<CIN 2]), and 3-year risks for CIN grade 3 or more severe (CIN 3+) or invasive cervical cancer after initial CIN 2. RESULTS: Immediate treatment was associated with a higher 3-year probability of <CIN 2 on excision compared with delayed treatment (36.2% vs. 7.8%). The IPW-standardized 3-year risks for cancer (0.39% vs. 0.43%) and CIN 3+ (8.85% vs. 10.31%) were similar under the 2 management strategies. LIMITATION: Lack of randomized assignment to interventions; cancer was rare. CONCLUSION: Immediate treatment did not reduce 3-year cancer risk compared with delayed treatment after CIN 2. Delaying treatment avoided some potentially unnecessary excisions but women with CIN 2 with immediate or delayed care were still at risk for cancer and required monitoring. PRIMARY FUNDING SOURCE: Intramural Research Program of the National Institutes of Health National Cancer Institute.