Herrin, Jeph

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium–glucose cotransporter‐2 inhibitors (SGLT2is) have favorable cardiovascular outcomes compared with dipeptidyl peptidase‐4 inhibitors (DPP4is) and sulfonylureas in adults with type 2 diabetes and high cardiovascular risk. How these benefits vary across lower levels of cardiovascular risk is unknown. Methods We used nationwide claims data to emulate a comparative effectiveness trial and examine the heterogeneity of treatment effects of GLP‐1RAs, SGLT2is, DPP4is, and sulfonylureas on major adverse cardiovascular events (MACEs) among adults with type 2 diabetes and moderate cardiovascular risk (annualized MACE risk 1%–5%, estimated using the annualized claims‐based MACE estimator). Results Among 386 276 included adults with type 2 diabetes, 25.2% had baseline ACME–predicted MACE risk >1% to ≤2% (lower‐risk patients) and 13.3% had ACME–predicted risk >4% to ≤5% (higher‐risk patients). By year 3 of treatment, higher‐risk patients derived greater absolute benefit than lower‐risk patients when treated with GLP‐1RAs versus sulfonylureas (absolute reduction in the estimated rate of MACE of 3.1% in higher‐risk patients and 1.6% in lower‐risk patients), SGLT2is versus sulfonylureas (absolute reduction, 3.9% in higher‐risk patients and 1.3% in lower‐risk patients), and GLP‐1RAs versus DPP4is (absolute reduction, 1.6% in higher‐risk patients and 0.5% in lower‐risk patients). The relative benefits for MACE were also greater in higher‐risk than lower‐risk patients with SGLT2is versus DPP4is (hazard ratio [HR], 0.78 [95% CI, 0.70–0.87] in higher‐risk patients; HR, 0.99 [95% CI, 0.88–1.12] in lower‐risk patients). Conversely, the relative benefits of DPP4is and GLP‐1RAs versus sulfonylureas were greater in lower‐risk patients: HR 0.76 (95% CI, 0.71–0.81) in lower‐risk and HR 0.91 (95% CI, 0.97–0.96) in higher‐risk patients for DPP4is versus sulfonylureas; HR 0.67 (95% CI, 0.58–0.78) in lower‐risk and HR 0.80 (95% CI, 0.70–0.93) in higher‐risk patients for GLP‐1RAs versus sulfonylurea. Benefits of SGLT2is and GLP‐1RAs were comparable across all risk levels. Conclusions Cardiovascular benefits of SGLT2is and GLP‐1RAs exist across all levels of moderate cardiovascular risk, reinforcing the importance of choosing glucose‐lowering therapies that can prevent MACE in all people with type 2 diabetes.

ImportanceUptake of human papillomavirus (HPV) vaccination varies by characteristics, exposing some children to higher HPV cancer risks than others.ObjectiveTo examine whether the effectiveness of a multilevel intervention on HPV vaccination differed by race and ethnicity, rurality, and Area Deprivation Index (ADI) in children ages 11 to 12 years.Design, Setting, and ParticipantsA stepped-wedge cluster randomized trial was conducted from April 2018 to August 2022 among children at 6 Mayo Clinic primary care practices in Minnesota to improve HPV vaccination. This secondary analysis was performed from March to June 2024.InterventionA multilevel intervention that included parent reminder/recall letters, which alerted parents of children due or past due for vaccination, and health care professional audit/feedback reports, which alerted health care professionals of their own vaccination rates.Main Outcome and MeasureVaccine initiation (first dose of the 2-dose HPV vaccine) and vaccine completion (second dose) were the primary study outcomes. In this secondary analysis, the effect of the intervention on HPV vaccine initiation and completion by race and ethnicity, rurality, and ADI quartiles (Qs) was assessed.ResultsA total of 6232 children aged 11 to 12 years (3285 [52.7%] male; 3481 [55.9%] aged 11 years and 2751 [44.1%] aged 12 years) were included in the analysis. Of the study participants, 304 (4.9%) were Asian, 561 (9.0%) Black, 146 (2.3%) Hispanic, 4501 (72.2%) White, and 720 (11.6%) other, including American Indian or Alaskan Native, Native Hawaiian or Pacific Islander, Other Pacific Islander, Samoan, unable to provide, unknown, chose not to disclose, or other unspecified. A total of 5434 participants (87.2%) were urban residents, and 2794 (44.8%) resided in ADI Q2 areas. With usual care, HPV vaccine initiation and completion rates were significantly lower with each increasing ADI quartile (initiation: Cochran-Armitage test for trend [SE], −0.02 [0.01]; P < .001; completion: Cochran-Armitage test for trend [SE], −0.05 [0.01]; P < .001) but did not differ by children’s race and ethnicity or rurality. With the intervention, vaccine initiation increased significantly for most children (range of rates, 9.2% [95% CI, 5.2%-13.3%] to 24.0% [95% CI, 7.5%-40.6%]) except those with Black race, in rural settings, and in ADI Q4 (highest area deprivation); vaccine completion increased significantly for most children (range of rates, 19.4% [95% CI, 5.5%-33.3%] to 31.2% [95% CI, 12.1%-50.3%]) except for those in ADI Q4.Conclusions and RelevanceIn this secondary analysis of a cluster randomized trial, a multilevel intervention was associated with increased HPV vaccination for most children but had limited effect for those residing in areas of highest deprivation. Future research should explore other intervention strategies that would effectively promote HPV vaccination among families in socioeconomically disadvantaged areas to reduce HPV vaccination disparities.Trial RegistrationClinicalTrials.gov Identifier: NCT03501992

AbstractThe Enhanced EHR-facilitated Cancer Symptom Control (E2C2) Trial is a pragmatic trial testing a collaborative care approach for managing common cancer symptoms. There were challenges in identifying cancer site and metastatic status.This study compares three different approaches to determine cancer site and six strategies for identifying the presence of metastasis using EHR and cancer registry data.The E2C2 cohort included 50,559 patients seen in the medical oncology clinics of a large health system. SPPADE symptoms were assessed with 0 to 10 numeric rating scales (NRS). A multistep process was used to develop three approaches for representing cancer site: the single most prevalent International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) code, the two most prevalent codes, and any diagnostic code. Six approaches for identifying metastatic disease were compared: ICD-10 codes, natural language processing (NLP), cancer registry, medications typically prescribed for incurable disease, treatment plan, and evaluation for phase 1 trials.The approach counting the two most prevalent ICD-10 cancer site diagnoses per patient detected a median of 92% of the cases identified by counting all cancer site diagnoses, whereas the approach counting only the single most prevalent cancer site diagnosis identified a median of 65%. However, agreement among the three approaches was very good (kappa > 0.80) for most cancer sites. ICD and NLP methods could be applied to the entire cohort and had the highest agreement (kappa = 0.53) for identifying metastasis. Cancer registry data was available for less than half of the patients.Identification of cancer site and metastatic disease using EHR data was feasible in this large and diverse cohort of patients with common cancer symptoms. The methods were pragmatic and may be acceptable for covariates, but likely require refinement for key dependent and independent variables.

Importance The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RA) demands a better understanding of their association with thyroid cancer. Objective To estimate the risk of incident thyroid cancer among adults with type 2 diabetes being treated with GLP-1RA vs other common glucose-lowering medications. Design, Setting, and Participants This was a prespecified secondary analysis of a target trial emulation of a comparative effectiveness study using claims data for enrollees in commercial, Medicare Advantage, and Medicare fee-for-service plans across the US. Eligible participants were adults with type 2 diabetes at moderate risk for cardiovascular disease and without history of thyroid cancer who had newly filled prescriptions for GLP-1RA, sodium-glucose cotransporter 2 inhibitor (SGLT2i), dipeptidyl peptidase-4 inhibitor (DPP4i), or sulfonylurea from January 1, 2014, to December 31, 2021. Data were analyzed February 1 to October 31, 2024. Main Outcomes and Measures Overall and piecewise (<1, 1-2, and ≥2 years since treatment initiation) hazard ratios (HRs) for thyroid cancer with use of GLP-1RA vs the other 3 drug classes were estimated using inverse propensity score weighted Cox proportional hazards models. Modified intention-to-treat (mITT) (primary) and as-treated (sensitivity) analyses were performed. Results Of 351 913 patients (mean [SD] age, 65.3 [8.5] years; 173 391 [49.3%] females and 178 522 [50.7%] males), 41 112 started treatment with GLP-1RA; 76 093, with DPP4i; 43 499, with SGLT2i; and 191 209, with sulfonylurea therapy. The numbers of patients diagnosed with thyroid cancer were 69 (0.17%) in the GLP-1RA group, 172 (0.23%) in the DPP4i group, 72 (0.17%) in the SGLT2i group, and 381 (0.20%) in the sulfonylurea group. In the mITT analysis, GLP-1RA initiation was not significantly associated with increased overall risk for thyroid cancer compared to the other 3 diabetes drugs (HR, 1.24; 95% CI, 0.88-1.76). However, the risk for thyroid cancer was significantly higher within the first year after GLP-1RA initiation (HR, 1.85; 95% CI, 1.11-3.08) and was amplified in the overall as-treated analysis that censored patients when therapy was discontinued or another medication was added (HR, 2.07; 95% CI, 1.10-3.95). Conclusions and Relevance This secondary analysis of a target trial emulation of a comparative effectiveness study found that despite the low absolute risk of thyroid cancer among patients receiving GLP-1RA therapy, there was an increased risk of new thyroid cancer diagnoses within the first year of GLP-1RA initiation compared to 3 other diabetes drugs. This finding may have been due to enhanced early detection; therefore, further research is necessary to understand the underlying causes of this association.

Abstract Context A national assessment of osteoporosis drug therapy (ODT) use can inform the extent of underdiagnosis and undertreatment of osteoporosis. Objective The aim was to describe trends in ODT use by age, sex, fragility fracture, and documented osteoporosis. Methods This was a retrospective analysis of patient-quarter observations for adults aged ≥50 years with commercial or Medicare Advantage health insurance in the OptumLabs Data Warehouse between 2011 and 2022. The primary outcome was the proportion of patient-quarter observations with ODT use stratified by age, sex, fragility fracture, and documented osteoporosis. Cuzick tests were performed to assess trends ODT use. Results Analysis of 166 673 420 patient-quarter observations revealed that over 70% of patients with fragility fractures did not have documented osteoporosis. Among women aged ≥65 years with documented osteoporosis, ODT fill rates increased between 2011 and 2022 from 36.3% to 50.1% for women without fragility fractures (P < .001) and from 30.8% to 43.7% for women with fragility fractures (P < .001). However, ODT fill rates declined (9.2% to 7.4% between 2011 and 2022) for women with fragility fractures and no documented osteoporosis (P = .015). Similar trends were observed among women aged 50-64 years and men. Conclusion ODT use for patients with documented osteoporosis has increased but remains low. Low rates of ODT use for patients with fragility fractures in the absence of documented osteoporosis suggests that underdiagnosis of osteoporosis contributes to underuse of ODTs.

Key Points Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists were superior to dipeptidyl peptidase-4 inhibitor and sulfonylurea for preventing kidney complications in patients with type 2 diabetes at moderate cardiovascular disease risk. Sodium-glucose cotransporter 2 inhibitor therapy compared favorably with glucagon-like peptide-1 receptor agonists for kidney disease outcomes. Background CKD is a serious diabetes-related complication. While guidelines recommend use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies to mitigate cardiorenal risk in high-risk patients, the benefit of early initiation of these agents relative to other commonly prescribed glucose-lowering agents in patients at lower baseline cardiovascular disease (CVD) risk remains less clear. Methods This retrospective observational study emulated an idealized target trial using claims data from OptumLabs data warehouse to test the comparative association of treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4i), SGLT2i, GLP-1RA, or sulfonylurea (SU) on a primary kidney composite outcome of incident CKD stages 3–5, kidney failure, or need for KRT in patients with type 2 diabetes and moderate CVD risk. A secondary composite outcome included all components of the primary composite outcome plus death. Results A total of 364,714 adults aged 21 years or older initiating treatment with a DPP-4i ( N =78,843), GLP-1RA ( N =42,049), SGLT2i ( N =45,466), or SU ( N =198,356) were identified. Relative to DPP-4i, SGLT2i (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.67 to 0.74; P < 0.001) and GLP-1RA (HR, 0.87; 95% CI, 0.83 to 0.92; P < 0.001) treatment was superior for the primary composite outcome. Similarly, SGLT2i (HR, 0.69; 95% CI, 0.66 to 0.73) and GLP-1RA (HR, 0.86; 95% CI, 0.82 to 0.91) treatment was associated with risk reductions for the primary outcome relative to SU treatment. When comparing SGLT2i with GLP-1RA therapy, SGLT2is were superior for the primary composite outcome (HR, 0.81; 95% CI, 0.75 to 0.86; P < 0.001). Similar findings were observed for the secondary composite outcome across all comparisons. Conclusions SGLT2is and GLP-1RAs were superior to DPP-4is and SUs for preventing kidney complications in a type 2 diabetes population with moderate baseline CVD risk. Clinical Trial registry name and registration number: NCT05214573.

In this emulated comparative effectiveness target trial of glucagon-like peptide 1 (GLP-1) receptor agonist, sodium–glucose cotransporter 2 (SGLT2) inhibitor, dipeptidyl peptidase 4 (DPP-4) inhibitor, and sulfonylurea therapy among adults with type 2 diabetes at moderate cardiovascular disease risk, sulfonylurea use was associated with a significantly higher risk of hypoglycemia requiring emergency department or hospital care than treatment with DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors. This consideration can guide the choice of glucose-lowering therapy in this highly prevalent patient population, in whom avoidance of hypoglycemia is important, yet among whom the risk of severe hypoglycemia has not been examined previously.

AbstractObjectivesTo report lessons from integrating the methods and perspectives of clinical informatics (CI) and implementation science (IS) in the context of Improving the Management of symPtoms during and following Cancer Treatment (IMPACT) Consortium pragmatic trials.Materials and MethodsIMPACT informaticists, trialists, and implementation scientists met to identify challenges and solutions by examining robust case examples from 3 Research Centers that are deploying systematic symptom assessment and management interventions via electronic health records (EHRs). Investigators discussed data collection and CI challenges, implementation strategies, and lessons learned.ResultsCI implementation strategies and EHRs systems were utilized to collect and act upon symptoms and impairments in functioning via electronic patient-reported outcomes (ePRO) captured in ambulatory oncology settings. Limited EHR functionality and data collection capabilities constrained the ability to address IS questions. Collecting ePRO data required significant planning and organizational champions adept at navigating ambiguity.DiscussionBringing together CI and IS perspectives offers critical opportunities for monitoring and managing cancer symptoms via ePROs. Discussions between CI and IS researchers identified and addressed gaps between applied informatics implementation and theory-based IS trial and evaluation methods. The use of common terminology may foster shared mental models between CI and IS communities to enhance EHR design to more effectively facilitate ePRO implementation and clinical responses.ConclusionImplementation of ePROs in ambulatory oncology clinics benefits from common understanding of the concepts, lexicon, and incentives between CI implementers and IS researchers to facilitate and measure the results of implementation efforts.

LBA12006 Background: Symptom burden and functional decline are prevalent, inconsistently treated, and associated with adverse health outcomes in patients with cancer. Symptom monitoring with electronic patient-reported outcome measures (ePROMs) has yielded mixed results due, in part, to care teams’ variable bandwidth and resourcing for symptom management. The collaborative care model (CCM) offers a validated means to address these issues and potentially improve clinical and health services outcomes. Capturing ePROMS through the electronic health record (EHR) for use in CCM delivery provides a potentially scalable approach to manage symptoms at the population level. Methods: E2C2 is a cluster-randomized, population-level, stepped wedge pragmatic trial that compares a bundled, EHR-facilitated, CCM-based intervention to improve control of SPPADE symptoms (Sleep interference, Pain, impaired Physical function, Anxiety, Depression, and Energy deficit/fatigue) with usual care. All patients, regardless of cancer type or stage, treated in the medical oncology clinics of a multi-state health system, were assigned to one of fifteen clusters. Control and intervention conditions monitored SPPADE symptoms with Epic EHR administered 11-point numerical rating scales (NRSs). Moderate and severe symptoms were defined as 4-6/10 and >7/10, respectively. The intervention added EHR clinician decision support; automated delivery of symptom self-management information; and options to address severe symptoms with a dedicated symptom care manager. The primary outcome was post-baseline SPPADE scores assessed using multivariate regression of six cluster-period mean SPPADE symptom scores against E2C2 exposure, fixed cluster and secular time effects. Results: From March 2019 to January 2023, 50,559 patients were assigned to E2C2 clusters and 40,295 completed at least one ePROM. At first assessment, participants’ mean age was 63.3 years; 58% were female; 26% were rural, and the prevalences of moderate or worse symptoms were fatigue 42%, impaired function 34%, sleep disturbance 34%, anxiety 27%, pain 26%, and depression 23%. The intervention significantly reduced mean composite SPPADE symptom scores, p <0.001, among all patients, as well as those with >1 moderate or worse symptom. All mean symptom scores were lower in the intervention group, with the largest effects detected among patients with fatigue -0.2 (-0.4, -0.07), anxiety -0.14 (-0.2, -0.03), and depression -0.1 (-0.2, -0.002). Conclusions: In this large cluster-randomized trial, an EHR-facilitated, bundled intervention that scaled CCM-based surveillance and management of SPPADE symptoms significantly reduced population-level symptom burden, particularly for fatigue, anxiety, and depression. This study provides real world evidence and the foundation for future national efforts aimed at controlling symptoms in patients with cancer. Clinical trial information: NCT03892967 .

11108 Background: Advances in cancer treatment have led to a growing population of patients living with metastatic cancer. Symptom burden for these patients is understudied. Our objective is to report the prevalence and severity of SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy /fatigue) in a large cohort of patients with metastatic cancer. Methods: These data are drawn from the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) stepped wedge pragmatic trial evaluating a symptom management intervention for cancer patients (NCT03892967). This analysis was limited to those identified with metastatic disease using ICD- codes and a natural language processing algorithm prior to or within 30 days of their baseline symptom survey. Symptom severity was measured on a 0-10 scale with scores of 1-3 categorized as “mild”, 4-6 as “moderate”, and ≥7 as “severe.” A SPPADE composite score was calculated by summing six individual symptom scores and is an indicator of total symptom burden. We report descriptive statistics for each symptom by severity category. We also test for differences in SPPADE composite score by race, disability status, employment status, education and cancer type using Kruskal-Wallis tests. Results: 12,824 patients with metastatic disease completed a survey between March 2019 and January 2023. Discretized score distributions for the SPPADE symptoms are reported in the Table. The SPPADE composite mean score for the cohort was 17.6 (SD +/- 12.0). Significant differences were found in total symptom burden by sociodemographic and clinical characteristics ( p<0.01): Higher total symptom burden (Mean [SD])was experienced by individuals who were American Indian/Alaska Native (AI/AN) (23.8[13.5]) or African American (AA) (20.5[14.7]), disabled (24.0[12.8]) or unemployed (21.1[13.0]), and had a high school education (20.0[13.3]) or less than high school education (18.5[12.4]). There were also statistically significant differences ( p<0.01) in symptom burden across cancer types, with patients with metastatic lung cancer reporting the highest symptom burden (20.0[12.2]) and those with metastatic melanoma reporting the lowest (14.7[11.4]). Conclusions: SPPADE symptoms are common in patients with metastatic cancer, especially fatigue, sleep disturbance, and physical function impairment. Symptom burden is especially high in AI/AN, AA, disabled/unemployed, and less educated patients. Further research is needed to tailor symptom interventions among those living with metastatic disease. [Table: see text]