OBJECTIVE: To analyse data from the All of Us Research Program to evaluate the real-world application and long-term effectiveness of semaglutide in treating type 2 diabetes and obesity patients in a large population.
METHODS: We identified patients prescribed semaglutide and analysed differences in route of administration and the time on semaglutide. For individuals diagnosed with obesity, we measured changes in body mass index (BMI) and weight from baseline, while measured changes in HbA1c for those patients with type 2 diabetes. We also examined the occurrence of newly diagnosed common adverse events from taking semaglutide.
RESULTS: For 3739 semaglutide patients, those on injectable semaglutide (3364 patients) averaged 301.54 days on the medication, with 20.36% having no end date, while those on oral semaglutide (435 patients) averaged 172.48 days, with 24.60% having no end date. We found average decreases of 1.54 kg/m2 in BMI, 4.65 kg in weight and 0.75% in HbA1c for semaglutide users. The decreases were larger in participants taking injectable formulation, probably because of higher starting values. Over time, improvements in these outcomes diminished, but the values remained significantly lower than baseline levels. Approximately only 1.0% of patients reported newly diagnosed common adverse events.
CONCLUSIONS: Consistent with clinical trial findings, this real-world data analysis showed that semaglutide was well tolerated and that, for a large population, it effectively reduced BMI, body weight and HbA1c, albeit to smaller magnitudes than observed in clinical trials. These findings provide valuable insights into real-world experience and the long-term effectiveness of semaglutide.

OBJECTIVE: To establish trust in real-world evidence (RWE) derived from CareLink Personal (CP), Medtronic\'s data management system for MiniMed system users, we show that this database and its analyses strictly adhere to the principles of RWE.
METHODS: The methodology is applicable to all MiniMed iterations. We described every step from raw data to predefined outcomes. In addition, we showed CP\'s fitness-for-research by the below metrics (using last year\'s MiniMed 780G system data as a case study): representative population, relevant endpoints, appropriate granularity, high data completeness, high data representativity and consistency in results.
RESULTS: The process from raw data to outcomes has been validated, and metrics/logics adhere to established definitions. Over 95% of users have a CP account; with 96% providing consent, this allows the use of >91% of the census population. There is no rationale for an over-representation of a specific phenotype among users not included. CP includes >50 endpoints, including \'International Consensus on Time in Range\' based metrics. Data are recorded at 5-min intervals (maximum 288 per day), and on average there were 263 data points per person per day. Ninety-nine per cent of uploads were automated. For the last year, only 1 in 6 users had a data gap >1 day, and 1 in 50 had a gap >1 week. The time in range from in-silico studies was similar to that of real-world studies from different geographies and with ever growing populations.
CONCLUSIONS: RWE from CP adheres to the principles of RWE and can serve as robust evidence on the performance and safety of MiniMed systems.

The innovative use of real-world data (RWD) can answer questions that cannot be addressed using data from randomized clinical trials (RCTs). While the sponsors of RCTs have a central database containing all individual patient data (IPD) collected from trials, analysts of RWD face a challenge: regulations on patient privacy make access to IPD from all regions logistically prohibitive. In this research, we propose a double inverse probability weighting (DIPW) approach for the analysis sponsor to estimate the population average treatment effect (PATE) for a target population without the need to access IPD. One probability weighting is for achieving comparable distributions in confounders across treatment groups; another probability weighting is for generalizing the result from a subpopulation of patients who have data on the endpoint to the whole target population. The likelihood expressions for propensity scores and the DIPW estimator of the PATE can be written to only rely on regional summary statistics that do not require IPD. Our approach hinges upon the positivity and conditional independency assumptions, prerequisites to most RWD analysis approaches. Simulations are conducted to compare the performances of the proposed method against a modified meta-analysis and a regular meta-analysis.

OBJECTIVE: To compare theoretical strengths and limitations of common immortal time adjustment methods, propose a new approach using multiple imputation (MI), and provide practical guidance for using MI in precision medicine evaluations centered on a real-world case study.
METHODS: Methods comparison, guidance, and real-world case study based on previous literature. We compared landmark analysis, time-distribution matching, time-dependent analysis, and our proposed MI application. Guidance for MI spanned (1) selecting the imputation method; (2) specifying and applying the imputation model; and (3) conducting comparative analysis and pooling estimates. Our case study used a matched cohort design to evaluate overall survival benefits of whole-genome and transcriptome analysis, a precision medicine technology, compared to usual care for advanced cancers, and applied both time-distribution matching and MI. Bootstrap simulation characterized imputation sensitivity to varying data missingness and sample sizes.
UNASSIGNED: Case study used population-based administrative data and single-arm precision medicine program data from British Columbia, Canada for the study period 2012 to 2015.
RESULTS: While each method described can reduce immortal time bias, MI offers theoretical advantages. Compared to alternative approaches, MI minimizes information loss and better characterizes statistical uncertainty about the true length of the immortal time period, avoiding false precision. Additionally, MI explicitly considers the impacts of patient characteristics on immortal time distributions, with inclusion criteria and follow-up period definitions that do not inadvertently risk biasing evaluations. In the real-world case study, survival analysis results did not substantively differ across MI and time distribution matching, but standard errors based on MI were higher for all point estimates. Mean imputed immortal time was stable across simulations.
CONCLUSIONS: Precision medicine evaluations must employ immortal time adjustment methods for unbiased, decision-grade real-world evidence generation. MI is a promising solution to the challenge of immortal time bias.

OBJECTIVE: To measure the effectiveness and sustainability of the Juniper UK digital weight-loss service (DWLS), which delivers 6 months of personalized, proactive lifestyle coaching supplemented with tirzepatide to patients through a multidisciplinary team (MDT).
METHODS: An observer-blinded randomized controlled trial (RCT) will be conducted on a cohort of non-diabetic patients of the Juniper DWLS in the UK. Participants in both the intervention and control groups will receive weekly subcutaneous injections of 2.5 mg tirzepatide for 4 weeks, uptitrating the dose to 5.0 mg from weeks 5 to 8, and by 2.5 mg every 4 weeks until reaching 15 mg in week 21, which they will maintain until the end of the intervention period at 6 months, when participants will be taken off the medication. The intervention group will receive personalized weeklylifestyle coaching with a focus on protein intake and resistance training for 6 months. Participants in the control group will attend a diet and exercise group counselling session at programme inception and will be sent a summary of the session\'s content at months 2 and 4. Aside from these events, health coaches will only interact with control group participants on a reactive basis. From month 6 to month 12, participants from both groups will no longer have access to their MDTs. The trial\'s co-primary endpoints include weight loss, fat-free to fat-mass ratio and composite strength measures at 12 months (6 months following the end of treatment), compared with baseline. Secondary endpoints include percentage change in weight, fat-free to fat-mass ratio, and composite strength from baseline to 6 months, side effect incidence, and change in cardiometabolic risk factors at 12 months. Quality of life and programme engagement represent the study\'s exploratory endpoints.
RESULTS: A total of 688 participants enrolled in the study, with a mean age of 44.6 (± 11.4) years and a mean body mass index of 34.8 (± 7.5) kg/m2; 81.0% of participants are women, and 72.8% are of White ethnicity. More than three-quarters of participants have at least one co-morbidity, with dyslipidaemia (42.4%), hypertension (35.3%) and high cholesterol (31.8%) being the most prevalent conditions.
CONCLUSIONS: This RCT will be the first to assess the effectiveness and sustainability of a real-world intensive, multidisciplinary DWLS, and it should highlight the potential of such a service for long-term obesity treatment compared with programmes that deliver standard health counselling.

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OBJECTIVE: There has been rapid growth in the variety and number of real-world data (RWD) sources, as well as the number of regulatory documents that provide guidance for assessing the suitability of RWD sources for pharmacoepidemiology studies. This study aims to assess differences in RWD guidance and variability in current practice for identifying and assessing RWD for studies with regulatory purpose.
METHODS: Key criteria for feasibility assessment were mapped against relevant regulatory guidance documents across US, EU, and Asia-Pacific regions. An online survey was designed and deployed to International Society for Pharmacoepidemiology members to understand current practice. Findings were summarized and used to inform key considerations and recommendations.
RESULTS: Eleven RWD guidance documents were identified and mapped against 14 RWD assessment criteria. Variability was seen across these documents in guidance for these criteria. Between December 2022 and January 2023, 37 survey respondents reported having used RWD for post-marketing commitments (34, 92%) and/or background epidemiology (28, 76%). RWD were mostly identified through literature (33, 89%) and data landscaping (26, 70%); guidance documents referenced included: Food and Drug Administration (20, 54%), European Network for Centres for Pharmacoepidemiology and Pharmacovigilance (17, 46%), European Medical Agency (16, 43%), and Structured Process to Identify Fit-For-Purpose Data (11, 30%). Challenges for conducting feasibility assessments included RWD accessibility, ability to complete validation, and RWD provider responsiveness.
CONCLUSIONS: Existing guidelines are used extensively by researchers, but key criteria for RWD identification and feasibility assessment are not reflected consistently and challenges remain. Recommendations have been made reflecting study findings.

BACKGROUND: Dyslipidemia remains the major cause of atherosclerotic cardiovascular disease (ASCVD). Lipid management in patients with increased cardiovascular (CV) risk needs improvement across Europe, and data gaps are noticeable at the country level.
OBJECTIVE: We described the current treatment landscape in Belgium, hypothesizing that lipid management in patients with ASCVD remains inadequate and aiming to understand the reasons.
METHODS: Using data from an anonymized primary care database in Belgium derived from 494 750 individuals, we identified those with any CV risk factor between November 2019 and October 2022 and described the clinical features of patients with ASCVD. The main outcomes were the proportion of patients (i) receiving lipid-lowering therapies (LLTs), (ii) per low-density lipoprotein cholesterol (LDL-C) threshold, stratified per LLT, (iii) reaching the 2021 ESC recommended LDL-C goals, and (iv) LDL-C reduction per type of LLT was also determined.
RESULTS: Among 40 888 patients with very high CV risk, 24 859 had established ASCVD. Most patients with ASCVD were either receiving monotherapy (59.6%) or had no documented LLT (25.1%). Further, 64.2% of those with no documented LLT exhibited LDL-C levels ≥ 100 mg/dL. Among common treatment options, one of the greatest improvements in LDL-C levels was achieved with combination therapy of statin and ezetimibe, reducing LDL-C levels by 41.5% (p < 0.0001). Yet, in this group, 24.8% of patients had still LDL-C levels ≥ 100 mg/dL and only 20.7% were at goal.
CONCLUSIONS: Our study emphasizes the importance of developing strategies to help patients achieve their LDL-C goals, with a focus on supporting the implementation of combination LLT in routine clinical practice.

OBJECTIVE: Sickle cell disease (SCD) affects all organ systems and is characterized by numerous acute and chronic complications and comorbidities. Standardized codes are needed for complications/comorbidities used in real-world evidence (RWE) studies that rely on administrative and medical coding. This systematic literature review was conducted to produce a comprehensive list of complications/comorbidities associated with SCD, along with their diagnosis codes used in RWE studies.
METHODS: A search in MEDLINE and Embase identified studies published from 2016 to 2023. Studies were included if they were conducted in US SCD populations and reported complications/comorbidities and respective International Classification of Diseases, Clinical Modification (ICD-CM) codes. All identified complications/comorbidities and codes were reviewed by a certified medical coding expert and hematologist.
RESULTS: Of 1851 identified studies, 39 studies were included. The most reported complications/comorbidities were stroke, acute chest syndrome, pulmonary embolism, venous thromboembolism, and vaso-occlusive crisis. Most of the studies used ICD-9-CM codes (n = 21), while some studies used ICD-10-CM codes (n = 3) or both (n = 15), depending on the study period. Most codes reported in literature were heterogeneous across complications/comorbidities. The medical coding expert and hematologist recommended modifications for several conditions.
CONCLUSIONS: While many studies we identified did not report their codes and were excluded from this review, the studies with codes exhibited diverse coding definitions. By providing a standardized set of diagnosis codes that were reported by studies and reviewed by a coding expert and hematologist, our review can serve as a foundation for accurately identifying complications/comorbidities in future research, and may reduce heterogeneity, enhance transparency, and improve reproducibility. Future efforts focused on validating these code lists are needed.

Patients with psoriasis often take multiple medications due to comorbidities, raising concerns about drug-drug interactions (DDIs) during the development of new medicines. DDI risk assessments of a new small molecule showed risks of CYP3A4 autoinduction and being a sensitive CYP3A4 substrate. We conducted a real-world evidence (RWE) claims analysis to assess the frequency of prescription claims for up to 12 months from the date of the initial psoriasis diagnosis for drugs that may interact with CYP3A4 substrates. We used 2013 to 2018 patient data from the US Merative MarketScan Research Database. Among patients diagnosed with psoriasis, less than 1% had a claim for a moderate/strong inducer, but up to 15% had a claim for moderate/strong inhibitor. Most prescriptions for CYP3A4 inhibitors or inducers included antibiotics and anticonvulsants. While CYP3A4 inducers were rarely used, those treated received more than >90 days treatment. Then, these RWE data were used to inform the early translational medicine strategy for the new investigational drug by strategically integrating DDI evaluations into a first-in-human healthy volunteer trial prior to studies in patients with psoriasis. The resulting DDI substudy showed that the investigational small molecule did not induce midazolam clearance but was sensitive to CYP3A inhibition, leading to the decision to exclude concomitant use of strong CYP3A4 inducers or inhibitors from clinical trials.