Natural history of self-reported symptoms following SARS-CoV-2 infection: A target trial emulation in a prospective community-recruited cohort.

Recent studies have suggested potential effects on magnesium homeostasis associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). We sought to determine whether these effects lead to a reduced risk of hypomagnesemia among adults with type 2 diabetes in clinical practice. We conducted a target trial emulation study using the multi-institutional cohort data from the TriNetX Global Collaborative Network. We compared 1:1 propensity score-matched patients with type 2 diabetes newly initiating SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors (n = 718,798), GLP-1 RAs versus DPP4 inhibitors (n = 623,390), and SGLT2 inhibitors versus GLP-1 RAs (n = 702,808) from 2016 to 2024. Propensity scores were estimated using logistic regression models that included baseline covariates such as age, sex, race, comorbidities, and medication and laboratory data. In each comparison, patients receiving DPP4 inhibitors were considered the active-comparator group. The primary outcome was incident hypomagnesemia, defined by clinical diagnosis or serum magnesium <1.80 mg/dL. Patients were followed until the occurrence of an outcome of interest, last clinical visit, death, or the end of database period (March 31, 2025), whichever came first. We found that initiation of SGLT2 inhibitors was associated with a significantly lower risk of hypomagnesemia, compared with both DPP4 inhibitors (Hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.79, 0.82; p < 0.05) and GLP-1 RAs (HR: 0.92; 95% CI: 0.91, 0.93; p < 0.05). Similarly, GLP-1 RA use was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors (HR: 0.89; 95% CI: 0.88, 0.91; p < 0.05). These associations were consistent across individual agents within each drug class. The main limitation of our study is that residual confounding inherent to retrospective observational research cannot be completely ruled out. Treatment with SGLT2 inhibitors and GLP-1 RAs was associated with a lower risk of hypomagnesemia, compared with DPP4 inhibitors. These findings suggest that SGLT2 inhibitors and GLP-1 RAs may be preferable options for patients at risk of hypomagnesemia.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) lower serum urate and are associated with a lower risk of recurrent gout flares. We used target trial emulation to compare rates of allopurinol initiation and use of anti-inflammatories (high-dose glucocorticoids, nonsteroidal anti-inflammatory drugs [NSAIDs], colchicine) and diuretics (prototypic serum urate-raising medication) among patients with gout using SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP-4is) (primary comparator), with glucagon-like peptide 1 receptor agonists (GLP-1RAs) as an alternative comparator. From a general population database, we identified patients with gout and comorbid type 2 diabetes and used Cox proportional hazards and Poisson regressions with inverse probability of treatment weighting to emulate randomization to SGLT2i or DPP-4i/GLP-1RA. We also replicated the analysis in an electronic health record data set with further adjustment for serum urate and BMI. Among 26,739 adults with gout and type 2 diabetes (mean age 66 years), 67% had polypharmacy. Allopurinol initiation was lower among SGLT2i initiators than DPP-4i, with a hazard ratio of 0.62 (95% CI 0.52-0.73). Associations were stronger among those using diuretics at baseline (P for interaction = 0.03) and persisted when comparing SGLT2i with GLP-1RA and accounting for serum urate and BMI in the secondary data set. SGLT2i was also associated with lower rates of high-dose glucocorticoid, NSAID, colchicine, and diuretic dispensing, with rate ratios of 0.78 (95% CI 0.74-0.83), 0.85 (95% CI 0.80-0.92), 0.87 (95% CI 0.83-0.92), and 0.87 (95% CI 0.85-0.89), respectively. For patients with gout and type 2 diabetes, SGLT2is may reduce gout-related medication use, which could, in turn, reduce exposure to the harmful cardiovascular-kidney-metabolic effects of NSAIDs and glucocorticoids in this high-risk population.

In the post-operative period of cardiac surgeries, the majority of patients are admitted to the intensive care unit (ICU) for ongoing management, where delirium frequently occurs as a complication. However, the association between various analgesic regimens and the onset of postoperative delirium in ICU patients following cardiac surgery remains poorly understood. The present study employs a target trial emulation (TTE) framework to examine the effects of early postoperative pain management on the incidence of delirium in patients immediately admitted to the ICU after cardiac surgery. Study participants were selected from the MIMIC-IV version 3.1 database, comprising 5356 adult patients who were admitted for the first time and underwent cardiac surgery, followed by immediate transfer to the intensive care unit (ICU). The TTE framework was applied, utilizing the clone-censor-weighting (CCW, refer to the Statistical Analysis section) method for data analysis. In this study of 5356 adult patients who underwent cardiac surgery and were immediately transferred (within 24 h post-surgery) to the intensive care unit postoperatively, in comparison with the morphine group, patients receiving fentanyl exhibited a significantly elevated risk of delirium within seven days postoperatively (hazard ratio [HR] = 1.69; 95% confidence interval [CI]: 1.41-1.95) and demonstrated an earlier onset of delirium. The findings of this study, conducted within a TTE framework, indicate that the utilization of fentanyl for pain management during the initial 24 h following cardiac surgery is associated with a higher incidence and earlier onset of postoperative delirium compared to morphine.

Type 2 diabetes mellitus (T2DM) paradoxically increases fracture risk despite normal or elevated bone mineral density. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in bone health, evidence remains controversial. This large-scale real-world study evaluated the primary outcome of femur fracture risk associated with GLP-1 RAs versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in T2DM patients using a rigorous target trial emulation approach. This retrospective cohort study adopted a large-scale target trial emulation framework with a new-user, active-comparator design using data from the TriNetX US Collaborative Network. Adults (≥18years) with T2DM identified between 2018 and 2022 (n=3,620,983) were classified as GLP-1 RA (n=491,936) or DPP-4i (n=345,484) users at treatment initiation. Propensity score matching (PSM) was performed to emulate random assignment and balance baseline characteristics. Cox proportional-hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for bone fractures during a maximum 5-year follow-up. After 1:1 PSM, each cohort included 172,381 patients (mean age 59years; 51% male) with a mean follow-up of 40months. GLP-1 RA users demonstrated significantly lower femoral fracture risk compared to DPP-4i users (HR 0.91, 95% CI 0.85-0.98), with consistent protective effects across all sensitivity analyses. Similar associations were observed when comparing GLP-1 RAs with most other antidiabetic medications. GLP-1 RA use was associated with a modest reduction in femur fracture risk. However, given the observational design, possible residual confounding, and multiple testing, these findings are exploratory and require prospective confirmation before clinical application.

Early-life socioeconomic status (SES) increases the risk of poor mental health outcomes in adulthood. However, the mechanistic pathways underlying this relationship remain poorly understood. While addressing socioeconomic inequalities remains a long-term goal, identifying specific mediating pathways could reveal more immediate opportunities for effective interventions. Using linked administrative data from New South Wales, Australia (1990-2022), we will emulate a target trial examining the relationship between SES at birth and acute mental health admissions and presentations between the ages of 18 and 25 years. An interventional mediation analysis will be used to examine the effect of multiple mediating pathways, including education, housing stability, child protection contact, parental incarceration and justice system involvement, on the outcome. The analysis will estimate direct and indirect interventional effects, quantifying how much of the SES-mental health relationship could be modified by interventions on specific mediators. This study has received ethics approval from the University of Newcastle (H-2024-0015) and Aboriginal Health and Medical Research Council (2265/24) Human Research Ethics Committees. All dissemination activities will be conducted in accordance with data access agreements and following approval from all relevant data custodians (New South Wales Health System Data Services). Key findings will be communicated to relevant government agencies and policymakers through policy briefs and stakeholder meetings, and publication in appropriate academic journals.

In 2018, France withdrew reimbursement for cholinesterase inhibitors (ChEIs) in Alzheimer's disease, citing modest efficacy, lack of long-term benefit, and safety concerns. This policy shift provided a unique opportunity to assess ChEI effectiveness in real-world settings, by evaluating, among patients treated with ChEI between 01/08/2017 and 01/08/2018, the impact of treatment discontinuation on cognitive decline (MMSE score) and survival. Using the French National Alzheimer's Database (BNA) and Meotis databases, we emulated a pragmatic, intention-to-treat trial comparing patients who discontinued ChEIs after delisting to those who continued treatment, under quasi-experimental conditions. To model cognitive trajectories, we used the inverse probability treatment-weighted (IPTW) cohort and applied mixed-effects models with random intercepts across all follow-up visits. Survival was estimated with a pooled logistic regression including treatment group, follow-up time, and an interaction between treatment and time. The mean difference in MMSE decline between discontinuers and continuers after one year was 0·97 points (95% CI 0·68-1·27, p < 0·001), reaching 1·81 points (0·91-2·71, p < 0·001), after four years. No significant difference in mortality (RR 1·10, 95% CI [0·95-1·29]) was observed over a five-year period. Our findings confirm and extend prior trials by demonstrating the sustained cognitive benefits of ChEIs in a real-world setting. While acknowledging the limitations associated with its retrospective nature, our study argues for reconsidering the 2018 delisting decision, as ChEIs remain safe and clinically relevant for mild-to-moderate Alzheimer's disease. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Observational studies have suggested that air pollution is associated with impaired glucose metabolism; yet randomized controlled trials to confirm the causality of this association are ethically and practically unfeasible. We emulated a hypothetical trial to evaluate the effects of sustained reductions in ambient air pollutants on homeostasis model assessment for insulin resistance (HOMA-IR) and fasting glucose (FG) in children and adolescents. Combining target trial emulation with g-computation, we estimated the effects of sustained hypothetical reductions of air pollutants on HOMA-IR and FG compared to no intervention (natural course). Our sample comprised 1417 children aged 2-9 years at baseline (2007/2008) participating in the pan-European IDEFICS/I.Family cohort. Ambient annual average levels of particulate matter<2.5μm (PM2.5), black carbon (BC), and NO2 were estimated at residential addresses using land use regression models. We found a clear dose-response relationship between sustained reductions in PM2.5 and BC and decreasing levels of HOMA-IR and FG. Hypothetically reducing PM2.5 to WHO's recommended annual level of 5μg/m3, the mean HOMA-IR z-score declined by -0.95 (95% CI: -1.65; -0.44). Similarly, lowering BC to 0.8×10-5/m reduced HOMA-IR by -0.36 (95% CI: -0.61; -0.12) and FG by -0.28 (95% CI: -0.50; -0.04). We found no clear evidence of NO2 reductions on HOMA-IR and FG. Even at relatively low pollution levels in our cohort, further reductions in PM2.5 and BC can improve HOMA-IR and FG levels in children and adolescents. Our findings provide evidence for the development of BC recommendations for air quality guidelines.

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure With Supra-Normal Ejection Fraction: A Target Trial Emulation Study.

Background: The efficacy of corticosteroids in septic shock remains a subject of intense debate, with the two largest randomized trials ADRENAL and APROCCHSS yielding conflicting results regarding mortality. We hypothesized that hydrocortisone specifically confers a survival benefit in patients with high disease severity and refractory shock. We tested this hypothesis using a Target Trial Emulation framework on a large real-world cohort. Methods: We conducted a retrospective cohort study using the MIMIC-IV v3.1 database (2008–2019). We identified adult patients with septic shock requiring high-dose vasopressors (norepinephrine equivalent &gt; 0.25 mcg/kg/min). Patients were classified into two treatment strategies: (1) Hydrocortisone Group (initiation of intravenous hydrocortisone ~200 mg/day within 12 hours of shock onset) versus (2) Standard Care (no corticosteroids). The primary endpoint was 28-day all-cause mortality. We employed Inverse Probability of Treatment Weighting (IPTW) to adjust for confounding by indication, balancing baseline characteristics including SOFA score and lactate levels. Results: The final analyzable cohort included 4,200 patients. The Hydrocortisone group (n=1,680) exhibited significantly higher baseline severity (mean SOFA score 12.0 vs. 9.0) compared to the Standard Care group (n=2,520). After weighting, standardized mean differences for all covariates were &lt; 0.1, indicating excellent balance. Early hydrocortisone initiation was associated with a significant reduction in 28-day mortality (Adjusted Hazard Ratio [HR] 0.60; 95% CI, 0.50–0.72; p &lt; 0.001). Sensitivity analysis yielded an E-value of 2.73, suggesting robustness to unmeasured confounding. Subgroup analysis demonstrated that the survival benefit was most pronounced in patients with SOFA scores &gt; 10. Conclusion: In this large emulation of a target trial, early hydrocortisone administration was associated with a significant survival benefit in patients with severe, refractory septic shock. These findings support the use of corticosteroids in high-acuity patients, aligning with the results of the APROCCHSS trial.

Annual reformulation and approval of seasonal influenza vaccines necessitate yearly evaluation of their effectiveness. Regulatory agencies, including the European Medicines Agency (EMA), rely on timely, real-world evidence to inform product-specific benefit-risk assessments. We explored the feasibility of conducting annual, brand-specific influenza vaccine effectiveness studies in Denmark, Finland and Sweden, starting with the 2024/25 season. These countries maintain population-wide vaccination, clinical and laboratory registers, linkable via personal identification numbers and updated in near real-time. We discuss suitable study designs and document that cohort studies using a target trial emulation (TTE) framework are feasible in all three countries; register-based test-negative case-control design (TND) studies are currently only feasible in Denmark. Supplementary methods, including regression discontinuity and negative control outcome analyses, can address residual bias. This Nordic collaboration has proven capacity for large-scale register-based studies and its infrastructure is able to address EMA's requirements for timely, robust post-authorisation evidence to guide public health and regulatory decisions.

Antibiotic therapy is essential for sepsis management, but the optimal empirical strategy remains uncertain. This study evaluated the effects of first-line antibiotic preference and initiation timing on in-hospital mortality among intensive care units (ICU) patients with sepsis. Using the MIMIC-IV database, we emulated a sequential target trial comparing patients who received antibiotics within 48h of sepsis diagnosis versus delayed initiation. Randomization was approximated through a clone-censor-weight process to address confounding by indication. The primary outcome was in-hospital mortality. Weighted Cox regression estimated hazard ratios (HRs), and sensitivity analyses tested robustness. Among 3,669 eligible patients, 3,568 (97%) received antibiotics within 48h. After weighting, covariate balance was achieved. Beta-lactam use was associated with lower in-hospital mortality (HR 0.88, 95% CI 0.78-0.95), with consistent reductions at 7, 14, and 60 days. Timing within the 48-hour window did not modify outcomes for either beta-lactams or glycopeptides. Empirical beta-lactam therapy was linked to improved survival among ICU sepsis patients, whereas timing of initiation showed no significant impact. These findings support prioritizing beta-lactam-based regimens as first-line empirical coverage in early sepsis management.

Target trial emulation (TTE) has demonstrated popularity because of its ability to improve the reliability of causal inference from observational data. Nevertheless, knowledge about the current use, potential challenges, and insights of target trials in oncology is scarce. A total of 90 TTE studies in cancer areas were identified through systematic reviews in PubMed and Embase. Among the 54 applications in cancer treatment, registry databases (44.4%) and overall survival (OS, 63.0%) were predominantly used as data sources and primary endpoints, respectively. Approximately 30 (55.6%) of the included TTE cases were associated with immortal time bias, and 21 (38.9%) were associated with prevalent user bias. Among the 21 trials from 13 studies that aimed to calibrate the results from preexisting randomized controlled trials (RCTs), only 42.9% met both statistical agreement and estimate agreement. The availability of fit-for-purpose data sources and uncertainty about result concordance were the main hurdles limiting the quantity and quality of TTE in oncology areas. Promoting regulatory acceptance by initiating special projects could be crucial for the expanded application of real-world data (RWD) using TTE. Potential solutions, such as the integration of electronic medical records at the regional or country level, linkage with insurance claims databases, the modernization of eligibility criteria, the use of OS as the primary endpoint, and other best practices, were recommended for improving the feasibility and quality of oncology TTE.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40779-026-00685-9.

BackgroundObservational studies increasingly inform treatment decisions for CDK4/6 inhibitors in metastatic breast cancer, yet their validity is compromised by immortal time bias, a mechanistic bias that inflates treatment benefits when follow-up begins at treatment initiation rather than at diagnosis. However, whether historical bias estimates generalise to contemporary CDK4/6 research with rapid treatment initiation remains unknown.MethodsWe conducted a simulation-based study comparing naive observational analysis (time-zero at treatment) with target trial emulation (time-zero at diagnosis) across three synthetic cohorts reconstructed from published CDK4/6 inhibitor studies: a Danish population registry (N equals 1196), the Rugo et al. Flatiron database (N equals 9146), and a germline BRCA subgroup analysis (N equals 4050). We quantified bias magnitude and examined associations with treatment delay, patient characteristics, and healthcare system factors.ResultsContrary to expectations, we observed minimal immortal time bias across all comparisons (mean absolute bias of 0.55 months, range 0.2 to 0.9 months; per cent bias of 0.5 to 2.1 per cent). Remarkably, all estimates showed underestimation by naive analysis, indicating that prevalent user bias (the exclusion of early deaths) dominated immortal time inflation. The duration of treatment delay accounted for only 25% of the variability in bias, indicating that context-dependent factors beyond delay duration determine bias magnitude.ConclusionsModern CDK4/6 inhibitor observational studies avoid historical immortal-time bias due to rapid treatment initiation and high event rates. These findings clarify that immortal time bias may be a smaller threat than historical cancer literature suggests in contemporary settings, though explicit time-zero specification remains a methodological best practice.

Novel treatments are needed for the primary and secondary prevention of heart failure in patients with type 2 diabetes, including individuals with and those without a history of heart failure. Conflicting trial evidence exists on whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of hospitalization for heart failure (HHF) in this broad population and whether this is a class effect or varies by specific agent. Furthermore, their comparative effectiveness against sodium-glucose cotransporter-2 inhibitors (SGLT-2is) is unknown. We emulated 2 target trials using population-based health care data from Stockholm, Sweden (2010-2021). Target trial 1 included adult patients with type 2 diabetes who newly initiated GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4is), and target trial 2 compared GLP-1RA with SGLT-2i. The primary outcome was HHF. Cox regression was used to estimate intention-to-treat hazard ratios, with inverse probability of treatment weighting used to balance 72 confounders. Major adverse cardiovascular events were used as the positive control outcome. Analyses were conducted for the GLP-1RA class overall and for individual agents, including liraglutide and semaglutide. Target trial 1 included 32 979 patients (42% GLP-1RA and 58% DPP-4i) with a mean age of 64 years and 40% female; and target trial 2 included 30 104 patients (49% GLP-1RA and 51% SGLT-2i) with a mean age of 63 years and 38% female. Starting a GLP-1RA was associated with a lower 3-year absolute risk of HHF than starting a DPP-4i (3.4% versus 4.3%), corresponding to a weighted hazard ratio of 0.77 (95% CI, 0.66-0.91). Absolute 3-year risks for GLP-1RA compared with SGLT-2i on HHF were 3.6% and 3.3% with a weighted hazard ratio of 1.02 (95% CI, 0.85-1.18). The absolute risk difference was largest for patients with higher predicted risk of heart failure at baseline. Results were consistent for single agents, in per-protocol analyses, and in the majority of subgroups. In positive control outcome analyses, GLP-1RA use was associated with a lower rate of major adverse cardiovascular events than DPP-4i use (weighted hazard ratio, 0.85 [95% CI, 0.74-0.99]), consistent with trial findings. GLP-1RA use is associated with a lower risk of HHF compared with DPP-4i and similar risks compared with SGLT-2i in routine clinical care for patients with type 2 diabetes.

In 2023, Mexico revised its Dietary Guidelines to promote healthy and sustainable diets, yet their impact on type 2 diabetes (T2D) prevention remains unexamined. We emulated a target trial within the Mexican Teachers Cohort to estimate the 9-year risk of T2D under an intervention adopting the Guidelines at baseline, compared to usual diet, using the parametric g-formula. Eligible participants were women aged ≥40 years without prior T2D, cardiovascular disease, or cancer between 2008-2010. Due to low baseline adherence to several components, we adapted thresholds so that ≥10% of the population met each recommendation. Incident T2D was identified through self-report or administrative data linkage. Among 11,307 eligible participants (mean age 46.0 years), 636 developed T2D over 9-years. The estimated 9-year risk of T2D was 8.44% (95% CI: 7.84, 9.12) under the usual diet and 7.11% (95% CI: 5.05, 9.82) under the intervention (risk ratio 0.84; 95% CI: 0.61, 1.15; risk difference -1.33 percentage points; 95% CI: -3.21, 1.29). These findings suggest a modest potential benefit if all participants had adhered to the adapted Guidelines at baseline compared with no intervention. The 95% confidence intervals indicate data are compatible with a small benefit, no effect, or a slight increase in risk.

Background: Severe pulmonary embolism (PE) with high-risk features is a critical cardiopulmonary emergency characterized by hemodynamic collapse and the urgent need for rapid re-establishment of pulmonary circulation. Despite advances in supportive care, the clinical evidence supporting extracorporeal circulatory support devices or various repercussion modalities remains insufficient and continues to be debated in current practice guidelines.Materials and Methods: Conducted an observational cohort study of 1,060 adults hospitalised with high-risk acute PE, of whom 991 were included in a target trial emulation to compare all-cause in-hospital mortality across advanced therapeutic strategies. Patients were categorised into four treatment groups: (I) stand-alone venoarterial extracorporeal membrane oxygenation (VA-ECMO; n = 126), (II) in-hospital systemic fibrinolysis (SYS; n = 643), (III) open surgical embolectomy (ST; n = 49), and (IV) image-guided percutaneous catheter-directed interventions (PCDT; n = 173). Use of VA-ECMO as a bridge to definitive reperfusion was allowed in groups II–IV. Marginal mortality risk estimates were derived using the g-formula implemented via logistic regression. Sensitivity analyses included targeted maximum likelihood estimation (TMLE) incorporating machine-learning methods, inverse probability of treatment weighting (IPTW), procedures to address missing data, and a secondary trial emulation excluding the VA-ECMO–only cohort.Results: Within the emulated trial cohort, the median patient age was 62 years, and 53.3% of the population were male. Probabilities of hospital mortality in the intention-to-treat framework were 57% (95% CI 47–67%) for VA-ECMO alone, 48% (95% CI 44–53%) for systemic thrombolysis, 34% (95% CI 18–50%) for surgical embolectomy, and 43% (95% CI 35–51%) for catheter-directed procedures. Relative mortality comparisons consistently favoured active repercussion therapies over VA-ECMO mono-therapy, a finding that remained stable in all supplementary statistical models. Survivors across all groups demonstrated a considerable likelihood of retaining favourable neurological function at discharge.Conclusion: Repercussion strategies including systemic thrombolysis, surgical embolectomy, and catheter-guided therapies appear to improve short-term survival outcomes compared with VA-ECMO used as sole support in patients presenting with high-risk pulmonary embolism. These data endorse prioritizations of active pulmonary recanalization over extracorporeal life support alone in this clinical setting.

The glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has demonstrated efficacy for the secondary prevention of cardiovascular disease among patients with overweight/obesity without diabetes mellitus. However, the comparative effectiveness of GLP-1 RA versus other antiobesity medications (e.g. phentermine-topiramate) not been evaluated. This was a retrospective, observational, cohort study using target trial emulation methodology using the Truveta electronic health record database of more than 120 million patients. Adult patients with a body mass index (BMI) >=27 kg/m 2 , a history of cardiovascular disease (prior ischemic stroke, transient ischemic attack, or myocardial infarction, or known coronary artery disease, heart failure, or peripheral artery disease) without diabetes mellitus were included in the study. The primary endpoint was time to first major adverse cardiovascular or cerebrovascular event (MACCE, defined as stroke or myocardial infarction). In total, 35,240 were included in the bupropion-naltrexone versus GLP-1 RA comparison, and 27,051 were included in the phentermine-topiramate versus GLP-1 RA comparison. In the pre-weighting cohort, GLP-1 RA use was associated with decreased hazard of MACCE compared to bupropion-naltrexone (HR 0.50 [95% confidence interval (CI) 0.36-0.69]) and phentermine-topiramate (HR 0.43 [95% CI 0.30-0.60]). In the propensity score-overlap weighted cohort, GLP-1 RA prescription was not associated with a lower hazard of MACCE than bupropion-naltrexone (aHR 0.69 [95% CI 0.47-1.00]) but was associated with a lower hazard compared to phentermine-topiramate (aHR 0.61 [95% CI 0.41-0.91]; adjusted absolute rate difference 0.98 per 1000 person-years). Prescription of a GLP-1 RA was associated with a lower risk of subsequent MACCE than phentermine-topiramate.

Target trial emulations often face challenges in accurately identifying the intended target population within real-world data (RWD) because eligibility criteria cannot always be directly mapped to available variables. This scoping review aimed to systematically characterize the proportion of eligibility criteria from oncology target trials that are successfully mapped to their emulated counterparts and to describe the approaches used for this mapping. We searched MEDLINE for peer-reviewed studies published between January 1, 2016, and April 23, 2025, that were designed to emulate oncology drug intervention trials using RWD. For each target trial emulation, we recorded design elements, database types, eligibility criteria, and methodological details. We identified how each target trial eligibility criterion was mapped to available RWD. For each applicable criterion, we assessed whether it was explicitly represented and conceptually consistent with the target trial; criteria meeting both were classified as mapped. Eligibility criteria were categorized into 11 domains representing key demographic, clinical, and safety considerations. Our search identified 200 studies, of which 47 reported the results of 74 individual target trial emulations. Of these 74, 42 (56.8%) were emulations of actual clinical trials and 32 (43.2%) were emulations of hypothetical target trials. Most target trial emulations used registry data (30, 40.5%) or electronic health records (29, 39.2%) as their primary data sources. Emulations of actual clinical trials specified a median of 29 (interquartile range [IQR] 25.0-34.0) eligibility criteria and mapped a median of 35.5% (IQR 27.3%-40.6%) of these criteria per emulation, whereas emulations of hypothetical trials specified a median of 5.5 (IQR 4.3-12.8) eligibility criteria and mapped a median of 91.7% (IQR 70%-100%) of these criteria per emulation. Among 1,222 individual criteria, demographic criteria were most frequently mapped (46, 93.9%), while safety and concomitant risk-related criteria were least frequently mapped (7, 3.7%). The most common mapping method was direct mapping using administrative coding systems (37, 72.5%); no studies reported using common data models or computational methods. This scoping review of oncology target trial emulations found substantial heterogeneity in how eligibility criteria were mapped, with potential implications for emulation results. These findings highlight the need for greater transparency and for methods that extend beyond reliance on structured administrative codes.

Target Trial Emulation—A Unifying Approach for Causal Inference From Observational Data