Citations

OBJECTIVE To examine kidney disease outcomes associated with dipeptidyl peptidase 4 inhibitors (DPP-4i). RESEARCH DESIGN AND METHODS In this target trial emulation, claims data from enrollees in commercial, Medicare Advantage, and traditional Medicare health plans were used to identify adults ≥21 years old with type 2 diabetes, with moderate cardiovascular risk, and without stage 3 or worse chronic kidney disease (CKD) initiating alogliptin, linagliptin, saxagliptin, or sitagliptin between 2014 and 2021. The primary outcome was a composite of incident CKD stages 3–5, kidney failure, or kidney replacement therapy. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method and incorporated as inverse probability of treatment weights into proportional hazards models. RESULTS The weighted study cohort included 3,026 individuals starting alogliptin, 38,213 starting linagliptin, 14,934 starting saxagliptin, and 115,091 starting sitagliptin. One year after treatment initiation, the primary outcome occurred in 1.4%, 2.7%, 2.2%, and 2.4% of patients initiating alogliptin, linagliptin, saxagliptin, and sitagliptin, respectively, increasing to 3.2%, 6.2%, 5.0%, and 5.4%, respectively, at 3 years. Alogliptin was associated with lower risk of stage 3 or worse CKD than linagliptin (hazard ratio [HR] 0.50; 95% CI 0.37–0.69), saxagliptin (HR 0.63; 95% CI 0.45–0.86), and sitagliptin (HR 0.58; 95% CI 0.42–0.79), while saxagliptin was associated with lower risk than linagliptin (HR 0.80; 95% CI 0.73–0.87). Conversely, linagliptin was associated with higher risk than sitagliptin (HR 1.15, 95% CI 1.10–1.21). CONCLUSIONS Alogliptin was associated with lower risk of moderate-to-severe kidney disease than other DPP-4i, while linagliptin was associated with higher risk. Limitations include lack of laboratory data and potential unmeasured confounding.

PURPOSE Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780 ). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score–matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Introduction To assess the within-class variation in kidney outcomes following initiation of sulfonylurea therapy. Research design and methods We used claims data of enrollees in commercial, Medicare Advantage, and traditional Medicare health plans between 2014 and 2021 to emulate a target trial including adults ≥21 years with type 2 diabetes at moderate cardiovascular risk to compare initiation of glimepiride, glipizide, or glyburide on the incidence of chronic kidney disease (CKD) stage 3 or worse, including initiation of kidney replacement therapy (primary outcome); secondary outcomes examined incident CKD stages 3-4, kidney failure (including kidney replacement therapy), all-cause mortality, and hypoglycemia requiring emergency department or hospital care. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method, and incorporated as inverse probability of treatment weights into proportional hazards models. Results The weighted study cohort included 295 092 individuals starting glimepiride (n=134 926), glipizide (n=145 984), and glyburide (n=14 182). One year after treatment initiation, stage 3 or worse CKD developed in 2.1% of patients in the glimepiride group, 2.2% in the glipizide group, and 1.8% in the glyburide group. Glyburide was associated with a lower risk of kidney complications compared with both glimepiride (HR 0.84, 95% CI 0.76 to 0.92) and glipizide (HR 0.81, 95% CI 0.73 to 0.89), despite a higher risk of severe hypoglycemia (HR 1.47, 95% CI 1.27 to 1.71 vs glipizide and HR 1.22, 95% CI 1.05 to 1.42 vs glimepiride). In contrast, the risk of kidney complications was modestly increased with glipizide compared with glimepiride use (HR 1.04, 95% CI 1.00 to 1.07). Conclusions Glyburide was associated with a modestly lower risk of kidney complications, despite a higher risk of hypoglycemia, while glipizide was associated with a higher risk of kidney complications. These hypothesis-generating findings suggest important within-class differences that warrant consideration in clinical decision-making and future research. Despite rigorous prespecified causal inference analytic methods, the risk of unmeasured confounding and bias by indication with the use of observational data remains. Trial registration number NCT05214573 .

Background SGLT2 (sodium‐glucose cotransporter 2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetes. However, no direct comparison of individual SGLT2 inhibitor drugs has been conducted, particularly among adults with moderate cardiovascular risk who comprise most people with type 2 diabetes. Methods We used data for commercial, Medicare Advantage, and Medicare fee‐for‐service beneficiaries to emulate a target trial of adults (≥21 years) with type 2 diabetes and moderate cardiovascular risk who started canagliflozin, dapagliflozin, or empagliflozin between 2015 and 2020. We estimated propensity scores using the super learner ensemble method and incorporated them as inverse probability of treatment weights into Cox models, estimating risk of MACE, expanded MACE, and hyperglycemic and hypoglycemic crises through December 31, 2022. Results The weighted cohort, balanced on all baseline covariates, included 137 232 patients (mean age 65.7 years [SD, 8.1], 75.3% non‐Hispanic White, 57.0% male, 81.9% on metformin, 11.4% on glucagon‐like peptide‐1 receptor agonists) starting canagliflozin (N=42 877), dapagliflozin (N=17 871), or empagliflozin (N=7648). The risk of MACE was lower among patients starting empagliflozin versus canagliflozin (hazard ratio [HR], 0.92 [95% CI, 0.87–0.97]), driven by reduced risk of all‐cause mortality (HR, 0.86 [95% CI, 0.80–0.94]). There was no difference in MACE between empagliflozin versus dapagliflozin or dapagliflozin versus canagliflozin therapy. There was no difference in remaining outcomes between the three drugs. Conclusions The 3 most used SGLT2 inhibitor medications demonstrate similar effectiveness on cardiovascular outcomes among patients with type 2 diabetes at moderate cardiovascular risk, with differences between these drugs small in magnitude. Clinicians and health systems should prioritize enhancing access to these cardioprotective therapies.

Introduction To examine within-class sulfonylurea safety, we compared risks of major adverse cardiovascular events (MACE) and severe hypoglycemia among adults with type 2 diabetes (T2D) and moderate cardiovascular risk following sulfonylurea initiation. Research design and methods We conducted a target trial emulation including adults ≥21 years old with T2D and moderate cardiovascular risk who initiated glimepiride, glipizide or glyburide between 2014 and 2021, using claims data from Optum Labs Data Warehouse and the Medicare fee-for-service 100% sample. Study outcomes were MACE (primary), expanded MACE and its components and emergency department or hospital encounters for hypoglycemia, ascertained during follow-up through 2022. Inverse probability of treatment weighting (IPTW) was applied using propensity scores estimated using the super learner ensemble, and outcomes were examined using IPTW Cox proportional hazards models. Results The weighted study cohort comprised 314 699 patients (mean age 66.9 years, 52.0% men, 76.6% non-Hispanic white). At 1 year, MACE was experienced by 2.5%, 2.7% and 2.8% of patients starting glimepiride, glipizide and glyburide, respectively. Compared with glimepiride, glyburide and glipizide were associated with higher risk of MACE (HR 1.10, 95% CI 1.05 to 1.16 for glyburide; HR 1.05, 95% CI 1.03 to 1.07 for glipizide). At 1 year, severe hypoglycemia was experienced by 0.3%, 0.3% and 0.4% of patients starting glimepiride, glipizide and glyburide, respectively. Glyburide was associated with a greater risk of severe hypoglycemia compared with glipizide (HR 1.43, 95% CI 1.23 to 1.65), while glipizide was associated with a lower risk compared with glimepiride (HR 0.82, 95% CI 0.77 to 0.87). Conclusions Among adults with T2D and moderate cardiovascular risk, glimepiride was associated with lowest risk of MACE and glipizide with lowest risk of severe hypoglycemia. These results can help inform treatment selection if sulfonylureas are used for glucose-lowering.

Abstract Background: Immune checkpoint inhibition (ICI) in combination with chemotherapy is associated with improved outcomes in a subset of patients with triple negative breast cancer (TNBC). However, biomarkers for predicting patient response, such as PD-L1 expression, have limited predictive efficiency. Voabil et al. has shown that ex vivo cytokine profiling of live tumor tissue resections treated with αPD-1 can predict patient response to ICI (Voabil et al., Nat Med. 2021). However, this method requires large amounts of tissue to address intra-specimen tumor heterogeneity, which is not feasible with standard of care (SOC) diagnostic core needle biopsies (CNBs) for breast cancer, where tissue is scarce. We show for the first time that ex vivo cytokine profiling is possible in live tumor fragments (LTFs) generated from CNBs in breast tissue. Methods: We present a cytokine profiling platform to assess response to ICI treatment in LTFs generated from CNBs. CNBs were collected from patients who were identified as potential candidates for SOC ICI (by treating physician) and enrolled in one of two prospective observational clinical trials (NCT05520099 and NCT06349642). CNBs were cut by an automated, proprietary cutting instrument to generate LTFs ofapproximately 300 µm in thickness. To address tissue heterogeneity and mitigate tissue scarcity in CNBs, we used a sequential treatment strategy in which control and ICI treatment were applied to LTFs in the same well, in a phased approach. This strategy provides a solution for the variability observed in cross-well comparisons. LTFs were encapsulated in hydrogel and treated with IgG control followed by αPD-1 (BioXCell). Cytokine production rates were measured longitudinally using multiplex assays assessing>45 cytokines, including 15 cytokines assayed by Voabil et al., and the fold changes of cytokine production rates in response to ICI over IgG control were calculated. Results: Using non-breast tumor tissue, we validated that our platform can measure changes in cytokine production in LTFs following sequential treatment, and that these measurements are comparable to those observed in a cross-well setting. In a small cohort of TNBC specimens, we show changes in cytokine production rates in response to ex vivo sequential control and ICI treatment. Ten cytokines, including IFN-γ and CXCL10, shown to be predictive of patient response to ICI in Voabil et al. were found upregulated in response to αPD-1 in TNBC specimens. Future determination of correlation with clinical response data (pathological complete response for early stage and RECIST 1.1 for metastatic patients) gathered from NCT05520099 and NCT06349642 will be used to validate platform responders and non-responders. To date, 11 patients with confirmed TNBC diagnoses have enrolled in these clinical studies. Conclusion: We report, for the first time to our knowledge, the ability to detect immune checkpoint inhibitor responses in live TNBC tissue obtained via CNBs. This proof-of-concept lays the groundwork for integrating functional tissue responses with clinical correlation data, with important implications for guiding current ICI therapies and advancing this platform for use in next-generation immuno-oncology treatments for TNBC. Citation Format: P. P. Advani, J. Harvey, J. Polley, M. Weidner, A. Arnold, D. Haley, R. Bollam, R. Rao, S. Chumsri, K. Hugghins, M. Acampora, C. Vivelo, H. Hernan, L. Hrycyniak, J. Zweng, H. Gierman, S. Bhattacharya, D. Mukhopadhyay. Ex vivo cytokine profiling of live triple negative breast cancer patient specimens from core needle biopsies illustrates proof of concept to assess tumor response to immune checkpoint inhibition [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-08.

Importance Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described. Objective To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors. Design, Setting, and Participants This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025. Exposures PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors. Main Outcomes and Measures Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated. Results A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors. Conclusions and Relevance In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.

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.

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

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.