Edward Chia-Cheng Lai

Aims: To compare cardiorenal outcomes, mortality and safety between sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) in adults with Type 2 diabetes (T2D). Materials and Methods: We conducted a retrospective, new‐user cohort study using the TriNetX global federated health research network. We identified 249 237 propensity score‐matched pairs (498 474 total patients) who initiated SGLT‐2i or GLP‐1 RA between 2018 and 2023. The primary outcome was a kidney failure/death composite, defined as kidney failure, dialysis, kidney transplantation or all‐cause mortality. Secondary outcomes included composite cardiovascular events, mortality and safety profiles. Results: SGLT‐2i initiation was associated with a lower risk of the kidney failure/death composite compared with GLP‐1 RA (HR: 0.87, 95% CI: 0.85–0.89). For the kidney‐specific component, SGLT‐2i initiation was associated with a lower risk of kidney failure, dialysis or kidney transplantation (HR: 0.74, 95% CI: 0.71–0.78), while all‐cause mortality was also lower (HR: 0.90, 95% CI: 0.88–0.93). The composite cardiovascular outcome (myocardial infarction, stroke, acute heart failure, cardiogenic shock, cardiac arrest or death) was broadly comparable between groups (HR: 0.98, 95% CI: 0.97–1.00). Conclusions: SGLT‐2i initiation was associated with lower risks of kidney failure‐related outcomes and all‐cause mortality compared with GLP‐1 RA initiation, while cardiovascular outcomes were broadly comparable. These findings may inform individualized treatment selection in adults with T2D.

Hyponatremia poses risks in type 2 diabetes, yet comparative electrolyte safety across glucose‐lowering therapies remains unclear. We evaluated the risk of incident hyponatremia associated with sodium–glucose cotransporter 2 (SGLT2) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), and dipeptidyl peptidase‐4 (DPP‐4) inhibitors in real‐world practice. Using electronic health records from 155 healthcare organizations in the TriNetX Global Collaborative Network, we conducted multicenter active‐comparator, new‐user target trial emulations with 1:1 propensity score matching. For each pairwise comparison, adults with type 2 diabetes initiating either drug class, with no record of either class during the preceding 365 days, were included. The primary outcome was incident hyponatremia (ICD‐10‐CM E87.1 or serum sodium ≤ 135 mmol/L); sensitivity outcomes included diagnosis‐only, laboratory‐only, and stricter laboratory thresholds. Among more than 300,000 matched pairs per comparison, SGLT2 inhibitors and GLP‐1 RAs were each associated with a 15% lower hazard of hyponatremia than DPP‐4 inhibitors (hazard ratio [HR], 0.850; 95% confidence interval [CI], 0.842–0.858 and HR, 0.847; 95% CI: 0.838–0.856). The lower risk persisted at stricter sodium thresholds and across clinically relevant subgroups, including patients with heart failure, chronic kidney disease, or high‐risk medications use. SGLT2 inhibitors and GLP‐1 RAs were broadly comparable (HR, 0.962; 95% CI: 0.952–0.971). Positive and negative control outcomes were consistent with expectations. Overall, SGLT2 inhibitors and GLP‐1 RAs were associated with a lower risk of incident hyponatremia than DPP‐4 inhibitors. These real‐world findings provide reassurance regarding the electrolyte safety of SGLT2 inhibitors and GLP‐1 RAs, complementing their established cardiorenal benefits.

Background and Objectives: This study compared the risks of rotator cuff disease and rotator cuff repair surgery in patients receiving dipeptidyl peptidase 4 inhibitors (DPP4is), thiazolidinediones (TZDs), and sulfonylureas (SUs). Materials and Methods: A retrospective cohort analysis of Taiwan’s National Health Insurance Research Database was conducted to identify patients with type 2 diabetes mellitus who were newly prescribed DPP4is, TZDs, or SUs between 2012 and 2020. The outcomes of interest were rotator cuff disease and rotator cuff repair surgery. Cox proportional hazard regression models were used to calculate HRs with 95% CIs for the outcomes. Results: Initially, 334,322 DPP4is users, 87,738 TZDs users, and 928,479 SUs users were included. After propensity scores with inverse probability of treatment weighting were calculated with 5% trimming, Sus users had a significantly lower risk of rotator cuff disease than DPP4is users (HR 0.914, 95% CI: 0.898–0.930) and TZDs users (HR 0.887, 95% CI: 0.871–0.904) did, and DPP4is users had a significantly lower risk of this disease than TZDs users had (0.956, 95% CI: 0.926–0.986). As for the risk of rotator cuff repair surgery, the effect sizes did not reach statistical significance. Conclusions: SUs users had the lowest risk of rotator cuff disease, followed by DPP4is and TZDs users.

Background: Cannabis use has reached historic highs worldwide, yet its long-term vascular safety remains uncertain. Evidence linking cannabis to venous thromboembolism derives largely from hospitalised trauma and surgical cohorts and is inconsistent. We examined whether cannabis use disorder is associated with incident venous thromboembolism over 10 years. Methods: Retrospective cohort study in the TriNetX US Collaborative Network, a federated electronic health record database. Adults aged ≥ 18 years with ≥ 2 encounters during 2014 were eligible, and cohort entry was the first emergency department visit in 2015. Cannabis use disorder required ≥ 2 abuse or dependence diagnoses during 2014 and ≥ 1 within the year preceding cohort entry; controls had no cannabis-related diagnosis recorded before entry. Patients were matched 1:1 on 36 prespecified covariates by propensity score and followed from day 90 to day 3,650. Hazard ratios were estimated with Cox models. Prespecified analyses varied the follow-up window, landmark period and exposure definition, and included positive control outcomes. Results: Of 5,162 exposed and 1,035,374 unexposed patients, 5,031 pairs were matched, with all standardized mean differences 0.06 or below and mean follow-up of 7.8 and 7.6 years. Cannabis use disorder was not associated with venous thromboembolism over 10 years (hazard ratio 1.01, 95% confidence interval 0.85 to 1.21), deep vein thrombosis (1.06, 0.85 to 1.32), pulmonary embolism (0.97, 0.78 to 1.20) or all-cause mortality (1.00, 0.91 to 1.11). Before matching, cannabis use disorder was associated with higher hazards of venous thromboembolism (1.14, 1.02 to 1.29), pulmonary embolism (1.33, 1.15 to 1.54) and all-cause mortality (1.23, 1.15 to 1.32). Estimates were similar across 1-year and 5-year windows, a 30-day landmark period, alternative exposure definitions and prespecified subgroups, whereas cyclical vomiting syndrome, a positive-control proxy for cannabinoid hyperemesis syndrome, was strongly associated (1.99, 1.44 to 2.74). Conclusions: Among adults presenting for emergency care, cannabis use disorder was not associated with an increased 10-year risk of venous thromboembolism. The crude association was attenuated after matching on comorbidity and concurrent substance use. These findings do not exclude a modest effect and do not extend to post-traumatic or perioperative settings.

Emerging evidence suggests potential respiratory benefits from sodium‐glucose cotransporter 2 (SGLT2) inhibitors, a glucose‐lowering agent. However, the effects of these agents on asthma exacerbations remain unclear. A retrospective cohort study used Taiwan's National Health Insurance Research Database, covering 2016–2020, and included adults with type 2 diabetes and asthma. Exposure was defined as the initiation of SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors, and the primary outcome was asthma exacerbation, defined as an asthma diagnosis accompanied by systemic corticosteroid use. Demographic characteristics, comorbidities, the Adapted Diabetes Complications Severity Index and concomitant medications were used to estimate propensity scores, and inverse probability of treatment weighting was applied. Altogether, 3,057 initiators of SGLT2 inhibitors and 15,050 initiators of DPP4 inhibitors were identified and followed from the index date until the occurrence of asthma exacerbation, death, or the end of the observation period (May 31, 2020). Over a mean follow‐up of 2.06 years, initiation of SGLT2 inhibitors was associated with a lower risk of asthma exacerbation (HR: 0.87, 95% CI: 0.81–0.93), corresponding to incidence rates of 3.73 vs. 4.03 events per 100 person‐years. The results were consistent across care settings, including outpatient‐ (HR: 0.88, 95% CI: 0.80–0.96), inpatient‐ (HR: 0.88, 95% CI: 0.78–1.00), and emergency department visits (HR: 0.72, 95% CI: 0.63–0.83), as also across subgroup and sensitivity analyses. Among adults with type 2 diabetes and asthma, initiation of SGLT2 inhibitors was associated with a reduced risk of asthma exacerbation, highlighting a potential respiratory benefit that warrants confirmation through future clinical trials.

Background: Evolocumab reduces major adverse cardiovascular events in randomized trials, but evidence of its effectiveness in real‐world clinical practice remains limited. Methods: US adults with atherosclerotic cardiovascular disease who initiated evolocumab between 2017 and 2023 were identified from the Komodo Healthcare Map. At day 75 after initiation (index date), patients were classified as treated (remained on evolocumab) or nontreated (discontinued evolocumab before day 75). Patients were followed until the earliest of outcome occurrence, evolocumab discontinuation (treated group) or reinitiation (nontreated group), insurance disenrollment, end of database, or death. The primary outcome was a composite of myocardial infarction, stroke, or coronary revascularization; the secondary outcome was a composite of myocardial infarction, stroke, or cardiovascular disease death. Four‐year cumulative incidence, risk ratios (RR), and 95% CIs were estimated, adjusting for confounders and informative censoring using inverse probability of treatment and censoring weights. Negative control outcomes were used to assess residual confounding before initiating comparative outcome analyses. Results: After weighting, baseline characteristics were well balanced between treated (n=87 102) and nontreated (n=24 609) groups. At 4 years, treated patients had a 20% lower risk of the primary outcome (RR, 0.80 [95% CI, 0.73–0.86]) and a 29% lower risk of the secondary outcome (RR, 0.71 [95% CI, 0.64–0.78]) compared with nontreated patients. Conclusions: In a large, diverse, real‐world population with atherosclerotic cardiovascular disease, evolocumab use was associated with significant reductions in major adverse cardiovascular events, supporting the effectiveness of guideline‐recommended PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor therapy in routine clinical practice.

Whether direct oral anticoagulants (DOACs) are an effective alternative to warfarin in patients with atrial fibrillation and mitral stenosis is unclear. In this study of 1034 Asian patients, DOACs ... Visual Real-World Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Mitral Stenosis Whether direct oral anticoagulants (DOACs)... Background: Whether direct oral anticoagulants (DOACs) are a safe and effective alternative to warfarin in patients with atrial fibrillation and mitral stenosis (AF-MS) remains controversial. Objec...

Background: Guidelines across countries demonstrate a lack of consensus regarding continued treatment with antidepressants during pregnancy, but little is known about how prescribing patterns vary in clinical practice.Methods: This cohort study used individual-level healthcare databases from Australia (2014-2019); Denmark (2010-2023); Hong Kong (2010-2022); Norway (2009-2020); South Korea (2016-2023); Sweden (2010-2022); Taiwan (2010-2021); and the UK (2010-2021). Individuals with ≥1 prescriptions or dispensings of antidepressants in each half of the 1-year pre-pregnancy period were included. We assessed antidepressant use in the year before pregnancy, during pregnancy, and in the year after delivery, including continuation rate, temporal trends, and switching patterns.Findings: We identified a total of 194,495 pregnancies from all collaborating sites. European countries, Australia, and Hong Kong exhibited substantially higher continuation rates (≥30%), which increased steadily over time (annual absolute change [%p/year]: Australia: +1.3; Denmark: +1.9; Hong Kong +1.3; Norway: +0.8; Sweden: +3.7; UK: +1.5). Conversely, less than one in ten pregnancies in South Korea and Taiwan continued treatment and the rate remained consistently low throughout the study period (South Korea: 0.0; Taiwan: +0.6). They also had relatively higher proportions of postpartum treatment reinitiators. Lastly, sertraline, a commonly recommended antidepressant for pregnant women, was the most frequently switched-to agent across countries.Interpretation: We observed substantial variation in the continuation rates and annual trends, potentially attributed to differences in national guidelines as well as underlying cultural contexts and healthcare systems. These findings emphasize the need for internationally harmonized clinical guidelines, grounded in robust evidence on the safety of antidepressant use during pregnancy, to promote optimal management of pregnant women with psychiatric conditions while supporting both maternal and fetal health.Funding: MFDS, South Korea (RS-2024-00393167); NRF, South Korea (RS-2026-25474077); SKKU fellowship program, South Korea; Hong Kong Research Grants Council General Research Fund (17114921); NSTC, Taiwan (NSTC 114-2628-B-006-005-).