Non-alcoholic fatty liver disease risk with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes: a nationwide nested case-control study.

BACKGROUND: Non-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive. METHODS: A nested case-control study was conducted using Taiwan's National Health Insurance Research Database for 2011-2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual's age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed. RESULTS: There were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46-1.52] and 0.85 [0.63-1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38-0.97]). CONCLUSION: GLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Long-term use and risk of major adverse cardiac events: Comparing enzalutamide and abiraterone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

Guillain-​Barré Syndrome Associated with COVID-19 Vaccination.

We conducted a multi-institutional study in Taiwan and a systematic review of the literature for reports of Guillain-​Barré syndrome after coronavirus disease vaccination. This condition, mostly the classic form and the acute inflammatory demyelinating polyneuropathy subtype, has been reported in 39 cases and has occurred within 2 weeks of vaccine administration.

Differences in outcomes of hospitalizations for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease.

BACKGROUND: The treatment effects on hospitalization for heart failure (hHF) from sodium-glucose cotransporter 2 (SGLT2) inhibitors may vary among type 2 diabetes (T2D) patients depending on whether or not they have established atherosclerotic cardiovascular diseases (ASCVD). We aimed to examine differences in hHF outcomes after dapagliflozin or empagliflozin use between T2D patients with and without a history of established ASCVD. METHODS: We conducted a retrospective multi-institutional cohort study in Taiwan. We included T2D patients newly receiving dapagliflozin or empagliflozin during 2016-2019, and followed them up until December 31, 2020. We implemented 1:1 propensity score matching to create homogenous groups for comparisons. We generated Cox proportional hazard models to compare the risk of hHF between dapagliflozin and empagliflozin (reference group). We included interaction terms of SGLT2 inhibitor and ASCVD history in the regression models to examine effect modification by ASCVD. RESULTS: We included a total cohort of 9,586 dapagliflozin new users and 9,586 matched empagliflozin new users. The overall hHF risks were similar for dapagliflozin and empagliflozin (HR: 0.90, 95% CI 0.74-1.09). However, differential hHF risks between dapagliflozin and empagliflozin were observed only in the subgroup without ASCVD (HR: 0.67, 95% CI 0.49-0.90), while not in the subgroup with ASCVD (HR: 1.12, 95% 0.87-1.45), and the p-value for examining interaction was 0.0097. CONCLUSION: In this study, history of established ASCVD was associated with different hHF risks among SGLT2 inhibitors. For T2D patients without ASCVD, dapagliflozin may offer a more favorable hHF reduction effect, compared to empagliflozin, in clinical practice. Future prospective studies should be conducted to validate our findings.

Comparative effectiveness of dulaglutide versus liraglutide in Asian type 2 diabetes patients: a multi-institutional cohort study and meta-analysis.

BACKGROUND: Head-to-head comparison of clinical effectiveness between dulaglutide and liraglutide in Asia is limited. This study was aimed to assess the real-world comparative effectiveness of dulaglutide versus liraglutide. METHODS: We conducted a retrospective cohort study by utilizing multi-institutional electronic medical records to identify real-world type 2 diabetes patients treated with dulaglutide or liraglutide during 2016-2018 in Taiwan and followed up until 2019. Effectiveness outcomes were assessed at every 3 months in the 1-year follow-up. Propensity score techniques were applied to enhance between-group comparability. Significant differences in changes of effectiveness outcomes between treatment groups during the follow-up were examined and further analyzed using mixed-model repeated-measures approaches. RESULTS: A total of 1512 subjects receiving dulaglutide and 1513 subjects receiving liraglutide were identified. At 12 months, significant HbA1c changes from baseline were found in both treatments (dulaglutide: - 1.06%, p < 0.001; liraglutide: - 0.83%, p < 0.001), with a significant between-group difference (- 0.23%, 95% confidence interval - 0.38 to - 0.08%, p < 0.01). Both treatments yielded significant declines in weight, alanine aminotransferase level, and estimated glomerular filtration rate from baseline (dulaglutide: - 1.14 kg, - 3.08 U/L and - 2.08 mL/min/1.73 m2, p < 0.01; liraglutide: - 1.64 kg, - 3.65 U/L and - 2.33 mL/min/1.73 m2, p < 0.001), whereas only dulaglutide yielded a significant systolic blood pressure reduction (- 2.47 mmHg, p < 0.001). Between-group differences in changes of weight, blood pressure, and liver and renal functions at 12 months were not statistically significant. CONCLUSIONS: In real-world T2D patients, dulaglutide versus liraglutide was associated with better glycemic control and comparable effects on changes of weight, blood pressure, and liver and renal functions.

Favorable pleiotropic effects of sodium glucose cotransporter 2 inhibitors: head-to-head comparisons with dipeptidyl peptidase-4 inhibitors in type 2 diabetes patients.

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors have shown greater reductions of cardiovascular event risks than dipeptidyl peptidase-4 (DPP4) inhibitors, whereby possible mechanisms may involve the better pleiotropic effects of SGLT2 inhibitors. However, no published data are currently available to directly compare glycemic and pleiotropic effects in real-world type 2 diabetes patients initiating SGLT2 inhibitors or DPP4 inhibitors. METHOD: We conducted a retrospective cohort study by analyzing the Chang Gung Research Database, the largest multi-institutional electronic medical records database in Taiwan. We included patients newly receiving SGLT2 inhibitor or DPP4 inhibitor intensification therapy for type 2 diabetes from 2016 to 2017. We matched SGLT2 inhibitor users to DPP4 inhibitor users (1:4) by propensity scores to ensure comparable characteristics between the groups. We primarily evaluated 1-year post-treatment changes of hemoglobin A1c (HbA1c) after SGLT2 inhibitor or DPP4 inhibitor initiation, using two-tailed independent t-test. We also evaluated post-treatment changes in body weight, systolic blood pressure (SBP), alanine aminotransferase (ALT) and estimated glomerular filtration rate (eGFR) values, associated with SGLT2 inhibitors and DPP4 inhibitors. RESULTS: We identified a cohort of 2028 SGLT2 inhibitors and 8112 matched DPP4 inhibitors new users. SGLT2 inhibitors and DPP4 inhibitors showed similar HbA1c reductions (- 1.0 vs. - 1.1%; P = 0.076), but patients receiving SGLT2 inhibitors had greater improvements in body weight (- 1.5 vs. - 1.0 kg; P = 0.008), SBP (- 2.5 vs. - 0.7 mmHg; P < 0.001) and ALT values (- 4.1 vs. - 0.0 U/l; P < 0.001) and smaller declines in eGFR values (- 2.0 vs. - 3.5 ml/min/1.73 m2; P < 0.001) when compared to DPP4 inhibitors. CONCLUSION: SGLT2 inhibitors had glucose-lowering effects comparable to those of DPP4 inhibitors but more favorable pleiotropic effects on body weight, ALT and eGFR changes, potentially improving type 2 diabetes patients' cardio-metabolic disease risks.

Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study.

Clinical trials have indicated that sodium-glucose co-transporter-2 (SGLT2) inhibitors have a favourable effect on serum alanine aminotransferase (ALT) levels in people with type 2 diabetes (T2D), but supporting evidence from real-world studies is lacking. We identified patients with T2D who initiated SGLT2 inhibitors during the period 2016 to 2017 from Chang Gung Research Database, which covers 1.3 million individuals from seven hospitals (6% of the Taiwan population). We classified patients by baseline ALT level and evaluated changes in ALT values from baseline to 1 year after initiation of SGLT2 inhibitors. We identified 11 690 new users of SGLT2 inhibitors with a mean (SD) age of 59.3 (11.8) years. The mean (SD) glycated haemoglobin and ALT levels were 8.9 (1.7)% and 34.7 (28.9) U/L at baseline, respectively. The mean change in ALT levels was -5.0 U/L (95% confidence interval [CI] -6.4, -3.5) 1 year after initiation of SGLT2 inhibitors. In patients with ALT levels ≤1× the upper limit of normal (ULN), the change in ALT levels was 1.6 U/L (95% CI -0.1, 3.4), while in those with ALT levels >1× ULN, the change in ALT levels was -26.5 U/L (95% CI -28.6, -24.3). The higher the baseline ALT level, the greater the decline after SGLT2 inhibitor treatment. Our findings suggest the initiation of SGLT2 inhibitors for T2D management could improve serum ALT levels in clinical practice, particularly in patients with especially high ALT levels.

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study.

BACKGROUND: To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. METHODS: We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium-glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients' age, sex, laboratory data, co-morbidities, and concomitant medications. RESULTS: We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73-1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14-2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49-1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80-1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49-0.95). CONCLUSION: The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

Dipeptidyl peptidase-4 inhibitor use is associated with decreased risk of fracture in patients with type 2 diabetes: a population-based cohort study.

AIMS: The aim of this study was to investigate the putative link between dipeptidyl peptidase-4 inhibitor (DPP-4i) use and the risk of fracture in patients with type 2 diabetes. METHODS: This propensity-score-matched population-based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3996 patients with type 2 diabetes used DPP-4i as a second-line antidiabetic drug. The same number of matched non-DPP-4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause-specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP-4i use and overall and cause-specific fractures stratified by age and sex. RESULTS: Over a maximum follow-up period of 5 years, 340 DPP-4i users and 419 non-DPP-4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1000 people per year, respectively. The Cox proportional hazard model revealed that DPP-4i use significantly reduced the risk of all-cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74-0.99) and 0.75 (95% CI: 0.59-0.95), respectively. The aforementioned associations of DDP-4i use with fracture were sustained across sex and age stratifications. CONCLUSIONS: The results of this study supported the premise that DPP-4i usage is associated with a reduced risk of all-cause fractures and upper extremity fractures in patients with type 2 diabetes.

Comparative cardiovascular risks of dipeptidyl peptidase 4 inhibitors with other second- and third-line antidiabetic drugs in patients with type 2 diabetes.

AIMS: Dipeptidyl peptidase 4 inhibitors (DPP4is) are suggested as a second- and third-line antidiabetic treatment for type 2 diabetes. Previous studies assessed only the cardiovascular effects of DPP4is as a second-line treatment, included sulphonylurea as the only comparator, and yielded inconclusive results on the risk of heart failure. The present study therefore evaluated the comparative cardiovascular risks of DPP4is with other second- and third-line antidiabetic drugs. METHODS: Based on a large nationwide diabetic cohort, 113 051 patients with type 2 diabetes newly on metformin-based dual or triple therapy were identified in 2009-2011 and followed until 2013, or death if this occurred sooner. Primary interest targeted hospitalizations for ischaemic stroke, myocardial infarction and heart failure. Secondary outcomes were hypoglycaemia and all-cause mortality. Cox proportional hazards models were performed to assess time-to-event hazard ratio between propensity score-matched antidiabetic treatment groups. RESULTS: DPP4is as a second-line add-on to metformin had a significantly lower stroke risk [hazard ratio (HR) 0.817 (95% confidence interval 0.687, 0.971)] and all-cause mortality [HR 0.825 (0.687, 0.992)] than those for sulphonylurea. DPP4is as a third-line add-on to metformin and sulphonylurea combined dual therapy had a significantly lower risk for stroke [HR 0.826 (0.740, 0.923)] and all-cause mortality [HR 0.784 (0.701, 0.878)] than those for acarbose, and significantly lower risks for stroke [HR 0.653 (0.542, 0.786)], heart failure [HR 0.721 (0.568, 0.917)] and all-cause mortality [HR 0.689 (0.594, 0.703)] than those for meglitinide. CONCLUSIONS: DPP4is as a second- or third-line add-on treatment provided cardiovascular benefits and posed no increased risks for heart failure, hypoglycaemia or death.

Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study.

BACKGROUND: Several antidiabetic drugs (i.e., sulfonylureas; SU, rosiglitazone) have been reported to be associated with increased risks of cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP4i) are newly available antidiabetic drugs. Most studies only compared DPP4i with a placebo or SU, or targeted a specific CVD event of interest (i.e., heart failure; HF). Comparative research of CVD risks of DPP4i with other antidiabetic drugs (i.e., metformin, thiazolidinediones, meglitinides, acarbose, and insulin) remains scarce. This study was aimed to assess comparative risks of CVD, including ischemic stroke, myocardial infarction (MI) and HF, and hypoglycemia of DPP4i with other antidiabetic drugs. METHODS: We utilized Taiwan's National Health Insurance Research Database. A total of 123,050 T2DM patients newly prescribed oral antidiabetic treatments were identified in 2009-2010 and followed until 2013. Outcome endpoints included a composite of CVD events: hospitalizations for ischemic stroke, MI and HF, and hypoglycemia. Time-varying Cox proportional hazards regression was applied to assess the time to event hazards of various antidiabetic drugs, adjusted for patients' demographics, comorbidity, diabetic complications, and co-medications. Additional analyses were performed for the patients with and without CVD history, respectively. RESULTS: DPP4i users had significantly lower CVD risks as compared to that of non-DPP4i users (adjusted hazard ratio [aHR]: 0.83, 95 % confidence interval [CI]: 0.76-0.91). Compared to DPP4i users, meglitinides (aHR 1.3, 95 % CI 1.20-1.43) and insulin users (aHR 3.73, 95 % CI 3.35, 4.14) had significantly higher risks for composite CVD, as well as those for stroke, MI, HF, and hypoglycemia. Additionally, metformin users had significantly lower risks for composite CVD risk (aHR 0.87, 95 % CI 0.79-0.94), as well as those for MI, HF, and hypoglycemia, as compared to those of DPP4i users. Although there was a trend toward low CVD risks in pioglitazone users, the role of potential confounding by indication cannot be excluded. CONCLUSIONS: DPP4i-treated T2DM patients had lower risks for CVD as compared to those for non-DPP4i users, except metformin users.

Real-world effectiveness of intravitreal dexamethasone implants - Comparison between eyes eligible and ineligible for clinical trials and their associated outcomes.

BACKGROUND: Concerns about the generalizability of pivotal randomized controlled trials (pRCTs) findings have been raised. We aimed to compare intravitreal dexamethasone implants' (IDIs) effectiveness for diabetic macular edema (DME) and central retinal vein occlusion (CRVO), between eyes eligible and ineligible for pRCTs. METHODS: This retrospective cohort study analyzed Taiwan's Chang Gung Research Database, including DME or CRVO eyes initiating IDIs during 2015-2020. We classified all treated eyes as eligible or ineligible for pRCTs following major selection criteria of the MEAD and GENEVA trials, and evaluated three-, six-, and twelve-month changes in central retinal thickness (CRT) and visual acuity (VA) after initiating IDIs. RESULTS: We included 177 IDI-treated eyes (DME: 72.3%; CRVO: 27.7%), of which 39.8% and 55.1% were ineligible for DME and CRVO pRCTs, respectively. LogMAR-VA and CRT changes at different times were comparable in DME eyes eligible (LogMAR-VA difference: 0.11 to 0.16; CRT difference: -32.7 to -96.9 µm) and ineligible (LogMAR-VA difference: -0.01 to 0.15; CRT difference: -54.5 to -109.3 µm) for the MEAD trial. By contrast, CRVO eyes ineligible for the GENEVA trial had greater LogMAR-VA changes (0.37 ~ 0.50) than those eligible (0.05 ~ 0.13), with comparable CRT reductions (eligible eyes: -72.3 to -106.4 µm; ineligible eyes: -61.8 to -110.7 µm) (all p-values <0.05 of the mean differences between eligible and ineligible CRVO eyes for all follow-ups). CONCLUSIONS: IDIs had similar VA and CRT outcomes among DME eyes, regardless of pRCT-eligibility. However, among CRVO eyes, those ineligible for pRCTs showed greater deterioration in VA than those eligible.

Risk of Thrombosis Following the First Dose of ChAdOx1 nCoV-19 Vaccine in Patients Undergoing Maintenance Hemodialysis: A Self-Controlled Case Series Study.

Background: The ChAdOx1 nCoV-19 vaccine is associated with vaccine-induced thrombosis and thrombocytopenia (VITT). Patients with end-stage renal disease (ESRD) under hemodialysis are at elevated risk of heparin-induced thrombocytopenia, which shares similar mechanisms with VITT. We aimed to examine the risk of VITT after the first dose of ChAdOx1 nCoV-19 vaccine using a self-controlled case series analysis (SCCS) in the hemodialyzed ESRD population. Methods: Drawing from the largest multi-center electronic medical records database in Taiwan, we identified adult patients, with or without hemodialysis, between 1st December, 2020, and 31st December, 2021, who received a first dose of ChAdOx1 nCoV-19 vaccine and had an outcome of thrombocytopenia, venous thrombosis, or arterial thrombosis. We calculated the incident rate ratios (IRRs) of outcomes in different periods at risk, compared to periods not at risk. Results:  We identified 59 hemodialysis patients and 41 non-dialysis patients with an outcome. The SCCS analyses showed, for the hemodialysis group, a significantly increased risk of outcomes during the period 31 to 60 days post-exposure to ChAdOx1 nCoV-19 vaccine (IRR: 2.823; 95% CI: 1.423-5.600). However, in non-dialysis patients there was no increase in risks during any of the post-exposure risk periods. Conclusion: For ESRD patients under hemodialysis, the first dose of ChAdOx1 nCoV-19 vaccine was associated with a 2.8-fold increase in risk of thrombosis.

Factors predictive of clinical outcome in advanced hepatocellular carcinoma patients receiving ramucirumab treatment: A real-world experience.

PURPOSE: The aim of this study was to investigate the factors predictive of clinical outcome in advanced hepatocellular carcinoma patients receiving ramucirumab treatment. METHODS: We conducted a retrospective study using a multi-institutional electronic medical records database in Taiwan. We included advanced HCC patients newly receiving ramucirumab as second-line or beyond systemic therapy between January 2016 and February 2022. The clinical outcomes were median progression-free survival (PFS) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST), overall survival (OS) and adverse events. We applied Kaplan-Meier methods to estimate median PFS and OS. Uni-variable and multi-variable Cox regression models were applied to identify the prognostic factors. RESULTS: We included 39 ramucirumab naive users with a median age of 65.5 (IQR: 57.0-71.0) years and treatment time of 5.0 (3.0-7.0) cycles, of whom 82.1% were male and 84.6% were Barcelona Clinic Liver Cancer (BCLC) stage C. After median follow-up time of 6.0 months, 33.3% of patients' AFP level had decreased more than 20% within 12 weeks. The median PFS and OS were 4.1 months and non-reach, respectively. Moreover, tumor burden beyond the up-to-11 criteria (HR: 2.95, 95% CI: 1.04-8.38) and a decrease in estimated glomerular filtration rate of more than 10% within 12 weeks (HR: 0.31, 0.11-0.88) were significantly related to PFS in the multi-variable analysis. No patient discontinued ramucirumab during the treatment on account of side effects. CONCLUSION: Ramucirumab was an effective treatment option with good AFP response for advanced HCC patients in real-world experience. Tumor burden beyond the up-to-11 criteria and a decrease in estimated glomerular filtration rate were independent predictive factors for progression-free survival.

Comparative Effectiveness and Safety of Standard-Dose and Low-Dose Pembrolizumab in Patients with Non-Small-Cell Lung Cancer: A Multi-Institutional Cohort Study in Taiwan.

Fixed doses at 200 mg of pembrolizumab or 2 mg/kg every 3 weeks are the standard dosages for first- and second-line treatment of non-small-cell lung cancer (NSCLC); however, in clinical practice, patients with NSCLC may receive lower doses of pembrolizumab due to drug product availability or economic factors. To date, the comparative effectiveness and safety of the standard dose and lower doses of pembrolizumab in these patients still remains limited. We conducted a retrospective cohort study by analyzing electronic medical records data from the largest multi-institutional hospital system in Taiwan. Advanced NSCLC patients newly receiving pembrolizumab with or without chemotherapy were included. Patients were classified into: (1) the standard-dose group (≥2 mg/kg), and (2) the low-dose group (<2 mg/kg). We applied inverse probability of treatment weighting (IPTW) to compare the overall survival (OS) and immune-related adverse events (irAEs) between the two treatment groups, and to evaluate the minimum clinically effective dose of pembrolizumab. We included a total of 147 NSCLC patients receiving standard-dose pembrolizumab (mean [range] age: 63.7 [58.0−73.0] years; male: 62.6%; mean [range] body weight: 60.5 [58.0−73.0] kg) and 95 patients receiving low-dose pembrolizumab (mean [range] age: 62.0 [50.0−68.8] years; male: 64.2%; mean [range] body weight: 63.9 [55.0−73.8] kg). After IPTW adjustments, the median OS was similar for both the standard-dose and low-dose pembrolizumab groups (19.3 vs. 14.3 months, log-rank p = 0.15). Also, the rate for all classes of irAEs was similar for both groups. We found that patients with a pembrolizumab dose ≥1.8 mg/kg were associated with better OS than those receiving <1.8 mg/kg. Our findings suggested no significant difference in OS and irAEs between patients receiving pembrolizumab ≥2 mg/kg and <2 mg/kg in clinical practice. A pembrolizumab dose ≥1.8 mg/kg may be the clinically most efficient dose.

Association between sodium glucose co-transporter 2 inhibitors and incident glaucoma in patients with type 2 diabetes: A multi-institutional cohort study in Taiwan.

PURPOSE: Type 2 diabetes (T2D) is an important risk factor for glaucoma, and sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to protect the optic nerves. We therefore aimed to evaluate the association between SGLT2 inhibitors and incident glaucoma. METHODS: This retrospective cohort study analyzed the largest multi-institutional electronic medical records database in Taiwan, containing data of over a million individuals. We included T2D patients newly prescribed SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) from 2016 to 2018. Our primary outcome was incident glaucoma diagnosis between initiation of SGLT2 inhibitors or GLP-1 RAs, and 31st March 2021. After applying inverse probability of treatment weighting (IPTW) to increase homogeneity between the two treatment groups, we estimated hazard ratios (HR) with 95% confidence intervals (CI) for the risk of glaucoma, based on Cox proportional hazards regression models. RESULTS: We included 9,927 and 1,065 T2D patients who had been newly prescribed SGLT2 inhibitors or GLP-1 RAs, respectively. Lower risk of incident glaucoma was observed in patients receiving SGLT2 inhibitors (7.9 events per 1,000 person-years), compared to those receiving GLP-1 RAs (10.0 events per 1,000 person-years), with an HR of 0.81 (95% CI: 0.69-0.95). Multiple sensitivity analyses and a negative control outcome analysis confirmed the robustness of our main findings. CONCLUSION: This study suggests that T2D patients newly prescribed SGLT2 inhibitors have a reduced risk of incident glaucoma, compared to those prescribed GLP-1 RAs, in clinical practice. Future prospective studies are suggested to confirm this association.

Comparison of Sodium-Glucose Cotransporter 2 Inhibitors vs Glucagonlike Peptide-1 Receptor Agonists and Incidence of Dry Eye Disease in Patients With Type 2 Diabetes in Taiwan.

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to improve low-grade systemic and tissue inflammation; however, the association between SGLT2 inhibitor use and the incidence of dry eye disease (DED) has not been explored. Objective: To investigate the association between SGLT2 inhibitor use and dry eye disease in patients with type 2 diabetes (T2D). Design, Setting, and Participants: A retrospective cohort analysis of the largest multi-institutional electronic medical records database in Taiwan was conducted to identify patients with T2D newly receiving SGLT2 inhibitors or glucagonlike peptide-1 receptor agonists (GLP-1 RAs) from 2016 to 2018. Data analysis was performed from March 1 to May 31, 2022. Propensity scores with inverse probability of treatment weighting were generated to enable homogeneous comparisons between the 2 groups. Exposures: Treatment with SGLT2 inhibitors or GLP-1 RAs. Main Outcomes and Measures: Incident dry eye disease, which was defined by clinical diagnoses, plus the related drug prescription. Cox proportional hazards regression models were used to estimate hazard ratios with 95% CIs for the risk of DED. Results: A total of 10 038 and 1077 T2D patients newly receiving SGLT2 inhibitors (mean [SD] age, 59.5 [12.1] years; 5689 [56.7%] men) or GLP-1 RAs (mean [SD] age, 58.5 [41.2] years; 587 [54.5%] men), respectively, were included in the analysis. The incidence of DED was lower in patients newly receiving SGLT2 inhibitors (9.0 events per 1000 person-years) compared with those receiving GLP-1 RAs (11.5 events per 1000 person-years), yielding a hazard ratio of 0.78 (95% CI, 0.68-0.89). Subgroup analyses indicated that the lowered DED risks associated with SGLT2 inhibitors in patients with T2D were similar across different age, sex, blood glucose level, and kidney function groups. Results from the sensitivity analyses (including the propensity score-matching approach, on-treatment analyses, and different follow-up periods of 1, 2, and 3 years) were similar to the main analyses. Conclusions and Relevance: The findings of this study suggest that patients with T2D newly receiving SGLT2 inhibitors may have a lower risk for DED compared with those receiving GLP-1 RAs. Prospective studies are needed to analyze these results.

Quantifying the Effects of Climate Factors on Carbon Monoxide Poisoning: A Retrospective Study in Taiwan.

Background: Carbon monoxide (CO) poisoning is the leading cause of poisoning death worldwide, but associations between CO poisoning and weather remain unclear. Objective: To quantify the influence of climate parameters (e.g., temperature, relative humidity, and wind speed) on the incidence risk of acute CO poisoning in Taiwan. Methods: We used negative binomial mixed models (NBMMs) to evaluate the influence of weather parameters on the incidence risk of acute CO poisoning. Subgroup analyses were conducted, based on the seasonality and the intentionality of acute CO poisoning cases. Results: We identified a total of 622 patients (mean age: 32.9 years old; female: 51%) with acute CO poisoning in the study hospital. Carbon monoxide poisoning was associated with temperature (beta: -0.0973, rate ratio (RR): 0.9073, p < 0.0001) but not with relative humidity (beta: 0.1290, RR: 1.1377, p = 0.0513) or wind speed (beta: -0.4195, RR: 0.6574, p = 0.0806). In the subgroup analyses, temperature was associated with the incidence of intentional CO poisoning (beta: 0.1076, RR: 1.1136, p = 0.0333) in spring and unintentional CO poisoning (beta: -0.1865, RR: 0.8299, p = 0.0184) in winter. Conclusion: Changes in temperature affect the incidence risk for acute CO poisoning, but the impact varies with different seasons and intentionality in Taiwan. Our findings quantify the effects of climate factors and provide fundamental evidence for healthcare providers to develop preventative strategies to reduce acute CO poisoning events.

APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling.

The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.

Sodium glucose co-transporter 2 inhibitors and cardiovascular event protections: how applicable are clinical trials and observational studies to real-world patients?

OBJECTIVE: This study evaluated the characteristics of new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) in clinical practice to assess the applicability of the findings from clinical trials (Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial, Canagliflozin Cardiovascular Assessment Study (CANVAS) program and the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS-CV) trial) and multinational observational studies (CVD-REAL Nordic study and CVD-REAL 2 study). RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using the largest electronic medical records database from seven hospitals in Taiwan. We included adult patients with type 2 diabetes initiating canagliflozin, dapagliflozin and empagliflozin between 1 January 2018 and 31 August 2019. We compared the patient characteristics with SGLT2i to examine the data representativeness of clinical trials and to evaluate channeling uses between canagliflozin, dapagliflozin and empagliflozin. RESULTS: We identified a cohort of 11 650 patients newly initiating SGLT2i, 49.9% of whom received empagliflozin. However, only 18.7%, 19.2%, 50.4% and 57.3% of real-world SGLT2i new users were included in the EMPA-REG OUTCOME trial, VERTIS-CV trial, DECLARE-TIMI 58 trial and CANVAS program, respectively. Reasons for exclusion were largely reduced cardiovascular disease risks in real-world patients, namely 72.8%, 73.6% and 34.2% for EMPA-REG OUTCOME trial, VERTIS-CV trial and DECLARE-TIMI 58 trial and CANVAS program, respectively. However, hemoglobin A1c out of range accounted for the most frequent reason (25.0%) for exclusion of real-world patients from the CANVAS program. We found channeling uses in different SGLT2i, for example, more patients receiving empagliflozin (15.3%) and canagliflozin (19.6%) had poorer renal functions (eg, estimated glomerular filtration rate <60 mL/min/1.73 m2), compared with dapagliflozin (9.3%). CONCLUSIONS: The findings provide clear evidence that results from current studies may be less applicable to real-world patients. Further studies are required to support the concept of real-world cardiovascular event protection through SGLT2i.