Lower risks of cirrhosis and hepatocellular carcinoma with GLP-1RAs in type 2 diabetes: A nationwide cohort study using target trial emulation framework.

BACKGROUND: To assess the association of cirrhosis and hepatocellular carcinoma (HCC) with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs), which are the two commonly prescribed injectable glucose-lowering agents (GLAs) for patients with type 2 diabetes (T2D) after the failure of multiple oral GLAs. METHODS: We emulated a target trial using the nationwide data of a Taiwanese cohort with T2D. Incident new users of GLP-1RAs and LAIs during 2013-2018 were identified, and propensity score (PS) matching was applied to ensure between-group comparability in baseline patient characteristics. The primary outcome was the composite liver disease including cirrhosis or HCC. Each patient was followed until the occurrence of a study outcome, death, or the end of 2019, whichever came first. Subdistribution hazard models were employed to assess the treatment-outcome association. Sensitivity (e.g., stabilized inverse probability of treatment weighting analysis, time-dependent analysis), E-value, and negative control outcome analyses were performed to examine the robustness of study findings. RESULTS: We included 7171 PS-matched pairs of GLP-1RA and LAI users with no significant between-group differences at baseline. Compared with LAIs, the use of GLP-1RAs was associated with significantly reduced risks of composite liver disease (subdistribution hazard ratio [95% confidence interval]: 0.56 [0.42-0.76]), cirrhosis (0.59 [0.43-0.81]), and HCC (0.47 [0.24-0.93]). Results were consistent across sensitivity analyses and among patients with different baseline characteristics. CONCLUSION: Among T2D patients who require injectable GLAs, the use of GLP-1RAs versus LAIs was associated with lower risks of cirrhosis and HCC.

Adaptation of risk prediction equations for cardiovascular outcomes among patients with type 2 diabetes in real-world settings: a cross-institutional study using common data model approach.

OBJECTIVE: To adapt risk prediction equations for myocardial infarction (MI), stroke, and heart failure (HF) among patients with type 2 diabetes in real-world settings using cross-institutional electronic health records (EHRs) in Taiwan. METHODS: The EHRs from two medical centers, National Cheng Kung University Hospital (NCKUH; 11,740 patients) and National Taiwan University Hospital (NTUH; 20,313 patients), were analyzed using the common data model approach. Risk equations for MI, stroke, and HF from UKPDS-OM2, RECODe, and CHIME models were adapted for external validation and recalibration. External validation was assessed by (1) discrimination, evaluated by the area under the receiver operating characteristic curve (AUROC) and (2) calibration, evaluated by calibration slopes and intercepts and the Greenwood-Nam-D'Agostino (GND) test. Recalibration was conducted for unsatisfactory calibration (p-value of GND test < 0.05) by adjusting the baseline hazards of original equations to address variations in patients' cardiovascular risks across institutions. RESULTS: The CHIME risk equations had acceptable discrimination (AUROC: 0.71-0.79) and better calibration than that for UKPDS-OM2 and RECODe, although the calibration remained unsatisfactory. After recalibration, the calibration slopes/intercepts of the CHIME-MI, CHIME-stroke, and CHIME-HF risk equations were 0.9848/- 0.0008, 1.1003/- 0.0046, and 0.9436/0.0063 in the NCKUH population and 1.1060/- 0.0011, 0.8714/0.0030, and 1.0476/- 0.0016 in the NTUH population, respectively. All the recalibrated risk equations showed satisfactory calibration (p-values of GND tests ≥ 0.05). CONCLUSIONS: We provide valid risk prediction equations for MI, stroke, and HF outcomes in Taiwanese type 2 diabetes populations. A framework for adapting risk equations across institutions is also proposed.

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.

Longitudinal economic burden of incident complications among metabolic syndrome populations.

BACKGROUND: This study quantifies the longitudinal economic burden for a wide spectrum of incident complications, metabolic syndrome (MS)-related risk factors, and comorbidities in patients with MS. METHODS: This retrospective study utilized linked data from the 2013 National Health Interview Survey and the 2012-2021 National Health Insurance Research Database to identify MS individuals and their characteristics. The incidence rate of each complication was calculated as the number of complication events in the study period divided by the total person-years during follow-up. The healthcare costs of complications were analyzed using a generalized estimating equation model to determine the cost impact of complications after adjustment for patients' characteristics. Sensitivity analyses on variables with high missing rates (i.e., cause of death, body mass index) were performed. RESULTS: Among 837 identified MS individuals over 8.28 (± 1.35) years of follow-up, the most frequent complications were microvascular diseases (incidence rate for nephropathy/retinopathy/neuropathy: 6.49/2.64/2.08 events per 100 person-years), followed by cardiovascular diseases (2.47), peripheral vascular diseases (2.01), and cancers (1.53). Death was the costliest event (event-year cost per person: USD 16,429) and cancers were the most expensive complications (USD 9,127-11,083 for non-MS- and MS-related cancers). Developing non-MS/MS-related cancers, cardiovascular diseases, and obesity-related medical conditions increased annual costs by 273% (95% CI: 181-397%)/175% (105-269%), 159% (118-207%), and 140% (84-214%), respectively. Microvascular diseases had the lowest cost impact on annual costs (i.e., 27% [17-39%]/27% [11-46%]/24% [11-37%] increases for nephropathy/neuropathy/retinopathy, respectively). Having existing comorbidities increased annual costs by 20% (osteoarthritis) to 108% (depression). Having morbid obesity (i.e., body mass index ≥ 35 kg/m2) increased annual costs by 58% (30-91%). CONCLUSIONS: The economic burden from costly incident complications (i.e., cardiovascular diseases, peripheral vascular diseases, cancers), MS-related risk factors (i.e., morbid obesity), and comorbidities (i.e., depression) highlight the urgent need for early intervention to prevent MS and its progression. The comprehensive cost estimates reported in this study can facilitate the parameterization of economic analyses to identify cost-effective interventions for these patients.

External validation and calibration of risk equations for prediction of diabetic kidney diseases among patients with type 2 diabetes in Taiwan.

BACKGROUND: Most existing risk equations for predicting/stratifying individual diabetic kidney disease (DKD) risks were developed using relatively dated data from selective and homogeneous trial populations comprising predominately Caucasian type 2 diabetes (T2D) patients. We seek to adapt risk equations for prediction of DKD progression (microalbuminuria, macroalbuminuria, and renal failure) using empiric data from a real-world population with T2D in Taiwan. METHODS: Risk equations from three well-known simulation models: UKPDS-OM2, RECODe, and CHIME models, were adapted. Discrimination and calibration were determined using the area under the receiver operating characteristic curve (AUROC), a calibration plot (slope and intercept), and the Greenwood-Nam-D'Agostino (GND) test. Recalibration was performed for unsatisfactory calibration (p-value of GND test < 0.05) by adjusting the baseline hazards of risk equations to address risk variations among patients. RESULTS: The RECODe equations for microalbuminuria and macroalbuminuria showed moderate discrimination (AUROC: 0.62 and 0.76) but underestimated the event risks (calibration slope > 1). The CHIME equation had the best discrimination for renal failure (AUROCs from CHIME, UKPDS-OM2 and RECODe: 0.77, 0.60 and 0.64, respectively). All three equations overestimated renal failure risk (calibration slope < 1). After rigorous updating, the calibration slope/intercept of the recalibrated RECODe for predicting microalbuminuria (0.87/0.0459) and macroalbuminuria (1.10/0.0004) risks as well as the recalibrated CHIME equation for predicting renal failure risk (0.95/-0.0014) were improved. CONCLUSIONS: Risk equations for prediction of DKD progression in real-world Taiwanese T2D patients were established, which can be incorporated into a multi-state simulation model to project and differentiate individual DKD risks for supporting timely interventions and health economic research.

Robust inference for causal mediation analysis of recurrent event data.

Recurrent events, including cardiovascular events, are commonly observed in biomedical studies. Understanding the effects of various treatments on recurrent events and investigating the underlying mediation mechanisms by which treatments may reduce the frequency of recurrent events are crucial tasks for researchers. Although causal inference methods for recurrent event data have been proposed, they cannot be used to assess mediation. This study proposed a novel methodology of causal mediation analysis that accommodates recurrent outcomes of interest in a given individual. A formal definition of causal estimands (direct and indirect effects) within a counterfactual framework is given, and empirical expressions for these effects are identified. To estimate these effects, a semiparametric estimator with triple robustness against model misspecification was developed. The proposed methodology was demonstrated in a real-world application. The method was applied to measure the effects of two diabetes drugs on the recurrence of cardiovascular disease and to examine the mediating role of kidney function in this process.

Long-Term Sulfonylurea Use and Impaired Awareness of Hypoglycemia Among Patients With Type 2 Diabetes in Taiwan.

PURPOSE: We undertook a study to investigate the relationship between duration of medication use and prevalence of impaired awareness of hypoglycemia (IAH) among patients with insulin-treated or sulfonylurea-treated type 2 diabetes in Taiwan. METHODS: A total of 898 patients (41.0% insulin users, 65.1% sulfonylurea users; mean [SD] age = 59.9 [12.3] years, 50.7% female) were enrolled in pharmacies, clinics, and health bureaus of Tainan City, Taiwan. Presence of IAH was determined with Chinese versions of the Gold questionnaire (Gold-TW) and Clarke questionnaire (Clarke-TW). Sociodemographics, disease and treatment histories, diabetes-related medical care, and health status were collected. We used multiple logistic regression models to assess the relationship between duration of medication use and IAH. RESULTS: Overall IAH prevalence was 41.0% (Gold-TW) and 28.2% (Clarke-TW) among insulin users, and 65.3% (Gold-TW) and 51.3% (Clarke-TW) among sulfonylurea users. Prevalence increased with the duration of sulfonylurea use, whereas it decreased with the duration of insulin use. After controlling for potential confounders, 5 or more years of sulfonylurea use was significantly associated with 3.50-fold (95% CI, 2.39-5.13) and 3.06-fold (95% CI, 2.11-4.44) increases in the odds of IAH based on the Gold-TW and Clarke-TW criteria, respectively. On the other hand, regular blood glucose testing and retinal examinations were associated with reduced odds in both insulin users and sulfonylurea users. CONCLUSIONS: The prevalence of IAH was high among patients using sulfonylureas long term, but the odds of this complication were attenuated for those who received regular diabetes-related medical care. Our study suggests that long-term sulfonylurea use and irregular follow-up increase risk for IAH. Further prospective studies are needed to confirm the observed associations.Annals Early Access article.

Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study.

BACKGROUND: Effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) on preventing progressive chronic kidney outcomes is uncertain for type 2 diabetes (T2D) patients requiring intensive glycemic control. This study aimed to evaluate comparative effectiveness of GLP-1RA versus LAI therapies on progressive chronic kidney outcomes among patients having poor glycemic control and requiring these injectable glucose-lowering agents (GLAs). METHODS: 7279 propensity-score-matched pairs of newly stable GLP-1RA and LAI users in 2013-2018 were identified from Taiwan's National Health Insurance Research Database and followed until death or 12/31/2019 (intention-to-treat). Subdistributional hazard model was utilized to assess the comparative effectiveness on a composite renal outcome (i.e., renal insufficiency [eGFR < 15 mL/min/1.73 m2], dialysis-dependent end-stage renal disease [ESRD], or renal death) and its individual components. Sensitivity analyses with the as-treated scenario, PS weighting, high-dimensional PS techniques, using cardiovascular diseases (CVDs) as positive control outcomes, and interaction testing were performed. RESULTS: In primary analyses, subdistribution hazard ratios (95% CIs) for initiating GLP-1RAs versus LAIs for the composite renal outcome, renal insufficiency, dialysis-dependent ESRD, and renal death were 0.39 (0.30-0.51), 0.43 (0.32-0.57), 0.29 (0.20-0.43), and 0.28 (0.15-0.51), respectively. Sensitivity analysis results were consistent with the primary findings. CVD history and the medication possession ratio of prior oral GLAs possessed modification effects on GLP-1RA-associated kidney outcomes. CONCLUSION: Using GLP-1RAs versus LAIs was associated with kidney benefits in T2D patients requiring intensive glycemic control and potentially at high risk of kidney progression. GLP-1RAs should be prioritized to patients with CVDs or adherence to prior oral GLAs to maximize kidney benefits.

Herpes zoster associated with stroke incidence in people living with human immunodeficiency virus: a nested case-control study.

BACKGROUND: The incidence of stroke is increasing among younger people with human immunodeficiency virus (HIV). The burden of stroke has shifted toward the young people living with HIV, particularly in low- and middle-income countries. People infected with herpes zoster (HZ) were more likely to suffer stroke than the general population. However, the association of HZ infection with the incidence of stroke among patients with HIV remains unclear. METHODS: A nested case-control study was conducted with patients with HIV registered in the Taiwan National Health Insurance Research Database in 2000-2017. A total of 509 stroke cases were 1:10 matched to 5090 non-stroke controls on age, sex, and date of first stroke diagnosis. Logistic regression models were used to estimate the odds ratio and 95% confidence intervals (CI) of stroke incidence. RESULTS: The odds ratio of stroke was significantly higher in the HIV-infected population with HZ (adjusted odds ratio [AOR]: 1.85, 95% CI: 1.42-2.41). A significantly increased AOR of stroke was associated with hypertension (AOR: 3.53, 95% CI: 2.86-4.34), heart disease (AOR: 2.32, 95% CI: 1.54-3.48), chronic kidney disease (AOR: 1.82, 95% CI: 1.16-2.85), hepatitis C virus infection (AOR: 1.49, 95% CI: 1.22-1.83), hyperlipidemia (OR: 1.41, 95% CI: 1.12-1.78), and treatment with protease inhibitors (AOR: 1.33, 95% CI: 1.05-1.69). CONCLUSIONS: Our findings suggest that HZ concurrent with HIV may increase the risk of stroke. The incidence rates of stroke were independent of common risk factors, suggesting strategies for early prevention of HZ infection among people living with HIV.

Cost-effectiveness of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors among patients with type 2 diabetes with and without established cardiovascular diseases: A model-based simulation analysis using 10-year real-world data and targeted literature review.

AIM: We conducted a model-based economic analysis of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in patients with type 2 diabetes (T2D), with and without established cardiovascular diseases (CVDs), using 10-year real-world data. MATERIALS AND METHODS: A Markov model was utilized to estimate healthcare costs and quality-adjusted life-years (QALYs) over a 10-year simulation time horizon from a healthcare sector perspective, with both costs and QALYs discounted at 3% annually. Model inputs were derived from analyses of Taiwan's National Health Insurance Research Database or published studies of Taiwanese populations. The primary outcome measure was the incremental cost-effectiveness ratios (ICERs). Incorporated with our study findings, a targeted literature review was conducted to synthesize updated evidence on the cost-effectiveness of SGLT2is versus DPP4is. RESULTS: Over 10 years, use of SGLT2is versus DPP4is yielded ICERs of $3244 and $4186 per QALY gained for patients with T2D, with and without established CVDs, respectively. Results were robust across a series of sensitivity and scenario analyses, showing ICERs between $-1074 (cost-saving) and $8467 per QALY gained for patients with T2D with established CVDs and between $369 and $37 122 per QALY gained for patients with T2D without established CVDs. CONCLUSIONS: Use of SGLT2is versus DPP4is was highly cost-effective for patients with T2D regardless of their CVD history in real-world clinical practice. Our results extend current evidence by showing SGLT2is as an economically rational alternative over DPP4is for T2D treatment in routine care. Future research is warranted to explore the heterogeneous economic benefits of SGLT2is given diverse patient characteristics in clinical settings.

Treatment-associated survival outcomes in real-world patients with de novo metastatic triple-negative breast cancer: Age as a significant treatment effect-modifier.

PURPOSE: Evidence for optimizing the first-line chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC) is lacking. This study assessed the utilization patterns of chemotherapy and associated survival outcomes in de novo mTNBC patients. METHODS: Taiwan's cancer registry was utilized to extract study patients with newly-diagnosed breast cancer during 2011-2015 and confirmed metastatic triple-negative status. The patients' medical records (e.g., diseases, treatments) and death status were obtained from the National Health Insurance Research Database. Utilization of first-line chemotherapy regimens was analyzed and associated survival outcomes were assessed using Cox models. RESULTS: 93.60% of the mTNBC patients (n = 297) received chemotherapy, where combination regimens (75.54%) were more common than single-agent regimens (24.46%) in the first-line setting. A non-statistically lower all-cause death associated with combination versus single-agent chemotherapy (hazard ratio: 0.830 [0.589, 1.168]) was observed. Age was identified as a significant effect-modifier in treatment-associated survival outcomes (p = 0.008); younger patients (aged < 40 and 40-59 years) versus older patients (aged ≥ 60 years) had a lower all-cause mortality when receiving combination versus single-agent chemotherapy. A lower all-cause mortality associated with taxane- versus non-taxane-based therapy was revealed among those on single-agent chemotherapy (hazard ratio: 0.557 [0.311, 0.999]). CONCLUSION: Generally, single-agent and combination chemotherapies yielded comparable survival outcomes as the first-line treatment for de novo mTNBC. Younger patients may benefit more from combination regimens, in terms of better survival outcomes. Single-agent chemotherapy may be preferable as the first-line choice for elderly patients who are vulnerable to the toxicity of multiple chemotherapy agents.

Incorporating sperm DNA fragmentation index with computer-assisted semen morphokinematic parameters as a better window to male fertility.

This study aimed to assess (1) the reproducibility of three sperm chromatin dispersion (SCD) assays for sperm DNA fragmentation, i.e., LensHooke R10® (R10), Halosperm G2® (G2), and BASO® (BA); (2) the correlation between computer-assisted semen analyzer (CASA) morphokinematic parameters and sperm DNA fragmentation index (DFI), and (3) the diagnostic value for male reproduction by combining semen morphokinematic parameters and DFI. Total 50 male participants were recruited, and all collected semen samples underwent semen analyses and SCD assays. Intra- and inter-observer variability of DFI data from different SCD measures was tested. In addition, the predictive ability of CASA parameters and DFI (with different cutoffs, i.e., 15% and 20%) for infertility was assessed using receiver operating characteristic curve analysis. We found that the G2 and R10 produced satisfactory variance coefficients (5.53%, 5.67%) compared to BA (14.8%). The DFI data from the R10 had lower intra-observer variability, in terms of higher intra-class coefficient (0.9615), than that of the G2 (0.8847) or BA (0.8824). Inter-observer variability of three SCD kits in scoring the DFI was comparable and satisfactory (concordance correlation coefficients ranging 0.9895-0.9630). The CASA parameters (i.e., total motility [r = -0.57], progression motility [r = -0.55], and rapidly progressive motility [r = -0.55]) were significantly correlated with DFI (P < 0.001). The predictive ability of the 15%-cutoff DFI data was better than that of the 20%-cutoff or continuous DFI data. The model comprising the CASA parameters, 15%-cutoff DFI, and 4%-cutoff normal morphology had the highest area under curve (0.8125) for infertility. For SCD assay, the R10 was the most reliable SCD assay to detect sperm DNA fragmentation. Combining the sperm DFI with CASA parameters might be a better diagnostic tool for male reproduction.

Cost-effectiveness of GLP-1 receptor agonists versus insulin for the treatment of type 2 diabetes: a real-world study and systematic review.

BACKGROUND: To conduct a real-word-study-based cost-effectiveness analysis of a GLP-1 receptor agonist (GLP-1RA) versus insulin among type 2 diabetes patients requiring intensified injection therapy and a systematic review of cost-effectiveness studies of GLP-1RAs versus insulin. METHODS: Individual-level analyses incorporating real-world effectiveness and cost data were conducted for a cohort of 1022 propensity-score-matched pairs of GLP-1RA and insulin users from Taiwan's National Health Insurance Research Database, 2007-2016. Study outcomes included the number needed to treat (NNT) to prevent one case of clinical events, healthcare costs, and cost per case of event prevented. Costs were in 2019 US dollars. Analyses were performed from a third-party payer and healthcare sector perspectives. Structured systematic review procedures were conducted to synthesize updated evidence on the cost-effectiveness of GLP-1RAs versus insulin. RESULTS: Over a mean follow-up of 2.3 years, the NNT using a GLP-1RA versus insulin to prevent one case of all-cause mortality and hospitalized hypoglycemia was 57 and 30, respectively. Using GLP-1RAs instead of insulin cost US$54,851 and US$29,115 per case of all-cause mortality and hospitalized hypoglycemia prevented, respectively, from the payer perspective, and saved US$19,391 and US$10,293, respectively, from the healthcare sector perspective. Sensitivity analyses showed that the probability of using GLP-1RAs versus insulin being cost-effective for preventing one case of all-cause mortality or hospitalized hypoglycemia ranged from 60 to 100%. The systematic review revealed a cost-effective profile of using GLP-1RAs versus insulin. CONCLUSIONS: Using GLP-1RAs versus insulin for type 2 diabetes patients requiring intensified injection therapy in clinical practice is cost-effective.

Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study.

BACKGROUND: To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2). METHODS: Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics. RESULTS: There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37-0.69), 0.51 (0.37-0.70), and 0.47 (0.31-0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups. CONCLUSIONS: This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.

Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.

BACKGROUND: With emerging evidence on the efficacy of adding dapagliflozin to standard care for patients with heart failure with reduced ejection fraction (HFrEF), this study assessed the cost-effectiveness of add-on dapagliflozin to standard care versus standard care alone for HFrEF from the perspective of healthcare systems in the Asia-Pacific region. METHODS: A Markov model was applied to project the outcomes of treatment in terms of lifetime medical cost and quality-adjusted life-years. The transition probabilities between health states in the model were obtained from the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial. Country-specific costs and utilities were extracted for modeling. The incremental cost-effectiveness ratio against a country-specific willingness-to-pay threshold was applied to determine the cost-effectiveness of treatment. A series of sensitivity analyses were performed to ensure the robustness of the study results. Costs are presented in 2020 United States dollars. RESULTS: The incremental cost-effectiveness ratios for add-on dapagliflozin versus standard care alone were $5277, $9980, $12,305, $16,705, and $23,227 per quality-adjusted life-year gained in Korea, Australia, Taiwan, Japan, and Singapore, respectively. When using add-on dapagliflozin to standard care versus standard care alone, ~ 100% of simulations were cost-effective at a willingness-to-pay threshold of one gross domestic product per capita of the given Asia-Pacific country; however, the probability of being cost-effective for using add-on dapagliflozin decreased when the time horizon for simulation was restricted to 18 months and when the cardiovascular mortality for the two treatments (43.8% and 33.0%, respectively) was assumed to be the same. The cost-effectiveness results were most sensitive to cardiovascular mortality of treatment. CONCLUSIONS: Adding dapagliflozin to standard care is cost-effective for HFrEF in healthcare systems in the Asia-Pacific region, which supports the rational use of dapagliflozin for HFrEF in this region.

Building an active medical product safety surveillance system in Taiwan: Adaptation of the U.S. Sentinel System common data model structure to the National Health Insurance Research Database in Taiwan.

PURPOSE: Using real-world data to support regulatory decision has become a global movement. However, a robust platform for active surveillance of medical product safety has not been established in Taiwan. METHODS: Following the common data model structure of the U.S. Food and Drug Administration's Sentinel System, we built the Taiwan Sentinel Data Model (TSDM) using the National Health Insurance Research Database with longitudinal claims data from 23 million individuals, linked death and cause of death data from a national registry, and linked electronic health record data from a delivery system. We examined the conversion of the TSDM using the Sentinel Data Quality Review and Characterization Programs in a sample of sex- and age-stratified cohort of 3 million individuals. RESULTS: The TSDM fulfilled the requirements of data quality assurance. Only about 6% of sex and 0.0007% of birth year were missing, and <0.001% of date data had illogical values. CONCLUSIONS: The TSDM-converted database could be a valuable data resource for domestic pharmacovigilance analysis in Taiwan and cross-country evaluation.

Quality of life with pregnancy outcomes: Further evaluating item properties for refined Taiwan's FertiQoL.

PURPOSE: We assessed the reliability and validity of Taiwan's version of FertiQoL, with a focus on the association between quality of life (QoL) and in-vitro-fertilization (IVF) pregnancy. METHODS: 410 women undergoing IVF treatment were included. QoL measured by Taiwan's version of FertiQoL was assessed before embryo transfer. Item properties were examined using corrected item-total correlation, Rasch mean-square (MnSq), and internal consistency. Known-group validity was assessed using IVF pregnancy (i.e., chemical pregnancy, ongoing pregnancy, live birth) as the outcomes of interest. RESULTS: Five FertiQoL items, namely Q4, Q5, Q15, Q21, and T5, had low corrected item-total correlation (i.e., -0.146-0.290) in their embedded domains; three other items, namely Q11, Q14, and T2, did not have acceptable MnSq values in the Rasch analysis (i.e., infit MnSq: 1.31-2.28; outfit MnSq: 1.95-4.57). These items were removed and a refined Taiwan's FertiQoL was generated. The internal consistency for the refined Taiwan's FertiQoL was improved (α = 0.928) with the capability of distinguishing women who had successful live birth from those who had failed live birth (i.e., 72.40 ± 12.71vs. 69.21 ± 13.26; p = 0.019). CONCLUSION: The study results demonstrate that the refined Taiwan's FertiQoL is valid and reliable, suggesting that this FertiQoL should refined to be culturally and language appropriate for Taiwanese population.

Managing medication supply chains: Lessons learned from Taiwan during the COVID-19 pandemic and preparedness planning for the future.

Coronavirus disease 2019 (COVID-19) has posed unprecedented challenges for nations worldwide, among which medication shortages can cause a devastatingly negative impact on global health. Using Taiwan as an example, this report describes the sources of potential medication shortages, discusses the preparedness and contingency strategies to address medication shortages, and outlines the evidence-based recommendations on ensuring a stable medication supply and improving the quality and security of medicines. Many drug shortages have focused on shortfalls of overseas manufacturing, but the effect of the COVID-19 crisis on misallocation of medications within the nation's internal supply chains is also a great concern. A wide range of stakeholders are involved in pharmaceutical supply chains, including government regulators, health care insurers, pharmaceutical companies, frontline physicians and pharmacists, patients and families, professional and patient associations or unions, and even individuals who acquire medications from abroad. Collaborative inputs and efforts from all these interdependent stakeholders are critical for establishing transparent preparedness and contingency plans to address drug shortages affected by disruptions of overseas manufacturing or stockouts in pharmacies owing to medication misallocation. Strategies have been documented and recommended in Taiwan and the United States to mitigate drug shortages and ensure the long-term quality and security of medicines. Barriers to accessing medicines are nothing new, but the COVID-19 pandemic poses urgent and even novel challenges to the stability and integrity of medication supply, which urges for a need to reconsider and reinforce effective management strategies for pharmaceuticals. Active management, transparent information, and timely communications are essential to ensure a stable supply of key therapeutic medications, especially during a pandemic.

Comparative cardiovascular safety of GLP-1 receptor agonists versus other glucose-lowering agents in real-world patients with type 2 diabetes: a nationwide population-based cohort study.

BACKGROUND: Current evidence about the cardiovascular safety of glucagon-like peptide-1 receptor agonist (GLP-1ra) possesses limited generalizability to real-world patients with type 2 diabetes (T2D) in usual practice. This study aimed to investigate the comparative cardiovascular safety of GLP-1ra in comparisons with dipeptidyl peptidase-4 inhibitor (DPP-4i), sulfonylurea (SU), and insulin in a real-world population with T2D. METHODS: Adults with newly-diagnosed T2D were identified from Taiwan's National Health Insurance Research Database in 2003-2014. A prevalent new-user cohort design was adopted to include a broad representation of real-world T2D patients being treated with GLP-1ra. The between-group comparability of baseline patient characteristics was achieved by matching on (1) initiation time of study drugs, (2) prior exposure to glucose-lowering agents, and (3) diabetes severity and complications, comorbidities, and concomitant cardiovascular medications using propensity scores. The primary outcome was a composite of cardiovascular disease (CVD) events and assessed up to the end of 2015. Cox modeling was employed to assess the association between study drugs and outcomes. RESULTS: A total of 3195 GLP-1ra stable users was identified in 2011-2014. 1893, 1829, and 1367 GLP-1ra stable users were 1:1 matched to DPP-4i, SU and insulin users, respectively. Compared to DPP-4i, SU and insulin, the use of GLP-1ra was associated with a lower risk of composite CVD events [hazard ratio (95% confidence interval) 0.73 (0.57-0.96), 0.76 (0.57-1.00), and 0.81 (0.62-1.07), respectively]. Subgroup analyses revealed that GLP-1ra versus DPP-4i yielded a greater cardiovascular benefit in those without established CVD versus those with established CVD. CONCLUSIONS: This comparison study extends the supporting evidence for the cardiovascular safety of GLP-1ra to a broad spectrum of real-world T2D patients using GLP-1ra.

Comparative predictive ability of visit-to-visit HbA1c variability measures for microvascular disease risk in type 2 diabetes.

BACKGROUND: To assess the associations of various HbA1c measures, including a single baseline HbA1c value, overall mean, yearly updated means, standard deviation (HbA1c-SD), coefficient of variation (HbA1c-CV), and HbA1c variability score (HVS), with microvascular disease (MVD) risk in patients with type 2 diabetes. METHODS: Linked data between National Cheng Kung University Hospital and Taiwan's National Health Insurance Research Database were utilized to identify the study cohort. The primary outcome was the composite MVD events (retinopathy, nephropathy, or neuropathy) occurring during the study follow-up. Cox model analyses were performed to assess the associations between HbA1c measures and MVD risk, with adjustment for patients' baseline HbA1c, demographics, comorbidities/complications, and treatments. RESULTS: In the models without adjustment for baseline HbA1c, all HbA1c variability and mean measures were significantly associated with MVD risk, except HVS. With adjustment for baseline HbA1c, HbA1c-CV had the strongest association with MVD risk. For every unit of increase in HbA1c-CV, the MVD risk significantly increased by 3.42- and 2.81-fold based on the models without and with adjustment for baseline HbA1c, respectively. The associations of HbA1c variability and mean measures with MVD risk in patients with baseline HbA1c < 7.5% (58 mmol/mol) were stronger compared with those in patients with baseline HbA1c ≥ 7.5% (58 mmol/mol). CONCLUSIONS: HbA1c variability, especially HbA1c-CV, can supplement conventional baseline HbA1c measure for explaining MVD risk. HbA1c variability may play a greater role in MVD outcomes among patients with relatively optimal baseline glycemic control compared to those with relatively poor baseline glycemic control.