Kidney outcomes with SGLT2is for type 2 diabetes patients: does background treatment with metformin or RASis matter?

Introduction: There is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes. Methods: SGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases. Results: After matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87-1.20)/1.09 (0.92-1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions. Conclusion: Using metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes.

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.

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.

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.

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.

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.

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.

Efficient estimation of a Cox model when integrating the subgroup incidence rate information.

Incidence rates for diseases are widely used in the field of medical research because they lead to clear and simple physical and clinical interpretations. In this study, we propose an efficient estimation method that incorporates auxiliary subgroup information related to the incidence rate into the estimation of the Cox proportional hazard model. The results show that utilizing the incidence rate information improves the efficiency of the estimation of regression parameters based on the double empirical likelihood method compared to that for conventional models that do not incorporation such information. We show that estimators of regression parameters asymptotically follow a multivariate normal distribution with a variance-covariance matrix that can be consistently estimated. Simulation results indicate that the proposed estimators significantly increase efficiency. Finally, an example of the effects of type 2 diabetes on stroke is applied to demonstrate the proposed method.

Effect of atosiban on in vitro fertilization pregnancy outcome among women with endometriosis in presence or absence of adenomyosis.

OBJECTIVE: This study aimed to assess the effect of atosiban on in vitro fertilization (IVF) pregnancy outcome among women with both endometriosis and adenomyosis, and compared it to that of patients with endometriosis but without adenomyosis and that of patients with tubal factor only. MATERIALS AND METHODS: 106 infertile women (176 embryo transfers) from a medical center in Taiwan were included in the analysis, where 34 (54), 34 (66), and 38 (56) cases (embryo transfers) were endometriosis without adenomyosis, endometriosis with adenomyosis, and tubal infertility factor only, respectively. Adenomyosis morphologies were classified using an ultrasound-based classification system. The logistic generalized estimating equation model was used to analyze the association between atosiban use and pregnancy outcomes. RESULTS: The crude pregnancy rates for the endometriosis-only group were significantly higher than those for the endometriosis + adenomyosis group (i.e., biochemical pregnancy: 50.0% versus 29.7%, p = 0.041; ongoing pregnancy: 35.2% versus 16.9%, p = 0.038). Significantly higher chances of biochemical pregnancy and ongoing pregnancy among endometriosis patients without adenomyosis versus those with both endometriosis and adenomyosis were found (odds ratios [95% confidence intervals]: 2.981 [1.307, 6.803]; p = 0.009, 2.694 [1.151, 6.304]; p = 0.022). A significant positive association between atosiban use and biochemical pregnancy existed among endometriosis cases without adenomyosis (a 2.43-fold [1.01, 5.89] increase in successful pregnancy; p<0.05), but not for the other groups. CONCLUSIONS: Poor pregnancy outcomes among adenomyosis-affected women were confirmed. The use of atosiban significantly enhanced IVF pregnancy among endometriosis patients without adenomyosis.

Effect of SGLT2 inhibitors versus DPP4 inhibitors on major and non-major osteoporotic fracture risks among general and high-risk type 2 diabetes patients: A nationwide retrospective cohort study.

AIMS: To retrospectively analyze the association of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) with a range of major and non-major fracture events, and explore heterogeneous treatment effect among high-risk patient subgroups. METHODS: Newly stable SGLT2i or DPP4i users in 2017 were identified in Taiwan's National Health Insurance Research Database and followed up until a fracture occurred, loss of follow-up, death, or December 31, 2018, whichever came first. Outcomes included composite major and non-major fractures and individual components in major fractures. Cox model and restricted mean survival time (RMST) analyses were utilized to assess the treatment effect on fractures. RESULTS: 21,155 propensity-score-matched SGLT2i and DPP4i users were obtained. Over 2 years, the hazard ratio and RMST difference for major fracture with SGLT2i versus DPP4i use were 0.89 (95% CI, 0.80, 1.00) and 1.51 (-0.17, 3.17) days, respectively, and those for non-major fracture with SGLT2i versus DPP4i use were 0.89 (0.81, 0.98) and 2.44 (0.47, 4.37) days, respectively. A 180-day lag time analysis for fracture outcomes showed consistent results with primary findings. A SGLT2is-associated harmful effect on major fractures (but not on non-major fractures) was observed among female patients and those with a diabetes duration of ≥ 8 years, prior fractures, and established osteoporosis. CONCLUSION: This study adds supporting real-world evidence for SGLT2is-associated bone safety for a wide range of fractures, which promotes the rational use of SGLT2is in routine care and highlights the importance of the close monitoring of patients with high fracture risks to maximize treatment benefits while reducing undesirable effects.

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.

Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data.

AIMS: To evaluate the cost-effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) in patients with type 2 diabetes (T2D) using real-world data. METHODS: A Markov model was utilized to estimate healthcare costs (US$) and quality-adjusted life-years (QALYs) of receiving treatments over 10 years from the healthcare sector perspective. Model inputs were derived from the analyses of Taiwan's National Health Insurance Research Database or published literature on Taiwanese T2D populations. Base-case analysis was performed for the overall study cohort and subgroup analyses were stratified by the presence or absence of established cardiovascular diseases (CVDs) or chronic kidney diseases (CKDs). RESULTS: Overall, using GLP-1RAs versus LAIs cost $6,053 per QALY gained. Results were robust across sensitivity and scenario analyses. Among patients with established CVDs and CKDs, GLP-1RA versus LAI therapy saved $673 (cost-saving) and cost $1,675 per QALY gained, respectively. Among patients without established CVDs and CKDs, GLP-1RA versus LAI therapy cost $9,093 and $7,659 per QALY gained, respectively. CONCLUSIONS: Using GLP-1RAs versus LAIs for T2D patients represented good economic value in real-world practice. Pronounced economic benefits of GLP-1RA therapy among those with prior CVDs or CKDs support rational treatment decisions and optimal healthcare resource allocation for these patients.

Cost-effectiveness of Novel Macrophage-Regulating Treatment for Wound Healing in Patients With Diabetic Foot Ulcers From the Taiwan Health Care Sector Perspective.

Importance: Diabetic foot ulcers (DFUs) and subsequent amputation incur enormous health and economic burdens to patients, health care systems, and societies. As a novel macrophage-regulating drug, ON101 is a breakthrough treatment for DFUs, which demonstrated significant complete wound healing effects in a phase 3 randomized clinical trial, but its economic value remains unknown. Objective: To assess the cost-effectiveness of an ON101 cream added on to general wound care (GWC; ie, conventional treatments for DFUs, which comprised initial and regular foot examinations, ulcer management, comorbidity control, patient education, and multidisciplinary care) vs GWC alone for DFUs from the Taiwan health care sector perspective. Design, Setting, and Participants: This economic evaluation used a hypothetical cohort of patients with diabetes, with characteristics mirroring those of the participants in the ON101 trial. A Markov state-transition simulation model was constructed to estimate costs and health outcomes associated with the ON101 with GWC and GWC alone strategies over a 5-year time horizon, discounting costs and effectiveness at 3% annually. Costs were in 2021 US dollars. Data were sourced from the ON101 trial and supplemented from published literature. Deterministic and probabilistic sensitivity analyses were performed to assess the uncertainty of input parameters and study generalizability. The analysis was designed and conducted from September 1, 2020, to January 31, 2022. Exposures: ON101 with GWC vs GWC alone. Main Outcomes and Measures: DFU-related complications, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Results: Patients in the hypothetical cohort had a mean age of 57 years and an uninfected DFU of 1 to 25 cm2 that was present for 4 or more weeks with a Wagner grade of 1 or 2. Over 5 years, the ON101 with GWC group vs the GWC alone group experienced more healing events, stayed for a longer time in the healing state, and had fewer infected DFUs, gangrene, and amputations (eg, 2787 additional healing events and 2766 fewer infected DFU, 72 fewer amputation, and 7 fewer gangrene events in the ON101 with GWC group vs GWC alone group). The ON101 with GWC strategy vs GWC alone yielded an additional 0.038 QALYs at an incremental cost of $571, resulting in $14 922/QALY gained. Economic results were most sensitive to healing efficacy, drug cost, and health utility of the healing state. Cost-saving results were observed in patient subgroups with poor glycemic control, larger ulcer sizes, longer ulcer durations, and current smoking. The ON101 with GWC strategy was considered cost-effective in 60% to 82% of model iterations against willingness-to-pay thresholds of $32 787/QALY gained to $98 361/QALY gained. Conclusions and Relevance: In this economic evaluation study using a simulated patient cohort, the ON101 with GWC strategy represented good value compared with GWC alone for patients with DFUs from the Taiwan health care sector perspective and may be prioritized for those with high risks for disease progression of DFUs.

Cost-effectiveness of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Researchers have not simultaneously compared the cost-effectiveness of six immunotherapies with chemotherapy for advanced non-small cell lung cancer. This study evaluated the cost-effectiveness across different programmed death-ligand 1 (PD-L1) levels. METHODS: A Markov model with lifetime horizon was created for seven regimens: pembrolizumab plus chemotherapy (pembro-chemo), nivolumab plus ipilimumab (nivo-ipi), nivolumab, ipilimumab plus chemotherapy (nivo-ipi-chemo), atezolizumab plus chemotherapy (atezo-chemo), atezolizumab, bevacizumab plus chemotherapy (atezo-beva-chemo), single-agent pembrolizumab, and chemotherapy alone. Input parameters were derived from trial data, a network meta-analysis, and other literature. We conducted the analysis from the perspective of US health care sector. RESULTS: For all patients without considering PD-L1 expression, the incremental cost-effectiveness ratio (ICER) of pembro-chemo versus chemotherapy was $183,299 per quality-adjusted life year (QALY). The preferred regimens based on ICERs differed by PD-L1 levels. For patients with PD-L1 ≥50%, pembrolizumab versus chemotherapy and pembro-chemo versus pembrolizumab resulted in ICERs of $96,189 and $198,913 per QALY, respectively. The other strategies were dominated. For patients with PD-L1 of 1%-49%, the ICER of pembro-chemo comparing to chemotherapy was $218,159 per QALY. The other regimens were dominated by pembro-chemo. For patients with PD-L1 <1%, nivo-ipi versus chemotherapy and nivo-ipi-chemo versus nivo-ipi resulted in ICERs of $161,277 and $881,975 per QALY, and the other regimens were dominated strategies. At the willingness-to-pay threshold of $150,000 per QALY, pembrolizumab had 87% and pembro-chemo had 1% probabilities being cost-effective in patients with PD-L1 ≥50% and 1%-49%, respectively. Nivo-ipi had a 34% probability being cost-effective in patients with PD-L1 <1%. CONCLUSIONS: The PD-L1 level should be incorporated into treatment decision-making. Our findings suggest that first-line pembrolizumab, pembro-chemo, and nivo-ipi are the preferred strategies for patients with PD-L1 ≥50%, 1%-49%, and <1%, respectively.

Restricted Mean Survival Time Analysis to Estimate SGLT2i-Associated Heterogeneous Treatment Effects on Primary and Secondary Prevention of Cardiorenal Outcomes in Patients With Type 2 Diabetes in Taiwan.

Importance: Increasing numbers of post hoc analyses have applied restricted mean survival time (RMST) analysis on the aggregated-level data from clinical trials to report treatment effects, but studies that use individual-level claims data are needed to determine the feasibility of RMST analysis for quantifying treatment effects among patients with type 2 diabetes in routine clinical settings. Objectives: To apply RMST analysis for assessing sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated cardiovascular (CV) events and estimating heterogenous treatment effects (HTEs) on CV and kidney outcomes in routine clinical settings. Design, Setting, and Participants: This comparative effectiveness study of Taiwan's National Health Insurance Research Database examined 21 144 propensity score (PS)-matched pairs of patients with type 2 diabetes with SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment for assessing CV outcomes, and 19 951 PS-matched pairs of patients with type 2 diabetes with SGLT2i and DPP4i treatment for assessing kidney outcomes. Patients were followed until December 31, 2018. Statistical analysis was performed from August 2021 to April 2022. Exposures: Newly stable SGLT2i or DPP4i use in 2017. Main Outcomes and Measures: Study outcomes were CV events including hospitalization for heart failure (HHF), 3-point major adverse CV events (3P-MACE: nonfatal myocardial infarction [MI], nonfatal stroke, and CV death), 4-point MACE (4P-MACE: HHF and 3P-MACE), and all-cause death, and chronic kidney disease (CKD). RMST and Cox modeling analyses were applied to estimate treatment effects on study outcomes. Results: After PS matching, the baseline patient characteristics were comparable between 21 144 patients with stable SGLT2i use (eg, mean [SD] age: 58.3 [10.7] years; 11 990 [56.7%] male) and 21 144 patients with stable DPP4i use (eg, mean [SD] age: 58.1 [11.6] years; 12 163 [57.5%] male) for assessing CV outcomes, and those were also comparable between 19 951 patients with stable SGLT2i use (eg, mean [SD] age: 58.1 [10.7] years; 11 231 [56.2%] male) and 19 951 patients with stable DPP4i use (eg, mean [SD] age: 57.9 [11.5] years; 11 340 [56.8%] male) for assessing kidney outcome. The 2-year difference in RMST between patients with SGLT2i use and patients with DPP4i use was 4.99 (95% CI, 3.56-6.42) days for HHF, 4.12 (95% CI, 2.72-5.52) days for 3P-MACE, 7.72 (95% CI, 5.83-9.61) days for 4P-MACE, 1.26 (95% CI, 0.47-2.04) days for MI, 2.70 (95% CI, 1.57-3.82) days for stroke, 0.69 (95% CI, 0.28-1.11) days for CV death, 6.05 (95% CI, 4.89-7.20) days for all-cause death, and 14.75 (95% CI, 12.99-16.52) days for CKD. Directions of hazard ratios from Cox modeling analyses were consistent with RMST estimates. No association was found between study treatment and the negative control outcome (dental visits for tooth care). Consistent results across sensitivity analyses using high-dimensional PS-matched and PS-weighting approaches supported the validity of primary analysis results. Largest difference in RMST of SGLT2i vs DPP4i use for HHF and CKD was found among patients with established heart failure (30.80 [95% CI, 5.08-56.51] days) and retinopathy (40.43 [95% CI, 31.74-49.13] days), respectively. Conclusions and Relevance: In this comparative effectiveness study, RMST analysis was feasible for translating treatment effects into more clinical intuitive estimates and valuable for quantifying HTEs among diverse patients in routine clinical settings.

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.

Reduced All-Cause Mortality With Bisphosphonates Among Post-Fracture Osteoporosis Patients: A Nationwide Study and Systematic Review.

We assessed the survival outcomes associated with real-world bisphosphonate use, stratified by fracture site, type, administration, and duration of treatment, among patients with osteoporosis. A systematic review that incorporates our findings was conducted to provide up-to-date evidence on survival outcomes with bisphosphonate treatment in real-world settings. Patients diagnosed with osteoporosis who had been hospitalized for major fractures were identified from Taiwan's National Health Insurance Research Database 2008-2017 and followed until 2018. There were 24,390 new bisphosphonate users who were classified and compared with 76,725 nonusers of anti-osteoporosis medications in terms of survival outcomes using Cox model analysis. An inverse probability of treatment weighted Cox model and landmark analyses for minimizing immortal time bias were also performed. Bisphosphonate users vs. nonusers had a significantly lower mortality risk, regardless of fracture site (hazard ratios (95% confidence intervals) for patients with any major fracture, hip fracture, and vertebral fracture: 0.90 (0.88, 0.93), 0.83 (0.80, 0.86), and 0.86 (0.82, 0.89), respectively). Compared with nonuse, zoledronic acid (0.77 (0.73, 0.82)) was associated with the lowest mortality, followed by ibandronate (0.85 (0.78, 0.93)) and alendronate/risedronate (0.93 (0.91, 0.96)). Using bisphosphonates for ≥ 3 years had lower mortality (0.60 (0.53, 0.67)) than using bisphosphonates for < 3 years (0.98 (0.95, 1.01)). Intravenous bisphosphonates had a lower mortality than that of oral bisphosphonates. Our results are consistent with the systematic review findings among real-world populations. In conclusion, bisphosphonate use, especially persistence to intravenous bisphosphonates (e.g., zoledronic acid), may reduce post-fracture mortality among patients with osteoporosis, particularly those with hip/vertebral fractures. This supports the rational use of bisphosphonates in post-fracture care.

Continuity and Completeness of Electronic Health Record Data for Patients Treated With Oral Hypoglycemic Agents: Findings From Healthcare Delivery Systems in Taiwan.

Objective: To evaluate the continuity and completeness of electronic health record (EHR) data, and the concordance of select clinical outcomes and baseline comorbidities between EHR and linked claims data, from three healthcare delivery systems in Taiwan. Methods: We identified oral hypoglycemic agent (OHA) users from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD), which was linked to the National Health Insurance Research Database (NHIRD), from June 2011 to December 2016. A secondary evaluation involved two additional EHR databases. We created consecutive 90-day periods before and after the first recorded OHA prescription and defined patients as having continuous EHR data if there was at least one encounter or prescription in a 90-day interval. EHR data completeness was measured by dividing the number of encounters in the NTUH-iMD by the number of encounters in the NHIRD. We assessed the concordance between EHR and claims data on three clinical outcomes (cardiovascular events, nephropathy-related events, and heart failure admission). We used individual comorbidities that comprised the Charlson comorbidity index to examine the concordance of select baseline comorbidities between EHRs and claims. Results: We identified 39,268 OHA users in the NTUH-iMD. Thirty-one percent (n = 12,296) of these users contributed to the analysis that examined data continuity during the 6-month baseline and 24-month follow-up period; 31% (n = 3,845) of the 12,296 users had continuous data during this 30-month period and EHR data completeness was 52%. The concordance of major cardiovascular events, nephropathy-related events, and heart failure admission was moderate, with the NTU-iMD capturing 49-55% of the outcome events recorded in the NHIRD. The concordance of comorbidities was considerably different between the NTUH-iMD and NHIRD, with an absolute standardized difference >0.1 for most comorbidities examined. Across the three EHR databases studied, 29-55% of the OHA users had continuous records during the 6-month baseline and 24-month follow-up period. Conclusion: EHR data continuity and data completeness may be suboptimal. A thorough evaluation of data continuity and completeness is recommended before conducting clinical and translational research using EHR data in Taiwan.

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.