Search

Although the advent of organoids has opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here, we established organoids from the thymus, the lymphoid organ responsible for T-cell development. We identified conditions enabling mouse thymic epithelial progenitor cell proliferation and development into organoids with diverse cell populations and transcriptional profiles resembling in vivo thymic epithelial cells (TECs) more closely than traditional TEC cultures. In contrast to these two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T-cell development upon reaggregation with T-cell progenitors. The reaggregates showed in vivo-like epithelial diversity and the ability to attract T-cell progenitors. Thymic epithelial organoids are the first organoids originating from the stromal compartment of a lymphoid organ. They provide new opportunities to study TEC biology and T-cell development in vitro, paving the way for future thymic regeneration strategies in ageing or acute injuries. [ABSTRACT FROM AUTHOR]

Three-dimensional organoid culture technologies have revolutionized cancer research by allowing for more realistic and scalable reproductions of both tumour and microenvironmental structures1–3. This has enabled better modelling of low-complexity cancer cell behaviours that occur over relatively short periods of time4. However, available organoid systems do not capture the intricate evolutionary process of cancer development in terms of tissue architecture, cell diversity, homeostasis and lifespan. As a consequence, oncogenesis and tumour formation studies are not possible in vitro and instead require the extensive use of animal models, which provide limited spatiotemporal resolution of cellular dynamics and come at a considerable cost in terms of resources and animal lives. Here we developed topobiologically complex mini-colons that are able to undergo tumorigenesis ex vivo by integrating microfabrication, optogenetic and tissue engineering approaches. With this system, tumorigenic transformation can be spatiotemporally controlled by directing oncogenic activation through blue-light exposure, and emergent colon tumours can be tracked in real-time at the single-cell resolution for several weeks without breaking the culture. These induced mini-colons display rich intratumoural and intertumoural diversity and recapitulate key pathophysiological hallmarks displayed by colorectal tumours in vivo. By fine-tuning cell-intrinsic and cell-extrinsic parameters, mini-colons can be used to identify tumorigenic determinants and pharmacological opportunities. As a whole, our study paves the way for cancer initiation research outside living organisms.Topobiologically complex mini-colons—which enable the faithful in vitro recapitulation of colorectal cancer tumorigenesis and its environmental determinants—offer the possibility to reduce animal use in a wide range of experimental applications. [ABSTRACT FROM AUTHOR]

Introduction: Adults aged ≥ 65 years contribute a large proportion of influenza-related hospitalizations and deaths due to increased risk of complications, which result in high medical costs and reduced health-related quality of life (HRQoL). Although seasonal influenza vaccines are recommended for older adults, the effectiveness of current vaccines is dependent on several factors including strain matching and recipient demographic factors. This systemic literature review aimed to explore the economic and humanistic burden of influenza in adults aged ≥ 65 years. Methods: An electronic database search was conducted to identify studies assessing the economic and humanistic burden of influenza, including influenza symptoms that impact the HRQoL and patient-related outcomes in adults aged ≥ 65 years. Studies were to be published in English and conducted in Germany, France, Spain, and Italy, the UK, USA, Canada, China, Japan, Brazil, Saudi Arabia, and South Africa. Results: Thirty-eight studies reported on the economic and humanistic burden of influenza in adults aged ≥ 65 years. Higher direct costs were reported for people at increased risk of influenza-related complications compared to those at low risk. Lower influenza-related total costs were found in those vaccinated with adjuvanted inactivated trivalent influenza vaccine (aTIV) compared to high-dose trivalent influenza vaccine (TIV-HD). Older age was associated with an increased occurrence and longer duration of certain influenza symptoms. Conclusion: Despite the limited data identified, results show that influenza exerts a high humanistic and economic burden in older adults. Further research is required to confirm findings and to identify the unmet needs of current vaccines. [ABSTRACT FROM AUTHOR]

Introduction: Adults aged 18–64 years comprise most of the working population, meaning that influenza infection can be disruptive, causing prolonged absence from the workplace, and reduced productivity and the ability to care for dependents. Influenza vaccine uptake is relatively low, even among the older adults in this population (i.e., aged 50–64 years), reflecting a lack of perceived need for vaccination. This systematic literature review (SLR) aimed to characterize the global burden of influenza in the 18–64 years population. Methods: An electronic database search was conducted and supplemented with conference and gray literature searches. Eligible studies described at least one of clinical, humanistic, or economic outcomes in adults aged 18–64 years and conducted across several global regions. Included studies were published in English, between January 1, 2012, and September 20, 2022. Results: A total of 40 publications were included, with clinical, humanistic, and economic outcomes reported in 39, 5, and 15, respectively. Risk of influenza-associated clinical outcomes were reported to increase with age among the 18–64 years population, including hospitalizations (Yamana et al. in Intern Med 60:3401–3408, 2021; Derqui et al. in Influenza Other Respir Viruses 16:862–872, 2022; Fuller et al. in Influenza Other Respir Viruses 16:265–275, 2022; Ortiz et al. in Crit Care Med 42:2325–2332, 2014; Yandrapalli et al. in Ann Transl Med 6:318, 2018; Zimmerman et al. in Influenza Other Respir Viruses 16:1133–1140, 2022). ICU admissions, mortality, ER/outpatient visits, and use of mechanical ventilation were recorded. Adults aged 18–64 years with underlying comorbidities were at higher risk of influenza-related hospitalizations, ICU admission, and mortality than otherwise healthy individuals. Length of hospital stay increased with age, although a lack of stratification across other economic outcomes prevented identification of further trends across age groups. Conclusions: High levels of hospitalization and outpatient visits demonstrated a clinical influenza-associated burden on patients and healthcare systems, which is exacerbated by comorbidities. Considering the size and breadth of the general population aged 18–64 years, the limited humanistic and economic findings of this SLR likely reflect an underreported burden. Greater investigation into indirect costs and prolonged absenteeism associated with influenza infection is required to fully understand the economic burden in this population. [ABSTRACT FROM AUTHOR]

Introduction: Influenza is a respiratory infection associated with a significant clinical burden globally. Adults aged ≥ 65 years are at increased risk of severe influenza-related symptoms and complications due to chronic comorbidity and immunosenescence. Annual influenza vaccination is recommended; however, current influenza vaccines confer suboptimal protection, in part due to antigen mismatch and poor durability. This systematic literature review characterizes the global clinical burden of seasonal influenza among adults aged ≥ 65 years. Methods: An electronic database search was conducted and supplemented with a conference abstract search. Included studies described clinical outcomes in the ≥ 65 years population across several global regions and were published in English between January 1, 2012 and February 9, 2022. Results: Ninety-nine publications were included (accounting for > 156,198,287 total participants globally). Clinical burden was evident across regions, with most studies conducted in the USA and Europe. Risk of influenza-associated hospitalization increased with age, particularly in those aged ≥ 65 years living in long-term care facilities, with underlying comorbidities, and infected with A(H3N2) strains. Seasons dominated by circulating A(H3N2) strains saw increased risk of influenza-associated hospitalization, intensive care unit admission, and mortality within the ≥ 65 years population. Seasonal differences in clinical burden were linked to differences in circulating strains. Conclusions: Influenza exerts a considerable burden on adults aged ≥ 65 years and healthcare systems, with high incidence of hospitalization and mortality. Substantial influenza-associated clinical burden persists despite increasing vaccination coverage among adults aged ≥ 65 years across regions included in this review, which suggests limited effectiveness of currently available seasonal influenza vaccines. To reduce influenza-associated clinical burden, influenza vaccine effectiveness must be improved. Next generation vaccine production using mRNA technology has demonstrated high effectiveness against another respiratory virus—SARS-CoV-2—and may overcome the practical limitations associated with traditional influenza vaccine production. [ABSTRACT FROM AUTHOR]

Influenza is a common respiratory infection associated with a substantial clinical, humanistic, and economic burden globally. Vaccines are essential to prevent and control influenza and are recommended by public-health agencies, such as the WHO and US CDC; however, vaccination rates vary considerably across the globe. This review aimed to investigate the perceived barriers and attitudes to influenza vaccination in the global population, in order to identify strategies that may improve influenza vaccination coverage. A structured literature search was undertaken to identify studies that reported on patient-reported attitudes towards influenza vaccination, focused on the adult general population in 16 prespecified countries. Eighty studies were included in this review. Negative attitude towards healthcare were found to be the most agreed upon barrier to vaccine uptake (31.1% agreement). The most agreed promoter of influenza vaccination was trust in healthcare services (62.0% agreement). Approximately 50% of participants intended to receive the influenza vaccine in the following season. To improve influenza vaccination coverage, healthcare workers must strengthen the foundation of substantial trust in healthcare services and provide educational materials that improve influenza vaccination knowledge among the adult general population. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to evaluate the glycemic control and safety of insulin degludec/insulin aspart (IDegAsp) co-formulation in Japanese patients with type 2 diabetes (T2D) in a real-world clinical setting, including elderly patients (aged > 75 years). Methods: Patients (≥ 18 years) diagnosed with T2D, previously treated with insulin were included from the Japanese Medical Data Vision database. Baseline data were taken at the index date, defined as the first IDegAsp prescription claim. Change in glycated hemoglobin (HbA1c) at 12 months was estimated using a mixed model repeated measures analysis. The proportion of patients achieving target HbA1c < 8.0% without experiencing hypoglycemia (identified by International Classification of Disease codes) was calculated at 12 months (365 ± 90 days) after baseline. Results: Overall, 10,798 patients were included, 3940 were aged > 75 years, and 913 had baseline HbA1c values available. Switching to IDegAsp was associated with significantly improved HbA1c values at 12 months (− 1.23% [− 1.43, − 1.02]95%CI, p < 0.001) versus baseline. Moreover, relative to baseline, a significantly greater proportion of patients achieved HbA1c < 8.0% without hypoglycemia at 12 months, relative rate (RR) 1.30 [1.15, 1.45]95%CI, p < 0.001. Results were similar for patients aged ≤ 75 years and aged > 75 years; 66% and 64% of patients, respectively, achieved HbA1c < 8.0% without hypoglycemia at 12 months. Conclusion: Switching from insulin to IDegAsp co-formulation was associated with significantly improved glycemic control and a reduction in hypoglycemia rate during 12 months of follow-up in Japanese patients with T2D, including those aged > 75 years. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Treatment intensification is commonly delayed in people with type 2 diabetes, resulting in poor glycemic control for an unacceptable length of time and increased risk of complications. Materials and Methods: This retrospective study investigated clinical inertia in 33,320 Japanese adults with type 2 diabetes treated with oral antidiabetic drugs (OADs) between 2009 and 2018, using data from the Computerized Diabetes Care (CoDiC®) database. Results: The median time from first reported glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) to treatment intensification was considerably longer and HbA1c levels were higher the more OADs the patient was exposed to. For patients receiving three OADs, the median times from HbA1c ≥7.0% (53 mmol/mol) to intensification with OAD, glucagon‐like peptide‐1 receptor agonist or insulin were 8.1, 9.1 and 6.7 months, with a mean HbA1c level at the time of intensification of 8.4%, 8.9% and 9.3%, respectively. The cumulative incidence for time since the first reported HbA1c ≥7.0% (≥53 mmol/mol) to intensification confirmed the existence of clinical inertia, identifying patients whose treatment was not intensified despite poor glycemic control. HbA1c levels ≥7.0% (≥53 mmol/mol) after ≥6 months on one, two or three OADs were observed in 42%, 51% and 58% of patients, respectively, showing that approximately 50% of patients are above HbA1c target regardless of how many OADs they take. Conclusions: Real‐world data here show clinical inertia in Japanese adults with type 2 diabetes from early diabetes stages when they are receiving OADs, and illustrate a need for earlier, more effective OADs or injectable treatment intensification and better communication around the existence of clinical inertia. [ABSTRACT FROM AUTHOR]

Introduction: In the randomized Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 10 trial, once-daily orally administered semaglutide—the first oral glucagon-like peptide 1 receptor agonist (GLP-1RA)—was similarly tolerated with comparable (at 7 mg) or better (at 14 mg) efficacy versus the injectable GLP-1RA dulaglutide 0.75 mg. Health-related quality of life (HRQoL) in PIONEER 10 was assessed using the Japanese-specific Diabetes Therapy-Related Quality of Life (DTR-QoL) questionnaire. Methods: The DTR-QoL comprises 29 questions, providing four domain and total scores. Answers were converted to a score between 0 and 100, with higher scores indicating greater HRQoL. Two estimands were prespecified: treatment policy (regardless of treatment discontinuation or rescue medication use) and trial product (assuming on treatment without rescue medication) in all randomized patients. Outcomes were assessed at weeks 26 and 52. Results: Mean baseline DTR-QoL domain scores were similar between treatment arms and were generally lower (giving more scope for improvement) for "anxiety and dissatisfaction with treatment" (62.1–65.3) and "satisfaction with treatment" (53.9–57.9) than "burden on social activities and daily activities" (76.5–77.7) and "hypoglycemia" (83.5–88.2). Using the treatment policy estimand, orally administered semaglutide 7 and 14 mg improved HRQoL versus dulaglutide 0.75 mg for the total score (estimated mean change from baseline [CfB] 7.3 and 8.1 vs 3.3; estimated treatment difference [ETD] 3.9 and 4.8) and the "anxiety and dissatisfaction with treatment" domain (CfB 9.7 and 10.9 vs 3.7; ETD 6.0 and 7.2) at week 52. Orally administered semaglutide 14 mg improved the "satisfaction with treatment" domain versus dulaglutide 0.75 mg (CFB 13.8 vs 5.7; ETD 8.1). DTR-QoL scores for orally administered semaglutide tended to be more durable (sustained over time) than for dulaglutide. Outcomes for the trial product estimand were similar. Conclusion: Orally administered semaglutide 7 and 14 mg improved the patients' HRQoL measured by the Japanese-specific DTR-QoL instrument versus dulaglutide 0.75 mg at week 52. Trial registration: ClinicalTrials.gov NCT03015220. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) approved to date are administered by injection; therefore, patient perceptions of an oral GLP-1 RA are unknown. This discrete choice experiment explored preferences for (unbranded) oral and injectable GLP-1 RA profiles among Japanese patients with type 2 diabetes (T2D). Methods: An online survey was designed using literature review and qualitative interview findings, and administered to Japanese patients with T2D and HbA1c ≥ 7.0% receiving oral antiglycaemic medication (with no experience of injectable antiglycaemic medication). Therapy profiles were created using Japanese head-to-head trial data for orally administered semaglutide (7 mg and 14 mg), injectable dulaglutide (0.75 mg), and injectable liraglutide (0.9 mg). Profiles were not labelled. Choice tasks tested preference between hypothetical profiles, preference between profiles with actual trial data, and willingness to initiate treatment. Relative importance of attributes was determined using conditional logit regression. Results: A total of 500 respondents were analysed: mean age 61.2 years; 93.8% male; mean HbA1c 7.6%; 78.2% with HbA1c ≥ 7.0 to < 8%; 89% with HbA1c above personal target. Mean BMI was 25.4 kg/m2; 49% had obesity (≥ 25 kg/m2). The treatment attribute with greatest importance was mode and frequency of administration (49.1%), followed by nausea risk (30.8%), weight change (11.3%), and HbA1c change (8.8%). Oral semaglutide 7 and 14 mg-like profiles were both preferred: the 7 mg-like profile was preferred over dulaglutide (by 91.0% of respondents) and liraglutide (by 89.4%); the 14 mg-like profile was preferred over dulaglutide (by 88.2%) and liraglutide (by 94.4%). Willingness to initiate treatment was also higher for orally administered semaglutide-like profiles: 62.4% with 7 mg and 64.0% with 14 mg, versus 13.6% and 11.0% with injectable GLP-1 RA-like profiles. Subgroup results were generally consistent with the overall sample. Conclusion: Japanese patients with T2D appear to prefer oral GLP-1 RA profiles over injectable GLP-1 RA profiles, and administration appears to be the most important factor in this decision. This highlights the unmet need for an effective and orally administered GLP-1 RA for the treatment of T2D in Japan. [ABSTRACT FROM AUTHOR]

Introduction: Reliable quality of life (QoL) measures and utility values are needed for patients with type 2 diabetes mellitus (T2DM) with a variety of comorbid conditions to help facilitate cost-effectiveness modeling. This study aimed to evaluate the Diabetes Treatment-Related Quality of Life (DTR-QOL) and EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaires in patients with T2DM with and without diabetes complications and comorbidities in Japan. Methods: This was an observational survey study involving 1000 patients with T2DM, at least 20 years old, receiving treatment at Nara University Hospital or Takamura Internal Medicine Clinic in Japan. Patients completed the DTR-QOL and EQ-5D-5L questionnaires and clinicians completed an accompanying case report form. The DTR-QOL and EQ-5D-5L are scored on a scale of 0–100 and 0–1, with 100 and 1 representing the best possible scores, respectively. Results: Out of 1000 recruited patients, 978 were included in the final analysis. Patients reported an average EQ-5D-5L value of 0.92 ± 0.11. Utility values corresponded to the degree of severity of health conditions while few differences were observed when stratified by the HbA1c 7% threshold, age, or BMI level, nor did the values correspond to the degree of clinical risk factors. Patients reported an average total DTR-QOL score of 79.26 ± 13.26. The DTR-QOL was sensitive to detect differences in patients with T2DM with a variety of complications and comorbidities, risk factors, and treatments. Conclusion: This is the largest study to report QOL values for patients with diabetes in Japan and the first to include a variety of comorbid diabetic conditions. These findings may be useful for cost-effectiveness modeling of patients with T2DM in Japan. [ABSTRACT FROM AUTHOR]

Introduction: In the head-to-head trial (SUSTAIN 7), the novel, injectable, once-weekly GLP-1 analogue semaglutide showed superiority in both glycemic outcomes and body weight reduction, compared with once-weekly dulaglutide in the treatment of type 2 diabetes (T2D). However, no economic evaluation using these data has yet been conducted in the Japanese setting. The objective of this analysis was to assess the short-term cost-effectiveness in Japan of once-weekly semaglutide 0.5 mg (the approved maintenance dose in Japan) compared with once-weekly dulaglutide 0.75 mg (the only licensed dose in Japan) over a 1-year period using Japanese cost data. Methods: Responder endpoints were obtained from the SUSTAIN 7 trial to assess the cost of successfully treating patients to these targets ("cost of control"). Responder endpoint definitions consisted of single, dual, and triple composite endpoints related to glycemic control, body weight, and hypoglycemia outcomes. The cost of treatment was accounted from a healthcare payer perspective, capturing drug costs only. Results: Treatment with once-weekly semaglutide 0.5 mg was associated with a lower cost and a lower cost per patient treated to target for all endpoints, compared with once-weekly dulaglutide 0.75 mg. For each JPY 1 spent on bringing patients to target with once-weekly semaglutide 0.5 mg, JPY 1.58, JPY 1.44, JPY 1.60, JPY 2.10, and JPY 2.33 would need to be spent on once-weekly dulaglutide 0.75 mg to achieve an equivalent outcome for endpoints of HbA1c ≤ 6.5%, HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia, and no weight gain, weight loss ≥ 5%, and ≥ 1.0% HbA1c reduction and ≥ 3.0% weight loss, respectively. Conclusions: These findings suggest that once-weekly semaglutide is a cost-effective treatment option compared with once-weekly dulaglutide for patients with T2D in Japan. In the future, this finding should be extrapolated to traditional long-term cost-effectiveness analysis, using common outcomes such as quality-adjusted life years. [ABSTRACT FROM AUTHOR]

Introduction: With one of the fastest aging populations in the world, demographic changes in Japan are a major public health concern due to the substantial burden that aging-associated diseases, such as type 2 diabetes (T2D), place on public healthcare systems. The aim of this analysis was to evaluate the short-term cost-effectiveness of switching Japanese patients with T2D receiving basal–bolus insulin therapy from their previous basal insulin to insulin degludec (degludec) under conditions of routine clinical practice. Methods: A previously published, open-source model developed in Microsoft Excel was used to evaluate the cost-effectiveness of switching basal–bolus insulin therapy from patients' previous basal insulin to degludec versus continuing the previous basal insulin therapeutic regimen in terms of costs (2018 Japanese Yen [JPY]) and quality-adjusted life years (QALYs), from a Japanese public healthcare payer perspective. The model captured hypoglycemia rates and insulin dosing over a 1-year time horizon, and was informed by Japanese real-world evidence from the T2D cohort (N = 135) of the Kumamoto Insulin Degludec Observational study. Results: Treatment with degludec was associated with improved effectiveness (+ 0.0354 QALYs), driven by lower daytime non-severe hypoglycemia rates with degludec, at slightly higher annual treatment costs (JPY 9510) versus continuing the previous basal insulin. Switching basal insulin to degludec was found to be a cost-effective intervention with an incremental cost-effectiveness ratio (JPY 268,811 per QALY gained) substantially below the willingness-to-pay threshold of 5 million JPY per QALY used in the Japanese Health Technology Assessment framework. Sensitivity analyses confirmed the robustness of this finding and indicated that the daytime non-severe hypoglycemia benefit with degludec was a key driver of outcomes in the base case. Conclusion: Based on Japanese real-world evidence, our analysis suggests that switching Japanese patients with T2D receiving a basal–bolus regimen from their previous basal insulin to degludec would be highly cost-effective. These data may help decision-makers in Japan allocate healthcare resources efficiently. Trial Registration: The KIDUNA study is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR): UMIN000021569. Funding: Novo Nordisk Pharma Ltd. Japan. [ABSTRACT FROM AUTHOR]

Introduction: The incidence and prevalence of type 2 diabetes mellitus (T2D) are increasing in Japan, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used to treat the disease. The objective of this study was to use a discrete choice experiment (DCE) to characterize patient preferences for clinical treatment features of two GLP-1 RAs—dulaglutide 0.75 mg and semaglutide 0.50 mg—among patients with T2D in Japan. Methods: Adult patients with T2D in Japan were administered the DCE via a web-based survey. The DCE examined patient preferences for five treatment attributes (each described by two or three levels), including method of administration, HbA1c change, reduction in cardiovascular (CV) risk, weight change, and common side effects (i.e., nausea). Results were analyzed using multinomial and mixed logit models, and predicted choice probability was calculated to determine the overall probability that either dulaglutide or semaglutide DCE levels were preferred. One DCE choice task included a direct comparison of the dulaglutide 0.75 mg versus semaglutide 0.50 mg treatment profiles. Results: 190 subjects completed the survey; 29 were excluded after failing the predefined internal validity assessments. In the final analysis sample (N = 161), the attribute with the largest effect on the subjects' choices was reduction in CV risk, followed by HbA1c change and common side effects. Patients' predicted choice probability for the semaglutide profile was 78%, versus 22% for the dulaglutide profile. 28% of patients were "very willing" to initiate treatment with semaglutide's product profile, versus 6% for dulaglutide. Conclusion: In this study, reduction in CV risk and HbA1c change were the key drivers of GLP-1 RA medication preference in Japanese patients with T2D. Overall, the majority of the patients preferred a product with attribute levels reflecting the semaglutide 0.50 mg profile, with a known CV risk reduction benefit and superior HbA1c reduction. Funding: Novo Nordisk. [ABSTRACT FROM AUTHOR]

Introduction: Semaglutide once-weekly (QW) is a novel glucagon-like peptide-1 (GLP-1) analogue administered at a 0.5 or 1.0 mg dose. In the absence of head-to-head trials between semaglutide QW and other GLP-1 receptor agonists (GLP-1 RAs) in a Japanese population, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of semaglutide QW vs GLP-1 RAs in Japanese patients with type 2 diabetes (T2DM), with a specific focus on the comparison between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW.Methods: A systematic review (SR) and supplementary Japanese searches were conducted to identify trials of GLP-1 RAs in Japanese patients on diet and exercise, who have previously received 0-1 oral antidiabetic drugs (OADs). Data at 52-56 weeks were extracted for the following outcomes (feasible for analysis in an NMA): glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, systolic blood pressure (SBP), and overall hypoglycemia. The data were synthesized using an NMA and a Bayesian framework.Results: Four trials, identified from the SR and Japanese-specific searches, were relevant for inclusion in the NMA. When compared to dulaglutide 0.75 mg QW, semaglutide 0.5 mg QW was shown to provide significant reductions in HbA1c [− 0.61% (12.3 mmol/mol)], weight (− 1.45 kg), SBP (− 5.03 mmHg), and FPG (− 1.26 mmol/L). No significant differences in the proportion of patients achieving a HbA1c level < 7% (53 mmol/mol) or the risk of overall hypoglycemia were observed between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW.Conclusion: Overall, semaglutide 0.5 mg QW was associated with significant reductions from baseline in HbA1c, weight, SBP, and FPG compared with dulaglutide 0.75 mg QW in Japanese patients with T2DM. These data may provide valuable evidence for clinical decision-making, cost-effectiveness analyses, and health technology appraisal (HTA) requirements.Funding: Novo Nordisk Pharma Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Treatment with IDegLira has the potential to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) without the weight gain and with a lower risk of hypoglycemia than with other therapies. The aim of the present analysis was to evaluate the long-term cost-effectiveness of IDegLira versus insulin glargine U100 with re-education and up-titration of the dose for treatment of patients with T2DM failing to achieve glycemic control on basal insulin in the US setting. Methods: Data were obtained from the DUAL V randomized controlled trial in which adults with T2DM failing to achieve glycemic targets with insulin glargine U100 were randomly allocated to receive either IDegLira or insulin glargine U100. Long-term projections of clinical outcomes and direct costs were made using the IMS CORE Diabetes Model. Costs were accounted from a healthcare payer perspective. Future costs and clinical benefits were discounted at 3% annually. Results: IDegLira was associated with improved discounted life expectancy (13.99 [standard deviation 0.19] versus 13.82 [standard deviation 0.20] years) and quality-adjusted life expectancy (9.14 [standard deviation 0.12] versus 8.87 [standard deviation 0.13] quality-adjusted life years [QALYs]) compared to insulin glargine U100. IDegLira was associated with increased direct costs of $16,970, yielding an incremental cost-effectiveness ratio (ICER) of $63,678 per QALY gained versus insulin glargine U100. Sensitivity analyses identified that the key driver of cost-effectiveness was the greater reduction in glycated hemoglobin with IDegLira compared with insulin glargine U100. Conclusions: Based on head-to-head clinical trial data, the present analysis suggests that IDegLira is likely to improve long-term clinical outcomes for patients with T2DM not achieving glycemic control on basal insulin compared to re-education and up-titration of the dose of insulin glargine U100, with these improvements coming at an increased cost from a healthcare payer perspective. An ICER within the range described as high care value was calculated, suggesting IDegLira is a cost-effective treatment option in the US. Funding: Novo Nordisk A/S and Novo Nordisk Inc. [ABSTRACT FROM AUTHOR]

Introduction: Effective glycemic control can reduce the risk of complications and their related costs in type 2 diabetes mellitus (T2DM). However, many patients fail to reach glycemic targets, often because of adverse effects of treatment (including hypoglycemia or weight gain). The present analysis evaluated the short-term cost-effectiveness of IDegLira versus continued up-titration of insulin glargine U100 in patients with T2DM failing to achieve glycemic control on basal insulin in the US setting.Methods: The cost per patient achieving treatment target (cost of control) was assessed for various single and composite endpoints for the entire trial population and in patients with baseline glycated hemoglobin (HbA1c) >8.0% and HbA1c >9.0%. The proportions of patients achieving treatment targets were analyzed using data obtained in the DUAL V study. Costs were accounted based on published wholesale acquisition costs.Results: When assessing the full trial population, IDegLira was associated with lower annual cost of control than continued up-titration of insulin glargine U100 for patients achieving HbA1c ≤6.5% without confirmed hypoglycemia (by $10,608), HbA1c ≤6.5% without weight gain (by $29,215), and HbA1c ≤6.5% without confirmed hypoglycemia and weight gain (by $57,351). A similar pattern was observed when multifactorial treatment targets were based on achieving a glycemic target of 7.0%. When only HbA1c was considered, IDegLira was associated with a lower cost per patient achieving HbA1c ≤6.5% (by $3306) but cost of control was equivalent for a target of HbA1c <7.0%. In patients with baseline HbA1c >8.0% and HbA1c >9.0%, IDegLira was associated with a lower cost of control for all treatment targets.Conclusion: The significantly greater clinical efficacy in terms of bringing patients to treatment targets identified in the DUAL V study results in lower cost of control values for IDegLira versus continued up-titration of insulin glargine U100 in the USA. This suggests IDegLira is a cost-effective treatment option in the USA.Funding: Novo Nordisk A/S and Novo Nordisk Inc. [ABSTRACT FROM AUTHOR]

Introduction: For people with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs (OADs), evidence from both randomized controlled trials (RCTs) and real-world studies has demonstrated that treatment intensification with liraglutide offers effective glycemic control, weight reduction, and a lower risk of hypoglycemia compared to treatment intensification with insulin or additional OADs. Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a new class of OADs that have also been shown to be effective in T2DM patients inadequately controlled with OADs. Currently there are no head-to-head RCTs comparing these to liraglutide. Methods: We aimed to evaluate the relative efficacy, using network meta-analysis (NMA), of treatment intensification with liraglutide and SGLT-2 inhibitors people with T2DM who have been treated with metformin (alone or in combination with SU, DPP-4, and TZD). We performed a systematic literature review to identify relevant RCTs comparing liraglutide (1.2 and 1.8 mg), canagliflozin (100 and 300 mg), empagliflozin (10 and 25 mg), or dapagliflozin (5 and 10 mg) to placebo. To strengthen the indirect evidence base, we also included non-placebo RCTs where sitagliptin (100 mg) was the active comparator. Bayesian NMA was performed on the following outcomes to assess the relative efficacy and safety of interventions: reduction (change) in HbA1c, weight, and fasting plasma glucose (FPG) as well as proportion reaching target HbA1c (<7%), and risk of hypoglycemia. Doses for each intervention were considered separately. Results: A total of 16 RCTs were identified. All trials were similar with respect to important baseline characteristics and study design. Both doses of liraglutide were generally statistically significantly superior to the SGLT-2s with respect to change from baseline in HbA1c and FPG as well as odds of reaching target HbA1c <7%. For weight, canagliflozin 300 mg was superior to liraglutide 1.2 mg, and SGLT-2s were generally associated with larger change from baseline in weight. For risk of major or minor hypoglycemia, no differences were found between treatments. Conclusions: Compared to SGLT-2 inhibitors, liraglutide offers improvement in HbA1c and FPG. Reductions in weight are likely comparable between liraglutide and SGLT-2s. Liraglutide did not differ from SGLT-2s in terms of risk of hypoglycemia. Given the lack of head-to-head evidence, this analysis provides valuable insight into the comparative outcomes of liraglutide versus SGLT-2 inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Adherence to diabetes medication has been linked to improved glycemic levels and lower costs, but previous research on adherence has typically involved oral antidiabetic medication or insulin. This study examines how adherence and persistence to once-daily liraglutide impact glycemic control and economic outcomes in a real-world population of adult type 2 diabetes (T2D) patients. Methods: A retrospective cohort study using administrative claims data from July 2009 through September 2013. Patients aged ≥18 years with T2D treated with liraglutide were identified (index date = first liraglutide prescription). Adherence was based on the proportion of days covered (PDC); with PDC ≥0.80 classified as adherent. Non-persistent patients were those with a gap in therapy of >90 days. Lab results for glycated hemoglobin (A1C) were used to identify whether patients achieved target levels of <7.0% and ≤ 6.5%, or experienced a reduction of ≥1.0% in A1C from pre-index (baseline) to post-index (follow-up). Logistic regression was used to estimate the likelihood of achieving the A1C goals, adjusted for baseline characteristics. Diabetes-related medical, pharmacy, and total costs were modeled and estimated for the adherence and persistence cohorts. Results: A total of 1321 patients were identified. The mean PDC was 0.59 and 34% of patients were classified as adherent, while 60% were persistent over 12 months of follow-up. Adherent and persistent patients were more likely to achieve each of the A1C goals than their non-adherent and non-persistent counterparts after adjusting for patient characteristics. Adherence and persistence were associated with higher adjusted diabetes-related pharmacy and total healthcare costs during follow-up; whereas persistent patients had significantly lower diabetes-related medical costs than non-persistent patients. Conclusions: Adherence and persistence to liraglutide are associated with improved A1C outcomes. Persistent patients showed significantly lower medical costs versus those discontinuing liraglutide. Total healthcare costs were higher for adherent and persistent cohorts driven by higher pharmacy costs. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials have shown that liraglutide effectively lowers glycated hemoglobin A1c (A1C) levels in adult patients with type 2 diabetes (T2D). However, no studies have evaluated the effectiveness of liraglutide by body mass index (BMI) in the United States (US) in clinical practice. This study examined liraglutide's clinical effectiveness to lower A1C and body weight after 6 months in T2D patients stratified by baseline BMI.Methods: This was a retrospective cohort study using the General Electric Centricity electronic medical records database. Adult patients with T2D (≥18 years and BMI≥ 25 kg/m(2)) and A1C >7% at baseline who started liraglutide between January 1, 2010 and January 31, 2013 and who did not use insulin or a glucagon-like peptide-1 analog 12 months before initiating liraglutide (N = 3,005) were selected. Changes from baseline, stratified by BMI, in A1C, body weight, A1C <7% goal attainment, and incidence of severe hypoglycemia at 6-month follow-up were examined.Results: After 6 months, A1C levels decreased on average by 0.95%, 1.02%, 0.99%, and 0.84% for BMI categories 25.0-29.9 (n = 333), 30.0-34.9 (n = 793), 35.0-39.9 (n = 821), and ≥40.0 kg/m(2) (n = 1,058), respectively (P = 0.30). The proportions of patients achieving A1C <7% at 6 months were 38.2%, 37.0%, 40.9%, and 41.0% (P = 0.54). The absolute body weight decreased by 1.5 to 4.0 kg across BMI and the rate of severe hypoglycemia (0.2%) was low.Conclusion: Patients with T2D experienced statistically significant decreases in A1C and body weight after initiating liraglutide regardless of their BMI. Liraglutide reduced A1C equally well across baseline BMI in clinical practice in the US. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials have shown that liraglutide effectively lowers glycated hemoglobin A1c (A1C) levels in adult patients with type 2 diabetes (T2D). However, no studies have evaluated the effectiveness of liraglutide by body mass index (BMI) in the United States (US) in clinical practice. This study examined liraglutide's clinical effectiveness to lower A1C and body weight after 6 months in T2D patients stratified by baseline BMI. Methods: This was a retrospective cohort study using the General Electric Centricity electronic medical records database. Adult patients with T2D (≥18 years and BMI≥ 25 kg/m) and A1C >7% at baseline who started liraglutide between January 1, 2010 and January 31, 2013 and who did not use insulin or a glucagon-like peptide-1 analog 12 months before initiating liraglutide ( N = 3,005) were selected. Changes from baseline, stratified by BMI, in A1C, body weight, A1C <7% goal attainment, and incidence of severe hypoglycemia at 6-month follow-up were examined. Results: After 6 months, A1C levels decreased on average by 0.95%, 1.02%, 0.99%, and 0.84% for BMI categories 25.0-29.9 ( n = 333), 30.0-34.9 ( n = 793), 35.0-39.9 ( n = 821), and ≥40.0 kg/m ( n = 1,058), respectively ( P = 0.30). The proportions of patients achieving A1C <7% at 6 months were 38.2%, 37.0%, 40.9%, and 41.0% ( P = 0.54). The absolute body weight decreased by 1.5 to 4.0 kg across BMI and the rate of severe hypoglycemia (0.2%) was low. Conclusion: Patients with T2D experienced statistically significant decreases in A1C and body weight after initiating liraglutide regardless of their BMI. Liraglutide reduced A1C equally well across baseline BMI in clinical practice in the US. [ABSTRACT FROM AUTHOR]

Objectives Obesity is a known risk factor for type 2 diabetes (T2D). We conducted a case-control study to assess the association between body mass index (BMI) and the risk of being diagnosed with T2D in the United States. Methods We selected adults (⩾ 18 years old) who were diagnosed with T2D (defined by ICD-9-CM diagnosis codes or use of anti-diabetic medications) between January 2004 and October 2011 ("cases") from an electronic health records database provided by an integrated health system in the Middle Atlantic region. Twice as many individuals enrolled in the health system without a T2D diagnosis during the study period ("controls") were selected based on age, sex, history of cardiac comorbidities or hyperinflammatory state (defined by C-reactive protein and erythrocyte sedimentation rate), and use of psychiatric or beta blocker medications. BMI was measured during one year prior to the first observed T2D diagnosis (for cases) or a randomly assigned date (for controls); individuals with no BMI measure or BMI < 18.5 kg/m² were excluded. We assessed the impact of increased BMI (overweight: 25-29.9 kg/m²; Obesity Class I: 30-34.9 kg/m²; Obesity Class II: 35-39.9 kg/m²; Obesity Class III: =40 kg/m²), relative to normal BMI (18.5-24.9 kg/m²), on a T2D diagnosis using odds ratios (OR) and relative risks (RR) estimated from multiple logistic regression results. Results We included 12,179 cases (mean age: 55, 43% male) and 25,177 controls (mean age: 56, 45% male). We found a positive association between BMI and the risk of a T2D diagnosis. The strength of this association increased with BMI category (RR [95% confidence interval]: overweight, 1.5 [1.4-1.6]; Obesity Class I, 2.5 [2.3-2.6]; Obesity Class II, 3.6 [3.4-3.8]; Obesity Class III, 5.1 [4.7-5.5]). Conclusions BMI is strongly and independently associated with the risk of being diagnosed with T2D. The incremental association of BMI category on the risk of T2D is stronger for people with a higher BMI relative to people with a lower BMI. [ABSTRACT FROM AUTHOR]

Introduction: While the liraglutide effect and action in diabetes (LEAD-6) clinical trial compared the efficacy and safety of liraglutide once daily (LIRA) to exenatide twice daily (EXEN) in adult patients with type 2 diabetes, few studies have explored the associated per-patient costs of glycemic goal achievement of their use in a real-world clinical setting. Methods: This retrospective cohort study used integrated medical and pharmacy claims linked with glycated hemoglobin A1C (A1C) results from the IMS Patient-Centric Integrated Data Warehouse. Patients' ≥18 years and naïve to incretin therapies during a 6-month pre-index period, with ≥1 prescription for LIRA or EXEN between January 2010 and December 2010, were included. Patients with evidence of insulin use (pre- or post-index) were excluded. Only patients who were persistent on their index treatment during a 180-day post-index period were included. Follow-up A1C assessments were based on available laboratory data within 45 days before or after the 6-month post-index point in time. Diabetes-related pharmacy costs over the 6-month post-index period were captured and included costs for both the index drugs and concomitant diabetes medications. Results: 234 LIRA and 182 EXEN patients were identified for the analysis. The adjusted predicted diabetes-related pharmacy costs per patient over the 6-month post-index period were higher for LIRA compared to EXEN ($2,002 [95% confidence interval (CI): $1,981, $2,023] vs. $1,799 [95% CI: $1,778, $1,820]; P < 0.001). However, a higher adjusted predicted percentage of patients on LIRA reached A1C < 7% goal (64.4% [95% CI: 63.5, 65.3] vs. 53.6% [95% CI: 52.6, 54.6]; P < 0.05), translating into lower average diabetes-related pharmacy costs per successfully treated patient for LIRA as compared to EXEN ($3,108 vs. $3,354; P < 0.0001). Conclusions: Although predicted diabetes-related pharmacy costs were greater with LIRA vs. EXEN, a higher proportion of patients on LIRA achieved A1C < 7%, resulting in a lower per-patient cost of A1C goal achievement with LIRA compared to EXEN. [ABSTRACT FROM AUTHOR]

Abstract: We present a combined experimental and theoretical study of the interaction of electrons with Bis(pentamethylcyclopentadienyl)titanium(IV) dichloride (Cp2*TiCl2) and difluoride (Cp2*TiF2). We report the experimental measurements of partial cross sections for the dissociative electron attachment (DEA) and the electron ionization (EI) mass spectra of isolated molecules. Estimates of the absolute cross sections are done on the basis of cross-calibration in the case of DEA and on the basis of binary-encounter-Bethe calculation in the case of EI. EI of both molecules is similar, concerning cross section amplitude and fragmentation pattern. DEA is different: DEA to Cp2*TiF2 primarily results in the formation of stable parent anion, while DEA to Cp2*TiCl2 results in the strong fragmentation, primarily into Cl− anion. Possible use of the molecules as the model species for studies of DEA efficiency in postirradiation chemistry is discussed. Graphical abstract: [ABSTRACT FROM AUTHOR]