Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo.

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.

Preference for Oral and Injectable GLP-1 RA Therapy Profiles in Japanese Patients with Type 2 Diabetes: A Discrete Choice Experiment.

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.

Lower Drug Cost of Successfully Treating Patients with Type 2 Diabetes to Targets with Once-Weekly Semaglutide versus Once-weekly Dulaglutide in Japan: A Short-Term Cost-Effectiveness Analysis.

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.

Real-world cost-effectiveness: lower cost of treating patients to glycemic goal with liraglutide versus exenatide.

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.

Retrospective real-world adherence in patients with type 2 diabetes initiating once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg.

BACKGROUND: The effectiveness of a drug is significantly influenced by a patient's adherence to the required regimen. OBJECTIVE: The goal of this retrospective database analysis was to determine the factors affecting adherence over a 12-month follow-up period in adults with type 2 diabetes mellitus (DM) initiating once-daily liraglutide (1.8 mg) or twice-daily exenatide (10 µg). METHODS: A patient-centric claims database was used, covering the period January 2009 to December 2011. Patients were included if they had ≥1 claim of once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg from January to December 2010 (index date [ID]), ≥2 diagnoses of type 2 DM before ID, continuous enrollment for 12 months before and after ID, and age ≥18 years at ID. Patients were required to be glucagon-like peptide-1 receptor agonist treatment-naive in the 12 months preceding ID and have a second prescription for once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg during the 12 months after ID. The medication possession ratio (MPR) was used as a continuous variable and to categorize patients as high-adherent (MPR ≥80%) or low-adherent (MPR <80%). Regression analyses were conducted to determine the predictors for nonadherence in the type 2 DM population, with bivariate testing of the MPR categories conducted initially to determine the predictors to be included in the final regression model. RESULTS: A total of 3623 patients (once-daily liraglutide 1.8 mg, n = 2036; twice-daily exenatide 10 µg, n = 1587) were identified. Variables found to reduce adherence were younger age, female sex, Southern geographic region, twice-daily exenatide treatment, and higher percentage of copayment from the claimant. After adjusting for confounding factors, patients receiving once-daily liraglutide 1.8 mg were ∼11% more adherent than patients receiving twice-daily exenatide 10 µg (95% CI, 7-14; P < 0.0001). The odds ratio for "poor" adherence (MPR <80%) with twice-daily exenatide 10 µg therapy compared with liraglutide 1.8 mg once-daily was 1.33 (95% CI, 1.16-1.53; P < 0.0001). CONCLUSIONS: This study found that adherence to once-daily liraglutide 1.8 mg treatment was superior to twice-daily exenatide 10 µg over a 12-month follow-up period. Nonadherence has important implications to the health care system, both in terms of clinical effectiveness and economic burden (eg, hospitalization, productivity losses). Using strategies to increase adherence is vital to reduce the future clinical and economic burden of diabetes.

Evaluating the long-term cost-effectiveness of liraglutide versus exenatide BID in patients with type 2 diabetes who fail to improve with oral antidiabetic agents.

BACKGROUND: The global clinical and economic burden of type 2 diabetes is substantial. Recently, clinical trials with glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide and exenatide) have shown a multifactorial clinical profile with the potential to address many of the clinical needs of patients and reduce the burden of disease. OBJECTIVE: The goal of this study was to evaluate the long-term cost-effectiveness of once-daily liraglutide versus exenatide BID in patients with type 2 diabetes who failed to improve with metformin and/or sulfonylurea, based on the results of a previous clinical trial in 6 European countries (Switzerland, Denmark, Norway, Finland, the Netherlands, and Austria). METHODS: A validated computer simulation model of diabetes was used to predict life expectancy, quality-adjusted life years (QALYs), and incidence of diabetes-related complications in patients receiving liraglutide (1.8 mg once daily) or exenatide (10 µg BID). Baseline cohort characteristics and treatment effects were derived from the Liraglutide Effect and Action in Diabetes 6 trial. Country-specific complication costs were taken from published sources. Simulations were run over 40 years from third-party payer perspectives. Future costs and clinical benefits were discounted at country-specific discount rates. Sensitivity analyses were performed. RESULTS: Liraglutide was associated with improvements of 0.12 to 0.17 QALY and a reduced incidence of most diabetes-related complications versus exenatide in all settings. Evaluation of total direct medical costs (treatment plus complication costs) suggest that liraglutide was likely to cost between Euro (€) 1023 and €1866 more than exenatide over patients' lifetimes, leading to incremental cost-effectiveness ratios per QALY gained versus exenatide of: Switzerland, CHF (Swiss francs) 10,950 (€6902); Denmark, Danish krone [kr] 88,160 (€11,805); Norway, Norwegian krone [kr], 111,916 (€13,546); Finland, €8459; the Netherlands, €8119; and Austria, €8516. CONCLUSIONS: Long-term projections indicated that liraglutide was associated with benefits in life expectancy, QALYs, and reduced complication rates versus exenatide. Liraglutide was cost-effective from a health care payer perspective in Switzerland, Denmark, Norway, Finland, the Netherlands, and Austria.