Area under the curve: Comparing the value of factor VIII replacement therapies in haemophilia A.

INTRODUCTION: In factor VIII (FVIII) prophylaxis for haemophilia A, cost comparisons have used price per international unit (IU) based on the once reasonable assumption of equivalent outcome per IU. Now, with several extended half-life (EHL) products available, new outcome-oriented ways to compare products are needed. Area under the curve (AUC) quantifies FVIII levels over time after infusion providing comparable data. AIM: To develop a decision analytical model for making indirect comparisons of FVIII replacement products based on AUC. METHODS: A literature search identified 11 crossover studies with relevant pharmacokinetic data. A common comparator FVIII level curve was calculated using pooled data from selected studies. Absolute curves for other products were estimated based on relative differences to the common comparator (% difference vs the anchor). Three scenarios were investigated: (1) Kogenate® versus Kovaltry® and Jivi® ; (2) Advate® versus Elocta® , NovoEight® , Kovaltry, Adynovate® , Afstyla® , and ReFacto® ; and (3) Jivi versus Elocta, Adynovate, and Kogenate. Sensitivity analyses investigated effects of assay type and dose. RESULTS: In scenario 1, Jivi (+50%) and Kovaltry (+14%) showed larger AUCs versus Kogenate. In scenario 2, EHL products, Elocta and Adynovate, had the largest AUC (+64% and +58%, respectively) versus Advate. Compared with all other products in scenario 3, Jivi had the largest AUC by +13%-28%. CONCLUSION: This analysis concludes that EHL products differ in relative AUC, have a larger AUC compared with standard half-life, and thus, different FVIII levels over time after infusion. This model may aid decision makers in the absence of head-to-head data.

Burden of established cardiovascular disease in people with type 2 diabetes and matched controls: Hospital-based care, days absent from work, costs and mortality.

AIMS: To assess hospital-based care, work absence, associated costs, and mortality in patients with type 2 diabetes with and without established cardiovascular disease (eCVD) compared to matched controls. MATERIALS AND METHODS: In a population-based cohort study, we analysed individual-level data from national health, social insurance and socio-economic registers for people diagnosed with type 2 diabetes before age 70 years and controls (5:1) in Sweden. Regression analysis was used to attribute costs and days absent due to eCVD. Mortality was analysed using Cox proportional hazard regression, stratified by birth year and adjusted for sex and education. RESULTS: Thirty percent (n = 136 135 of 454 983) of people with type 2 diabetes had ≥1 person-year with eCVD (women 24%; men 34%). The mean annual costs of hospital-based care for diabetes complications were EUR 2629 (95% confidence interval [CI] 2601-2657) of which EUR 2337 (95% CI 2309-2365) were attributed to eCVD (89%). The most costly person-years (10th percentile) were observed in a broad subgroup, 42% of people with type 2 diabetes and eCVD. People with type 2 diabetes had on average 146 days absent (95% CI 145-147) per year, of which 68 days (47%; 95% CI 67-70) were attributed to eCVD. The mortality hazard ratio for type 2 diabetes with eCVD was 4.63 (95%CI 4.58-4.68) and without eCVD was 1.86 (95% CI 1.84-1.88) compared to controls without eCVD. CONCLUSION: The sizable burden of eCVD on both the individual with type 2 diabetes and society calls for efficient management in order to reduce the risks for those living with eCVD and to postpone its onset.

Model-based predictions on health benefits and budget impact of implementing empagliflozin in people with type 2 diabetes and established cardiovascular disease.

AIM: To perform a model-based analysis of the short- and long-term health benefits and costs of further increased implementation of empagliflozin for people with type 2 diabetes and established cardiovascular disease (eCVD) in Sweden. MATERIALS AND METHODS: The validated Institute for Health Economics Diabetes Cohort Model (IHE-DCM) was used to estimate health benefits and a 3-year budget impact, and lifetime costs per quality-adjusted life years (QALY) gained of increased implementation of adding empagliflozin to standard of care (SoC) for people with type 2 diabetes and eCVD in a Swedish setting. Scenarios with 100%/75%/50% implementation were explored. Analyses were based on 30 model cohorts with type 2 diabetes and eCVD (n = 131 412 at baseline) from national health data registers. Sensitivity analyses explored the robustness of results. RESULTS: Over 3 years, SoC with empagliflozin (100% implementation) versus SoC before empagliflozin resulted in 7700 total life years gained and reductions in cumulative incidence of cardiovascular deaths by 30% and heart failures by 28%. Annual costs increased by 15% from higher treatment costs and increased survival. Half of these benefits and costs are not yet reached with current implementation below 50%. SoC with empagliflozin yielded 0.37 QALYs per person, with an incremental cost-effectiveness ratio of 16 000 EUR per QALY versus SoC before empagliflozin. CONCLUSIONS: Model simulations using real-world data and trial treatment effects indicated that a broader implementation of empagliflozin, in line with current guidelines for treatment of people with type 2 diabetes and eCVD, would lead to further benefits even from a short-term perspective.

Healthcare costs of dementia diseases before, during and after diagnosis: Longitudinal analysis of 17 years of Swedish register data.

INTRODUCTION: This study examines health-care costs attributed to dementia diseases in the 10 years prior to, during, and 6 years after diagnosis. METHODS: Using administrative register data for people diagnosed with dementia (2010-2016) in southern Sweden (n = 21,184), and a comparison group without dementia, health-care costs over 17 years were examined using longitudinal regression analysis. RESULTS: Average annual health-care costs per person were consistently higher before diagnosis in the dementia group (10 years before: Swedish krona (SEK) 2063, P < .005 and 1 year before: SEK8166, P < .005). At diagnosis, health-care costs were more than twice as high (SEK44,410, P < .005). Four to 6 years after diagnosis, there was no significant different in costs compared to comparators. DISCUSSION: Excess health-care cost arise as early as 10 years before a formal diagnosis of dementia, and while there is a spike in cost after diagnosis, health-care costs are no different 4 years after. These findings question currently accepted assumptions on costs of dementia.

Costs of diabetes complications: hospital-based care and absence from work for 392,200 people with type 2 diabetes and matched control participants in Sweden.

AIMS/HYPOTHESIS: The risk of complications and medical consequences of type 2 diabetes are well known. Hospital costs have been identified as a key driver of total costs in studies of the economic burden of type 2 diabetes. Less evidence has been generated on the impact of individual diabetic complications on the overall societal burden. The objective of this study was to analyse costs of hospital-based healthcare (inpatient and outpatient care) and work absence related to individual macrovascular and microvascular complications of type 2 diabetes in Sweden in 2016. METHODS: Data for 2016 were retrieved from a Swedish national retrospective observational database cross-linking individual-level data for 1997-2016. The database contained information from population-based health, social insurance and socioeconomic registers for 392,200 people with type 2 diabetes and matched control participants (5:1). Presence of type 2 diabetes and of diabetes complications were derived using all years, 1997-2016. Costs of hospital-based care and of absence from work due to diabetes complications were estimated for the year 2016. Regression analysis was used for comparison with control participants to attribute absence from work to individual complications, and to account for joint presence of complications. RESULTS: Use of hospital care for complications was higher in type 2 diabetes compared with control participants in 2016: 26% vs 12% had ≥1 hospital contact; there were 86,104 vs 24,608 outpatient visits per 100,000 people; and there were 9894 vs 2546 inpatient admissions per 100,000 people (all p < 0.001). The corresponding total costs of hospital-based care for complications were €919 vs €232 per person (p < 0.001), and 74.7% of costs were then directly attributed to diabetes (€687 per person). Regression analyses distributed the costs of days absent from work across diabetes complications per se, basic type 2 diabetes effect and unattributed causes. Diabetes complications amounted to €1317 per person in 2016, accounting for possible complex interactions (25% of total costs of days absent). Key drivers of costs were the macrovascular complications angina pectoris, heart failure and stroke; and the microvascular complications eye diseases, including retinopathy, kidney disease and neuropathy. Early mortality in working ages cost an additional €579 per person and medications used in risk-factor treatment amounted to €418 per person. CONCLUSIONS/INTERPRETATION: The economic burden of complications in type 2 diabetes is substantial. Costs of absence from work in this study were found to be greater than of hospital-based care, highlighting the need for considering treatment consequences in a societal perspective in research and policy. Graphical abstract.

Days absent from work as a result of complications associated with type 2 diabetes: Evidence from 20 years of linked national registry data in Sweden.

AIMS: To analyse days absent from work related to individual microvascular, macrovascular and other complications of type 2 diabetes (T2D) and to identify key drivers of absence. MATERIALS AND METHODS: National health and socio-economic individual-level data were analysed for the years 1997 to 2016 for people with T2D, and age-, sex- and residential region-matched controls (5:1) using linkage to Swedish national administrative registers, based on personal identity numbers. Regression analyses accounting for individual-level clustering and education were estimated to obtain days absent by individual complications. Alternative analyses, for example, workforce indicator and age subgroups, were explored for robustness and comparison purposes. RESULTS: A total of 413 000 people with T2D aged <66 years, comprising 4.9 million person-years, was included. The crude proportion with any absence was higher among those with T2D compared to controls (47% vs. 26%) in the index year, and the median (IQR) number of days was higher (223 [77;359] vs. 196 [59;352]) if any absence. Regression analyses showed that complications per se were a key driver of days absent: stroke (+102 days); end-stage renal disease (+70 days); severe vision loss (+56 days); and angina pectoris, heart failure, and osteoarthritis (+53 days each). The alternative analyses showed similar levels of days absent and age subgroups differed in expected directions. CONCLUSIONS: This study provides evidence of the persisting impact on productivity from complications that supports continued efforts to reduce risk factors in T2D. Future studies on burden of disease and economic evaluations of new therapies and disease management may use this new set of complication-specific estimates to improve understanding of the value of reducing complications.

Why childhood-onset type 1 diabetes impacts labour market outcomes: a mediation analysis.

AIMS/HYPOTHESIS: Previous studies show a negative effect of type 1 diabetes on labour market outcomes such as employment and earnings later in life. However, little is known about the mechanisms underlying these effects. This study aims to analyse the mediating role of adult health, education, occupation and family formation. METHODS: A total of 4179 individuals from the Swedish Childhood Diabetes Register and 16,983 individuals forming a population control group born between 1962 and 1979 were followed between 30 and 50 years of age. The total effect of having type 1 diabetes was broken down into a direct effect and an indirect (mediating) effect using statistical mediation analysis. We also analysed whether type 1 diabetes has different effects on labour market outcome between the sexes and across socioeconomic status. RESULTS: Childhood-onset type 1 diabetes had a negative impact on employment (OR 0.68 [95% CI 0.62, 0.76] and OR 0.76 [95% CI 0.67, 0.86]) and earnings (-6%, p < 0.001 and -8%, p < 0.001) for women and men, respectively. Each of the mediators studied contributed to the total effect with adult health and occupational field accounting for the largest part. However, some of the effect could not be attributed to any of the mediators studied and was therefore likely related to other characteristics of the disease that hamper career opportunities. The effect of type 1 diabetes on employment and earnings did not vary significantly according to socioeconomic status of the family (parental education and earnings). CONCLUSIONS/INTERPRETATION: A large part of the effect of type 1 diabetes on the labour market is attributed to adult health but there are other important mediating factors that need to be considered to reduce this negative effect.

Precision medicine in neurodegeneration: the IHI-PROMINENT project.

Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of over 400 billion EUR annually. Recent advances in diagnostics and approval for new pharmaceutical treatments for Alzheimer's disease (AD), the most common etiology of dementia, heralds the beginning of precision medicine in this field. However, their implementation will challenge an already over-burdened healthcare systems. There is a need for innovative digital solutions that can drive the related clinical pathways and optimize and personalize care delivery. Public-private partnerships are ideal vehicles to tackle these challenges. Here we describe the Innovative Health Initiative (IHI) public-private partnership project PROMINENT that has been initiated by connecting leading dementia researchers, medical professionals, dementia patients and their care partners with the latest innovative health technologies using a precision medicine based digital platform. The project builds upon the knowledge and already implemented digital tools from several collaborative initiatives that address new models for early detection, diagnosis, and monitoring of AD and other neurodegenerative disorders. The project aims to provide support to improvement efforts to each aspect of the care pathway including diagnosis, prognosis, treatment, and data collection for real world evidence and cost effectiveness studies. Ultimately the PROMINENT project is expected to lead to cost-effective care and improved health outcomes.

Long-Term Cost Effectiveness of Oral Semaglutide Versus Empagliflozin and Sitagliptin for the Treatment of Type 2 Diabetes in the Swedish Setting.

OBJECTIVE: The aim of this study was to assess the cost effectiveness of oral semaglutide versus other oral glucose-lowering drugs for the management of type 2 diabetes (T2D) in Sweden. METHODS: The Swedish Institute for Health Economics Diabetes Cohort Model was used to assess the cost effectiveness of oral semaglutide 14 mg versus empagliflozin 25 mg and oral semaglutide 14 mg versus sitagliptin 100 mg, using data from the head-to-head PIONEER 2 and 3 trials, respectively, in which these treatments were added to metformin (± sulphonylurea). Base-case and scenario analyses were conducted. Robustness was evaluated with deterministic and probabilistic sensitivity analyses. RESULTS: In the base-case analyses, greater initial lowering of glycated haemoglobin levels with oral semaglutide versus empagliflozin and oral semaglutide versus sitagliptin, respectively, resulted in reduced incidences of micro- and macrovascular complications and was associated with lower costs of complications and indirect costs. Treatment costs were higher for oral semaglutide, resulting in higher total lifetime costs than with empagliflozin (Swedish Krona [SEK] 1,245,570 vs. 1,210,172) and sitagliptin (SEK1,405,789 vs. 1,377,381). Oral semaglutide was shown to be cost effective, with an incremental cost-effectiveness ratio (ICER) of SEK239,001 per quality-adjusted life-year (QALY) compared with empagliflozin and SEK120,848 per QALY compared with sitagliptin, from a payer perspective. ICERs were lower at SEK191,721 per QALY compared with empagliflozin and SEK95,234 per QALY compared with sitagliptin from a societal perspective. Results were similar in scenario analyses that incorporated cardiovascular effects, and also in sensitivity analyses. CONCLUSIONS: In a Swedish setting, oral semaglutide was cost effective compared with empagliflozin and sitagliptin for patients with T2D inadequately controlled on oral glucose-lowering drugs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02863328 (PIONEER 2; registered 11 August 2016) and NCT02607865 (PIONEER 3; registered 18 November 2015).

For any disease, it is important to consider whether new treatments, which may be more effective but also more expensive, are worth paying for compared with treatments that are already being used. This is called a cost-effectiveness analysis and helps health authorities and other organisations (such as insurance companies) that pay for medications to decide whether or not to pay for the new treatment. Cost effectiveness differs between individual countries because each has its own health system, health costs and approved treatments. Semaglutide is a type of medication called a glucagon-like peptide-1 receptor agonist (or GLP-1RA) that is used by people with type 2 diabetes to help control their blood glucose (sugar). Semaglutide is administered by injection but has recently become the first GLP-1RA to be available in a once-daily oral (tablet) form. We used information from the Swedish Institute for Health Economics and two clinical trials of oral semaglutide that compared it with other oral glucose-lowering drugs­empagliflozin and sitagliptin­to work out whether oral semaglutide was a cost-effective treatment in Sweden. We found that oral semaglutide was more expensive than empagliflozin and sitagliptin over the entire time on treatment but also led to greater lowering of blood sugar. This means that patients had fewer other illnesses linked to diabetes and lower health costs as a result. Balancing the higher upfront cost of the drug versus savings from fewer illnesses linked to diabetes, we found that in Sweden, oral semaglutide was cost effective compared with empagliflozin and sitagliptin.

Effect of self-managed lifestyle treatment on glycemic control in patients with type 2 diabetes.

The lack of effective, scalable solutions for lifestyle treatment is a global clinical problem, causing severe morbidity and mortality. We developed a method for lifestyle treatment that promotes self-reflection and iterative behavioral change, provided as a digital tool, and evaluated its effect in 370 patients with type 2 diabetes (ClinicalTrials.gov identifier: NCT04691973). Users of the tool had reduced blood glucose, both compared with randomized and matched controls (involving 158 and 204 users, respectively), as well as improved systolic blood pressure, body weight and insulin resistance. The improvement was sustained during the entire follow-up (average 730 days). A pathophysiological subgroup of obese insulin-resistant individuals had a pronounced glycemic response, enabling identification of those who would benefit in particular from lifestyle treatment. Natural language processing showed that the metabolic improvement was coupled with the self-reflective element of the tool. The treatment is cost-saving because of improved risk factor control for cardiovascular complications. The findings open an avenue for self-managed lifestyle treatment with long-term metabolic efficacy that is cost-saving and can reach large numbers of people.

Cost Effectiveness of Once-Weekly Semaglutide Versus Once-Weekly Dulaglutide in the Treatment of Type 2 Diabetes in Canada.

OBJECTIVE: The aim of this study was to assess the cost effectiveness of semaglutide versus dulaglutide, as an add-on to metformin monotherapy, for the treatment of type 2 diabetes (T2D), from a Canadian societal perspective. METHODS: The Swedish Institute for Health Economics Cohort Model of T2D was used to assess the cost effectiveness of once-weekly semaglutide (0.5 or 1.0 mg) versus once-weekly dulaglutide (0.75 or 1.5 mg) over a 40-year time horizon. Using data from the SUSTAIN 7 trial, which demonstrated comparatively greater reductions in glycated hemoglobin (HbA1c), body mass index and systolic blood pressure with semaglutide, compared with dulaglutide, a deterministic base-case and scenario simulation were conducted. The robustness of the results was evaluated with probabilistic sensitivity analyses and 15 deterministic sensitivity analyses. RESULTS: The base-case analysis indicated that semaglutide is a dominant treatment option, compared with dulaglutide. Semaglutide was associated with lower total costs (Canadian dollars [CAN$]) versus dulaglutide for both low-dose (CAN$113,287 vs. CAN$113,690; cost-saving: CAN$403) and high-dose (CAN$112,983 vs. CAN$113,695; cost-saving: CAN$711) comparisons. Semaglutide resulted in increased quality-adjusted life-years (QALYs) and QALY gains, compared with dulaglutide, for both low-dose (11.10 vs. 11.07 QALYs; + 0.04 QALYs) and high-dose (11.12 vs. 11.07 QALYs; + 0.05 QALYs) comparisons. The probabilistic sensitivity analysis showed that for 66-73% of iterations, semaglutide was either dominant or was considered cost effective at a willingness-to-pay threshold of CAN$50,000. CONCLUSIONS: From a Canadian societal perspective, semaglutide may be a cost-effective treatment option versus dulaglutide in patients with T2D who are inadequately controlled on metformin monotherapy.

Labor market consequences of childhood onset type 1 diabetes.

This paper examines the effect of the onset of Type 1 Diabetes Mellitus (T1DM) before 15 years of age on labor market outcomes and contributes to the literature on effects of childhood health on adult socioeconomic status. Using national Swedish socioeconomic register data 1991-2010 for 2485 individuals born 1972-1978 with onset of T1DM in 1977-1993, we find that T1DM in childhood has a negative effect on labor market outcomes later in life. Part of the T1DM effect is channeled through occupational field which may be related to both choice and opportunities. Although the magnitude of the effect is only directly generalizable to illnesses with similar attributes as T1DM, the results suggest that causality in the often observed correlation between health and socioeconomic status, at least partly, is explained by an effect running from health to earnings. This has implications for research and policy on strategies to reduce socioeconomic-related health inequality. Our findings also shed light on productivity losses, measured by employment status and earnings due to childhood onset T1DM, which have implications for both the individual and society.

Willingness-to-pay to access Ingenol Mebutate Gel for Actinic Keratosis Treatment in the U.S. Setting.

Background: Currently available topical treatments for actinic keratosis (AK) adversely affect patients' quality of life because of long treatment durations and long-lasting local skin reactions (LSRs), which may result in poor treatment adherence and patient outcomes. Ingenol mebutate gel, a recently introduced treatment for AK, is administered for 2 or 3 days, and LSR's are predicable in onset and duration. Objectives: The objective of the study was to estimate the value of ingenol mebutate gel's shorter treatment duration and tolerability profile to potential patients, versus existing topical treatments (imiquimod 3.75%, imiquimod 5% and diclofenac 3%) in the United States. Methods: The open-ended Contingent Valuation (CV) approach was used to estimate incremental willingness-to-pay (WTP) for ingenol mebutate gel rather than treatment with imiquimod 5%, imiquimod 3.75% and diclofenac 3%. Profiles for each therapy differed in regards to treatment duration, time-to-LSR resolution, and price. Subjects were asked to state their maximum out-of-pocket WTP to receive ingenol mebutate gel instead of each of the three alternatives. Results: 103 subjects provided usable answers. Between 48% and 63% of subjects were willing to pay extra to gain access to treatment with the ingenol mebutate gel profile instead of the comparators, and the mean incremental WTP ranged from $475 to $518. Subjects with experience of topical treatment stated higher WTP for accessing ingenol mebutate gel. Subjects whose most bothersome AK area was the full scalp or forehead also claimed higher WTP for ingenol mebutate gel. Conclusions: Patients diagnosed with AK indicated an unmet need for fast-acting topical treatment with shorter LSR resolution time.