[ ISSN : 2573-3680 ]
Economic evaluation; Exenatide once weekly; Basal insulins
Purpose: Diabetes is an increasing and relevant public health problem due to the increasing prevalence and incidence. Despite the recommendations, a large proportion of patients do not achieve the desired level of glycemic control even after starting basal insulin. In the past years new therapeutic options have been made available, providing an alternative to insulin treatment initiation after the failure of oral therapy; for these reason, we performed an economic evaluation to estimate the impact on the Italian National Health Service (INHS) expenditure of treating with exenatide once weekly those patients for whom basal insulin would be the treatment of choice.
Patients and Methods: A budget impact model based on Italian data (drug market composition, healthcare resource use and costs) was developed as indicated by international guidelines.
Results: Hypothesizing a greater uptake of exenatide once weekly versus basal insulin’s, even considering the high cost of exenatide once weekly, the model estimates a relevant saving for INHS expenditure due to the reduction in use and related costs for consumables, outpatients and hospitalization. The reduction in healthcare expenditure is estimated at national level in €5.8 million the first year, €15.5 million the second year and €27.3 million the third.
Conclusions: The increased use of exenatide once weekly as a possible effective and safe treatment option in patient’s candidate to basal insulin, by reducing healthcare resource use as ospitalizations, outpatients and consumables, could be associated with a reduction in total healthcare expenditure in Italy.
National and international clinical practice guidelines emphasize the importance of achieving and maintaining a good glycemic control to avoid long-term diabetes complications [1,2]. In addition to its clinical impact, a prolonged poor glycemic control can also affect patient’s quality of life, causing frustration, distress, lack of motivation and reduced self-care activities, pessimism toward therapy and depression [3-6]. Despite the recommendations, many patients do not achieve the desired level of control, and patient and physician inertia has been often described as a barrier to therapy intensification [7-10]. In Italy, data from the AMD Annals initiative [11], documented that patients with Type 2 Diabetes (T2D) starting basal insulin had an average HbA1c level of 8.9%; of these patients, around 50% already had a HbA1c >8.0% (> 64 mmol/mol) two years before adding basal insulin [12].
Even after starting basal insulin, around 50% of the patients still showed HbA1c levels >8.0% (> 64 mmol/mol) after one year and after two years. Therapeutic inertia may be driven by physician and patient concerns about hypoglycaemia, weight gain, fear of needles, lack of confidence in how to start insulin, and the complexities of living with diabetes [13-16]. Recently, new therapeutic options have been made available, providing an alternative to insulin treatment initiation after the failure of oral therapy [17]. In particular, GLP1 receptor agonists have been proven to be effective in improving glycemic control, while minimizing the risk of hypoglycemia and leading to a reduction in body weight [18,19].
The cardiovascular safety of this class of drugs has been also clearly demonstrated [20]. Considering the relevant burden of treatment with insulin in terms of costs related to the management (e.g. hospitalizations, consumables), we performed a budget impact analysis to evaluate the impact on the Italian National Health Service (INHS) expenditure of treating with exenatide once weekly (Bydureon® , AstraZeneca SpA) those patients for whom basal insulin would be the treatment of choice.
The present analysis is based on the results of the DURATION-3 study, an open label, randomized trial comparing exenatide once weekly (subcutaneous injections, 2 mg) with insulin glargine in patients not adequately controlled with metformin with or without sulfonylurea at maximum tolerate dosages [21]. This study highlighted that patients treated with exenatide once weekly had a better HbA1c control and a lower incidence of hypoglycaemia than patients treated with insulin glargine in a 3-year period. Moreover, these patients achieved and maintained weight loss during the study.
A budget impact analysis needs an estimation of the present and future forecasted market shares of different therapeutic approaches indicated for a specific disease/therapy line, the identification of the target population for whom the drug is indicated and the unit cost per patient of the different treatment options in order to evaluate the related healthcare costs (according to the International Society for Pharmacoeconomics and Outcomes Research Task Force on Good Research Practice) [22].
The present analysis aimed to evaluate the economic impact on expenditure in charge to INHS of the use of exenatide once weekly as alternative therapy in patients not adequately controlled using oral glucose-lowering drugs and candidate to the first use of insulin.
In our analysis, two different scenarios were compared: the current scenario with exenatide once weekly with a limited forecasted increase in sales and a more thriving one. Considered time horizon is 3 years. As consequence of the hypothesized place in therapy for exenatide once weekly (in substitution to the beginning of the first insulin treatment), the reference market considered is the basal insulin market (degludec insulin, detemir insulin, glargine insulin– with both originator and biosimilar considered-estimated based on IMS Health data, year 2015).
The market growth of the entire insulin market over the three years period considered (+1.2%, +1.8% and +2.0%), was estimated on the basis of the previously years’ trend. The uptake of the biosimilar of glargine (Abasaglar® , Eli Lilly SpA), was estimated considering the average uptake for biosimilar products reported in the “National Report on Medicines use in Italy” [23]. Among total insulin treated patients, the percentage with Type II Diabetes Mellitus was identified through IMS Health data to be 63.7%.
Starting from IMS Health data in terms of number of packs sold, the potential number of patients treated per year was estimated considering a daily consumption of insulin of 15 Units (U).
This daily consumption was determined based on the Italian real-world data published by CINECA Osservatorio SID-ARNO: the incidence of population treated with basal insulin versus total observed population was reported to the entire Italian population (Italian National Institute of Statistics, ISTATdata) and then, by using IMS Health sales data, the average yearly and daily dosage per patient were estimated [24,25].
The average consumption per patient/year of insulin was estimated in 15U/patient on the basis of the sales of the three available types of basal insulin’s. From the economic point of view, this data is conservative as for all basal insulin the Defined Daily Dose (DDD) established by World Health Organization (WHO) is 40U [26]. For the purpose of the budget impact estimates, as exenatide once weekly is already on the market, we considered a first scenario with a growth in line with current sales (1.3% of the basal insulin market at year zero, 1.6% the first year, 1.8% the second year and 2.0% the third year) which was compared with a more aggressive scenario where, starting from the same market share at year zero (as scenario 1), forecasted for exenatide an uptake of 2.5%, 4.2% and 6% in the first three years. This hypothesis (scenario 2) is in line with the maximum number of new patients starting basal insulin treatment per year and considers that exenatide once weekly treated patients remain on treatment the following year (Table 1).
Table 1: Forecasted market shares.
Both scenarios consider that exenatide once weekly achieves additional market share by the basal insulin available proportionally with market composition during years, except for the biosimilar of insulin glargine, which is hypothesized to grow in the same way in the two scenarios taking its market shares by all other basal insulins (also the ones for which the biosimilar is not yet available).
Unitary costs
Costs considered in the model were the ones in charge to INHS: drugs, estimated using the ex-factory price in charge to INHS net from mandatory price reductions (table 2); consumables for blood glucose monitoring (in order to reflect the INHS perspective, as each Italian Region have different approaches in terms of acquisition costs and number of consumables delivered for free to patients, the per patient annual cost was estimated as an average cost weighted by regional population); hospitalizations and outpatients (estimated using real world data reported by a recently published Italian study [27]: 3034€ for basal insulins (ATC class A10A associated with ATCA10B,2479€ for hospitalizations and 555€ for outpatients) and 1320€ for exenatide once weekly (ATC class A10B, 941€ for hospitalizations and 379€ for outpatients). We assumed that in the proposed place in therapy (before the beginning of insulin use), hospitalizations and outpatients’ costs of exenatide once weekly were the same as oral agents (all ATCA10B drugs); in the above mentioned study [27], in fact, exenatide was included in this class due to its tolerability profile which is similar to that of oral agents; this assumption could also be considered as conservative as in the class of oral agents also sulfonyl ureas, characterised by a greater prevalence of hypoglycaemia episodes, are included. Moreover, this approach could be considered conservative as other real world recent Italian studies highlights even lower costs associated with exenatide use [28,29].
Table 2: Summary of drugs cost and average daily dosage considered in the model.
Regarding drugs cost, whereas both exenatide and basal insulin treatments is additional to similar baseline therapy also in randomized clinical trials, we did not monetize other glucose lowering drug costs by considering them the same in both groups. We also performed sensitivity analysis, in order to test the robustness of the results of the model, setting the daily costs of all insulins at current price of the biosimilar of glargine (0.37€/day, thelowest price of all basal insulins) and increasing hospitalizations and outpatients’ costs for exenatide once weekly by 50% and 80%.
The summary of the results of the present budget impact analysis is reported in table 3. The increased uptake of exenatide once weekly in patients candidate to the initiation of a treatment with basal insulin (scenario 2), even if associated with higher drug costs, leads to a total reduction of INHS expenditure due to the reduction in consumables, outpatients and hospitalization related expenditure. With the hypothesized market shares, increased use of exenatide once weekly before the beginning of basal insulin treatment, could lead to a total saving ranging from €5.8 million the first year to €27.3 million the third year (mainly due to reduction in hospitalizations). Sensitivity analysis considering for all insulins the daily costs of biosimilar of insulin glargine substantially confirms the results of the base case (year 1: €5.5 million saving; year 2: €14.8 million saving and year 3: €26.1 million saving). Moreover, in order to test the sensitivity of the model to the costs of hospitalizations and outpatients associated to the treatment with exenatide once weekly, those were increased by 50% and 80%: in both cases the budget impact result in saving associated to the use of exenatide once weekly varying in the three years period from €2.3 million to €11 million and from € 0.3 million to €1.3 million respectively.
Table 3: Summary of results.
Resource consumption and cost associated with the treatment of diabetes and its complications have a relevant burden on Italian National Health Service (INHS) with increasing costs associated to increasing co-morbidities [28-31]. Optimizing diabetes treatment through the use of drugs associated with a favourable risk-benefit profile can help overcome clinical inertia and facilitate the attainment of the desired therapeutic goals, with a positive clinical, social and economic impact. The increased use of exenatide once weekly as a possible effective and safe treatment option in patient’s candidate to basal insulin, by reducing the use of healthcare resource as hospitalizations, outpatients and consumables, could be associated with a reduction in total healthcare expenditure although associated with higher drug costs. Several economic evaluations have been performed comparing exenatide versus basal insulin across different Countries and Health care Settings [32-36].
The cost-effectiveness of exenatide twice daily vs. insulin glargine as add-on to oral therapy was documented in UK,Germany, Spain,China, and Switzerland [37-41]. More recently, the cost effectiveness of once weekly exenatide vs. insulin glargine was also documented in different countries; in all these analyses, the cost per QALY gained for weekly exenatide when compared with insulin glargine in type 2 diabetes was within the range normally considered cost effective [33,34,42,43].
Furthermore, an observational study found a reduction in total healthcare costs related to the treatment with exenatide once weekly versus basal insulin [44].
While cost-effectiveness analyses are based on long-term projections of the benefits documented in clinical trials, our analysis shows that increasing the use of exenatide once weekly as an alternative to beginning basal insulin treatment could lead to cost savings starting from the first year, with even larger savings the third year. These findings have important clinical and economic implications, considering that in Italy over 30% of patients on dual or triple oral therapy show HbA1c levels over 8.0% [12]. Patient and physician reluctance to initiate insulin therapy, mainly driven by the fear of hypoglycemia and weight gain and to the added complexity of treatment, determine a substantial delay in therapy intensification, thus leading to long periods of exposure to elevated blood glucose levels. On the other hand, the initiation of insulin therapy is responsible for additional costs related to the need for more frequent blood glucose self-monitoring and increased healthcare resource utilization, mainly related to hypoglycemic episodes. In this respect, weekly exenatide represents a valuable alternative option, due to its efficacy and safety profile. Furthermore, its weekly administration and the lack of need for additional blood glucose self-monitoring adds a low level of complexity to the everyday management of the disease, thus facilitating treatment compliance. These positive aspects overcome the higher costs of treatment as compared to insulin glargine, translating into substantial cost savings for the national healthcare system.
In conclusion, our budget impact study shows that in the Italian national healthcare system weekly exenatide represents an important option for patients not adequately controlled with oral agents and candidate to basal insulin therapy. The higher costs of the treatment are offset by the savings deriving from the lower use of healthcare resources such as hospitalizations, outpatients and consumables. Future studies should evaluate the comparative effectiveness of GLP-1 receptor agonists vs. basal insulin strategies in community settings to facilitate more precise estimation of clinical and economic tradeoffs.
1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2017; 40.
12. Monografie degli Annali AMD 2012. Cambiamento delle terapie nel diabete di Tipo 2.
Roggeri A, Nicolucci A and Roggeri DP. Optimization of Treatment with Exenatide once Weekly versus Basal Insulins for Patients with Type 2 Diabetes: A Budget Impact Analysis. SM J Clin Med. 2018; 4(2): 1036s
The purpose of this statement is none other than to highlight the importance of ethical standards and quality required in basic and applied research currently being done so we can subsequently inform health care professionals of new developments that are taking place in this area.
Ma. Esperanza Rodríguez-van Lier*
Chemotherapy is commonly used in cancer treatment. So far, chemotherapy agents can be categorized into three types: classical chemotherapeutic drugs, molecular target agents and cellular machineries target drugs.
Ziyou Wang1,2 and Zunnan Huang1,2*
Blood transfusion can cause some transfusion adverse reactions. In order to understand the incidence of adverse transfusion reactions, we performed a meta-analysis in Chinese hospitals. Of 809 literatures, seven studies involving a total of 211, 050 patients with blood transfusion treatment were included in this meta-analysis. Meta-analysis showed that the total incidence of adverse reactions was 0.4% [95% CI (0.2, 0.9), P < 0.0001]. Further subgroup analysis showed that the incidence of febrile and allergic reactions was 0.2% [95% CI (0.1, 0.5), P < 0.0001] and 0.2% [95% CI (0.1, 0.3), P < 0.0001], respectively. The common blood components caused adverse reactions were red blood cell, plasama, and platelet in clinical practice.
Yulu Gao1 , Qinyun Li2 , Zongshuai Gao2 , Yunxia Zhu4 , Yanqiu Liao5 , Changtai Zhu2 *# , Yongning Sun3 *#
Background: CT scanning remains one of the most routinely used diagnostic tools in a setting of Interstitial Lung Disease (ILD). New and improved technologies, such as High Resolution Computer Tomography (HRCT) have revolutionized the quality of imaging, leading to a prominent increase in number of incidental findings that may or may not be of any clinical significance. The aim of this study was to evaluate the prevalence of incidental findings on thoracic CT and their clinical significance.
Methods: Retrospective analysis was conducted on a cohort of 84 patients referred to our academic center as cases of ILD. Patients were referred for further evaluation between January 2000 and January 2014 and were followed over the disease course. CT scans were done annually as part of clinical management and patients were screened for any incidental findings. All incidental findings were reviewed, recorded in a clinical database and followed up on subsequent visits.
Results: 25 (30%) patients were found to have incidental findings. Liver abnormalities were found in 12 (14.29 %) patients. 11(13.10 %) patients were reported to have coronary artery calcifications. 5 (5.95 %) and 3 (3.57%) patients had thyroid abnormalities and renal cysts, respectively. A malignant lesion was found in 1 patient each in liver and thyroid abnormality subgroup.
Conclusion: Incidental findings are common on thoracic CT scans providing valuable and unexpected findings which warrant investigation by health care providers to exclude malignant processes.
Sonu Sahni1,2*, Sameer Verma1,2, Reeju S Thomas1 , Barbara Capozzi3 and Arunabh Talwar1,2
Hepatitis C Virus infection (HCV) is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350.000 yearly deaths from HCV-related complications.
Nesrine Gamal and Pietro Andreone*
We report a case of large cell undifferentiated lung carcinoma in a middle aged patient with previously treated tuberculosis and scarring. 20 pack years of smoking history was noted. He presented with metastasis at multiple sites including trochanter, liver and acute bilateral lateral rectus palsy. Chest radiography showed fibrosis of right upper zone with homogenous opacity. Sputum examination for AFB was negative. Computerized tomography of the thorax showed an irregular heterogeneously enhancing mass involving right upper lobe with cavitation, necrosis along with lymph node involvement and the erosion of the 4th rib with liver metastasis. Radiography of hip joint was suggestive of lesser trochanteric metastasis. MRI brain was suggestive of mass at base of brain in parasellar area. Fine needle aspiration cytology and CT guided biopsy confirmed undifferentiated large cell carcinoma of lung. Tuberculosis and smoking may increase the risk of lung scarring and malignancy and pulmonary scarring may be associated with increased lung carcinoma in ipsilateral lung. Clinician needs to be more sensitive to look for malignancy association particularly in patient with or previously treated for tuberculosis and even more emphasis to be laid if scarring of lung is observed.
Sreenivasa Rao Sudulagunta1 *, Shyamala Krishnaswamy Kothandapani2 , Mahesh Babu Sodalagunta3 , Hadi Khorram2 , Mona Sepehrar4 and Zahra Noroozpour1
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Nessrine Akasbi*, Fatima Ezzahra Abourazzak and Taoufik Harzy
Sedigheh Mirhashemi1 , Mohammad Hosein Kalantar Motamedi1 *, Amir Hossein Mirhashemi2 and Hamid Reza Rasouli1
We encountered two autopsy cases of huge cardiomegaly with over 1000g in weight. Histochemical characteristics were examined using conventional staining including HE and Azan stains and immunohistochemical staining using antibodies against Complement Component 9 (CC9), RNA Binding Protein Motif 3(RBM3), Endothelial Type NO Synthase (eNOS) and Hypoxic Inducible Factor1α (HIF1). The reactive area with anti CC9 antibody, which presumed to be a marker of hypoxic change of myocardium, overlapped with eosinophilic area by HE and basophilic one by Azan. Although the reactive area with anti CC9 antibody showed relatively weak in the cytoplasm by anti eNOS antibody and no in the nucleus of cardiocytes with anti RBM3 antibody, outside of the reactive area with anti CC9 antibody there were intensive reactivity with anti eNOS antibody in cytoplasm and in a nucleus with anti RBM3 antibody. Anti HIF1 antibody showed weak reactivity with cytoplasm of endocardial cardiocytes and no with cytoplasm of cardiocytes in another area. The results obtained from the present cases revealed that the hypoxic change was equivalent even though the cause of cardiomegaly was deferred between two cases, and conventional staining such as HE and Azan utilized to detect hypoxic change in the heart and immunohistochemical studies seemed to be a useful tool for clarifying the cascade of hypoxic changes in the myocardium.
Satoshi Furukawa1,2*, Mayumi Kataoka1 , Satomu Morita1,2, Akari Uno2 , Masahito Hitosugi2 , Hiroshi Matsumoto1,3 and Katsuji Nishi1,2
A 45-year-old woman with multiple sclerosis was admitted to our hospital after out of hospital cardio-pulmonary resuscitation. The first ECG showed ventricular fibrillation. Following direct current defibrillation and mechanical reanimation, spontaneous circulation was restored and the ECG unremarkable without any signs of ischemia. Coronary angiography showed unobstructed coronary arteries Figure 1, (Panel A). Left ventriculography revealed apical wall obstruction, suggestive of apical aneurysm (Panel B, supplementary videos). Transthoracic echocardiography and Cardiac Magnetic Resonance Imaging (CMR) eventually lead to the diagnosis of a rare case of Apical Hypertrophic Cardiomyopathy (AHC) with ace of spades-form (Panel C,D). The patient underwent Cardioverter-Defibrillator Implantation (ICD) and amiodarone medical therapy for secondary prophylaxis. Patient’s family history and screening for HCM were unsuspicious.
Wiedemann S# *, Heidrich FM# , Speiser U and Strasser RH