Diabetes Ther (2021) 12:2329–2342 https://doi.org/10.1007/s13300-021-01064-4 ORIGINAL RESEARCH Cost Analysis of FreeStyle LibreÒ 2 System in Type 2 Diabetes Mellitus Population Itziar Oyagüez . Fernando Gómez-Peralta . Sara Artola . Francisco J. Carrasco . Juana Carretero-Gómez . Javier Garcı́a-Soidan . Ricardo Gómez-Huelgas . Juan F. Merino-Torres . Antonio Pérez Received: March 9, 2021 / Accepted: April 20, 2021 / Published online: May 4, 2021 Ó The Author(s) 2021 ABSTRACT was modelled for patients with T2DM on a basal-bolus insulin regimen. The cost estimate Introduction: FreeStyle LibreÒ 2 system is a included annual consumption for glucose sensor-based flash-monitoring system that mea- monitoring (strips, lancets and sensors) and sures interstitial fluid glucose. The study aimed to severe hypoglycaemic events (SHE) manage- compare cost of FreeStyle Libre 2 system and self- ment. A published rate of SHE monitoring of blood glucose (SMBG) in the (2.5 episodes/patient-year) was considered. A type 2 diabetes mellitus (T2DM) population from reduction of SHE (- 48.8%) associated with the Spanish Health System perspective. FreeStyle Libre 2 system, derived from the Methods: On the basis of data collected from a REPLACE trial, was applied. Hospital attendance literature review, the cost of glucose monitoring for 20.5% of SHEs (with subsequent hospital- ization in 16.0%) was applied. Consumption of strips and lancets was set at 6/day for SMBG The shape of the circle sensor unit, FreeStyle, Libre, and (derived from national monitoring recommen- related brand marks are owned by Abbott. J. Garcı́a-Soidan I. Oyagüez (&) Porriño Primary Care Centre, Pontevedra, Spain Pharmacoeconomics and Outcomes Research Iberia (PORIB), Paseo Joaquı́n Rodrigo 4 - letra I, Pozuelo R. Gómez-Huelgas de Alarcón, 28224 Madrid, Spain Servicio de Medicina Interna, Hospital Regional e-mail: ioyaguez@porib.com Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de F. Gómez-Peralta Málaga; and Ciber Fisiopatologı́a de la Obesidad y la Unidad de Endocrinologı́a y Nutrición, Hospital Nutrición (CIBEROBN), Instituto de Salud Carlos III, General de Segovia, Segovia, Spain Madrid, Spain S. Artola J. F. Merino-Torres Centro de Salud José Marvá, Madrid, Spain Endocrinologı́a y Nutrición, Departamento F. J. Carrasco Medicina, Hospital Universitario y Politécnico La Fe, UGC Medicina Interna, Hospital Universitario Juan Universitat de València, Valencia, Spain Ramón Jiménez, Huelva, Spain A. Pérez J. Carretero-Gómez Servicio de Endocrinologı́a y Nutrición. Hospital de Servicio de Medicina Interna, Hospital de Zafra, la Santa Creu i Sant Pau, IIB-Sant Pau, CIBERDEM, Badajoz, Spain Universitat Autònoma de Barcelona, Barcelona, Spain 2330 Diabetes Ther (2021) 12:2329–2342 dations), and 0.2/day for FreeStyle Libre 2 sys- Using the FreeStyle Libre 2 system in this tem users, with 26 FreeStyle Libre 2 sensors/ population could avoid severe year. Unitary costs (€, year 2020 excluding VAT) hypoglycaemic episodes (up to 1220 in a were derived from literature (€0.28/strip; €0.09/ 1000 patients annually). lancet; €3.09/daily FM sensor; €3804/hospital- ized SHE; €1794/hospital-attended non-admit- In Spain, the FreeStyle Libre 2 system ted SHE; €389/community-attended SHE). could be associated with annual savings of Results: Costs were €2700 and €2120/year/pa- up to €581 per patient for the National tient using SMBG or FreeStyle Libre 2 system, Health System. respectively. For 1000 patients with T2DM These results could be useful in the using basal-bolus insulin, 1220 SHEs/year (with decision-making process related to public 48 hospitalizations) could be prevented and reimbursement and resource allocation in FreeSytle Libre 2 system could generate cost the diabetes mellitus field. savings of up to €580,953/year versus SMBG (- 21.5%). Conclusion: FreeStyle Libre 2 system is a potential cost-saving strategy in patients with T2DM in Spain on a basal-bolus insulin DIGITAL FEATURES regimen. This article is published with digital features, including a summary slide, to facilitate under- Keywords: Cost; Diabetes; Flash; FreeStyle standing of the article. To view digital features Libre; Glucose monitoring for this article go to https://doi.org/10.6084/ m9.figshare.14447457. Key Summary Points Why carry out this study? INTRODUCTION A flash monitoring system for glucose The latest report of the International Diabetes monitoring in patients with diabetes Federation (IDF) estimated that nearly 463 mellitus has been demonstrated to be million adults are diagnosed with diabetes effective and cost savings in some mellitus (DM) worldwide [1], and this figure is healthcare settings. expected to rise to 578 million and 700 million in 2030 and 2045, respectively [1]. Type 2 DM The present analysis estimates the (T2DM) accounts for the clear majority (around economic impact related to the use of a 90.0%) of diabetes cases [1]. The most recent flash monitoring system, FreeStyle Libre 2, update of a larger epidemiological study on DM in an adult population with type 2 (Di@bet.es study) [2] confirmed that known diabetes (T2DM) treated with basal-bolus T2DM prevalence in Spain is at 7.8%. insulin in Spain. In addition to the increasing clinical burden What was learned from the study? [3], DM and its complications are associated with an important economic impact. The cost Use of FreeStyle Libre 2 system in patients of care for people with diabetes can be up to with T2DM treated with basal-bolus four times higher than in those without dia- insulin could be associated with annual betes [4, 5]. Annual global health expenditure savings for the Spanish National System. on diabetes is estimated to be USD 760 billion Savings linked to avoided hypoglycaemic [1]. episodes are the main contributor to these In Spain, DM was ranked as the 15th most savings. common cause of mortality in both sexes in 2016 [6], and the 9th most frequently treated Diabetes Ther (2021) 12:2329–2342 2331 health problem in the public primary care glucose variability, better quality of life and health system [7], and it has been estimated more lifestyle flexibility [17–19]. that the direct costs associated with the disease The FreeStyle LibreÒ 2 system is an intersti- may reach €5100 million, representing 8.0% of tial fluid glucose flash monitoring system with global public health expenditure [8]. optional alarms, marketed and available in The therapeutic cornerstone for patients Spain, fully reimbursed under the Basic Services with T2DM lies in the promotion of a healthy Portfolio of the Spanish National Health System lifestyle including a balanced diet, regular (Sistema Nacional de Salud [SNS]) for the type 1 physical activity, smoking cessation and main- DM population (T1DM) [20]. The FreeStyle tenance of a healthy body weight. When Libre system is fully or partially reimbursed in attempts to change lifestyle are insufficient in 36 markets across the world for T1DM and controlling blood glucose levels, oral medica- T2DM; in most European countries (France, UK, tion with metformin should be the first-line Germany, Austria, Italy, Portugal, etc.), reim- treatment. Beyond this, a range of combination bursement for patients with T2DM has started therapy options are now available, but if oral with patients with T2DM treated with three or medications are insufficient to maintain blood more insulin doses a day, including premixed glucose within the recommended ranges, insu- and basal-bolus insulin regimens. The latter is lin-based regimens may be required. considered a preferred subgroup in national [21] Insulin concentration elevations in blood and international [22] guidelines. inevitably involve the risk of all types of hypo- The FreeStyle Libre 2 system is accompanied glycaemia so the use of insulin secretagogues by a digital ecosystem with free mobile appli- and insulin-based regimens are risk factors for cations (FreeStyle Libre Link and FreeStyle the development of hypoglycaemic episodes LibreLinkUp) and virtual software (Libre View) [9]. The incidence of hypoglycaemia is higher that simplify glucose monitoring, allowing among insulin-treated patients with T2DM better management of the disease and facilitat- [10, 11], primarily those with complex insulin ing communication between professionals and regimens following the use of basal insulin, who patients. also required personalized treatment adjust- The clinical evidence of the FreeStyle Libre ments with several types of insulin. 2 system has been evaluated in many ran- Hypoglycaemia is a major contributing fac- domised clinical trials, like the IMPACT study tor to long-term complications and reduced [23, 24] for T1DM and the REPLACE trial survival in patients with DM, in addition to its [25, 26] in patients with T2DM and several real- detrimental impact on health-related quality of world data studies. Treatment satisfaction with life and increased overall associated costs [12]. the FreeStyle Libre 2 system has been also tested Glucose monitoring is a useful tool for con- in the T2DM population [27]. trolling glycosylated haemoglobin (HbA1c) The findings in the REPLACE study showed levels; however, monitoring based on the self- that patients in the FreeStyle Libre 2 system arm monitoring of blood glucose (SMBG) has sig- experienced a decrease in the number and mean nificant limitations [13], because it is cumber- duration of hypoglycaemic episodes compared some, painful and costly. Several barriers with those in the SMBG-only arm [25]. More- (physical, such as pain and discomfort; psy- over, the FreeStyle Libre 2 system users reduced chological, such as fear and frustration; social, their need for finger-prick blood glucose mea- such as interference with lifestyle) are directly surements by up to 95.0% versus SMBG. related to low patient adherence to the moni- The overall cost for management in patients toring recommendations established by with T2DM treated with insulin regimens is national [14] and international scientific soci- expected to be reduced following the lower eties [15, 16]. consumption of SMBG supplies and the Monitoring of glucose in interstitial fluid decreased need for healthcare resources due to poses an alternative to the traditional SMBG, the reduced incidence of hypoglycaemic and is associated with better HbA1c levels, less 2332 Diabetes Ther (2021) 12:2329–2342 episodes associated with the use of the FreeStyle A wide variation of severe hypoglycaemia Libre 2 system. rates per patient-year was found during the lit- In this study a cost analysis was conducted of erature review. The Hypoglycaemia Assessment the FreeStyle Libre 2 system compared to SMBG Tool (HAT) study, an observational study con- in adults with T2DM treated with basal-bolus ducted in 24 countries, was initially chosen in insulin in Spain, which complements a previous view of its robustness (sample size, multicentric analysis published for T1DM [28]. nature and representativeness of the Spanish population) [31] to obtain base case results. In the aforementioned study an annual incidence METHODS of 2.5 severe hypoglycaemic episodes was reported per patient for the T2DM population A cost analysis model previously developed for [31]. T1DM [28] was used to estimate the economic The efficacy of the FreeStyle Libre system in impact associated with glucose monitoring and T2DM was evaluated by the REPLACE study the management of hypoglycaemic events in a [25], a phase III, randomized, multicentre clin- hypothetical cohort of 1000 adult ([ 18 years) ical trial that included 224 patients under patients with T2DM treated with basal-bolus intensive insulin therapy from 26 diabetes insulin regimen, using the FreeStyle Libre centres in three European countries (France, 2 system as compared to standard practice based Germany and UK). A reduction in hypogly- on SMBG only. The FreeStyle Libre 2 system has caemia associated with the use of the FreeStyle been considered in the analysis, as this version Libre system (- 48.8% for episodes with glucose of the FreeStyle Libre system will be available in level \ 2.5 mmol/L [45 mg/dL]) was reported Spain as of early 2020. [25]. This article is based on previously conducted A proposal for reporting hypoglycaemia studies and does not contain any new studies events in clinical trials (based on three levels) with human participants or animals performed has been issued by the International Hypogly- by any of the authors. All the inputs for the caemia Study Group [32]. However, in the model were derived from a literature review, so REPLACE trial [25] severe hypoglycaemia epi- they were not directly collected from any study. sodes (requiring third-party assistance) were not The perspective of the Spanish National specifically reported. For the purpose of this Health System was used to estimate the annual analysis, level 1 episodes according to the costs derived from the consumption of resour- American Diabetes Association (ADA) proposed ces associated with glucose monitoring (strips classification were equated to severe hypogly- and lancets, plus FreeStyle Libre sensors in caemic episodes with glucose level \ 2.5 mmol/ FreeStyle Libre 2 system users) and the man- L (45 mg/dL) (Table 1). agement of severe hypoglycaemia. For the management of hypoglycaemic The values of the parameters, obtained from events, the information source was the Emer- the published literature, were validated by a gency Care of the Person with Diabetes Project panel of eight experts (three endocrinologists, (PAUEPAD, for its initials in Spanish) [33]. This two primary care physicians and three special- is a retrospective study of all registered hypo- ists in internal medicine) with expertise in the glycaemia-related emergency calls taken by the management of patients with diabetes. emergency medical services in Andalusia, Spain A review of the scientific literature was per- (8.5 million inhabitants). Hospital attendance formed to identify the available evidence on was considered necessary in 20.5% of the epi- hypoglycaemia rates in the T2DM population. sodes of severe hypoglycaemia. The rate of In line with the widely accepted definition, subsequent hospital admission (15.6% of them) severe hypoglycaemic episodes were regarded as comes from a survey in people with insulin- those requiring help from another person treated T2DM who have experienced severe [29, 30]. hypoglycaemic events in Germany, Spain or the UK [34]. Diabetes Ther (2021) 12:2329–2342 2333 Table 1 Baseline characteristics of the patients and main [26], meaning a daily consumption of 0.2 strips results of the REPLACE study [25] and lancets which was used for calculations in the present analysis. Parameter SMBG FreeStyle (N = 75) Libre system Considering the labelling requirements (N = 149) about sensor replacement [35] (one every 14 days), an annual consumption of 26 Free- Age, years 59.5 ± 11.0 59 ± 9.9 Style Libre 2 system sensors was applied in the (22–80) (33–81) cohort of patients with T2DM using the Free- Style Libre 2 system. Duration of diabetes, 18.0 ± 8.0 17.0 ± 8.0 The unit costs (in € year 2020 and excluding years (11–31) (4–37) VAT) were obtained from the reviewed litera- Baseline HbA1c, % 8.9 ± 1.0 8.7 ± 1.0 ture (€0.28 /strip [28], €0.09/lancet [28], (7.5–11.7) (7.5–11.6) €3.09/daily FreeStyle Libre 2 sensor [28], €3804.17/severe hypoglycaemic episode with Baseline daily frequency 3.9 ± 1.3 3.6 ± 1.3 hospital admission [36], €1793.74/severe hypo- of SMBG glycaemic episode with emergency hospital care Number of episodes with Baseline: Baseline: but no admission [33], €388.83/severe hypo- glucose \ 2.5 mmol/L 0.1 ± 0.3 0.2 ± 0.4 glycaemic episode without hospital care [37]). (45 mg/dL) Final: Final: Sensitivity Analysis 0.1 ± 0.2 0.1 ± 0.1 Difference FreeStyle Libre vs Sensitivity analyses (SAs) were conducted to SMBG: - 48.8% assess the model’s robustness by modifying the parameters with the greatest uncertainty. The Number of episodes with Baseline: Baseline: following one-way SA were carried out: alter- glucose \ 3.9 mmol/L 0.6 ± 0.7 0.6 ± 0.6 native severe hypoglycaemia rate (1.3 episodes (70 mg/dL) Final: Final: per patient-year as indicated in the HAT study 0.5 ± 0.6 0.4 ± 0.4 for the Northern European and Canadian pop- ulation) [38] (SA1); reduction of consumption Difference FreeStyle Libre vs of strips and lancets in patients with SMBG to 3 SMBG: - 27.7% daily (SA2); variation of consumption of strips Data are presented as mean ± SD or mean ± SD (range) and lancets in FreeStyle Libre 2 users to 0.66 per SD standard deviation, SMBG self-monitoring of capillary day based on recently published real-world data blood glucose in Spain [39] (SA3); alternative daily consump- tion of strips and lancets (3 for SMBG only patients and 0.66 for FreeStyle Libre 2 users) (SA4); theoretical consumption of strips and A daily consumption of six strips was con- lancets in patients with SMBG only estimated sidered for patients with T2DM treated with a by assuming equivalence to the monitoring basal-bolus insulin regimen, estimated as the frequency with FreeStyle Libre system observed average of national recommendations for glu- in a real-world study [39] (13 daily) (SA5). cose monitoring in these patients according to An additional scenario was also tested, con- their level of blood glucose control [14], and in sidering non-severe hypoglycaemia events line with FL2 reimbursement criteria in Spain (SA6), equated to those episodes with glucose for patients with T1DM with the same insulin level C 2.5 mmol/L (45 mg/dL) and and glucose monitoring requirements. The use \ 3.9 mmol/L (70 mg/dL). A rate of 17.02 non- of one lancet per SMBG measurement was also severe hypoglycaemia episodes per patient-year assumed. reported on the HAT study [31] was considered. The REPLACE showed a frequency of A reduction of 27.7% for episodes with a glucose 0.2 ± 0.6 tests a day in FreeStyle Libre users 2334 Diabetes Ther (2021) 12:2329–2342 Table 2 Hypoglycaemia episodes for a cohort of 1000 patients with T2DM Parameter SMBG FSL2 Absolute difference FreeStyle Libre 2 system vs SMBG (percentage variation) Severe 2500 1280 - 1220 (- 48.8%) hypoglycaemic episodes SHE with 98 50 - 48 (- 48.8%) hospital admission SHE with 416 213 - 203 (- 48.8%) hospital care, no admission SHE without 1986 1017 - 969 (- 48.8%) Fig. 1 Detailed annual costs per patient with T2DM hospital care receiving basal-bolus insulin therapy. FreeStyle Libre 2 system, SMBG self-monitoring of capillary blood glucose SHE severe hypoglycaemia episode, SMBG self-monitoring of capillary blood glucose, T2DM type 2 diabetes mellitus level \ 3.9 mmol/L (70 mg/dL) reported in the REPLACE trial [25] for FreeStyle Libre sys- The management of severe hypoglycaemic tem users was applied to the non-severe hypo- episodes represented an annual cost of €1890 glycaemic events rate. A unitary cost of €15.07/ per SMBG patient. In patients with FreeStyle non-severe hypoglycaemia episode [40] was Libre 2 system, the annual cost was €967 per used in calculations. patient. The hypoglycaemic episodes prevented annually with the FreeStyle Libre 2 system RESULTS would result in a cost saving of €922 (- 48.8%). The use of the FreeStyle Libre 2 system as The total annual cost estimated in this analysis compared to SMBG would be associated with an for the SMBG-only arm was €2700 per patient annual total cost saving of €581 (- 21.5%) per with T2DM receiving basal-bolus insulin. In the patient with basal-bolus insulin (Fig. 1). FreeStyle Libre 2 user arm, the total annual cost In a cohort of 1000 patients with T2DM with was €2120 per patient. intensive insulin therapy (basal-bolus regimen), The costs associated with glucose monitoring a total of 2500 severe hypoglycaemic episodes in SMBG were €811 per patient. The glucose would occur using SMBG versus 1280 with the monitoring cost in patients using the FreeStyle FreeStyle Libre 2 system. Thus, the FreeStyle Libre 2 system was €1152 per patient-year. Sav- Libre 2 system would annually prevent 1220 ings derived from the reduction in the use of severe hypoglycaemic episodes (48.8% reduc- daily strips and lancets were €783 (- 96.7%) per tion), and among them 48 cases of hospitaliza- patient with T2DM receiving basal-bolus insu- tions due to severe hypoglycaemia (Table 2). lin, which offset the FreeStyle Libre 2 system The use of the FreeStyle Libre 2 system would sensor acquisition cost, estimated to be €1125 generate total annual savings per 1000 patients per patient-year. of up to €580,953 compared with SMBG in patients with T2DM treated with basal-bolus Diabetes Ther (2021) 12:2329–2342 2335 Table 3 Annual costs for a cohort of 1000 patients with T2DM receiving basal-bolus insulin therapy Parameter SMBG FreeStyle Libre 2 Absolute difference FreeStyle Libre 2 system vs SMBG system (percentage variation) Patients with T2DM treated with basal-bolus insulin therapy Cost of SHE management €1,889,644 €967,498 - €922,146 (- 48.8%) Cost of glucose monitoring €810,855 €1,152,048 €341,193 (42.1%) Cost of strips and lancets €810,855 €27,029 - €783,827 (- 96.7%) Cost of FreeStyle Libre 2 €0 €1,125,020 €1,125,020 (100.0%) system sensors Total cost €2,700,499 €2,119,546 - €580,953 (- 21.5%) SHE severe hypoglycaemic episodes, SMBG self-monitoring of capillary glucose, T2DM type 2 diabetes mellitus insulin (Table 3), thus representing a 21.5% would be related to annual cost savings of reduction in overall costs. €138,323 (- 7.7%), derived from the reduction SA results confirmed the model robustness of 634 severe hypoglycaemic episodes yearly for the 1000 patients with T2DM receiving (Table 4). basal-bolus insulin. The modifications in daily use of strips and The SA using the alternative severe hypo- lancets also produced savings associated with glycaemia rate (1.3 episodes per patient-year) the use of the FreeStyle Libre 2 system versus [38] showed that FreeStyle Libre 2 system use SMBG that ranged between €113,360 (- 4.9%) Table 4 Results of the sensitivity analyses Total annual cost per 1000 patients with T2DM SMBG FreeStyle Absolute difference FreeStyle Libre 2 Libre 2 system vs SMBG (percentage system variation) Base case for T2DM with basal-bolus insulin €2,700,499 €2,119,546 - €580,953 (- 21.5%) SA1 (1.3 severe hypoglycaemic episodes/patient- €1,7938,470 €1,655,147 - €138,323 (- 7.7%) year) [38] SA2 (3 strips & lancets a day for SMBG) €2,295,071 €2,119,546 - €175,525 (- 7.6%) SA3 (0.66 strips & lancets a day for FreeStyle €2,700,499 €2,181,712 - €518,787 (- 19.2%) Libre 2 users) [39] SA4 (3 strips & lancets a day for SMBG, and 0.66 €2,295,071 €2,181,712 - €113,360 (- 4.9%) for FreeStyle Libre 2 users) SA5 (13 strips and lancets a day for SBMG, €3,646,496 €2,119,546 - €1,526,950 (- 41.9%) equivalent to daily scans in real-world studies)[39] SA6 (including severe and non-severe €2,951,884 €2,309,089 - €642,795 (- 21.8%) hypoglycaemic episodes) SA sensitivity analysis, SMBG self-monitoring of capillary blood glucose, T2DM type 2 diabetes mellitus 2336 Diabetes Ther (2021) 12:2329–2342 with a daily consumption of 3 strips and lancets terms of glucose monitoring. Additionally, in SMBG and 0.66 for FreeStyle Libre 2 users and reductions in the cost of severe hypoglycaemia €1,526,950 (- 41.9%) for 13 strips and 3 lancets events management were also shown (- $852 a day in SBMG (Table 4). per patient/year). In the additional scenario considering severe At the European level, cost savings following and non-severe hypoglycaemic episodes, the the use of theFreeStyle Libre 2 system have been total annual cost reached €2,951,884 and demonstrated for the UK setting in analyses €2,309,089 for the cohort with SMBG and the comprising patients with T1DM [44], as well as FreeStyle Libre 2 system, respectively. In this in models focused on patients with T2DM [45]. scenario it was shown that the use of the Free- The latter one showed annual savings of Style Libre 2 system would prevent 5407 hypo- £191/patient associated with the use of the glycaemic episodes a year. Of these avoided FreeStyle Libre 2 system in the T2DM popula- hypoglycaemic events 1220 would correspond tion when considering three daily SMBG to severe episodes (- 48.8%), and 4187 to non- measurements. severe episodes (- 24.6%). Cost savings with One main limitation of this model involves the use of the FreeStyle Libre 2 system as com- the incidence of hypoglycaemia. There are a pared to SMBG would be up to €642,795 per wide range of values available in the literature, year (- 21.8%) (Table 4). very likely because of differences in the methodology and criteria used in the different studies. For the purpose of the present analysis, DISCUSSION the expert panel selected a multicentre (2004 healthcare centres), multinational (24 coun- The efficacy of the FreeStyle Libre 2 system in tries), large-scale study (27,585 patients with the T2DM population has been proven in clin- diabetes; 19,563 patients with T2DM) [31] as the ical trials [25, 26], and corroborated by real- most robust data source. To reduce uncertainty world studies which have revealed reductions in about this parameter a SA was performed with hospitalizations due to DM complications, such an alternate hypoglycaemia rate, which also as hypoglycaemic events [41] or ketoacidosis presented savings with the FreeStyle Libre [42]. 2 system. Additionally, a SA including non- The present analysis proves the FreeStyle severe hypoglycaemic events was also Libre 2 system to be a strategy that results in performed. savings for the clinical management of patients Reductions of biochemical hypoglycaemia with T2DM treated with basal-bolus insulin in episodes associated with use of the FreeStyle Spain. On the basis of the assumptions descri- Libre 2 system reported in the REPLACE study bed throughout the paper, the present model [25] were applied to the incidence of clinical showed that the FreeStyle Libre 2 system would hypoglycaemia in this analysis. This is a con- decrease the total annual cost by up to €580 troversial issue, because evidence on the rela- (- 21.5%) per patient with T2DM treated with tionship between low glucose levels and basal-bolus insulin, generating annual savings symptomatic hypoglycaemic episodes is lim- for the Spanish National Health System of more ited, although a recent publication has con- than half a million euros per cohort of 1000 cluded that the occurrence of biochemical treated patients. hypoglycaemia (\ 3.9 mmol/L or 3 mmol/L) is The cost savings associated with the use of associated with an increased risk of severe the FreeStyle Libre 2 system have also been hypoglycaemia [46]. observed in other settings such as the USA [43], To the better address the issue of hypogly- where annual reductions of $1682 per patient caemia risk, the International Hypoglycaemia with T2DM receiving intensive insulin therapy Study Group issued a recommendation to the were estimated in relation to the use of the diabetes community to adopt common glucose FreeStyle Libre 2 system in comparison to SBMG levels when reporting outcomes about hypo- (with a use of six strips and lancets per day), in glycaemic episodes in studies [32]. However, Diabetes Ther (2021) 12:2329–2342 2337 since hypoglycaemic events were not specifi- (- €1,526,950 per 1000 patients with T2DM, cally reported in the trial used in this analysis as yearly). efficacy source, an assumption was needed to The value of glucose monitoring in the equate those episodes with glucose control of diabetes and the strong association levels \ 2.5 mmol/L (45 mg/dL) to hypogly- between higher SMBG frequency and lower caemic episodes requiring external care. Given HbA1c levels are undeniable [47]; however, the results of the REPLACE trial, this assump- several scientific publications [17, 48] revealed tion represents a conservative scenario, as the poor adherence to the recommendations set out proposed definition for severe hypoglycaemic in the current clinical guidelines [14]. Consid- episodes could also be applied to events with ering possible low adherence to these monitor- glucose levels C 2.5 mmol/L (45 mg/dL). ing recommendations, SAs with variations in As a result of the short time horizon of the optimum consumption were performed. cost analysis, the long-term benefits of FreeStyle Although the daily number of SMBG measure- Libre 2 system related to the prevention of other ments in patients with T2DM was lower than diabetes complications such as cardiovascular recommended, the savings derived from the disease, renal failure, blindness, amputations, prevented hypoglycaemic episodes would offset etc. owing to the improved glycaemic control the costs of purchasing FreeStyle Libre 2 sensors. were not included, so these results should be Patients’ reasons for poor adherence to the considered as representative of a conservative monitoring vary greatly and include lack of scenario in this sense. time, invasiveness and needle phobia [48, 49]. This analysis assumed that the findings from The features of the FreeStyle Libre 2 system the REPLACE study are fully transferable to could eliminate some of these barriers [50], FreeStyle Libre 2 system, but with FreeStyle thereby increasing the daily number of glucose Libre 2’s optional alarms and the most recent determinations as has been proven by all the improvements in accuracy, the use of the Free- clinical studies and real-world data on the Style Libre 2 system could result in an even FreeStyle Libre system (like the study from Spain greater reduction of severe hypoglycaemia that found a mean number of 13 daily scans) events, which could result in higher savings due [39]. to the prevention of hypoglycaemic events The savings identified in this cost study are a (especially in patients with hypoglycaemia conservative estimate, as savings linked to unawareness). hyperglycaemic events prevention by the Free- In addition to the prevented hypoglycaemic Style Libre 2 system have not been included. episodes, the use of the FreeStyle Libre 2 system A Spanish study calculated that the mean cost was associated with a decrease in the number of of a hospital admission for hyperglycaemic cri- SMBG measurements required by the patients. sis was €3364.6 [36]. Another study found that Frequency of SMBG and therefore the daily the mean cost per episode involving emergency consumption of strips and lancets is the second room care would add an additional cost of critical issue of the present model. The SA cor- €1476.80 per episode [51]. Given that the Free- roborated that even in scenarios with a lower Style Libre 2 system now has an optional alarm number of SMBG measurements, the use of for high glucose values, the FreeStyle Libre 2’s FreeStyle Libre 2 system would be associated contribution to the prevention of hypergly- with cost reductions of 7.6% as compared to the caemic events cannot be disregarded, with its use of SMBG alone, generating direct cost sav- associated savings owing to events prevented. ings of €175,525 per 1000 patients/year. In a Furthermore, savings linked to the use of the theoretical scenario where the number of fin- FreeStyle Libre 2 system and LibreView as a ger-prick blood glucose measurements would telemedicine tool have not been considered in total 13 a day, which is the number of daily the present analysis. A literature review revealed scans with the FreeStyle Libre 2 systems a study in which patients in the telemedicine observed in a Spanish real-world study [39], the group showed a substantial reduction in their reduction of total cost would be 41.9% HbA1c levels compared to their counterparts in 2338 Diabetes Ther (2021) 12:2329–2342 conventional care, with patients with T2DM accompanying the FreeStyle Libre 2 system (Li- being the most favoured (Hedges g = - 0.48) breView, FreeStyle Libre Link, FreeStyle Libre compared to T1DM (Hedges g = - 0.26) [52]. LinkUp) can also have an impact on patients, Another meta-analysis [53] of randomized clin- their relatives and healthcare professionals. ical trials identified that the telemedicine, compared to conventional care, reduces hypo- glycaemia (odds ratio = 0.42%). Although not CONCLUSIONS specifically referring to patients with DM, a local study has shown that telemedicine could The use of FreeStyle Libre 2 flash glucose mon- save up to €15 per visit. Patients are the greatest itoring system for patients with T2DM treated beneficiaries of these savings (owing to shorter with basal-bolus insulin therapy is an efficient waiting time and travel costs) but it is also more strategy for the Spanish National Health System efficient from the healthcare perspective [54]. thanks to the savings it can generate, owing to The added benefits of telemedicine in the era of both the decrease in hypoglycaemia episodes the COVID-19 crisis and lockdown, for patients, and to the direct cost savings in blood glucose healthcare professional and the healthcare sys- monitoring. tem, cannot be disregarded, even though they Considering the assumptions and costs are not the focus of this analysis. This analysis described, in comparison with SMBG, the Free- showed savings from the National Health Sys- Style Libre 2 system would potentially allow tem perspective, but in addition to the direct cost savings of up to €580,953 per year in a medical resources, hypoglycaemic events often cohort of 1000 patients with T2DM receiving entail pain, suffering and work absenteeism basal-bolus insulin. which could also impact on the glucose moni- toring cost. FreeStyle Libre 2 has been shown to improve quality of life and work productivity ACKNOWLEDGEMENTS [55, 56]. The FreeStyle Libre 2 system has been positively evaluated in patients with T1DM and T2DM by health technology agencies in a Funding. Abbott Diabetes Care provided number of countries and regions (France, Nor- unconditional financial support to performing way, Scotland, Sweden, England, Wales, etc.), the analysis, medical writing and the journal’s and published cost-effectiveness analyses have Rapid Service Fee. shown the efficiency of the FreeStyle Libre 2 system in several settings [57–62]. Authorship. All named authors meet the Previous analysis in Spain showed annual International Committee of Medical Journal cost savings of nearly €2 million (euros year Editors (ICMJE) criteria for authorship for this 2019) per 1000 adults patients associated with article, assume responsibility for the integrity of the use of the FreeStyle Libre 2 system in T1DM the work as a whole, and have given their populations treated with multiple daily doses of approval for this version to be published. insulin [28]. The use of the FreeStyle Libre 2 system as a Authors’ Contribution. Itziar Oyagüez substitute for test strips in SMBG may result in developed the model, reviewed the scientific savings for the National Health System, while literature, performed the analyses and drafted simultaneously improving disease control and the manuscript. Fernando Gómez-Peralta, Sara patient quality of life. It would be particularly Artola, Francisco J Carrasco, Juana Carretero- interesting to conduct future studies and/or Gómez, Javier Garcı́a-Soidán, Ricardo Gómez- registries on the use of this technology in real Huelgas, Juan F Merino-Torres, and Antonio life, with a view to obtaining information on Perez validated the model structure and the the clinical, economic and quality of life inputs and provided information about clinical repercussions for patients in our setting—par- management of patients with diabetes mellitus ticularly considering that the digital ecosystem in Spain. All the authors contributed to Diabetes Ther (2021) 12:2329–2342 2339 interpretation of the results and reviewed and line to the material. If material is not included approved the final version of the manuscript. in the article’s Creative Commons licence and your intended use is not permitted by statutory Prior Presentation. Preliminary results of regulation or exceeds the permitted use, you this work were submitted XXXI annual congress will need to obtain permission directly from the of the Diabetes Spanish Association (Sociedad copyright holder. To view a copy of this licence, Española de Diabetes), held on June 22–24, visit http://creativecommons.org/licenses/by- 2020. nc/4.0/. Disclosures. Itziar Oyagüez is an employee of Pharmacoeconomics & Outcomes Research Iberia (PORIB), a consultant specialized in the REFERENCES economic evaluation of healthcare interven- tions, which provided technical and editorial 1. International Diabetes Federation. 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