Original Title: Efectividad, seguridad y coste-efectividad del sistema flash de monitorización de glucosa en líquido intersticial (FreeStyle Libre®) para la diabetes mellitus tipo 1 y 2 (Apéndice de actualización)

Authors' objectives: The objective of this report is to identify, evaluate and synthesize the available scientific knowledge on the safety, effectiveness, cost-effectiveness and budget impact of a flash glucose monitoring system (FreeStyle Libre®) versus traditional self-monitoring, in patients with DM1 and DM2.

Authors' results and conclusions: RESULTS: SAFETY AND EFFECTIVENESS: [ TYPE-1 DIABETES MELLITUS ] One good quality multicenter RCT (IMPACT study) in adults with DM1, HbA1c <7.5% and 6 months of follow up, did not find significant differences in the number of patients who suffered severe (4.2% in the intervention group (IG) vs. 3.3% in the control group (CG), RR = 1.27, 95%CI: 0.33, 4.86) or total adverse effects (52% vs. 50%, RR = 1.04, 95%CI: 0.81, 1.34). There were not significant differences in the number of patients who suffered severe hypoglycemia events (1.7% vs. 2.5%, RR = 0.67, 95%CI: 0.11, 3.95) or in the reduction of HbA1c levels (mean difference. = 0.00%; 95% CI -0.11 to 0.12). Time in biochemical hypoglycemia (<70 mg/dL) was significantly lower in the IG (m.d. = -1.24 h/day, 95% CI: -1.71, -0.77), representing a decrease of 38%. In other measures of biochemical hypoglycemia (<55 mg/dL, <40 mg/dL, diurnal/nocturnal, variability, number of events) results were also statistical and clinically significant favoring the IG. Two subscales of the Diabetes Treatment Satisfaction Questionnaire (DTSQ) also showed significant increases favoring the IG: "total satisfaction" (m.d. = 6.1, 95% CI: 4.45, 7.75) and "perceived frequency of hyperglycemia" (m.d. = -1.0, 95% CI -1.43, -0.57), representing effect sizes of 0.94 and 0.59, respectively. [ TYPE-2 DIABETES MELLITUS ] One good quality multicenter RCT (REPLACE study) in insulin-dependent adults with DM2, HbA1c 7.5%-12% and 6 months of follow up, did not find significant differences in the number of patients who suffered severe adverse effects (10.7% vs. 16%, RR = 0.67, 95%CI: 0.33, 1.34). More total adverse effects were observed in the IG (76.5% vs. 62.7%, RR = 1.22, 95%CI: 1.00, 1.49). There were not significant differences in the number of patients who suffered severe hypoglycemic events (2% vs. 1.3%, RR = 1.51, 95%CI: 0.16, 14.3) or in the reduction of HbA1c levels (mean difference. = 0.03, 95%CI: -0.20, 0.25). When patients younger and older than 65 years were analyzed separately, the reduction in HbA1c was significant for the former (-0.33%, 95%CI: -0.62, -0.03). Time in hypoglycemia was significantly lower for the IG in all the thresholds analyzed: 70 mg/dL (-0.47, p <0.001), 55 mg/dL (-0.22, p = 0.001), 50 mg/dL (-0.14, p = 0.001) and 40mg/dL (-0.10, p = 0.002). These differences represent a reduction of 43%, 53%, 64% and 67% respectively. The same variables analyzed only during the night period (23:00-06: 00) also offered results significantly favorable to the IG, with reductions between 54% -68%. There were significant differences favoring the IG in the DTSQ (-4.00, p < 0.001), but not in the Diabetes Quality of Life (DQoL) questionnaire. ECONOMIC EVALUATION: The electronic search did not identify previously published economic evaluations on the technology under consideration. The economic evaluation provided by Abbott Diabetes Care conducted a cost-effectiveness analysis of the FreeStyle Libre® system compared to SMBG for DM1 and DM2 patients treated with multiple daily injections. The economic evaluation used the CORE Diabetes Model (CDM). The analysis was performed from the perspective of the NHS accounting for direct health costs. The time horizon was 40 and 50 years for DM1 and DM2, respectively, considering annual cycles. The FreeStyle Libre® system is reported as a cost-effective device for glucose monitoring for both DM1 and DM2 patients treated with multiple daily injections. However, these results account for several limitations associated to relevant model inputs which provides a high uncertainty, mainly those regarding the effectiveness improvements and the relationship between the device’s adherence and effectiveness. Besides, sensitivity analyses were not correctly implemented which confirms the limit validity of these results to make-decisions on funding. The FreeStyle Libre® system is reported as a cost-saving health technology for the Spanish NHS. Savings are not expected to occur for unrealistic scenarios. Besides, neither the economic evaluation nor the budget impact analysis conservatively considered potential savings derived from the reduction of long-term complications. Different from the economic evaluation, the material and methods used for the budget impact analysis are fair. CONCLUSIONS: SAFETY AND EFFECTIVENESS: - There is low quality evidence about the safety of FreeStyle Libre® System, compared to traditional monitoring. However, there has been no serious adverse events that may be attributed to the device and previous research on continuous glucose monitoring systems shows that they generally only produce mild skin AEs in the insertion area of the sensor. Nonetheless, its recommendation have to be accompanied by a detailed explanation to the patient with DM over its potential adverse effects and risk/benefits, in a shared decision making framework. - FreeStyle Libre® System does not reduce severe hypoglycemic events compared to SMBG in patients with DM1 or DM2 (low quality evidence). - FreeStyle Libre® System is more effective than traditional monitoring in reducing time and events elapsed in biochemical hypoglycemia (defined according to different thresholds), both during the day and at night, in patients with DM1 and HbA1c levels <7.5%, and patients with DM2, without a worsening of HbA1c levels (moderate quality evidence). -FreeStyle Libre® System reduces HbA1c levels in patients with DM2 younger than 65 years, but not in older ones (low quality evidence). -FreeStyle Libre® System increases patients’ satisfaction with treatment (low quality evidence). -The device use in children and adolescents seems to be safe, but there is no controlled evidence about its effectiveness. It can be assumed that, at least in younger children, parents’ control will achieved an adequate adherence to the device. -Evidence on the safety and effectiveness of FreeStyle Libre® System is of low/moderate quality for the outcomes analyzed, mainly due to the paucity of studies, the imprecision of the results of the two RCTs identified, and the methodological limitations inherent to this type of studies (impossibility of blinding). However, it has been considered that the potential benefit of the device in the populations included in such studies far outweighs its risks. In addition, the high acceptance of the device by patients has been valued. ECONOMIC EVALUATION: - The electronic search did not find previously published economic evaluations. - After several reviews, the economic evaluation provided by Abbott Diabetes Care does not answer all previously identified limitations communicated by assessors. However, remaining limitations does not totally invalidate its use to make-decisions on the FreeStyle Libre® system financing by the Spanish NHS. However, the decision-makers should be aware of the remaining uncertainties regarding the effectiveness improvements of the FreeStyle Libre® system. In addition, the relationship between the device’s adherence and effectiveness is omitted in favor of the FreeStyle Libre® system. On the contrary, the economic evaluation assumes that the non-severe hypoglycemic events cost is equal to zero, assumption that does not account for a potential cost saving if the FreeStyle Libre® system. These issues support a high uncertainty about the cost-effectiveness results presented. - The budget impact analysis performed by Abbot Diabetes Care provides valid information on the potential budget impact resulting from the adoption of the FreeStyle Libre® system in the Spanish NHS.

Authors' recommendations: - A conditional recommendation is made in favor of the FreeStyle Libre® System for adult patients with DM1 with controlled HbA1c levels (<7.5%), and with a previous good adherence to self-monitoring blood glucose. - A conditional recommendation is made in favor of the use of the FreeStyle Libre® System for adult patients with DM2 with a previous good adherence to self-monitoring blood glucose.

Authors' methods: Effectiveness and safety: A systematic review (SR) was performed in the electronic databases Medline, PREMEDLINE, Embase, Cochrane Central and Systematic Reviews and Web of Science were consulted until June 2016, and updated in September 2017. We searched for SR with meta-analysis (MA), clinical practice guidelines (CPG), other reports of health technology assessment (HTA) and randomized controlled trials (RCT) that assessed the effectiveness and safety of flash glucose monitoring FreeStyle Libre® system for DM1 and DM2, compared to SMBG or other CGMS-TR, in patients of any age. The risk of bias of the primary studies was assessed using the Cochrane Collaboration tool. Global quality of evidence was assessed with the GRADE system. Economic evaluation: A SR of economic evaluations for FreeStyle Libre® system versus SMBG for glucose monitoring in patients with DM was performed. The search strategies were the same applied for the effectiveness and safety review. Comprehensive economic assessments were included, i.e., those in which both costs and effectiveness of at least two alternatives were compared. Both economic evaluations developed in parallel to clinical trials and economic models were included. Besides, critical appraisals were carried out for four different reports (economic evaluations and budget impact analysis for DM 1 and 2), provided by the promoter industry for the Spanish National Health System, according to the Economic Assessment Guide (EAG) and the Budget Impact Guideline (BIG).

Project Status: Completed

Year Published: 2017

URL for published report: https://sescs.es/sistema-flash-de-monitorizacion-de-glucosa-en-liquido-intersticial-freestyle-libre-para-dm-1-y-2-apendice-de-actualizacion/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

Organisation Name: Canary Health Service

Contact Address: Dirección del Servicio. Servicio Canario de la Salud, Camino Candelaria 44, 1ª planta, 38109 El Rosario, Santa Cruz de Tenerife

Contact Name: sescs@sescs.es

Contact Email: sescs@sescs.es