REPLACE STUDY¹

FreeStyle Libre system^₼– a safe and effective replacement for
SMBG

Impact of flash glucose monitoring in type 2 diabetes

The open-label randomised controlled trial REPLACE demonstrates that the FreeStyle Libre system (FSL) can safely and successfully replace self-monitoring of blood glucose (SMBG) for type 2 diabetes (T2D) patients on intensive insulin therapy.¹ The results were published in the journal Diabetes Therapy by Haak and colleagues.¹

Study objective

The randomised controlled trial aimed to evaluate the impact of the FSL system on glycaemic control (HbA_1c) compared to SMBG testing in patients with T2D treated with intensive insulin therapy (IIT) or continuous subcutaneous insulin infusion (CSII) therapy.

The primary outcome of the study was the difference in HbA1c change in patients using FSL vs. SMBG for 6 months. Prespecified secondary outcomes included time in hypoglycaemia, effect of age and patient satisfaction.¹

Study design and study population

In the REPLACE trial, the FreeStyle Libre system^₼ was shown to be a safe and effective replacement for SMBG¹

About the REPLACE trial¹

The REPLACE trial (ClinicalTrials.gov identifier: NCT02082184) was conducted at 26 diabetes centres in France, Germany and the UK using a randomised controlled design. 224 participants aged 18 years or older with T2D treated with IIT or CSII therapy were enrolled. FSL use resulted in no difference in overall HbA1c change compared to SMBG testing and reduced hypoglycaemia in T2D patients on IIT, thus offering a safe, effective replacement for SMBG.

REPLACE trial design¹

The REPLACE trial was conducted as a prospective, open-label, non-masked, two-arm randomised controlled study at 26 diabetes centres in France, Germany and the UK for 6 months.
Participants (n=224) were centrally randomised in a 2:1 ratio to FSL or to SMBG.
The primary outcome was the difference in HbA1c between FSL and SMBG groups at 6 months. Prespecified secondary endpoints included subgroup analyses by age (< 65 years vs. > 65 years of age), sensor-derived glycaemic measures from baseline to 6 months and participant questionnaire responses.
Sensor-derived glycaemic measures comprised the number and duration of hypoglycaemic events, time in range, number and duration of hyperglycaemic events, mean glucose and glucose variability measures. Results for the user questionnaire were assessed at 6 months. Patient-reported outcome and quality of life (QoL) measures were assessed using validated questionnaires: Diabetes Distress Scale (DDS), Diabetes Quality of Life (DQoL) and Diabetes Treatment Satisfaction (DTSQs and DTSQc).
Safety endpoints incorporated all adverse events.

Figure 1: Study design of the REPLACE trial¹

Key Inclusion criteria^†

Has T2D on insulin therapy for ≥6 months and on their current regimen for ≥3 months prior to study entry.
Their insulin management must be one of the following: 
- An injection regimen of prandial insulin -
- Prandial insulin plus basal intensive insulin
- CSII with no plans to change during the study.
HbA1c result ≥7.5% (58 mmol/mol) and ≤12.0% (108 mmol/mol) on entry to the study.
Aged 18 years or over.

Key Exclusion criteria^†

Insulin regimen different from those described above.
Has known allergy to medical-grade adhesives.
Currently using a continuous glucose monitoring (CGM) device or has used one within the previous 4 months.
Total daily dose of insulin (TDD) is >1.75 IU/kg at entry to the study.
A female subject who is pregnant or planning to become pregnant within the study duration.
Has experienced any episode of severe hypoglycaemia, requiring third-party assistance, in the previous 6 months.
Has experienced any episode of diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS) in the previous 6 months.
Is receiving steroid therapy for any condition.

Study limitations¹

Absence of a treatment algorithm for modifying insulin therapy.
Inclusion of only adults with IIT performing regular glucose testing.
Intervention was non-masked to subjects as sensor wear was experienced by all with assessment and some treatment decisions based on the same sensor glucose values.
No adjustment was made for multiple testing of secondary endpoints. Many of the endpoints, particularly those derived from sensor glucose values, are highly interrelated and should not be considered in isolation.

Study results

Key patient baseline characteristics¹

Table 1: Baseline characteristics

Data are presented as mean SD± (min, max) or n (%)

Primary and secondary outcomes¹

No difference in overall HbA_1c change with FreeStyle Libre system vs. SMBG

FSL use resulted in no difference in overall HbA_1c change and reduced hypoglycaemia in T2D patients on IIT, thus offering a safe, effective replacement for SMBG.

Table 2: Differences in HbA1c change between FSL and SMBG after 6 months.

HbA_1c reduction in participants under 65 years of age using FreeStyle Libre system vs. SMBG¹

A significant difference in HbA_1c reduction was detected in participants aged <65 years [-5.7 ± 0.96 mmol/mol (-0.53 ± 0.09%) and -2.2 ± 1.31 mmol/mol (-0.20 ± 0.12%), respectively; p = 0.0301].

Significant reduction in hypoglycaemia with FreeStyle Libre system vs. SMBG¹

The use of FSL significantly reduces time spent in hypoglycaemia (<70 mg/dL).
Throughout the entire day, time in hypoglycaemia (<70 mg/dL) was reduced by 0.47 ± 0.13 h/day [mean ± SE (p = 0.0006)] or 43% compared with controls.
Nocturnal hypoglycaemia (<70 mg/dL, from 23.00 – 06.00; p=0.0001) was reduced by 54% compared with controls.
Clinically significant hypoglycaemia (<55 mg/dL) was reduced by 0.22 ± 0.07 h/day [mean ± SE (p = 0.0014)] or 53% for intervention participants compared with controls.

Reduces hypoglycaemia throughout the day

(<70 mg/dL; time in hour, from 00.00 – 00.00) (p=0.0006)

Reduces nocturnal  hypoglycaemia

(<70 mg/dL; time in hour, from 23.00-6.00) (p= 0.0001)

Reduces clinically significant hypoglycaemia

(<55 mg/dL; time in hour, from 00.00 – 00.00) (p=0.0014)

Table 3 - Glycaemic measures.

Higher treatment satisfaction with FreeStyle Libre system vs. SMBG¹

The total treatment satisfaction was significantly improved for participants using FSL. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) score was 13.1 ± 0.50 (mean ± SE) for FSL users and 9.0 ± 0.72 in controls (p=0.0001).
Satisfaction with treatment results using DQoL (Diabetes Quality of Life) demonstrated significant improvement for the intervention group (-0.2 ± 0.04, mean ± SE) versus the control group (0.0 ± 0.06; p = 0.0259).

Scores from the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Error bars show 95% CIs.

Extension study confirms REPLACE results for the long term²

An extension of the 6-month, open-label REPLACE study included 108 of the 149 participants that had been randomised to the FSL group in the original REPLACE study, who continued using FSL for a further 6 months in an open-access phase.
Time in hypoglycaemia (<3.9 mmol/L (70 mg/dL)) was reduced by 50% (-0.70 ± 1.85 h/day; mean ± SD) at 12 months post-baseline compared with baseline (p = 0.0002). Time in clinically significant hypoglycaemia (<3.1 mmol/L (55 mg/dL)) was reduced by 62% (-0.40 ± 1.09 h/day) at 12 months post-baseline compared with baseline (p = 0.0002). Nocturnal hypoglycaemia [<3.9 mmol/L (70 mg/dL, from 23.00 – 06.00] was reduced by 52% (-0.31 ± 0.84 h per 7 h) at 12 months post-baseline compared with baseline (p = 0.0002).
The use of FSL for 12 months was associated with a sustained reduction in hypoglycaemia and safely and effectively replaced SMBG in T2D patients on IIT.

Table 4: Change from baseline for the parameters TIR, hypoglycaemia, severe hypoglycaemia and nocturnal hypoglycaemia after 12 months.

† 70–180 mg/dL (3.9–10.0 mmol/L);
§ <70 mg/dL (3.9 mmol/L) within 24 h;
# <55 mg/dL (3.1 mmol/L) within 24 h;
¶ Glucose <70 mg/dL (3.9 mmol/L) at night (23.00–06.00)

Summary

The FreeStyle Libre System use in T2D with IIT results in no difference in HbA1c change compared to SMBG and reduces hypoglycaemia.¹
The use of FreeStyle Libre System for 12 months was associated with a sustained reduction in hypoglycaemia.² 
The FreeStyle Libre System offers a safe and effective replacement for SMBG.¹

₼ Sales of the original FreeStyle Libre system has been discontinued in EU & UK markets. In these markets, the FreeStyle Libre 2 and 3 systems are for sale, providing the same benifits as the original FreeStyle Libre system, with the added functionalities of optional Real-Time Alarams.
AUC= area under curve; CI= confidence interval; SD=standard deviation; SE=standard error.
§ A comprehensive list of criteria can be found at https://clinicaltrials.gov/study/NCT02082184.

References

1. Haak, T. et al Flash Glucose- Flash Glucose-Sensing Technology as a Replacement for Blood Glucose Monitoring for the Management of Insulin-Treated Type 2 Diabetes: a Multicenter, Open-Label Randomized Controlled Trial. Diabetes Ther. 2017;8(1): 55-73.
2. Haak, T. et al Use of Flash Glucose-Sensing Technology for 12 months as a Replacement for Blood Glucose Monitoring in Insulin-treated Type 2 Diabetes. Diabetes Ther 2017; 8(3):573–586.

REPLACE STUDY¹

Impact of flash glucose monitoring in type 2 diabetes

Study objective

Study design and study population