MEDICAL DEVELOPMENT DIVISION

MINISTRY OF HEALTH MALAYSIA

INFORMATION BRIEF

TITLE: Free Style Libre Flash Glucose Monitoring

PURPOSE
To provide brief information on the safety, effectiveness and cost-effectiveness of Free
Style Libre Flash Glucose Monitoring based on request from the Special Officer to the
Director General of Health, Ministry of Health Malaysia following proposal by a company
to introduce the technology to Ministry of Health Malaysia.

BACKGROUND
Globally, the prevalence of people with diabetes is increasing with 90% having type 2
diabetes, a fifth of whom are on insulin.1,2 Improving glycaemia reduces the risk of
diabetes complications and is a key management objective. 3 HbA1c remains the gold
standard for monitoring glycaemic control and given the detrimental effects of
hyperglycaemia, guidelines recommended tight HbA1c targets. 4 However, stringent
metabolic control with low haemoglobin A1c (HbA1c) level might increase risk of
hypoglycaemia.5 Hence, management of type 1 Diabetes Mellitus (T1DM) using
intensive insulin involves a balance between reducing hyperglycaemia and minimising
risk of hypoglycaemia. 6 Management of T1DM places a large financial burden owing to
the cost of glucose monitoring, insulin and essential medicines.7 In 2011, UK National
Health Service (NHS) spent £158million on self monitoring blood glucose (SMBG),
which accounted for 21% of prescription costs associated with diabetes. 8

Immediate glycaemic status is best determined by SMBG, which is the current standard
of care of glucose monitoring using blood glucose meters, lancets and test strips. 9 The
NICE guideline recommends that adults with T1DM tests up to at least four times a day,
and up to ten times per day.8 The American Diabetes Association guidelines specify
patient using intensive insulin regimen should test six to ten times (or more) daily. 9 In
Malaysia, Clinical Practice Guidelines on T1DM recommended that SMBG should be
performed four to six times a day and more frequent in certain conditions such as sick
day or during exercise.10 However, many patients do not perform frequent SMBG
following inconvenience, invasiveness and social stigma.11 Moreover, SMBG by
intermittent capillary sampling gives only snapshots of blood glucose concentration with
no information of the glycaemic profile in between the sampling time. 12

Continuous blood glucose monitoring (CGM) is an alternative to SMBG, but the use of
conventional CGM has been limited due to the need for repeated calibration using
capillary glucose testing, relatively short sensor life and high cost. 13 The availability of
CGM since last 15 years, through sensor inserted subcutaneously to measure glucose
level in the interstitial fluid reduces discomfort and provides more glucose data. 14
However, there is a time lag between subcutaneous glucose and capillary blood
glucose concentration due to the transport of glucose from vascular to the interstitial
space resulting in a difference in a measured glucose level.15 Accuracy of CGM remains
1
 a challenge as most of the available system requires calibration with capillary BG at
least twice daily to allow sufficient reliable correlation between interstitial and capillary
glucose.16 Types of CGM available are (1) real-time CGM (rtCGM) and (2) intermittently
viewed CGM, also called Flash Glucose Monitoring (FGM). Both systems provide
information about current and previous glucose level, trend and anticipated glycaemic
status with each unique feature (Table 1).

The FGM sensor collects real time glucose reading each time user actively scans the
sensor with the device reader or via an app on their smartphone. Freestyle Libre system
is claimed to be the only FGM available.17 The FreeStyle Libre system is a minimally
invasive sensor-based flash glucose monitoring system, indicated for use in adults and
children with diabetes mellitus, which measure interstitial fluid glucose level. Data are
wirelessly transferred from a sensor (applied to the back of the upper arm and lasts for
up to 14 days) to a handheld reader. A dedicated reader is placed over the on-body
patch to collect the current glucose and glucose trend, which is automatically stored
every 15 minutes. For a complete glycaemic picture, scan once in every eight hours.
The reader can capture data from the sensor when it is within one to four cm of the
sensor. Sensor is water resistant in up to one metre (three feet) of water for a maximum
of thirty minutes. The FreeStyle Libre sensor communicates with the FreeStyle Libre
reader that started it or the FreeStyle LibreLink app that started it. 18 The FGM is factory
calibrated. In these circumstances SMBG is needed to check readings: 1) during times
of rapidly changing glucose, 2) in order to confirm hypoglycaemia or impending
hypoglycaemia and 3) if their symptoms do not correlate with the flash monitoring
system reading. The commercial availability of the system began in 2014 in seven
European countries (Germany, UK, France, Italy, Spain, Sweden and Netherlands). 13
(Figure 1).

Table 1: Difference between real time CGM and FGM

Feature rtCGM FGM

Glucose sensing
Recommended sensor site
Calibration
Data update cycle
Duration of sensor life
Immediate access to glucose
value
High/low glucose alert
interstitial fluid
abdomen (transcutaneous),
upper arm (implantable)
Once/twice daily with SMBG
Every 5 minute automatically
6 days (Enlite),
7 days (DexcomG5),
6months (Eversense)
Button push
Yes
interstitial fluid
back of upper arm
Factory calibrated
When sensor is scanned with
the reader or smartphone app
14 days (EU)
10 days (US)
By scanning
No

2
 Figure 1: FreeStyle Libre sensor at the back of upper arm (left) and
handheld reader (right)

EVIDENCE / INFORMATION SUMMARY

A total of 27 titles were retrieved from the scientific databases such as Medline, EBM
Reviews, EMBASE via OVID, Pubmed and from the general search engines [Google
Scholar and US Food and Drug Administration (USFDA)]. Five articles were found to be
relevant and included in this review which comprised of randomised controlled trials
(two), non randomised trial (one), cross sectional study (one), and cost analysis (one).

EFFECTIVENESS/EFFICACY

Bolinder J, et al (2016) conducted a RCT to assess whether factory calibrated, sensor-

based, flash glucose-monitoring system compared with self-monitored glucose testing
reduced exposure to hypoglycaemia in patients with T1DM. This was a multicentre
RCT, involving 241 adults (aged 18 years or older diagnosed with T1DM five years or
longer) with well controlled T1DM [(HbA1c ≤58mmol/mol (7.5%)] from 23 European
diabetes centres (Sweden, Austria, Germany, Spain and Netherland). Patients were
randomly assigned to flash sensor-based glucose monitoring (intervention group,
n=120) or to self monitoring blood glucose with capillary strips (control group, n=121).
Patient reported outcome measure (with Hypoglycaemia fear Survey, Diabetes
Treatment Satisfaction Questionnaire, Diabetes Quality of Life Questionnaire and
Diabetes Distress Scale) were assessed at baseline and six months. The primary
outcome was change in time in hypoglycaemia [<3.9mmol/l(70mg/dl)] between baseline
and six months. They found reduced time in hypoglycaemia in intervention group
(3.38h/day to 2.03 h/day) using the device compared with the control group (3.44h/day
to 3.27h/day), equating to 38% decrease in time spent with sensor glucose lower than
3.9mmol/l (p<0.0001). At six months, 65% of the intervention group compared with 33%
of the control group reduced their time in hypoglycaemia (<3.9mmol/l) by at least 30%
(p<0.0001). Time spent in hyperglycaemia (>13.3mmol/l) was reduced more in
3
intervention group (1.85h/day to 1.67h/day) compared to control group (1.91h/day to
2.06h/day), p=0.0247. At six months, HbA1c concentration in the intervention group was
essentially unchanged compared with the control group. There was no difference in total
daily doses of insulin or bolus/basal insulin ratios between group. Patient satisfaction
with treatment was significantly improved following intervention, p<0.0001. Diabetes
quality of life did not significantly different between groups. Use of novel flash glucose
sensor system resulted in significant reduction in time in hypoglycaemia without
deterioration in HbA1c level, demonstrating the system is safe replacement for self
monitoring blood glucose and acceptable to individuals with T1DM. Future studies are
needed to assess the effectiveness of the technology among less controlled diabetes
and younger age group. 19

Haak et al. (2017) in another RCT evaluated flash glucose sensing technology as a
replacement for blood glucose monitoring for the management of insulin treated T2DM.
This multicentre RCT involved 224 adults with T2DM on insulin therapy for at least six
months, with HbA1c level between 58 and 108mmol/l (7.5-12.0%) from 26 European
diabetes centres in Germany, France and UK. Following two weeks of blinded sensor
wear, 2:1 randomisation was done to control (SMBG, n=75) or intervention (glucose
sensing technology, n=149). For the six months treatment phase, the sensor based
glucose monitoring system was unblinded for intervention group to continuously use
glucose data for self-management. Their historical glucose data was uploaded at
subsequent visit and report generated by healthcare provider with patient using the
device software. Control participants used a standard blood glucose device (Abbott
Diabetes Care, Witney, UK) and a glucose diary. HbA1c was measured in all
participants at baseline, three and six months. All participants completed quality of life
and patient reported outcomes questionnaire at baseline and six months. Primary
outcome was difference in HbA1c at six months. They found at six months, there was
no difference in the change of HbA1c between intervention and control groups; -3.1
±0.75mmol/l (-0.29±0.07) and -3.4±1.04mmol/mol (-0.31±0.09). Time in hypoglycaemia
(<3.9mmol/l) (reduced by 0.47±0.13h/day (p=0.0006), reduction of 43% in intervention
group. Nocturnal and daytime hypoglycaemia (<3.9mmol/l) reduced by 54% and 31%
for intervention participants compared with control; p=0.0001, p=0.0374. Frequency of
events with glucose <3.9mmol/l reduced by 28% in intervention group compared with
control, p=0.0164. There was no difference detected between intervention and control
group in total daily dose of insulin, basal or bolus insulin doses. Treatment satisfaction
was higher in intervention group compared with controls (Diabetes Treatment
Satisfaction Questionnaire, DTSQ) of 13.1±0.50 and 9.0±0.72, p<0.0001. They
concluded flash glucose sensing technology use in type 2 DM with intensive insulin
therapy results in no difference in HbA1c, and reduced hypoglycaemia thus offering a
safe and effective option for glycaemic management in this patient. 20

Massa et al. (2018) evaluated the accuracy and usability of FreeStyle Libre Flash
Glucose Monitoring System in children and adolescent with T1DM in Belgium. This
nonrandomised, nonblinded single arm trial was performed with FreeStyle Libre FGM
applied to the participants, measuring glucose concentration in the interstitial fluid for up
to 14 days. This study involved 67 T1DM children aged four to 18 years treated with
multiple daily injections of insulin or continuous subcutaneous insulin infusion with
4
infusion pump at the childhood diabetic centre of the Jessa Hospital, Belgium between
June and October 2016. The study lasted for two weeks, whereby participants wore a
sensor on the back of their upper arm. For the first 14 days, they regularly measured
their capillary blood glucose (BG), with their usual BG meter; [Accu-Chek Mobile (ACM),
Roche, n=24; Contour Next Link, Bayer (CNL), n=26; and One Touch Verio, LifeScan
(OTV), n=17], followed by sensor glucose (SG) scanning. After 14 days, subjects were
asked to fill in a questionnaire on the usability of the FGM. There were 2,626 paired SG-
BG observations. They found the FGM readings were highly correlated with BG
(r=0.926, p<0.001). Overall mean difference was 7.5mg/dl, varied with BG meter (ACM
10.4mg/dl, CNL 14.2 mg/dl and OTV -3.6mg/dl), (p<0.001). The MD and Mean Relative
Difference (MRD) were inversely related to Body Mass Index, BMI (r=-0.261, p<0.05;
and r=-0.266, p<0.05) respectively. The median pain score was 0(0 to 1). Nearly all
participants (97%) agreed that it was easy to put the sensor on. The usability
questionnaires indicated high level of satisfaction. They concluded there was a
reasonable agreement between the FGM SG reading and capillary BG measurement in
children, with interindividual variability observed especially those with low BMI. 15

Dunn et al. (2018) reviewed the use of FGM over 20 months in a worldwide glucose
reader database to establish testing frequency and association with glycaemic
parameters. In this cross sectional study, glucose results were de-identified and
uploaded onto a dedicated database once readers were connected to an internet ready
computer. Data between September 2014 and May 2016 comprising of 50,831 readers
and 279,446 sensors worldwide (Germany, UK, France, Italy, Spain, Sweden,
Netherlands and others) were analysed. Scan rate per reader was determined, each
reader was sorted into groups categorised by scan frequency. Glucose parameters
were calculated for each group including HbA1c. The following glycaemic markers were
analysed, estimated HbA1c, time spent in euglycaemia (3.9-10.0mmol/l),
hyperglycaemia (>10.0mmol/l), and hypoglycaemia (<3.9,<3.1 and <2.5mmol/l). They
found users performed a mean of 16.3 scans/day (median(IQR):14(20).Estimated
HbA1c gradually reduced from 8.0% to 6.7% as scan rate increased from lowest to
highest scan groups (4.4 and 48.1 scans/day, p<0.001). Simultaneously, time below
3.9, 3.1 and 2.5 mmol/l decreased by 15%, 40% and 49% respectively (p<0.001),
comparing the lowest to the highest scan groups. Time above 10.0mmol/l decreased
from 10.4 to 5.7h/day (44% reduction, p<0.001), while time in range (time spent in
euglycaemia) increased from 12.0 to 16.8h/day (40% increase, p<0.001) comparing the
lowest to the highest scan users. They concluded in real world condition, FGM allows
frequent glucose checks with higher rates of scanning linked to improve glycaemic
markers including increased time in euglycaemia, and reduced time in hyper and
hypoglycaemia. 13

SAFETY

The Free style Libre Flash Glucose Monitoring system was approved by the USFDA for
people 18 years of age and older with diabetes. 21 The FGM was approved in Europe for
use in children aged more than four years attended by a caregiver of at least 18 years
(CE 597686). 15
5
 Bolinder et al. (2016) in the RCT conducted found 13 adverse events, reported by ten
participants related to the sensor, four of allergy events, itching (one), rash (one),
insertion site symptom (four), erythema (two), oedema (one). Seven participants
withdrew due to device-related adverse events or repetitive occurrence of sensor
insertion related symptoms.19

Haak et al (2017) in another RCT showed six intervention participants reported nine
adverse events for sensor wear reactions (two severe, six moderate, one mild).These
were sensor-sensitive reactions, primarily treated with topical preparations. 20

Massa et al. (2018) in the nonrandomised trial conducted found 29 out of 67 patients
(43.3%) reported sensor problems, the most encountered inconvenience was early
detachment of the sensors. Twenty-three (34%) subjects reported itching, four (6%)
pain and five (7%) pressure feeling during the time they wore the sensor. 15

COST-EFFECTIVENESS

Hellmund et al. (2018) conducted a cost analysis for a FGM system in UK adults with
T1DM receiving intensive insulin treatment, from a UK National Health Service (NHS)
perspective. The base-case cost calculation was created using the maximum frequency
of glucose monitoring recommended by the 2015 National Institute for Health and Care
Excellence (NICE) guidelines (four to ten tests per day). Annual cost of glucose
monitoring was assessed for a single patient with T1DM using intensive insulin and
either the FGM or routine SMBG. Costs were calculated from UK NHS perspective in
the 2015 to 2016 financial year, and include the acquisition cost of FGM sensor (£35.0
per sensor), the cost of lancet (£0.04 per lancet), and test strip (£0.29 per test strip).
The FGM reader is assumed to be provided at no cost. The SMBG consumable costs
were based on mean weighted price for the top ten suppliers in the UK market.
Scenario analysis considered SMBG at the frequency observed in the IMPACT clinical
trial (5.6 tests per day) and at the frequency of flash monitoring observed in a real world
analysis (16 tests per day). They found in the base case, the annual cost per patient
using FGM was £970, which was £234 (19%) lower compared with routine SMBG (10
tests per day) with annual cost of £1205. In scenario analysis, the annual cost per
patient of FGM (£970) compared with 5.6 and 16 times SMBG tests per day was £296
higher and £957 lower, respectively. Table 2 summarize estimated annual glucose
monitoring cost using GFGM and SMBG. They concluded the FGM has a modest
impact on glucose monitoring costs for the UK NHS for patients with T1DM using
intensive insulin.22

Table 2: Annual glucose monitoring cost using GFGM and SMBG

Base case Scenario 1 Scenario 2
Cost (routine SMBG user: (Routine SMBG user: (Routine SMBG user:
a
10 tests per day) 5.6 tests per day) 16 tests per day)
Flash monitoring ( £)
Cost per reader 0 0 0
Cost per sensor 35.00 35.00 35.00
b PPPY
Cost of reader and sensor 910.00 910.00 910.00
6
SMBG ( £)
Cost per lancet 0.04 0.04 0.04
Cost per test strip 0.29 0.29 0.29
Cost of lancet & test strip 0.33 0.33 0.33
PPPY
For flash monitoring user 60.23 60.23 60.23
PPPY
For routine SMBG 1204.50 674.52 1927.20
PPPY
Cost of flash monitoring, ( £) 970.23 970.23 970.23
Additional cost of flash -234.28 +295.71 -956.98
PPPY
monitoring vs SMBG
a
Assumption: use of 10 SMBG tests per day according to maximum frequency recommended by 2015 NICE guidelines
b
Assumption: use of 26 sensors per year (sensor life is up to 14 days)

CONCLUSION

There was limited evidence retrieved on FGM for treatment of children and adults with
DM treated with insulin. The FGM appeared to be effective in reducing time in
hypoglycaemia, and hyperglycaemia without deterioration in HbA1c level, and improve
patient satisfaction in adult with T1DM and insulin treated T2DM in the short term.
Performance of FGM was as good as SMBG with reasonable agreement demonstrated
in T1DM children. However, the long-term effect could not be determined.

The FGM appeared save with minor adverse reactions reported, and has been
approved for people 18 years of age and older with diabetes (USFDA), and in children
aged more than four years attended by a caregiver of at least 18 years (Europe). The
FGM may be cost saving for patient who requires frequent glucose monitoring (≥10
SMBG tests per day).

REFERENCES

1. Chiu CJ, Wray LA. Factors predicting glycaemic control in middle-aged and older
adults with type 2diabetes. Prev Chronic Dis 2010; 7(1):A08.
2. Holman RR, Pul SK, Bethel MA, et al. 10-year follow up of intensive glucose
control in type-2 diabetes. N Eng J Med 2008; 359:557-589.
3. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and
vascular outcomes in patients with type 2 diabetes. N Eng J Med 2008;
358(24):2560-2572.
4. Fullerton B, Jeitler K, Seitz M, et al. Intensive glucose control versus
conventional glucose control for type 1 diabetes mellitus. Cochrane Database
Syst Rev 2014(2):CD009122.
5. The Diabetes Control and Complications Trial Research Group. The effect of
intensive treatment of diabetes on the development and progression of long term
complications in insulin-dependent diabetes mellitus. N Eng J Med 1993;
329:977-986.
6. World Health Organisation. Global report on diabetes. Available from
apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf (Accessed
on 30 January 2020)

7
7. Zhu H, Zhu Y, Leung SW. Is self monitoring blood glucose effective in improving
glycaemic control in type 2 diabetes without insulin treatment: a meta analysis of
randomised controlled trials. BMJ Open 2016;6:e010524.
8. National Institute for Health and Care Excellence.Type 1 diabetes in
adults:diagnosis and management.2015. Available from
https://www.nice.org.uk/guidance/ng17 (Accessed 29 January 2020)
9. Standards of medical care in diabetes 2017: Summary of revisions. Diabetes
care 2017;40:S4-5.
10. Ministry of Health.CPG Management of Type 1 Diabetes Mellitus in Children &
Adolescents 2015.
11. Ong WM, Chua SS, Ng CJ. Barriers and facilitators to self monitoring of blood
glucose in people with type-2 diabetes using insulin: a qualitative study.Patient
Prefer adherence 2014;8:237-246.
12. Evans M. Curent methods of assessing blood glucose control in diabetes.Br J
Diabetes 2016; 16 Suppl1:S7-9
13. Dunn TC, Xu Y, Hayter G, et al. Real world flash glucose monitoring patterns and
associations between self monitoring frequency and glycaemic measures: A
European analysis of over 60 million glucose tests. Diabetes Research And
Clinical Practice 2018;137:37-46
14. Ajjan RA. How can we realize the clinicalbenefits of continous glucose
monitoring? Diabetes Technol Ther 2017;19:S27-36.
15. Massa GG, Gys I, Endyt AO, et al. Evaluation of the FreeStyle Libre Flash
Glucose Monitoring system in children and adolescents with type1 diabetes.
Horm Res Paediatr 2018;89:189-199.DOI:10.1159/000487361
16. Andelin M, Kropff J, Matuleviciene V, et al. Assessing the accuracy of continous
glucose monitoring calibrated with capillary values using capillary or venous
glucose level as reference. J Diabetes Sci Technol 2016;10(4):876-884.
17. Bruttomesso D, Laviola L, Avogaro A, et al. The use of real time continuous
glucose monitoring or flash glucose monitoring in the management of diabetes: A
consensus view of Italian diabetes experts using the Delphi method. Nutrition,
Metabolism & Cardiovascular disease 2019;29:421-431.
18. Freestyle Libre Flash glucose monitoring. Available at
https://www.freestylelibre.co.uk/libre/ (Accessed on 31 January 2020)
19. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, et al. Novel glucose sensing
technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked,
randomised controlled trial. Lancet 2016;388:2254-2263.
20. Haak T, Hanaire H, Ajjan R, 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;8:55-73.
21. USFDA. Freestyle Libre 14 Day Flash Glucose Monitoring System -
P160030/S017. https://www.fda.gov/medical-devices/recently-approved-
devices/freestyle-libre-14-day-flash-glucose-monitoring-system-p160030s017
(Accessed 1 February 2020)
22. Hellmund R, Weitgasser R, Blissett D. Cost calculation for a flash glucose
monitoring system for UK adults with type 1 diabetes mellitus receiving intensive
insulin treatment. Diabetes Research and Clinical Practice 2018;138:193-200.

8
Prepared by:
Dr Roza binti Sarimin
Senior Principal Assistant Director,
Health Technology Assessment Section, Medical Development Division,
Ministry of Health

Dr Junainah binti Sabirin

Deputy Director,
Health Technology Assessment Section, Medical Development Division,
Ministry of Health

3 February 2020

DISCLAIMER

This information brief is a brief report, prepared on an urgent basis, to assist health care decision-
makers and health care professionals in making well-informed decisions related to the use of
health technology in health care system, which draws on restricted review from analysis of best
pertinent literature available at the time of development. This report has not been subjected to an
external review process. While effort has been made to do so, this report may not fully reflect all
scientific research available. Other relevant scientific findings may have been reported since the
completion of this report. MaHTAS is not responsible for any errors, injury, loss or damage arising
or relating to the use (or misuse) of any information, statement or content of this report or any of
the source materials.

Please contact htamalaysia@moh.gov.my if further information is required.