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Diabetes Complications in People
With Type 1 or Type 2 Diabetes
After Initiation of Flash Glucose
Monitoring in France: The
RELIEF Study
Diabetes Care 2021;44:1368–1376 | https://doi.org/10.2337/dc20-1690
Ronan Roussel,1,2,3
Jean-Pierre Riveline,2,3,4 Eric Vicaut,5
Gerard de Pouvourville,6
Bruno Detournay,7 Corinne Emery,7
Fleur Levrat-Guillen,8 and Bruno Guerci9
OBJECTIVE
The RELIEF study assessed rates of hospitalization for acute diabetes complications in France before and after initiation of the FreeStyle Libre system.
RESEARCH DESIGN AND METHODS
A total of 74,011 patients with type 1 diabetes or type 2 diabetes who initiated the
FreeStyle Libre system were identified from the French national claims database with
use of ICD-10 codes, from hospitalizations with diabetes as a contributing diagnosis,
or the prescription of insulin. Patients were subclassified based on self-monitoring of
blood glucose (SMBG) strip acquisition prior to starting FreeStyle Libre. Hospitalizations for diabetic ketoacidosis (DKA), severe hypoglycemia, diabetes-related coma,
and hyperglycemia were recorded for the 12 months before and after initiation.
RESULTS
Hospitalizations for acute diabetes complications fell in type 1 diabetes (49.0%)
and in type 2 diabetes (39.4%) following FreeStyle Libre initiation. DKA fell in type
1 diabetes (56.2%) and in type 2 diabetes (52.1%), as did diabetes-related comas
in type 1 diabetes (39.6%) and in type 2 diabetes (31.9%). Hospitalizations for hypoglycemia and hyperglycemia decreased in type 2 diabetes (10.8% and 26.5%,
respectively). Before initiation, hospitalizations were most marked for people noncompliant with SMBG and for those with highest acquisition of SMBG, which fell by
54.0% and 51.2%, respectively, following FreeStyle Libre initiation. Persistence with
FreeStyle Libre at 12 months was at 98.1%.
CONCLUSIONS
This large retrospective study on hospitalizations for acute diabetes complications
shows that a significantly lower incidence of admissions for DKA and for diabetesrelated coma is associated with use of flash glucose monitoring. This study has
significant implications for patient-centered diabetes care and potentially for longterm health economic outcomes.
For people with type 1 diabetes or type 2 diabetes on insulin therapy, regular monitoring of blood glucose levels is an essential part of diabetes care (1). This can be
1
Department of Diabetology, Endocrinology, and
Nutrition, Bichat-Claude Bernard Hospital, Paris,
France
2
Unite INSERM U1138 Immunity and
Metabolism in Diabetes, ImMeDiab Team,
Centre de Recherches des Cordeliers, Paris,
France
3
Universite de Paris, Paris, France 4
Department of Diabetology and Endocrinology,
Lariboisiere Hospital, Paris, France 5
Clinical Research Unit, Fernand Vidal Hospital,
Paris, France
6
Department of Economics, ESSEC Business
School, Cergy-Pontoise, France
7
CEMKA, Bourg-la-Reine, France
8
Abbott Laboratories, Maidenhead, Berkshire,
U.K.
9
Department of Endocrinology, Diabetology, and
Nutrition, Brabois Adult Hospital, University of
Lorraine, Vandoeuvre-les-Nancy, France
Corresponding author: Ronan Roussel, ronan.
<PRESIDIO_ANONYMIZED_EMAIL_ADDRESS>
Received 7 July 2020 and Accepted 2 March
2021
This article contains supplementary material online
at https://doi.org/10.2337/figshare.14143874.
This article is featured in a podcast available at
https://www.diabetesjournals.org/content/
diabetes-core-update-podcasts.
© 2021 by the American Diabetes Association.
Readers may use this article as long as the
work is properly cited, the use is educational
and not for profit, and the work is not altered.
More information is available at https://www.
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EMERGING TECHNOLOGIES: DATA SYSTEMS AND DEVICES
1368 Diabetes Care Volume 44, June 2021
done by periodic self-monitoring of
blood glucose (SMBG) using finger prick
testing, or by the use of continuous glucose monitoring (CGM), which involves
a sensor that measures glucose in the
interstitial fluid and provides a wealth
of information on daily glucose levels
that the user can access using a reader
or a smartphone app (2). In so-called intermittently scanned CGM, also called
flash glucose monitoring, glucose levels
are measured continuously but are
available to the user only when the sensor is scanned with the reading device
or smartphone app (2). Flash glucose
monitoring is currently only supported
by the FreeStyle Libre system (Abbott
Diabetes Care, Witney, Oxon, U.K.).
Poor glucose control in either type 1
diabetes or type 2 diabetes can lead to
episodes of uncontrolled hyperglycemia
or hypoglycemia requiring hospitalization. Such acute events include severe
hypoglycemia, severe hyperglycemia,
and diabetic ketoacidosis (DKA), each of
which may also result in coma (3–9). Although these health care emergencies
can be prevented by frequent glucose
monitoring, the burden of emergency
room attendance and hospital admissions for these acute events is increasing and is associated with significant
health care use and expenditure (3–9).
Data on the efficacy of the FreeStyle
Libre system in acute diabetes complications are now starting to emerge. The
Flash Glucose Monitoring Study for Diabetes (FUTURE) with 1,913 people with
type 1 diabetes across three specialized
centers in Belgium did find a significant
fall in rates of hospitalization for acute
diabetes complications following access
to the FreeStyle Libre system (10). However, specific reductions in individual
rates of hospitalization for DKA, severe
hypoglycemia, or coma related to diabetes were not evident in this study. A
study of 900 adults with type 1 diabetes
indicated a reduction in hospital admissions for DKA at two centers in Edinburgh in the 6 months following
national reimbursement for the FreeStyle Libre system in Scotland (11). The
number of DKA cases reported was
small, but the fall in admissions was significant (P 5 0.043).
The FreeStyle Libre flash glucose
monitoring system was approved for reimbursement by the National Sickness
Fund in France on 1 June 2017 for
people treated with insulin (at least
three injections per day or continuous
subcutaneous insulin infusion [CSII]) >4
years old with diabetes—not limited to
type 1 diabetes. The FreeStyle Libre system efficacy had been demonstrated in
the Randomised Controlled Study to
Evaluate the Impact of Novel Glucose
Sensing Technology on Hypoglycaemia
in Type 1 Diabetes (IMPACT) and Randomised Controlled Study to Evaluate
the Impact of Novel Glucose Sensing
Technology on HbA1c in Type 2 Diabetes
(REPLACE) (12,13) in adults with type 1
diabetes or type 2 diabetes on insulin
to reduce time in hypoglycemia <70
mg/dL by 38% (IMPACT) and 43% (REPLACE) over 26 weeks in comparison
with SMBG testing. However, the efficacy of FreeStyle Libre system in the case
of acute diabetes complications remains
to be demonstrated.
The overall objective of the RealWorld Evidence of FreeStyle Libre Analysis of the SNDS Database in France
(RELIEF) study was to use the French national health claims database, Systeme
National des Donnees de Sante (SNDS),
to define how prescription and use of
the FreeStyle Libre device is being implemented for people with diabetes and to
understand the impact on acute health
care outcomes and associated costs in
standard practice in France after 1 and 2
years of use. SNDS (14) covers the entire
French population (66 million people)
and includes extensive information on all
health care resource use, including outpatient visits, dispensed medication, procedures, and chronic conditions, as well
as hospital admission diagnoses and procedures, and date of death, on an individual level.
The aims of this current analysis were
to assess the risk of hospitalization related
to acute diabetes complications in the 12
months before and after access to the
FreeStyle Libre system in France in type 1
diabetes or in type 2 diabetes. Acute
events considered were hospitalizations
for DKA, hypoglycemia, diabetes-related
coma, and hyperglycemia.
RESEARCH DESIGN AND METHODS
This longitudinal retrospective cohort
study was carried out with use of data
extracted from the national French
database SNDS covering the period between 1 January 2015 and 31 December
2018. Costs for the FreeStyle Libre system have been reimbursed in France
since 1 June 2017, but the FreeStyle Libre
system was marketed before this date
without reimbursement. In our study, initiation of the FreeStyle Libre system was
defined as a first reimbursement of sensor or reader in the SNDS over the period after 1 August 2017 without any
reimbursement of reader or sensors in
the previous months of 2017. We chose
to consider in our study only individuals
with diabetes who initiated the FreeStyle
Libre system during the period between
1 August 2017 and 31 December 2017.
These individuals did not purchase FreeStyle Libre sensors or readers between 1
June 2017 and 1 August 2017 and so
were considered new users of the FreeStyle Libre system. We then analyzed
SNDS data from these patients over the
12 months prior to their initiation of the
FreeStyle Libre system and in the 12
months following initiation (Fig. 1).
Patient Selection
An algorithm was used to define and
qualify any patient who used the FreeStyle Libre system as having diabetes
only if they had received at least three
reimbursements for antidiabetes drugs
(oral or insulin) over 1 year or within
the 2 years preceding or 1 year after
FreeStyle Libre initiation (or at least two
reimbursements if one large pack size
was dispensed) or, alternatively, if the
patient had been hospitalized at least
once with a diagnostic ICD-10 code
(15)—E10 (type 1 diabetes), E11 (type 2
diabetes), or E14 (unspecified diabetes)—or was identified in the French
health care system as having a longstanding condition with the same ICD10 codes during the same period. Exclusion criteria included the following: patients with only one FreeStyle Libre
reader reimbursement without any further reimbursements for FreeStyle Libre
sensors over the study period, patients
deceased before the first sensor reimbursement, and patients <18 years old
without insulin therapy 6 months before
and 6 months after FreeStyle Libre
initiation.
Eligible patients enrolled in the study
were then classified according to their
diabetes type and their use of SMBG
test strips in the 12-month period before initiation of the FreeStyle Libre
care.diabetesjournals.org Roussel and Associates 1369
system. A previously published decision
algorithm (Charbonnel et al. [16]) was
used to distinguish patients with type 1
diabetes from those with type 2 diabetes, with the latter considered the diagnosis by default. This algorithm was
based on the ICD-10 codes associated
with Long Standing Condition (LSC) status or associated with hospitalizations,
and on the prescription of insulin.
Quantities of strips supplied as documented by pharmacy claims were used
for calculation of SMBG strip usage
(e.g., 100 test strips dispensed 5 100
tests assumed). SMBG buyers were distinguished according to the average daily number of blood glucose test strips
(none, 1–3, 4–5, and >5) estimated
over a 12-month period based on the
reported number of strips delivered.
Hospital Episode Statistics for Acute
Diabetes Complications
Hospitalizations for DKA were recorded
in the 12 months prior to initiation of
the FreeStyle Libre system and in the 12
months following initiation with use of
ICD-10 code E10.1 (type 1 diabetes with
ketoacidosis) and E11.1 (type 2 diabetes
with ketoacidosis) as the main or related diagnosis. It was not possible to exclude hospitalizations for DKA at the
point of diabetes diagnosis.
Hospitalizations for severe hypoglycemia
were recorded in the 12 months prior to
initiation of the FreeStyle Libre system and
in the 12 months following initiation with
ICD-10 codes E16.0 (drug-induced hypoglycemia without coma), E16.1 (other hypoglycemia), E16.2 (hypoglycemia, unspecified),
and T38.3 (poisoning by adverse effects of
insulin and oral hypoglycemic [antidiabetes]
drugs).
Hospitalizations for diabetes-related
comas were identified with ICD-10 codes
E10.0 (type 1 diabetes with coma), E11.0
(type 2 diabetes with coma), and E14.0
(diabetes unspecified with coma) and hyperglycemia-related stays with ICD-10
code R739 (hyperglycemia, unspecified).
Persistence With Use of the FreeStyle
Libre System
Persistence with the FreeStyle Libre system was defined between first delivery
of a FreeStyle Libre sensor and discontinuation of the FreeStyle Libre system.
Discontinuation was assumed when no
sensors were delivered to the patient
over a consecutive 6-month period. The
date of discontinuation was calculated
by noting of the last recorded date of
sensor delivery and then addition of the
associated 28-day sensor-wear period
for two sensors (i.e., if two sensors
were delivered in the last recorded
claim, the date of discontinuation was
the date of the last claim plus 1 month
for taking into account that two sensors
will last 28 days).
Statistical Analysis
As this study was conducted on a single
nationwide database, no statistical probability tests were performed to compare
the frequency of events before and after
FreeStyle Libre system initiation. We first
compared crude rates of patients with at
least one diabetes-related acute event
without any adjustment until the end of
the study period. We did not recode
missing values.
We also conducted a multivariable
analysis using a linear model to examine
the separate factors that may be associated with hospitalization for any acute
diabetes-related events before and after
initiation of the FreeStyle Libre system,
considering age, sex, diabetes type, universal health coverage for people with
low socioeconomic status, treatment,
and SMBG acquisition level before the
FreeStyle Libre system initiation.
RESULTS
With application of the protocol we
identified 74,011 individuals with diabetes with first reimbursement for FreeStyle Libre sensors during the period
between 1 August 2017 and 31 December 2017. Among them, we identified 33,165 and 40,846 people with
type 1 diabetes or type 2 diabetes,
respectively (Supplementary Table 1),
initiating the FreeStyle Libre system
during the selection period. Of these
patients, 88% were treated with multiple daily injections of insulin (MDI)
(n 5 46,828) or CSII (n 5 18,593).
The remaining 12% were mainly people with type 2 diabetes treated with
a single basal insulin injection or with
oral agents only.
Impact of Starting the FreeStyle Libre
System on Rates of Hospitalization
for Acute Diabetes Complications
There was a highly significant reduction
in the proportion of people with diabetes
who were hospitalized for at least one
acute diabetes complication in the 12
months following their start with the
Figure 1—Patient selection in the RELIEF study. Initiation of the FreeStyle Libre system was defined as a first reimbursement (T0) of sensor or reader in the SNDS during the period between 1 August 2017 and 31 December 2017. SNDS data on these patients were then analyzed for the 12
months before T0 and in the 12 months after T0.
1370 Flash Glucose Monitoring and Diabetes Complications Diabetes Care Volume 44, June 2021
FreeStyle Libre system in comparison
with the 12 months prior to starting
(Fig. 2). Amongst the whole study population, hospitalization for acute diabetes
complications fell by 45.7%, from 3,204
patients in the year prior to starting FreeStyle Libre to 1,740 in the year after starting. The fall was most marked in type 1
diabetes (Fig. 2A), with a reduction of
49.0%, from 2,114 patients to 1,079. The
reduction in acute diabetes complications
in type 2 diabetes (Fig. 2B) was also significant, from 1,090 to 661, in the year after starting FreeStyle Libre in comparison
with the year before, a drop of 39.4%.
Hospitalization Classified According
to the Type of Acute Diabetes
Complications
The fall in DKA hospitalization rates was
more marked than for other acute complications in both types of diabetes.
Hospitalization rates for DKA fell by
55.0%, from 2,508 patients in the year
prior to starting FreeStyle Libre to 1,128
in the year after starting (56.2% [type
1 diabetes] and 52.1% [type 2 diabetes]) (Fig. 2). A slight but significant decrease was also observed for diabetesrelated comas. Overall, the percentage
of patients with at least one hospitalization for a diabetes-related coma fell by
35.7%. The fall was by 39.6% for type 1
diabetes and by 31.9% for type 2 diabetes (Fig. 2). Amongst the whole study
population, hospitalizations rates for hypoglycemia and hyperglycemia fell by
6.4% and 13%, respectively, in each
case, with a decrease mainly observed
in type 2 diabetes (10.8% and
26.5%) (Fig. 2B). The data broken
down by age and sex of the study population are provided in Supplementary
Table 3, and the frequency of events
per 1,000 patient-years is presented in
Supplementary Table 2.
Interestingly, we conducted separate
analyses comparing the frequency of
acute events per 1,000 patient-years over
3, 6, and 12 months after starting the
FreeStyle Libre system (Supplementary
Table 4). In comparison with the overall
frequency of events prior to starting FreeStyle Libre in Supplementary Table 2, a
marked decrease in the frequency of DKA
was observed over the first months after
starting FreeStyle Libre, whereas the effect on hypoglycemia is somewhat delayed in time.
The before and after results were
similar in the subgroup of 65,183 patients (88%) treated with MDI (n 5
43,041) or CSII (n 5 18,282) therapy
and therefore aligned with the conditions of reimbursement of the FreeStyle
Libre system in France (see
Supplementary Table 5).
Hospitalizations for Acute Diabetes
Complications Classified by Use of
SMBG Prior to Starting the FreeStyle
Libre System
We analyzed hospitalization rates among
study individuals who had been subcategorized based on their assumed average
daily frequency of SMBG usage prior to
their first FreeStyle Libre sensor use. The
assumed average daily frequency of
SMBG categories were no strips, 1–3
strips, 4–5 strips, >5 strips, as described
in Table 1. Both the incidence and
the fall in rates of hospitalizations for
acute diabetes complications were most
marked for the 19,396 people who were
not compliant with SMBG testing, as indicated by no consumption of test strips,
but also for people with the most regular
use of SMBG testing (>5 strips) (Fig.
3A). A reduction in hospitalizations of
54.0% and 51.2%, respectively, was
observed in these two groups. Patients
with acute diabetes complications in the
subgroups using one to three or four to
five SMBG test strips per day showed a
significant reduction of 35.2% and
32.2%, respectively, in each case in the
year after starting the FreeStyle Libre
system (Fig. 3A). These patterns of
Figure 2—Annual percentage of patients with type 1 diabetes–related (A) and type 2 diabetes–related (B) acute events before and after initiation
of the FreeStyle Libre system. Data show percentage of patients with at least one acute diabetes complication in the 12 months before and after
FreeStyle Libre initiation.
care.diabetesjournals.org Roussel and Associates 1371
reductions were observed both in type 1
diabetes (Fig. 3B) and in type 2 diabetes
(Fig. 3C).
Multivariable Analysis of Acute
Diabetes Complications in the
Hospital Before and After FreeStyle
Libre Initiation in the Population of
Reimbursement
Before initiation, hospitalization rates
were mainly related to age (<25 years
old as compared to older age classes),
universal health coverage for people
with low socioeconomic status (odds ratio 1.83 [95% CI 1.65–2.02]), and use of
MDI as compared with CSII therapy
(odds ratio 1.37 [95% CI 1.24–1.51])
(Fig. 4). After initiation of the FreeStyle
Libre system, if no changes were observed with regard to the impact of age
and universal health coverage for people with low socioeconomic status, use
of MDI as compared with CSII therapy was
no more a risk factor for hospitalization
related to acute diabetes complications.
Persistence With the FreeStyle Libre
System
Based on the definition outlined in the
methods section, persistence with the
FreeStyle Libre system at 12 months
after initiation (i.e., proportion of people still purchasing the device) was
98.1% (95% CI 98.0–98.2) across all
users (Supplementary Table 6). Importantly, persistence with FreeStyle Libre
was consistently high across all categories of SMBG test buyers, with no
difference between FreeStyle Libre
users who were not SMBG compliant
(0 strip use, 97.3%) and those at all
levels of average daily SMBG test strip
acquisition (Supplementary Table 6).
These results were observed both in
MDI and in CSII subgroups.
CONCLUSIONS
Results from our retrospective observational real-world nationwide cohort
study show that access to the FreeStyle
Libre system for people with intensively
insulin-treated diabetes is associated
with a subsequent drop in rates of
hospitalizations for acute diabetes
complications, mainly DKA and diabetes-related comas; these results were
observed in both MDI and CSII subgroups (Supplementary Table 5). For
74,011 people in this group who had
their first FreeStyle Libre sensor prescribed between 1 August and 31 December 2017, rates of hospitalization
for acute complications of diabetes fell
by 45.7% in the year after starting.
The fall was most marked in type 1
diabetes, with a 49.0% reduction in
hospitalizations. The reduction in hospitalizations for acute complications in
type 2 diabetes was also significant,
with a drop of 39.4%. Results were
particularly notable for hospitalizations related to DKA and diabetes-related comas (overall drop of 52.1%
and 31.9%, respectively), but falls
were also observed for hypoglycemia
and hyperglycemia (10.9% and 26.5%).
These data from a large nationwide sample
size support and extend the outcomes
from the smaller studies with inconclusive
findings (10,11). The generalizability of
our results is worthy of comment. Although our sample corresponds to the
whole population of French patients
starting the FreeStyle Libre system
over a 5-month period, they represent
25% of the theoretical full target population estimated as benefiting every
year from this device by the French
Health Authorities (n 5 300,000 patients) (17). Further studies based on
new data extraction will complement
this current work.
We hypothesized that a patient who
was not reimbursed for any sensors/
readers in the months before starting
the FreeStyle Libre system (over a period of 2–7 months) did not use the system over the full year before the index
date used as the device starting date.
This could lead to an underestimation
of the outcomes, as some patients may
have experienced the system previously
(with a rather long interruption). We
also agree that individuals could have issues learning how to use the system or
incorrectly use the system at initiation,
and this could also lead to a decrease in
the potential impact of FreeStyle Libre
in comparison of the first year of use
with the previous year.
When the study individuals were categorized by frequency of SMBG acquisition prior to their first sensor use, the
fall in hospitalization for acute diabetes
complications was most marked for
people who were not compliant with
SMBG testing, as evidenced by lack of
test strip acquisition. This is understandable given that poor awareness of glucose control may induce the occurrence
of acute diabetes complications. The
problem of noncompliance in type 1 diabetes has previously been raised (18),
with concern about outcomes for poorly
compliant patients. In that small-scale
study of 19 adults with type 1 diabetes,
the use of CSII in conjunction with the
FreeStyle Libre system was seen to significantly reduce HbA1c as well as the
reported incidence of severe hypoglycemia and DKA. Our nationwide analysis
on 74,011 people with type 1 diabetes
or type 2 diabetes shows that important
reductions in hospitalization for acute
diabetes complications in this poorly
compliant group are associated with application of flash glucose monitoring.
We hypothesized that the number of
strips supplied was directly related to
Table 1—Number of patients with categorization by diabetes type and SMBG acquisition prior to starting the FreeStyle Libre
system
0 test strips per day 1–3 test strips per day 4–5 test strips per day >5 test strips per day
n % n % n % n %
Type 1 diabetes 9,531 28.7 6,311 19.0 8,731 26.3 8,592 25.9
Type 2 diabetes 9,865 24.2 11,371 27.8 12,643 31.0 6,967 17.1
Totals 19,396 26.2 17,682 23.9 21,374 28.9 15,559 21.0
Data show SMBG buyers categorized based on their predicted average daily number of blood glucose test strips estimated over a 12-month
period based on the reported number of strips delivered.
1372 Flash Glucose Monitoring and Diabetes Complications Diabetes Care Volume 44, June 2021
Figure 3—Hospitalizations for diabetes acute complications classified by use of SMBG tests in the 12 months prior to FreeStyle Libre initiation for the total study population (A) and by patients with type 1 (B) and type 2 (C) diabetes separately. Data show rates of hospitalizations
with acute diabetes complications in the 12 months before and after FreeStyle Libre initiation. For numbers of patients in each SMBG
test subgroup, see Table 1. The percentage reduction in rates of hospitalization in the 12 months following FreeStyle Libre initiation is
indicated.
care.diabetesjournals.org Roussel and Associates 1373
the number of strips used by the patients, although we accept that is a potential limitation. Interestingly, the data
also show that the people with the highest SMBG test strip acquisition had the
second-highest incidence of hospitalization
for acute diabetes complications in the
year prior to starting FreeStyle Libre and
that this fell markedly in the 12 months
after their first sensor prescription. The
rate of hospitalization for acute diabetes
complications in this high-testing group
may be explained by the fact that they
use SMBG more frequently as a consequence of the inherent instability of their
blood glucose, so called brittle diabetes,
which ultimately puts them at higher risk
of acute diabetes complications, especially
DKA (19). Presumably, access to the FreeStyle Libre system allows them to scan
their sensors with an even higher daily
frequency, which then provides them with
awareness of trends in their glucose control that helps them to manage their risk
of acute complications better. Another
hypothesis may be that some patients
had intensified their insulin therapy
with FreeStyle Libre initiation, including a possible switch from MDI to CSII.
This hypothesis was not supported by a
subgroup analysis that considered only
patients who maintained either MDI or
CSII treatment before and after FreeStyle Libre system initiation (data not
shown). Furthermore, the reduction in
hospitalization rates seen following FreeStyle Libre initiation (Supplementary
Table 5) and the multivariable analysis
(Fig. 4) was also observed with independent consideration of whether the patients were treated with MDI or CSII.
Given the high numbers of patients
in the study cohort who were noncompliant with SMBG testing or with low
strip usage prior to starting the FreeStyle Libre system, persistence with the
FreeStyle Libre system was high, with
98.1% of starters still dispensed FreeStyle Libre sensors at 12 months. Importantly, persistence with FreeStyle Libre
was consistently high across all categories of SMBG test buyers, with no difference between FreeStyle Libre users
who were noncompliant with SMBG
testing (0 strip use, 97.3%) and those
at all levels of average daily SMBG
test strip acquisition (Supplementary
Table 6). This suggests that noncompliant and low-frequency SMBG users
are concerned about their glycemic
control and risk of complications but
the burden of finger pricking is particularly high for them. Persistence with
FreeStyle Libre was also consistent
across the MDI and CSII subgroups
(Supplementary Table 6). This compares well with the limited data on
discontinuation rates for the FreeStyle
Libre system, which have been reported to be as high as 17% (20).
However, this last observation was reported in a small-scale study on 130
patients with type 1 diabetes, all of
whom were self-funding their use of
the FreeStyle Libre system.
Another important observation from
this analysis is that hospitalizations for
severe hypoglycemia were only marginally reduced in the year following access
of patients to the FreeStyle Libre
system. At first glance, this contrasts
with the data from clinical trials in patients with type 1 diabetes and type 2
diabetes on insulin that flash glucose
monitoring significantly reduces the frequency and incidence of hypoglycemia
<70 mg/dL and clinically relevant hypoglycemia <54 mg/dL (12,13). However,
since most severe hypoglycemia does
not result in hospitalization, direct comparison with the clinical trial data is not
informative here. Also, it is worth pointing out that the pre–FreeStyle Libre
rates of hospitalization for severe hypoglycemia in France revealed in this study
are much lower than other reported
frequencies (21). In the U.K., Zhong
et al. (3) reported an annual frequency
of hospitalizations of 14.1 events per
1,000 person-years in 2013 in patients
Figure 4—Multivariable analysis of hospitalizations for acute events related to diabetes before and after FreeStyle Libre initiation. T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; CMUc, couverture maladie universelle complementaire (universal health coverage).
1374 Flash Glucose Monitoring and Diabetes Complications Diabetes Care Volume 44, June 2021
with type 1 diabetes in comparison with
the 7.1 events per 1,000 person-years
observed here (Supplementary Table 2).
Also, other studies have shown that
rates of hypoglycemia do not necessarily
change following introduction of the
FreeStyle Libre system in children with
type 1 diabetes (22) or adults with type
2 diabetes on insulin therapy (23), and at
least one prospective observational study
on 900 people with type 1 diabetes reported an increase in asymptomatic and
symptomatic hypoglycemia following introduction of FreeStyle Libre (11). The
data in our analysis are only focused on
hospitalization events, which is an outcome different from the outcomes assessed in these cited reports, but the
data are not inconsistent with their findings. Of note in this context, the FUTURE
study in 1,913 people with type 1 diabetes also reported no change in hospitalizations for hypoglycemia in the 12
months following introduction of flash
glucose monitoring (10).
In this nationwide survey, the observed rates of hospitalization for DKA
are high compared with those reported
in other published studies in type 1 diabetes (7,20) and especially in type 2 diabetes (7,24). A possible explanation for
this is that the analysis covers people
who have been provided with access to
flash glucose monitoring soon after the
date of approval of reimbursement. This
may indicate a selection bias toward
more motivated patients with acknowledged poor glycemic control and at
higher risk of diabetes complications.
It is important to point out that our
study has limitations. The lack of a control group is a limitation, since a control
group would also have highlighted the
impact of other factors on acute diabetes complications over the study period.
Furthermore, it is possible that previous
experience of DKA would be a factor in
the decision to initiate the FreeStyle Libre system. This could contribute to the
DKA frequency reduction after FreeStyle
Libre system initiation. Because it is a
longitudinal retrospective cohort study
with a 24-month study window, it is
possible that confounding factors, other
than use of the FreeStyle Libre system,
had an impact on the outcomes. For example, initiation of the FreeStyle Libre
system could have been accompanied
by device training or diabetes education, as well as more focused time with
health care professionals during the initiation process. Patient empowerment
may have ensued. Each of these can
result in improved diabetes self-care
behavior that may affect the frequency
of acute complications. This possibility
for enhanced self-care cannot be controlled for in this retrospective cohort
analysis. Interestingly, changes to treatment with insulin that may have been
implemented after starting FreeStyle Libre did not alter rates of DKA or hypoglycemia. As previously mentioned, our
data cannot exclude DKA at the point
of diagnosis, which may have occurred
during the 12 months prior to initiation. A potential calendar effect could
not be excluded without use of a control group. However, an ancillary analysis of the French National Drug-Related
Group hospital payments database did
not show any change over the period
2015–2018 in the proportion of hospital stays with DKA as a main reason for
hospitalization among patients with
type 1 diabetes and showed only a
slight increase among patients with
type 2 diabetes (data not shown).
These results are not in favor of such a
calendar effect.
A further limitation is the fact that
other real-time CGM systems could not
be included in the request for data submitted to SNDS. This has implications
for the generalizability of our data as
previously discussed. Another limitation
is the lack of clinical or biological data,
such as HbA1c measurements, due to
the nature of this administrative database. Similarly, the data give no indication as to daily sensor-scan rates in the
12 months after starting FreeStyle Libre.
We know these rates can have an impact on overall glycemic control (25),
and their lack in our study limits detailed interpretation. As such, it is complementary to other analyses, such as
the FUTURE study (10), which on the
other hand was on a much smaller
scale. The method of classification of
types of diabetes may also be challenged. However, the algorithm used
here has previously been used in several published studies (21,25,26). Lastly,
the accuracy of the outcomes relies on
the quality of coding, which was not assessable in the work. However, the consistency with other studies with a
different design is reassuring, and it is
not expected that outcomes like DKA
would be miscoded frequently. Strengths
of the study include its large size and a
nationwide recruitment scope in the
context of a very generous reimbursement scheme.
In conclusion, this is the largest study
of its kind to date, using health episode
statistics of people with diabetes from a
nationwide database, that quantifies
the association of intervention with
flash glucose monitoring with the incidence of hospitalization for acute diabetes complications in France, both in
type 1 diabetes and in type 2 diabetes.
This analysis has significant implications
for patient-centered clinical care in diabetes and supports the further investigation of the long-term health economic
benefits at a national level.
Duality of Interest. The authors acknowledge
funding support from Abbott Diabetes Care.
R.R. is an advisory panel member for Astra
Zeneca, Sanofi, Merck Sharp & Dohme (MSD),
Eli Lilly, Boehringer Ingelheim, Janssen, Mundipharma, Novo Nordisk, and Physiogenex
and has received research funding from and
provided research support to Amgen, Diabnext, Sanofi, and Novo Nordisk. J.-P.R. is an
advisory panel member for Sanofi, MSD, Eli
Lilly, Novo Nordisk, Abbott, and Medtronic
and has received research funding and provided
research support to Abbott, Air Liquide, Sanofi,
and Novo Nordisk. G.d.P. is a health economist
and an advisory board member for the following companies: Abbott, Amgen, AstraZeneca,
Bayer, Bristol-Myers Squibb (BMS), Boehringer
Ingelheim, Janssen, MSD, Novartis, Novo Nordisk, Roche, and Sanofi. He has received research funding from Amgen, BMS, Boehringer
Ingelheim, MSD, Novartis, Roche, and Sanofi.
He has received honoraria for his participation
on the RELIEF study advisory board. E.V. is a
consultant specializing in the methodology and
statistical analysis of clinical trials for Abbott,
BMS, Celgene, Edwards, Novartis, Pfizer, and Sanofi. He has received honoraria for his participation. B.D. and C.E. are employees of CEMKA,
a French heath care Clinical Research Organization. B.D. has also received advisory board and
lecture fees from Sanofi, MSD, Eli Lilly, Novo
Nordisk, Pfizer, and Janssen. F.L.-G. is employed
by Abbott Diabetes Care. B.G. is an advisory
board member for Sanofi, Eli Lilly, Novo Nordisk, Novartis, GSK, MSD, Boehringer Ingelheim,
AstraZeneca, Abbott, Medtronic, and Roche
Diagnostics. He is a clinical investigator for Sanofi,
Eli Lilly, Novo Nordisk, GSK, BMS, AstraZeneca,
Medtronic, Abbott, Roche Diagnostics, MSD, Novartis, Janssen, and Boehringer Ingelheim. He receives research support from Medtronic, Vitalaire,
Sanofi, Eli Lilly, and Novo Nordisk. No other potential conflicts of interest relevant to this article
were reported.
The funding support from Abbott Diabetes
Care did not affect the collection, analysis, or
presentation of the data.
care.diabetesjournals.org Roussel and Associates 1375
Author Contributions. J.-P.R. contributed to
the methodology, the analyses, and the manuscript writing. E.V. contributed to the methodology, the analyses, and the manuscript
writing. G.d.P. contributed to the methodology,
the analyses, and the manuscript writing. B.D.
and C.E. contributed to the methodology, conducted the statistical analyses, and contributed
to the manuscript writing. F.L.-G. contributed to
the methodology, the analyses, and the manuscript writing. B.G. contributed to the methodology, the analyses, and the manuscript writing.
R.R. is the guarantor of this work and, as such,
had full access to all the data in the study and
takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Prior Presentation. Parts of this study were
presented in abstract form at the 80th Scientific Sessions of the American Diabetes Association, 12–16 June 2020.
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1376 Flash Glucose Monitoring and Diabetes Complications Diabetes Care Volume 44, June 2021