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Lutz Heinemann, Guido Freckmann, Dominic Ehrmann, Gabriele Faber-Heinemann, Stefania Guerra, Delia Waldenmaier, Norbert Hermanns
 
Abstract
Summary
Background
The effectiveness of real-time continuous glucose monitoring (rtCGM) in avoidance of hypoglycaemia
among high-risk individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) is unknown.
 
We aimed to ascertain whether the incidence and severity of hypoglycaemia can be reduced through use of rtCGM in these individuals.
 
Methods
The HypoDE study was a 6-month, multicentre, open-label, parallel, randomised controlled trial done at
12 diabetes practices in Germany. Eligible participants had type 1 diabetes and a history of impaired hypoglycaemia awareness or severe hypoglycaemia during the previous year. All participants wore a masked rtCGM system for 28 days and were then randomly assigned to 26 weeks of unmasked rtCGM (Dexcom G5 Mobile system) or to the control group (continuing with self-monitoring of blood glucose). Block randomisation with 1:1 allocation was done centrally, with the study site as the stratifying variable. Masking of participants and study sites was not possible. Control participants wore a masked rtCGM system during the follow-up phase (weeks 22–26). The primary outcome was the baseline-adjusted number of hypoglycaemic events (defined as glucose ≤3·0 mmol/L for ≥20 min) during the follow-up phase. The full dataset analysis comprised participants who wore the rtCGM system during the baseline and follow-up phases. The intention-to-treat analysis comprised all randomised participants.
 
This trial is registered with ClinicalTrials.gov, number NCT02671968.
 
Findings
Between March 4, 2016, and Jan 12, 2017, 149 participants were randomly assigned (n=74 to the control group;
n=75 to the rtCGM group) and 141 completed the follow-up phase (n=66 in the control group, n=75 in the rtCGM
group). The mean number of hypoglycaemic events per 28 days among participants in the rtCGM group was reduced from 10·8 (SD 10·0) to 3·5 (4·7); reductions among control participants were negligible (from 14·4 [12·4] to 13·7 (11·6]). Incidence of hypoglycaemic events decreased by 72% for participants in the rtCGM group (incidence rate ratio 0·28 [95% CI 0·20–0·39], p<0·0001). 18 serious adverse events were reported: seven in the control group, ten in the rtCGM group, and one before randomisation. No event was considered to be related to the investigational device.
 
Interpretation
Usage of rtCGM reduced the number of hypoglycaemic events in individuals with type 1 diabetes
treated by MDI and with impaired hypoglycaemia awareness or severe hypoglycaemia.
 
 
From the text
Introduction
Hypoglycaemia remains a limiting factor in achievement
of optimal glycaemic control in individuals with type 1
diabetes.1 Use of real-time continuous glucose monitoring
(rtCGM) systems in these individuals has the potential to
avoid low glucose concentrations and severe hypoglycaemia
through the availability of low-glucose alarms and use of
trend information (eg, trend graphs and rate of change
[ROC] arrows) to proactively respond to falling or near-low
glucose values.
 
Results of meta-analyses have shown that use of rtCGM
can help to optimise glucose control without increasing
the incidence of hypoglycaemic events in individuals with
type 1 diabetes.2 These findings have encouraged research
into the effect of rtCGM in individuals with problematic
hypoglycaemia,3,4 a subgroup of people with diabetes
that faces substantial clinical challenges due to the
high prevalence of impaired hypoglycaemia awareness or
previous severe hypoglycaemia episodes, or a combination
of both factors; both conditions predispose these
individuals to future severe hypoglycaemia episodes.5,6
However, available evidence about the benefits of rtCGM
in problematic hypoglycaemia is scarce. Most previous
studies of rtCGM were not designed to reach a hypoglycaemia-
specific primary endpoint2,3 or had relatively
small sample sizes.3,4,7 Many studies also excluded
individuals with frequent or severe hypoglycaemia or with
impaired hypoglycaemia awareness.8,9
 
The vast majority of individuals with type 1 diabetes are
treated with multiple daily insulin injections (MDI), which
is likely to be because of the increased costs associated
with continuous subcutaneous insulin infusion therapy
(CSII).10 However, most evidence about the benefits of
rtCGM in individuals with problematic hypoglycaemia
was generated in clinical studies that had few or no
participants treated with MDI.3,4 Compared with MDI
treatment, CSII enables individuals to adjust insulin doses
in a more flexible manner to address circadian changes in
insulin requirements and lifestyle factors (eg, physical
activity), which facilitates avoidance of low glucose values;11
therefore, the results obtained in these studies might not
be generalisable to individuals treated with MDI.
GOLD12 and DIAMOND,13 two landmark studies
investigating the effects of rtCGM exclusively in
individuals with type 1 diabetes treated by MDI, showed
significant reductions of glycated haemoglobin (HbA1c),
which were accompanied by an improvement in
biochemical hypoglycaemia. However, because both
studies selected their study sample on the basis of an
unfavourable HbA1c value (>7.5% or 58.5 mmol/mol),
individuals with problematic hypoglycaemia were (or
might have been) excluded from the trials. For example,
individuals with a history of recurrent severe hypoglycaemia
were specifically excluded from participating
in the DIAMOND trial,13 whereas eligibility criteria
for the GOLD study required investigators to exclude
participants who were determined to be unsuitable
for participation,12 which might have been applied to
individuals with problematic hypoglycaemia. Thus, the
potential benefits of rtCGM in reducing hypoglycaemia
in high-risk individuals with type 1 diabetes treated by
MDI remains an open question.
 
The aim of the investigator-initiated HypoDE study
was to test the hypothesis that use of rtCGM reduces the
frequency of hypoglycaemic events when compared with
use of self-monitoring of blood glucose (SMBG) 
highrisk adults with type 1 diabetes treated by MDI.
 
Research in context
Evidence before this study
We searched the PubMed database up to Oct 31, 2017, using the
search terms “type 1 diabetes” and “continuous glucose
monitoring or CGM” and “multiple daily insulin injections or
MDI” and “hypoglycemia or hypoglycaemia” and “randomized
or randomised or randomized trial or randomised trial” for
randomised controlled trials that had investigated the effect of
real-time continuous glucose monitoring (rtCGM) on
hypoglycaemia-related outcomes in patients with type 1
diabetes treated by multiple daily insulin injections (MDI).
The search identified 48 publications, of which only 11 met the
inclusion criteria (rtCGM vs self-monitoring of blood glucose
[SMBG] in patients with type 1 diabetes treated with MDI).
Among these were two reviews: one examined the effect of
continuous glucose monitoring (CGM) on glycaemic control in
pregnant women, while the other investigated the effect of
CGM with alarms versus CGM without alarms. We identified only
five studies investigating the effect of rtCGM in patients with
type 1 diabetes treated with MDI. Two studies (IN CONTROL and
HypoCOMPaSS) selected patients with type 1 diabetes who had
hypoglycaemia. However, both studies included patients with
type 1 diabetes on MDI therapy or continuous subcutaneous
insulin infusion (CSII) therapy. Both studies also had relatively
small sample sizes, thus limiting the post-hoc analyses of rtCGM
in patients with type 1 diabetes on MDI, and they were done in a
small number of study sites (two for IN CONTROL, five for
HypoCOMPaSS). Three studies (GOLD, DIAMOND, and the
DIAMOND follow-up study) included only patients with type 1
diabetes on MDI. However, all three studies had the primary
objective of studying the effect of rtCGM on the reduction of
glycated haemoglobin (HbA1c). Participants in these studies were
selected on the basis of an elevated HbA1c and not the presence
of problematic hypoglycaemia. In summary, we found no
sufficient evidence from the available randomised controlled
trials about the efficacy of rtCGM on hypoglycaemia-specific
outcomes in adult patients with type 1 diabetes and with
problematic hypoglycaemia, who are exclusively treated by MDI.
 
Added value of this study
The results of the HypoDE study show the efficacy of rtCGM
on hypoglycaemia-specific outcomes in patients with type 1
diabetes on MDI with impaired hypoglycaemia awareness or
severe hypoglycaemia. These results also indicate the potential
of rtCGM to avoid both biochemical and clinical hypoglycaemia
in such patients. Avoidance of biochemical hypoglycaemia was
corroborated by blood glucose measurements. Additionally,
this study shows that, in a well controlled sample of adult
patients with type 1 diabetes, avoidance of hypoglycaemia
by rtCGM usage was not achieved at the expense of a
deterioration in HbA1c.
 
Implications of all the available evidence
MDI therapy is the most common insulin therapy regimen in
patients with type 1 diabetes. Worldwide, usage of MDI ranges
from 70% to 99% of all patients with type 1 diabetes.
 
Therefore, the finding that both biochemical and clinical
hypoglycaemia can be avoided by use of rtCGM in patients on
MDI therapy is of high importance for most patients with
type 1 diabetes. Health-care expenditures for CSII are several
times higher than for MDI. The same is true for the costs of
rtCGM compared with those for conventional SMBG. The
potential combination of the most expensive insulin delivery
method with rtCGM could put considerable strain on
health-care systems.
 
Therefore, the finding that substantial
benefits for avoidance of hypoglycaemia can be achieved by
rtCGM in standalone mode in patients with type 1 diabetes
treated with MDI and with impaired hypoglycaemia awareness
or severe hypoglycaemia is both clinically and economically
meaningful. Putting the findings of this study into context
with those from the HypoCOMPaSS study and the post-hoc
analysis of the IN CONTROL study (which showed that
hypoglycaemia avoidance in patients with type 1 diabetes on
CSII and rtCGM is not better than in patients on MDI and
rtCGM), a head-to-head comparison between MDI and CSII
with rtCGM is now needed.
 
Discussion
The results of this multicentre randomised study in
individuals with type 1 diabetes treated with MDI and
with impaired hypoglycaemia awareness or severe
hypoglycaemia show that the number of hypoglycaemic
events can be markedly reduced by use of rtCGM
compared with reliance on SMBG. Other measures of
biochemical hypoglycaemia or markers of future
hypoglycaemic risk, such as percentage of hypoglycaemic
values and the LBGI, were also significantly improved in
the rtCGM group. Additionally, use of rtCGM lowered the
frequency of clinical severe hypoglycaemia
and reduced
glycaemic variability. Importantly, the slight improvement
in HbA1c values in the rtCGM group and the similar
HbA1c values between both study groups indicate that
hypoglycaemia reduction was not achieved at the expense
of a deterioration of overall glycaemic control. These
findings show that use of rtCGM can effectively address
problematic hypoglycaemia in individuals with type 1
diabetes treated by MDI.
 
According to recent international consensus recommendations,
a rtCGM reading below a threshold of
3.0 mmol/L (<54 mg/dL) for at least 15 mins is considered
a hypoglycaemic event.23 Glucose concentrations below
this threshold cause severe neuroglycopenic dysfunction
of the brain that limits the ability to self-treat.24 This
dysfunction not only increases the risk of severe hypoglycaemia24
but is also associated with hazards in daily life
if it occurs during potentially dangerous activities such as
driving or while operating machines.1 In the absence of
third-party assistance, severe hypoglycaemia has a high
probability of resulting in a life-threatening condition
such as a coma or seizure. Thus, a reduction in the
frequency of hypoglycaemic episodes requiring any thirdparty
assistance could also be protective against further
deterioration of severe hypoglycaemia resulting in coma
or seizure.25
 
We found no difference in the incidence of severe
hypoglycaemia requiring medical assistance for recovery.
This result indicates that, despite use of rtCGM, a
subgroup of participants had a persistently elevated
hypoglycaemia risk.6 Because these events are rare, this
study might not have had sufficient statistical power to
detect differences within this subgroup of participants
with severe hypoglycaemia.26
We noted no relevant difference in the self-reported
hypoglycaemia unawareness score between study groups.
This observation corroborates findings from other studies,
which showed a reduction in the incidence of severe
hypoglycaemia but no difference in hypoglycaemia
unawareness scores.3,4 Self-reported unawareness might
be a good predictor of future hypoglycaemia in epidemiological
studies,15 but it is less suited to measure the
physiological effect of hypoglycaemia avoidance on
hypoglycaemia-associated autonomic failure in the context
of rtCGM.
 
Glycaemic variability was also reduced by use of
rtCGM. This result indicates that rtCGM participants
achieved a more stable glucose profile than did
participants in the control group, which is also a
protective factor against hypoglycaemia.27 As reported,
rtCGM participants showed a significant reduction in
glycaemic variability, from 39.3% at baseline to 34.1% at
follow-up; glycaemic variability less than 36% is
considered stable.23
Patient-reported outcomes showed a positive effect of
rtCGM use on hypoglycaemia-related distress and on
satisfaction with glucose monitoring systems. No effects
were seen on fear of hypoglycaemia and overall diabetesrelated
distress or self-reported health status. This
result indicates that use of rtCGM specifically affected
participants’ satisfaction with this method for glucose
monitoring and participants’ hypoglycaemia-related
distress.
Findings from the most recent studies that investigated
use of rtCGM exclusively in individuals with type 1
diabetes treated by MDI were similar to the results
reported here. In the GOLD study,12 an open-label
crossover randomised trial, use of rtCGM was associated
with a notably lower percentage of time participants
spent in the hypoglycaemic range (<3.0 mmol/L)
compared with conventional treatment with SMBG
(0.79% vs 1.89%). Similar differences in the percentage
of time spent with glucose concentrations less than
3.3 mmol/L were observed in the DIAMOND trial13
among rtCGM users compared with SMBG users
(1.4% vs 2.7%, p=0.002).
 
Conversely, the hypoglycaemic outcomes reported in
the IN CONTROL trial3 and the sensor-augmented CSII
study by Ly and colleagues4 were less robust. For
example, the percentage of glucose values less than or
equal to 3.9 mmol/L was notably higher among rtCGM
users in the sensor-augmented study4 (4.2%) and the
IN CONTROL study3 (6.8%) than in our study (median
1.6%; IQR 0.9–3.7). Glycaemic variability was also
higher with use of rtCGM in the IN CONTROL study
than in our study (39.5% vs 34.1%). However, there
are substantial differences between the three studies.
Whereas the HypoDE study included only participants
treated by MDI, 44% of participants in the IN CONTROL
study and 100% of those in the study by Ly and
colleagues used CSII therapy. The differences in these
findings might also be a consequence of demographic
differences; duration of diabetes within the
IN CONTROL population was 10 years longer than
in the HypoDE study population. The analytical
performance of different rtCGM systems used in these
studies might also be an important contributor to
these findings. Nevertheless, considering that rtCGM
combined with CSII is the most expensive choice
of therapy in type 1 diabetes, the finding that
MDI combined with rtCGM has similar effects
on hypoglycaemia could have significant healtheconomic
implications. Therefore, head-to-head studies
with MDI and CSII combined with rtCGM are
clearly needed.
 
A key strength of the HypoDE study is that we only
enrolled individuals with type 1 diabetes treated by MDI
and with impaired hypoglycaemia awareness or severe
hypoglycaemia. As discussed earlier, this population has
not been well studied in previous trials. Thus, this study
provided evidence of the significant effect of rtCGM on
problematic hypoglycaemia in individuals treated by
MDI. Findings from a recent study comparing outcomes
of rtCGM in participants treated with MDI or CSII28 and
comparative effectiveness research29 suggest that the
combination of CSII and rtCGM has an unexpectedly
limited ability to reduce hypoglycaemia. A further
strength of the HypoDE study is that the glycaemic
outcomes related to rtCGM could be confirmed by
SMBG measurements, thus excluding the possibility
that these outcomes were an artifact. Absence of external
validation of the rtCGM results was a major criticism of
the IN CONTROL study.30
 
Some limitations should also be considered. First,
neither participants nor study personnel could be
masked to the intervention. Second, participants were
required to wear their rtCGM device 85% of the time
during the baseline phase to continue in the study. This
requirement might have resulted in selection bias,
which could potentially limit the generalisability of our
findings to all high-risk individuals with type 1 diabetes.
The use of SMBG data to assess the effect of rtCGM on
glycaemic outcomes could also be problematic since
the control group might have tested blood glucose
several times during one hypoglycaemic event. This
repeated testing might have biased the effect of SMBG
on hypoglycaemia-related outcomes. Additionally, the
frequency of SMBG was substantially different during
the follow-up period between the groups, which
necessitated the use of a post-randomisation covariate.
The absence of adjustment for multiplicity for
secondary outcomes can be regarded as another
limitation.
 
In summary
our findings indicate that individuals
with type 1 diabetes treated by MDI and with impaired
hypoglycaemia awareness or severe hypoglycaemia can
minimise both biochemical and clinical hypoglycaemia
through use of rtCGM without compromising overall
glycaemic control. Since the majority of individuals
with type 1 diabetes are treated by MDI, this finding has
high clinical relevance.
 
From the Lancet 180406
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