Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Closed loop insulin delivery in diabetes


Tadej Battelino, M.D., Ph.D. a, b, *, Jasna Suput Omladi
c, M.D. a,
Moshe Phillip, M.D., Director c, d
a
Department of Endocrinology, Diabetes and Metabolism, UMC e University Children's Hospital, Ljubljana,
Slovenia
b
Faculty of Medicine, University of Ljubljana, Slovenia
c
Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood
Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
d
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

a r t i c l e i n f o
The primary goal of type 1 diabetes treatment is attaining near-
Article history: normal glucose values. This currently remains out of reach for
Available online 10 March 2015 most people with type 1 diabetes despite intensified insulin
treatment in the form of insulin analogues, educational in-
Keywords: terventions, continuous glucose monitoring, and sensor
closed loop insulin delivery augmented insulin pump. The main remaining problem is risk of
artificial pancreas hypoglycaemia, which cannot be sufficiently reduced in all patient
sensor augmented insulin pump groups. Additionally, patients' burn-out often develops with years
continuous glucose monitoring of tedious day-to-day diabetes management, rendering available
hypoglycaemia
diabetes-related technology less efficient. Over the past 40 years,
glycaemic range
several attempts have been made towards computer-programmed
mean blood glucose
glucose variability insulin delivery in the form of closed loop, with faster de-
velopments especially in the past decade. Automated insulin de-
livery has reduced human error in glycaemic control and
considerably lessened the burden of routine self-management. In
this chapter, data from randomized controlled trials with closed-
loop insulin delivery that included type 1 diabetes population
are summarized, and an evidence-based vision for possible routine
utilization of closed loop is provided.
© 2015 Elsevier Ltd. All rights reserved.

* Corresponding author. University Children's Hospital, Bohoriceva 20, 1000 Ljubljana, Slovenia. Tel.: þ386 1 522 9235;
Fax: þ386 1 232 0190.
E-mail address: tadej.battelino@mf.uni-lj.si (T. Battelino).

http://dx.doi.org/10.1016/j.beem.2015.03.001
1521-690X/© 2015 Elsevier Ltd. All rights reserved.
316 T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325

Introduction

Type 1 diabetes is one of the most common chronic diseases in young people [1], and represents a
considerable burden for affected individuals and society [2]. From the middle of the 20th century, a
number of populations showed an upturn in the incidence of type 1 diabetes [3,4]. The current overall
rate of increase in Europe is about 3e4% per annum, with the most rapid increase in children aged 0e5
years, and the incidence in children in this age group is expected to double by 2020 [5].
Intensive insulin therapy is considered to be the standard treatment for type 1 diabetes [6,7];
however, maintaining near normoglycaemia, a recommendation proposed by the Diabetes Control and
Complication Trial more than 21 years ago [8], is proving difficult [9e11] The main problem is the risk of
hypoglycaemia, which is a terrifying acute complication [12] [13], along with considerable disease-
related burden [14e16].
Modern insulin pumps initiated the re-entry of advanced technology into diabetes management and
considerably improved patients' wellbeing as well as metabolic control [17]. Real-time continuous
glucose monitoring (CGM) measuring interstitial glucose levels was first tested in a randomized
controlled trial (RCT) in 2006 [18], and subsequently in several RCTs demonstrating its efficacy in
reducing HbA1c [19], time spent in hypoglycaemia [20] and severe hypoglycaemia [21]. Pairing with an
insulin pump can improve glycosylated haemoglobin [22,23] and decrease time spent in hypoglycaemia
[23]. The risk of hypoglycaemia is further mitigated by the use of low-glucose threshold insulin suspend
feature [24,25], albeit not completely eliminated even with this latest routinely available technology.
Attempts towards computer-programmed insulin delivery have been made over the past last 40 years.
The first use of machine-programmed insulin delivery goes back to the 1970s, with reports of improved
states of metabolic control [26,27]. Closed-loop insulin delivery today most commonly links subcutaneous
CGM with an external insulin pump through computerized control algorithms, which dictate insulin
delivery in response to glucose sensor data [28,29]. The first ‘modern’ feasibility clinical trial comparing
CGM and insulin pump with closed-loop insulin delivery was published in 2006, with increased time in
target glycaemic range during closed loop, and no significant difference in mean blood glucose levels [30].
Two types of closed-loop systems are being tested: single-hormone closed loop, which delivers solely
insulin, and dual-hormone closed loop, which delivers insulin and glucagon mini-boluses [31]. Several
hybrid closed-loop systems, using manual boluses for covering meals, are also being investigated [32].
In this chapter, an overview of current data from RCTs comparing closed-loop insulin delivery with
routinely available combination of an insulin pump and CGM therapy is provided.

Data source

All articles found in MEDLINE between January 2004 to September 2014 that contained the words
‘closed loop’ or ‘artificial pancreas’ and ‘type 1 diabetes’ were screened on October 1 2014 (Fig. 1).
Criteria for inclusion were RCTs comparing closed-loop insulin delivery and combined CGM with
continuous subcutaneous insulin infusion (CSII) or with sensor augmented insulin pump (SAP), in
participants with type 1 diabetes. The following variables of metabolic control had to be reported:
mean glucose levels or time within the target range (as defined by the investigators), time spent in
hypoglycaemia (as defined by the investigators) or time spent in severe hypoglycaemia (as defined by
the investigators) as primary end points, along with measures of glucose variability as secondary end
points. Finally, 22 papers were included in the main comparison.

Time in target glycaemic range

Twenty-two trials presenting data from 518 patients with type 1 diabetes reported diverse results
(Table 1).
The first RCT comparing closed loop with SAP, reported in 2010, included 19 children and adoles-
cents with type 1 diabetes. The trial comprised three RCTs, but only two compared closed loop with
SAP: the first during overnight glycaemic control and the second during overnight glycaemic control
after physical activity in the afternoon. Significantly (p ¼ 0.00225) more time was spent in target
glycaemic range during closed loop than during SAP in both studies [33].
 T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325 317

Fig. 1. PRISMA diagram of study selection process.

Six additional RCTs, including 147 children with type 1 diabetes, have been reported to date; four on
smaller groups (10e20 children), and two on larger groups (37 and 56 children, respectively). In the
one larger study (n ¼ 34) and two smaller studies (n ¼ 20 and n ¼ 10 children, respectively) [35,36],
time spent in target glycaemic range during closed loop was increased, but not significantly (p ¼ 0.207,
p ¼ 0.233 and p ¼ 0.12, respectively). In the two smaller studies and one larger study, there is a sig-
nificant (p ¼ 0.0001, p ¼ 0.02 and p < 0.05) increase of time in target range during closed loop
compared with SAP [37e39].
A trial comparing closed loop with SAP included 24 adults with type 1 diabetes and focused on
overnight glycaemic control after eating out or eating in. Overall time in target glycaemic range was
significantly (p < 0.001) increased during closed loop compared with SAP [40].
One RCT, which included 11 adolescents and 27 adults with type 1 diabetes, consisted of two RCTs
that both lasted for 22 h and compared closed loop with SAP; the difference between the two was that
the task of the second study was to keep optimal glucose control within a target range. Both studies
showed significant (p < 0.01 and p < 0.05, respectively) increase in time spent in target glycaemic range
during closed loop compared with SAP [41].
Six RTCs included 96 adults with type 1 diabetes and studied overnight glycaemic control
comparing closed loop and SAP. In five studies with 81 participants, time spent in target glycaemic
range was significantly increased (p < 0.08, p < 0.05, p < 0.003, p < 0.004, p < 0.001, respectively)
[42e46], whereas no significant difference was found (p ¼ 0.0479) in one of the trials [47].
Out of three RTCs on 48, 17 and 20 adults with type 1 diabetes comparing closed loop and SAP
during the night and day, two found no significant difference in time spent in target between the two
interventions [48,49], whereas the third showed significantly (p < 0.005) increased amount of time
spent in the target range during closed loop [50].
Two RTCs comparing dual-hormone closed loop with SAP included 15 and 52 patients with type 1
diabetes, respectively, and showed significant (p < 0.003, p < 0.001) increase in time spent in the target
glycaemic range [31,51].

Time spent in hypoglycaemia

During the first RCT trial in 2010, significantly (p < 0.0304) less time was spent in hypoglycaemia
during closed loop compared with SAP [33].
Table 1

318
Overview of Randomized Controlled Trails on Use of Closed loop in type 1 diabetes by years (CL e closed loop; SAP e sensor augmented pump: any insulin pump coupled with any sensor for
continuous glucose monitoring).

Year Study author Number Mean age Study Intervention Primary Outcome:
(reference of patients duration study end intervention
number) point vs control

T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325
2010 Hovorka [33] 21 13.5 2e5 days CL vs SAP Time in target 20% (p ¼ 0.00225);
glycaemic range; 2 (p ¼ 0.0304)
time in hypoglycaemia
2011 Hovorka [40] 24 37.5 2e7 days CL vs SAP Time in target 15% (p ¼ 0.002,
glycaemic range eating in); 28%
(p ¼ 0.01, eating
out)
2011 Murphy [54] 12 32.9 48 h CL vs SAP Time in target 81% vs 81%
glycaemic range; (p ¼ 0.75);
time in hypoglycaemia 0.0 vs 0.03
(p ¼ 0.04)
2012 Breton [41] 38 41 (adults), 22 h CL vs SAP Time in near 12.9%
14.5 (adolescent) normoglycaemia, (p ¼ 0.01),
time in tight glycaemic 2.5%
range, time in hypoglycaemia (p ¼ 0.66),
2.7 (p ¼ 0.01)
2013 Haidar [31] 15 / 30 h Dual-hormone Time in target glycaemic 13.4%
CL vs SAP range; time in hypoglycaemia (p ¼ 0.003),
10.2% (p ¼ 0.01)
2013 Elleri [38] 12 15.0 36 h CL vs SAP Time in target glycaemic 35% (p ¼ 0.02),
range, mean plasma glucose level 37 mg/dl (p ¼ 0.02)
2013 Sherr [37] 12 16.8 96 h CL vs SAP Night hypoglycaemia, time 2.5% (sedentary),
in target glycaemic range 6% (exercise)
(p ¼ 0.04), 30%
(sedentary),
14% (exercise)
(p < 0.0001)
2013 Schmidt [42] 6 45 2 nights CL vs SAP Time in target glycaemic 12.9% (p ¼ 0.08),
range, mean glucose, 18 mg/dl (p ¼ 0.38),
hypoglycaemic events 3.7% (p ¼ 0.22)
2013 Philip [39] 56 13.8 2 nights CL vs SAP Number of hypoglycaemic 15 (p ¼ 0.003),
events, time spent in 0 (p ¼ 0.02),
hypoglycaemia, mean 14 mg/dl,
overnight glucose level, 1.4 (p < 0.05)
time in target range
2013 Nimri [47] 15 19 8 nights CL vs SAP
 Time in hypoglycaemia, 44.9 min
percentage of nights with (p ¼ 0.0034),
mean glucose in target range 17% (p ¼ 0.5692)
2013 Luijf [48] 48 41.5 72 h CL vs SAP Time in target glycaemic 5.3% (p ¼ 0.377),
range, mean glucose level, 4.3% (p ¼ 0.001),
time in hypoglycaemia 18 mg/dl (p ¼ 0.001)

T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325
2013 Dauber [36] 10 5.1 2 nights CL vs SAP Time in target glycaemic 2.1 h (p ¼ 0.12),
range, time in hypoglycaemia 0.04 h (p ¼ 0.86)
2014 Capel [43] 10 46.7 2 nights CL vs SAP Time in target glycaemic 29.5% (p < 0.05),
range, time in hypoglycaemia 4.2% (p < 0.05)
2014 Hovorka [46] 16 / 6 weeks CL vs SAP Time in target glycaemic 15% (p < 0.001),
range, mean overnight glucose, 14 mg/dl (p <
time in hypoglycaemia 0.001), 7% (p < 0.01)
2014 Kovatchev [49] 20 / 80 h CL vs SAP Time in target glycaemic range, 4.6% (p > 0.1),
LGBI, hypoglycaemic events, 0.64 (p ¼ 0.003),
mean BG, time in hypoglycaemia 1.2 (p < 0.02), 9
mg/dl (p < 0.04),
0.55% (p > 0.1)
2014 Leelarathna 17 34 16 days CL vs SAP Time in target range, mean BG, 13% (p ¼ 0.005),
[50] time spent in hypoglycaemia 12.6 mg/dl
(p ¼ 0.027),
1.3% (p ¼ 0.339)
2014 Ly [35] 20 / 106 nights CL vs SAP Time in target glycaemic range 7% (p ¼ 0.233)
2014 Nimri [44] 24 28.6 2 nights CL vs SAP Time in hypoglycaemia, time in 2.13%
target glycaemic range (p ¼ 0.02),
10.95%
(p ¼ 0.003)
2014 Oron [34] 37 12.4 2 weeks CL vs SAP Nocturnal hypoglycaemia episodes, 2.8%
time in target range (p ¼ 0.443),
4.8% (p ¼ 0.207)
2014 Russell [51] 52 40 (adults), 5 days Bihormonal Mean plasma glucose level; time in 26 mg/dl
16 (adolescents) Cl vs SAP hypoglycaemia (adults, p < 0.001),
16 mg/dl
(adolescent,
p ¼ 0.004); 3.2%
(adults, p ¼ 0.01),
1.8% (adolescents,
p ¼ 0.05)
2014 Thabit [45] 25 43 11e12 weeks CL vs SAP Time in target glycaemic range 6.4% (p ¼ 0.0016)

CL, closed loop; SAP, sensor augmented insulin pump.

319
320 T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325

In the six additional trials, including 147 children with type 1 diabetes, significantly (p < 0.04,
p < 0.003, p < 0.110) less time was spent in hypoglycaemia in three trials, including 88 participants
during closed loop [35,37,39], whereas the remaining three trials showed no significant difference
(p ¼ 0.85, p ¼ 0.86, p ¼ 0.443) [34,36,38].
The trial focussing on glycaemic control during the night after eating out also showed significantly
(p < 0.04) less time spent in hypoglycaemia during closed loop compared with SAP [40].
In the six overnight RCTs including 96 adults with type 1 diabetes, significantly (p < 0.05, p < 0.02,
p ¼ 0.0034) less time was spent in hypoglycaemia in three trials [43,44,47] including 49 participants;
however, the other three trials failed to demonstrate a significant difference [42,45,46].
The day-and-night RCT of 48 adults with type 1 diabetes found significantly less (p < 0.001) time
spent in hypoglycaemia during closed loop [48]. The same conclusions were reached in the other day-
and-night trial of 20 adults with type 1 diabetes (p < 0.02) [49].
Two separate analyses conducted in 15 and 52 adults, respectively, with type 1 diabetes and
comparing dual-hormone closed loop and SAP showed significantly (p < 0.01) less time was spent in
hypoglycaemia during closed loop [31,51].

Mean blood glucose

A trial of 24 adults with type 1 diabetes reported no significant difference (p ¼ 0.91) in mean
overnight blood glucose when comparing closed loop and SAP [46].
A separate analysis on 38 participants with type 1 diabetes, 11 of which were adolescents,
confirmed no significant difference (p ¼ 0.36) in mean blood glucose when comparing closed loop and
SAP; however, a significant (p < 0.01) decrease was observed in blood glucose during closed loop that
focused on target range blood glucose compared with SAP [41].
Two RTCs of 24 children with type 1 diabetes showed significantly (both p ¼ 0.02) reduced mean
blood glucose during closed loop [37,38], whereas no significant difference was found (p ¼ 0.378,
p ¼ 0.18) in three other RCTs including 103 children [34,36,39].
No significant difference (140.4 ± 41.4 versus 122.4 ± 34.2 mg/dl; p ¼ 0.38, p ¼ 0.8148) was found in
the overnight mean blood glucose between SAP and closed loop in three trials of 31 adults with type 1
diabetes [42,43,47]. On the other hand, two trials of 49 adults with type 1 diabetes showed significantly
(p ¼ 0.008, p ¼ 0.0052) reduced mean blood glucose during closed loop [44,45].
In two day-and-night trials of 48 and 20 adults with type 1 diabetes, mean blood glucose was re-
ported to be significantly (p ¼ 0.001) lower during SAP compared with closed loop [48,49]. On the
contrary, mean blood glucose is significantly lower (p ¼ 0.027) during closed loop in another day and
night trial on 17 adults [50].
One RTC of 15 patients comparing dual hormone closed loop and SAP showed no significant change
(p ¼ 0.74) in mean blood glucose between the two [31]. Conversely, the second RCT comparing dual-
hormone closed loop and SAP in 52 patients with type 1 diabetes showed significantly (p < 0.001)
lower mean blod glucose during dual-hormone closed loop [51].

Glucose variability

The first RCT comparing closed loop with SAP, conducted in 19 children and adolescents with type 1
diabetes, reported lower (p < 0.13) glucose variability after midnight during closed loop [33].
A separate analysis of 38 patients with type 1 diabetes (11 adolescents) showed significantly
(p ¼ 0.01) reduced glucose variability during closed loop compared with SAP [41].
The RCT of 56 children also showed significantly lower glucose variability (p < 0.05) when
comparing closed loop with SAP [39].
Reduction of the blood glucose risk index achieved statistical significance (p < 0.05; p ¼ 0.0043) in
overnight closed loop compared with SAP in three trials of adults [43,47,45]. Two overnight RCTs
comparing closed loop with SAP in adults showed no significant difference (p ¼ 0.21; p ¼ 0.044) in
glucose variability [42,44].
No significant difference was observed in glucose variability during day-and-night trial of adults
with type 1 diabetes [48].
 T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325 321

Closed-loop and pregnancy

For women with type 1 diabetes self-management is particularly challenging during the physiologic
and hormonal changes of pregnancy. These contribute to extremely labile glucose levels in early
pregnancy and progressive insulin resistance with advancing gestation [52]. Despite the increased use
of insulin pumps and fast-acting insulin analogues, self-management during pregnancy complicated
with type 1 diabetes is still not optimal [53]. Two trials analysing data on 22 pregnant women with type
1 diabetes reported that overnight closed-loop insulin delivery could be used safely during pregnancy.
One trial conducted among 12 pregnant women with type 1 diabetes and relatively high exposure
to hypoglycaemia (3 h per day at 70 mg/dl and 1 h per day at 50 mg/dl) reported less time spent in
hypoglycaemia (p < 0.04) and equal amount of time spent in target glycaemic range when comparing
closed loop with CIIS [54] conducted among 10 pregnant women with type 1 diabetes, which tested
only closed loop, with no comparison. Closed loop in early versus late pregnancy showed a high
percentage of time spent in target glycaemic range (81% versus 100%; p ¼ 0.09) and less time in
hypoglycaemia (7% versus 0%; p ¼ 0.25) [55].

Discussion

Type 1 diabetes is a chronic disease that requires constant and life-long vigilance from patients,
which is exhausting and difficult to sustain. Technological development in the form of insulin pumps,
CGM and SAP enables patients to make better-informed decisions; however, the burden of diabetes
self-management is rather increased than decreased, despite the often better metabolic outcomes and
improved therapy-related satisfaction [56e59]. Several technical and psychological barriers still pre-
clude the wider routine and sustained use of CGM, especially among children [10,60,61] Closed-loop
insulin delivery could alleviate considerably this lingering disease-related burden as most or the
entire decision making is transferred from the patient to the computer algorithm.
At present, data suggest that the use of closed loop in type 1 diabetes, whether single- or dual-
hormone, is safe [62] and efficient, as it may significantly decrease the risk of hypoglycaemia and
significantly increase the time spent in target glycaemic range among adults with type 1 diabetes
[31,38,41,46] as well among children with type 1 diabetes [34,36e39], and possibly also during
pregnancy complicated with type 1 diabetes [54].
Currently, dual-hormone closed loop data from RCTs seems comparable to insulin-only closed loop
systems [63]. Despite the clear theoretical advantage of having the possibility of preventing imminent
hypoglycaemia with a glucagon bolus, dual-hormone closed loop does not completely eliminate the
need of rescue carbohydrates administered by the patients upon a closed loop triggered alarm [51,64].
Additionally, the stability [65] and consequences of long-term subcutaneous glucagon administration
are not resolved. It seems, therefore, more likely that an insulin-only closed loop system with possible
co-treatment with adjunct injectable, oral medications, or both, will be the first to get the market
approval from the regulatory bodies.
Insulin-only closed loop can be hybrid (with meals boluses administered manually or announced by
the patient) [66e68], nocturnal [45,47], or day-and-night [50]; however, only modest postprandial
advantage is seen with hybrid closed loop systems, along with the obvious disadvantage of the ne-
cessity of continuous patient's involvement.
Intra-peritoneal insulin administration has several advantages over the subcutaneous delivery and
closed loop systems using intraperitoneal insulin delivery are efficient particularly because of the
shorter delay in insulin action and higher portal vein concentrations after delivery by the system
[69,70]. Important technical shortcomings, however, need proper solutions before intra-peritoneal
closed loop systems can reach a wider patient population.
There is ample room for technical improvements in all components of the closed loop systems.
Insulin pumps can become smaller, more energy efficient and with more safety features for early
detection of failure of insulin delivery. Accuracy of CGM can be improved, along with improvement in
accuracy-supervising-algorithms, minimizing the subcutaneous part of the sensor for increased
comfort, or possibly developing a long-term implantable sensor [71]. Closed-loop algorithms must also
include additional safety components with real-time learning and prediction modules for prevention
322 T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325

of improper insulin dosing. On the basis of currently published clinical data, however, available closed-
loop systems seem to be safe and consistently more efficient compared with the best routinely
available technology. It is, therefore, reasonable to expect closed loop market approval from the reg-
ulatory bodies in the foreseeable future.
Finally, significant cost and restrictive reimbursement represent an important barrier for a more
routine use of diabetes-related technology. Insulin pumps are cost effective and reimbursed in most
developed countries; however, CGM reimbursement remains partial at best [72]. The cost of closed
loop system is currently impossible to predict, but will likely be substantial. If the current data on
efficacy and safety is reflected also in routine clinical use, the long-term cost-benefit, including costs
from acute (e.g. hypoglycaemia) and chronic complications, will almost certainly tilt to the benefit for
patients and the society.

Summary

Diabetes-related technology thoroughly changed treatment modalities in type 1 diabetes, with

insulin pumps used in more than one-half of the patient population in developed health-care systems
and with an increasing use of CGM [10,13,73,74]. Closed-loop insulin delivery represents a natural
development of existing technology, with current data from RTCs demonstrating a significant and
clinically relevant additional benefit in metabolic control and probably above all in the quality of life.

Practice points

 Intensive insulin therapy is the standard of care for people with type 1 diabetes.
 Insulin pumps and continuous glucose monitoring is used increasingly in addition to the self-
monitoring of blood glucose.
 A large population of people with type 1 diabetes do not reach glycaemic targets recom-
mended by professional associations despite considerable effort.
 Hypoglycaemia is still a major obstacle to achieving good metabolic control.
 Life-long day-to-day management of type 1 diabetes is burdensome, may reduce quality of
life and can result in burn-out.
 Closed loop insulin delivery with an artificial pancreas reduces hypoglycaemia and patients'
burden in clinical trials.

Research agenda

 Pivotal randomized controlled trials need to be completed in collaboration with regulatory

bodies.
 Timely regulatory approval is paramount for routine clinical use and further development.
 Additional clinical trials for specific situation (e.g. extreme sport) are being conducted.

Conflict of interest statement

T. Battelino is a board member of Novo Nordisk, Sanofi, Eli Lilly, Boehringer, Medtronic, and Bayer
Health Care; Consultant of Spring. T. Battelino's Institution received research grant support, with
 T. Battelino et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 315e325 323

receipt of travel and accommodation expenses in some cases, from Abbott, Medtronic, Novo Nordisk,
GluSense, Sanofi, Sandoz, and Diamyd. T. Battelino received honoraria for participating on the speaker's
bureaux of Eli Lilly, Bayer, Novo Nordisk, Medtronic, Sanofi, and Roch. J. Suput Omladic has no conflicts
of interest. M. Phillip is a member of the Advisory Board of AstraZeneca, Sanofi, Animas, Medtronic,
Bayer Health Care and Board Member of C.G.M.3 Ltd., Consultant of Bristol-Myers Squibb, D-medical,
Ferring Pharmaceuticals, Andromeda Biotech. The Institute headed by M. Phillip received research
support from Medtronic, Novo Nordisk, Abbott Diabetes Care, Eli Lilly, Roche, Dexcom, Sanofi, Insulet
Corporation, Animas, Andromeda, Macrogenics. M. Phillip has been paid lecture fees by Sanofi, Novo
Nordisk, Roche, Pfizer. He is a Stock/Shareholder of C.G.M.3 Ltd. M. Phillip reports two patent
applications.

Acknowledgements

T. Battelino was supported in part by the Slovene National Research Agency grants #J3-6798, J3-
4116, and P3-0343. No other funding source was used.

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