Received: 19 June 2019 Revised: 31 October 2019 Accepted: 4 November 2019

DOI: 10.1111/dom.13911

ORIGINAL ARTICLE

Liraglutide reduces hyperglycaemia and body weight in

overweight, dysregulated insulin-pump-treated patients with
type 1 diabetes: The Lira Pump trial—a randomized, double-
blinded, placebo-controlled trial

Thomas F. Dejgaard MD1,2* | Signe Schmidt MD1,2,3 | Christian S. Frandsen MD2 |

Dorte Vistisen MSc1 | Sten Madsbad MD2 | Henrik U. Andersen MD1 |
Kirsten Nørgaard MD1,2

1
Steno Diabetes Center Copenhagen,
University of Copenhagen, Denmark
2
Department of Endocrinology, Copenhagen
University Hospital Hvidovre, Hvidovre,
Denmark
3
Danish Diabetes Academy, Odense, Denmark
Correspondence
Thomas F. Dejgaard, Steno Diabetes Center
Copenhagen, Niels Steensens Vej 2-4, DK-
2820 Gentofte, Denmark,
Email: thomas.fremming.dejgaard@regionh.dk
Funding information
Novo Nordisk, Grant/Award Number:
Unrestricted grant; Copenhagen University
Hospital; European Association for the Study
of Diabetes; American Diabetes Association
Peer Review
The peer review history for this article is
available at https://publons.com/publon/10.
1111/dom.13911.
Abstract
Aim: To investigate the efficacy of adding the glucagon-like peptide-1 receptor ago-
nist liraglutide to continuous subcutaneous insulin infusion (CSII) in overweight or
obese persons with type 1 diabetes and non-optimal glycaemic control.
Materials and methods: A 26-week, randomized, double-blind, placebo-controlled
trial including 44 overweight or obese adults with type 1 diabetes randomized 1:1 to
liraglutide 1.8 mg once daily (QD) or placebo added to CSII treatment. The primary
endpoint was change in haemoglobin A1c (HbA1c). Secondary endpoints included
change in insulin dose, CSII settings, glycaemic variability, body weight and patient-
reported outcome measures. Finally, adverse effects including hypoglycaemic events
were registered.
Results: HbA1c was reduced by 5 mmol/mol (0.5%) from a baseline of 66 mmol/mol
(8.2%) in patients treated with liraglutide compared with a non-significant change of
+2.3 mmol/mol (0.2%) from a baseline of 66 mmol/mol (8.1%) in patients treated
with placebo (between-group difference 7 mmol/mol [0.7%], P < 0.001). Liraglutide
reduced total insulin dose by 8 units/day or 16% of total insulin dose (P = 0.008).
Mean body weight was reduced by 6.3 kg (P < 0.001) compared with placebo. Con-
comitantly, time spent in glycaemic target range 4–10 mmol/L (71–180 mg/dL)
increased while the risk of hypoglycaemia did not differ between groups at the end
of treatment.
Conclusion: Liraglutide treatment reduced HbA1c, total daily insulin dose and body
weight without increasing the risk of hypoglycaemia in CSII-treated patients with
type 1 diabetes and insufficient glycaemic control. Liraglutide may be considered a
potential add-on therapy to insulin in this subgroup of patients.

1 | INTRODUCTION
*Parts of this study were presented in abstract form at the American Diabetes Association
(ADA) 77th Scientific Sessions, San Diego, 9-13 June 2017 and at the 53rd Annual Meeting
Intensified insulin treatment is associated with hypoglycaemia and
of the European Association for the Study of Diabetes (EASD), Lisbon, 11-15
September 2017. substantial weight gain. Currently, more than 50% of persons with

Diabetes Obes Metab. 2019;1–9. wileyonlinelibrary.com/journal/dom © 2019 John Wiley & Sons Ltd 1
2 DEJGAARD ET AL.
type 1 diabetes in the industrialized part of the world are overweight,
and interventions to prevent weight gain are strongly warranted.1,2
Compared with multiple daily injections (MDI) subcutaneous insu-
lin infusion (CSII) therapy improves glycaemic control and reduces the
incidence of severe hypoglycaemia, most pronounced in persons with
frequent hypoglycaemia and insufficient glycaemic control.3 The use
of CSII is recommended by international guidelines as a therapeutic
option for patients with type 1 diabetes who do not achieve target
glycaemic control on treatment with MDI.4 The T1D Exchange Clinic
Registry reports that >55% of US adults with type 1 diabetes are cur-
rently treated with CSII and the number is increasing.5,6 However,
more than two-thirds of adults with type 1 diabetes do not achieve
the recommended glycaemic target [haemoglobin A1c (HbA1c)
<53 mmol/mol (7.0%)] despite improved insulin-delivery systems and
insulin analogues with optimized pharmacokinetic characteristics com-
bined with improved methods for self-glucose monitoring.4,5
Insulin treatment has several shortcomings and does not address
important abnormalities in type 1 diabetes. First, the gastric emptying rate
may be altered depending on the preprandial blood glucose level resulting
in rapid and large postprandial glucose excursions.7 Second, the absence
of adequate portal insulin levels results in enhanced fasting and postpran-
dial glucagon levels contributing to hyperglycaemia.8 Third, intensified
treatment with MDI or CSII is associated with weight gain. Glucagon-like
peptide-1 receptor agonists (GLP-1RAs) could potentially address these
shortcomings because of their pleiotropic effects of inducing satiety,
inhibiting glucagon secretion and delaying gastric emptying rate.
In patients with MDI-treated type 1 diabetes the efficacy has only
been modest with A1c reductions of about 2–3 mmol/mol (0.2%–0.3%)
compared with placebo, but clinically significant weight loss of 4–6 kg
and reduced insulin requirements of 5% have been reported.9-13
We investigated whether adding liraglutide 1.8 mg once daily
(QD) to CSII treatment could improve glycaemic control and reduce
weight in overweight patients with type 1 diabetes.
2 | MATERIALS AND METHODS
2.1 | Trial design
The trial was a 26-week randomized, double-blinded, placebo-
controlled trial performed at the Steno Diabetes Center Copenhagen,
Gentofte, Denmark and Copenhagen University Hospital Hvidovre,
Hvidovre, Denmark. After written informed consent was obtained and
the screening visit (week −1) performed, eligible patients were ran-
domized (week 0) 1:1 to receive liraglutide 1.8 mg (Novo Nordisk A/S,
Maalev, Denmark) or a corresponding volume of placebo (saline injec-
tion) QD by a placebo pen that was indistinguishable from the
liraglutide pen. The treatment was initiated with an injection of 0.6 mg
liraglutide/0.1 mL placebo QD, increased to 1.2 mg liraglutide/0.2 mL
placebo QD after 1 week and increased to 1.8 mg/0.3 mL placebo
after another week. Intervals between the increments could be
extended at the discretion of the investigator. To reduce the risk of
hypoglycaemia the basal insulin rate was reduced by 10% and the
insulin sensitivity factors and insulin-to-carbohydrate ratios were
increased 15% at initiation of the investigational medicinal product
(IMP). The basal rates, insulin sensitivity factors and insulin-to-
carbohydrate ratios were subsequently increased or decreased if nec-
essary during the trial in accordance with international guidelines.4 The
randomization list was provided by the manufacturer Novo Nordisk
A/S and the study personnel who did the randomization had no further
involvement in the trial.
To evaluate endogenous insulin production, a meal test was per-
formed at randomization. C-peptide (Cobas 6000; Roche Diagnostics
GmbH, Mannheim, Germany) and plasma glucose (Cobas 6000; Roche
Diagnostics GmbH) were measured at time −10, 0, 30, 60, 90 and
120 min following ingestion of a standardized liquid mixed meal
(Boost Original; Nestle HealthCare Nutrition, NJ, USA).
After randomization, one telephone contact (week 1) and three
clinic visits were scheduled (weeks 3, 13 and 26).
During weeks 0, 3, 13 and 26, participants wore a blinded contin-
uous glucose monitor (CGM) (Ipro2; Medtronic, Minneapolis, MN,
USA) for six consecutive days.
The trial was approved by the Scientific-Ethical Committee of the
Capital Region of Denmark (H-3-2014-094), the Danish Medicines Author-
ity (EudraCT: 2014–002285-76), and the Data Protection Agency. Further-
more, the trial was registered with ClinicalTrials.gov (NCT02351232) and
conducted under the surveillance and guidance of the Good Clinical Prac-
tice unit, University of Copenhagen, Copenhagen, Denmark.
2.2 | Trial participants
Patients eligible for inclusion were adults with an age between 18 and
70 years and clinically diagnosed with type 1 diabetes ≥12 months
before the screening visit. Patients had to be treated with CSII, in
non-optimal glycaemic control with an HbA1c >58 mmol/mol (7.5%)
and use carbohydrate counting and the insulin pump bolus calculator
for all meals. No upper limit of HbA1c was specified. Finally, partici-
pants had to be overweight or obese with a body mass index (BMI)
>25 kg/m2.
Key exclusion criteria included the use of medicine affecting glu-
cose metabolism (other than insulin) during the study period or within
30 days before the screening; impaired renal or liver function (esti-
mated glomerular filtration rate <60 mL/min/1.73 m2 or alanine ami-
notransferase >2.5 the upper limit of the reference interval,
respectively), history of acute or chronic pancreatitis and people with
personal or family history of medullary carcinoma of the thyroid or
multiple endocrine neoplasia syndrome type 2. People with a history
of severe hypoglycaemia, hypoglycaemia unawareness or people with
a history of ketoacidosis were not excluded.
2.3 | Outcome measures
The primary objective was to study the efficacy of liraglutide 1.8 mg
QD added to CSII treatment on glycaemic control measured by the
DEJGAARD ET AL. 3

change in HbA1c from baseline to end of treatment at week 26. Sec- TABLE 1 Baseline characteristics
ondary objectives included the efficacy of liraglutide from baseline to Liraglutide
Placebo
week 26 on total insulin dose, including basal and bolus insulin, insulin 1.8 mg
pump settings, glycaemic variability and percentage of time spent in
(N = 22) (N = 22)
hypoglycaemia [blood glucose <4 mmol/L (71 mg/dL)], target range
Age (years) 50 ± 14 43 ± 12
[blood glucose 4–10 mmol/L (71–180 mg/dL)] and hyperglycaemia
Female sex 68% 68%
[>10 mmol/L (180 mg/dL)] evaluated by six consecutive days of
Duration of type 1 diabetes (years) 21 (15; 34) 20 (15; 35)
blinded CGM, lipids and body weight. Change in treatment satisfac-
tion [Diabetes Treatment Satisfaction Questionnaire (DTSQ)] and CSII treatment (years) 5 (3; 7) 6 (5; 9)

symptoms of depression [Hospital Anxiety and Depression Scale HbA1c (%) 8.2 ± 0.5 8.1 ± 0.5

(HADS)] were evaluated. HbA1c (mmol/mol) 66 ± 6 66 ± 6

Key safety assessments included adverse events (AEs), frequency Stimulated C-peptide (pmol/L) 9 (7; 18) 9 (6; 12)
of mild and severe hypoglycaemia as defined by the American Diabe- Stimulated C-peptide <30 pmol/L, n (%) 19 (86) 21 (95)
tes Association,4 heart rate, systolic and diastolic blood pressure and CSII total daily insulin dose (units) 48 ± 15 54 ± 19
laboratory safety variables, including amylase and lipase. To evaluate Total basal dose (units) 25 ± 9 28 ± 7
the effect of liraglutide on kidney function by serum creatinine and Total bolus dose (units) 23 ± 9 26 ± 14
urine albumin-to-creatinine ratio (UACR), first morning voids of three
Body weight (kg) 85 ± 10 88 ± 14
consecutive days before randomization, visit 3 (week 13) and end-of- 2
BMI (kg/m ) 30 ± 2 29 ± 3
treatment (week 26) were collected.
BMI 27–30 kg/m2, n (%) 9 (41) 10 (45)
BMI >30 kg/m2, n (%) 10 (45) 8 (36)
DTSQs 32 (31; 34) 31 (28; 34)
2.4 | Statistical analyses
Blood pressure (mmHg)

The sample size was determined to detect a minimum difference in Systolic 129 ± 18 127 ± 15

HbA1c of 0.3% (3 mmol/mol) between liraglutide 1.8 mg and placebo Diastolic 80 ± 9 82 ± 9

after 26 weeks of treatment with a power of 80%, a 5% significance
level and a standard deviation of 0.3% (3 mmol/mol) based on data
obtained from an observational study with GLP-1RA added to CSII
treatment in persons with type 1 diabetes.14 To allow for a 22% drop-
out rate, 44 participants were included in the study, 22 in each arm.
Baseline characteristics are presented as means ± standard devia-
tions or as medians with interquartile range for characteristics with a
skewed distribution (Table 1).
During follow-up, the primary outcome HbA1c was measured at
two visits (13 and 26 weeks) after randomization. Secondary out-
comes were additionally measured at week 3 and insulin doses were
further assessed at weeks 1, 2, 6.5 and 19.5 after randomization. For
the analysis of change in total insulin per body weight, weight at
weeks 1, 2, 6.5 and 19.5 was interpolated from weight at randomiza-
tion and weeks 3, 13 and 26, respectively.
In the repeated measurement analysis, changes in primary out-
come HbA1c and secondary outcomes over the intervention period
were modelled by linear mixed-effects models with an individual-
specific random intercept to account for the correlation of repeated
measurements within participants. Treatment groups and follow-up
visits (weeks 0, 1, 2, 3, 6.5, 13, 19.5 and 26) were used as fixed effects
in the analyses. We tested for a difference in change between the
treatment groups at the follow-up visits.
All analyses were performed as an intention-to-treat analysis
(i.e. including all available measurements for the participants). Out-
comes with a skewed distribution were log-transformed before ana-
lyses to fulfil the assumption of normally distributed model residuals.
Statistical significance was inferred at a two-tailed P < 0.05. All P-
Heart rate (b.p.m.) 70 ± 13 72 ± 12
UACR (mg/g) 3 (2; 5) 3 (2; 7)
Abbreviations: BMI, body mass index; CSII, continuous subcutaneous
insulin infusion; DTSQ, Diabetes Treatment Satisfaction Questionnaire;
HbA1c, haemoglobin A1c; UACR, urine albumin-to-creatinine ratio.
values for secondary endpoints were adjusted for multiple compari-
sons using Benjamin and Hochberg. After adjustment, the found asso-
ciations remained statistically significant.
Statistical analyses were conducted in R version 3.3.3 (The R
Foundation for Statistical Computing, http://www.R-project.org) and
SAS version 9.4 (SAS Institute, Cary, NC, USA).
3 | RE SU LT S
From February 17, 2015 to April 4, 2016, 171 patients with CSII-
treated type 1 diabetes were assessed, of whom 54 were screened
and 44 persons were randomized for the study and exposed to the
trial product (Figure S1; see Supporting Information). We identified no
differences in baseline characteristics in relation to gender, age, diabe-
tes duration, HbA1c and BMI between individuals who did or did not
agree to participate (data not shown). During the 26 weeks of inter-
vention, all persons assigned to the placebo completed the study;
however, two people assigned to receive liraglutide discontinued the
trial due to AEs not related to the trial product (i.e. breast cancer and
multiple sclerosis; 3 and 20 weeks after randomization, respectively).
4 DEJGAARD ET AL.
Baseline characteristics were similar between groups (Table 1).
3.1 | Efficacy
After 26 weeks of treatment the HbA1c level decreased from
66 mmol/mol (8.2%) to 61 mmol/mol (7.7%) (P < 0.001) for persons
treated with liraglutide while no significant change was found with
placebo 66 mmol/mol (8.1%) to 68 mmol/mol (8.3%) (P = 0.058). Thus,
the difference between groups at end of treatment was 7 mmol/mol
(0.7%) (P < 0.001). The significant difference between groups was
already present after 13 weeks of treatment (Table 2 and Figure 1). At
end-of-treatment, 20% versus 5% achieved an HbA1c <53 mmol/mol
(7%) in the liraglutide versus placebo group, respectively.
At baseline, the absolute time spent in hypoglycaemia, target range
and hyperglycaemia evaluated by blinded CGM did not differ between
groups. However, after 26 weeks of treatment persons treated with
liraglutide had more time in target range compared with placebo, 57%
versus 45% (P = 0.044). This difference was a consequence of less time
spent in hyperglycaemia for persons treated with liraglutide (Figure S2;
see Supporting Information). Furthermore, glycaemic variability esti-
mated by the standard deviation of mean glucose significantly
decreased in persons treated with liraglutide compared with placebo
after 13 weeks of treatment; however, at 26 weeks no significant dif-
ference was found between groups. The coefficient of variation of glu-
cose did not change at any time point in the groups (Table 2).
The total daily insulin dose decreased in persons treated with
liraglutide compared with placebo (P = 0.008). This difference was
mainly due to a difference between groups of 7 IU/day of bolus insu-
lin after 13 weeks and 8 IU/day at end of treatment. When adjusted
for body weight no significant change was found in either the total
bolus or the total basal insulin doses in the groups during the study
(Table 2). Concomitantly, the total daily carbohydrate intake after
13 weeks decreased by 32 g/day in patients treated with liraglutide
compared with placebo (P = 0.031). However, at end of study this dif-
ference decreased to 20 g/day and no difference was found between
groups (P = 0.188; Table S1, see Supporting Information).
The insulin sensitivity factors and the insulin-to-carbohydrate
ratios between 06:00 and 11:00 h, between 11:00 and 16:00 h and
between 16:00 and 24:00 h (weighted means) did not change within
or between groups after 26 weeks of treatment.
No differences within or between groups were found in total cho-
lesterol, triglycerides, low-density lipoprotein and high-density lipo-
protein at any time point.
Compared with placebo, liraglutide led to a significant reduction
in body weight from baseline to week 26 (Figure 1C). Already after
13 weeks of treatment a reduction of 5.2 kg was found in persons
treated with liraglutide (P < 0.001), increasing to −6.8 kg after
26 weeks (P < 0.001) compared with 0.4 kg (P = 0.491) for placebo,
with a difference between groups of −6.3 kg (P < 0.001) (Table 2).
Liraglutide treatment positively affected patient-reported out-
come measures. The mean change in treatment satisfaction scores
assessed with the DTSQ version c increased in both groups; however,
significantly more in persons treated with liraglutide compared with
placebo (P = 0.005; Table 2). No differences between groups were
found in relation to the perceived frequency of hypoglycaemia or
hyperglycaemia during the intervention. No significant treatment dif-
ferences between liraglutide and placebo were found in the DTSQs
and the HADS questionnaires.
In a post hoc analysis we adjusted the change in HbA1c for the
change in bodyweight, BMI and the total insulin dose, but no signifi-
cant changes compared with the unadjusted data were found.
3.2 | Safety
The number of events of documented self-monitored blood glucose
<3.9 mmol/L (70 mg/dL) or <3.0 mmol/L (54 mg/dL) were 1736 and
739 in total over the 26-week follow-up period with no difference in
the rate of events between the treatment groups (<3.9: liraglutide
83 events per person-year and placebo 74 events per person-year,
P = 0.695; <3.0: liraglutide 30 and placebo 37, P = 0.494).
Similarly, when evaluating the percentage of time spent in
hypoglycaemia level 1 [glucose value <4.0 mmol/L (71 mg/dL)]
and hypoglycaemia level 2 [glucose value <3.0 mmol/L (54 mg/dL)],
hypoglycaemia during three periods of six consecutive days of blinded
CGM, no difference was found between liraglutide and placebo
(6% vs. 6% of time spent in level 1 and 1% vs. 2% of time in level
2, respectively).
Ambulatory systolic blood pressure decreased 7 mmHg shortly
after initiating liraglutide treatment, while no significant change was
found in persons treated with placebo, resulting in a difference
between groups of 10 mmHg. However, after 26 weeks of treatment
this effect was diminished, and no difference was found between
groups (P = 0.340). Concomitantly with the initial drop in systolic
blood pressure, ambulatory heart rate increased significantly, with
11 beats per min (b.p.m.) compared with 5 b.p.m. in persons treated
with placebo. At the end of treatment, a difference between groups
of 8 b.p.m. was found (P = 0.008). Ambulatory diastolic blood pressure
measurements did not change at any time point in the two groups.
In relation to the effect of liraglutide treatment on kidney func-
tion, no significant effect on serum-creatinine or UACR was found
during the 26 weeks of treatment.
Mean lipase levels were approximately 20 U/L at randomization
and increased with liraglutide treatment to a difference between
groups of 32 U/L, P = 0.023. Similarly, the mean amylase levels were
initially 14 U/L with an increase in the group treated with liraglutide,
resulting in a difference between groups of 22 units/L (P = 0.019). No
cases of pancreatitis were reported.
The overall rate of AEs was more common in persons treated
with liraglutide compared with placebo (90% vs. 59%). Most of the
AEs were mild in severity and, in general, liraglutide treatment was
well tolerated. Gastrointestinal AEs were reported more frequently in
persons treated with liraglutide compared with placebo (nausea 64%
vs. 32%, diarrhoea 18% vs. 9% and vomiting 18% vs. 5%). Although
gastrointestinal AEs were transient, five patients who received
TABLE 2 Estimated changes from baseline in primary and secondary outcomes by treatment group

13 weeks 26 weeks
Liraglutide Placebo Liraglutide Liraglutide Placebo Liraglutide vs. placebo
DEJGAARD ET AL.

Change
HbA1c (mmol/mol)
HbA1c (% point)
Weight (kg)
Total daily insulin dose
(IU/day)
Basal insulin (IU/day)
Daily basal insulin
06:00–24:00 h (IU/day)
Nightly basal insulin
00:00–06:00 h (IU/day)
Bolus insulin (IU/day)
CGM high (% point) −10.2 (−17.2; −3.3)
CGM target (% point)
CGM low (% point)
CGM mean glucose
CGM SD
CGM CV (% point)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Heart rate (beats/min)
DTSQs sumscore
DTSQs hyperglycaemia
question 2
DTSQs hypoglycaemia
question 3
DTSQc sumscore
DTSQc hyperglycaemia
(question 2)
DTSQc hypoglycaemia
(question 3)
vs. placebo
P Change P Change Pdiff Change P Change P Change P–diff
−5.2 (−7.7; −2.7) <0.001 1.7 (−0.8; 4.1) 0.182 −6.9 (−10.4; −3.4) <0.001 −5.0 (−7.5; −2.4) <0.001 2.3 (−0.1; 4.7) 0.058 −7.3 (−10.8; −3.8) <0.001
−0.5 (−0.7; −0.2) <0.001 0.2 (−0.1; 0.4) 0.182 −0.6 (−0.9; −0.3) <0.001 −0.5 (−0.7; −0.2) <0.001 0.2 (0.0; 0.4) 0.058 −0.7 (−1.0; −0.3) <0.001
−5.2 (−6.5; −3.9) <0.001 0.8 (−0.5; 2.0) 0.244 −5.9 (−7.8; −4.1) <0.001 −6.8 (−8.1; −5.4) <0.001 −0.4 (−1.7; 0.8) 0.491 −6.3 (−8.2; −4.5) <0.001
−4.4 (−8.5; −0.3) 0.037 2.2 (−1.7; 6.1) 0.273 −6.6 (−12.2; −0.9) 0.024 −4.9 (−9.1; −0.7) 0.021 2.8 (−1.1; 6.7) 0.164 −7.7 (−13.5; −2) 0.008
−1.2 (−2.7; 0.2) 0.098 −0.4 (−1.8; 1.0) 0.551 −0.8 (−2.9; 1.2) 0.434 −1.8 (−3.3; −0.3) 0.017 −0.5 (−1.9; 0.9) 0.473 −1.3 (−3.4; 0.8) 0.214
−0.7 (−2; 0.7) 0.331 0.5 (−0.8; 1.8) 0.454 −1.1 (−3.0; 0.7) 0.223 −0.9 (−2.3; 0.4) 0.164 0.7 (−0.5; 1.9) 0.259 −1.7 (−3.5; 0.2) 0.074
−0.1 (−0.5; 0.3) 0.587 −0.1 (−0.5; 0.3) 0.546 0.0 (−0.5; 0.5) 0.976 −0.1 (−0.5; 0.3) 0.579 −0.1 (−0.5; 0.2) 0.411 0.0 (−0.5; 0.6) 0.882
−3.4 (−7.1; 0.3) 0.074 2.6 (−0.9; 6.2) 0.15 −6.0 (−11.1; −0.9) 0.022 −3.1 (−6.8; 0.7) 0.113 3.3 (−0.3; 6.9) 0.069 −6.4 (−11.6; −1.2) 0.016
0.004 1.7 (−5.2; 8.6) 0.627 −12.0 (−21.8; −2.2) 0.017 −7.2 (−14.6; 0.1) 0.053 2.7 (−4.1; 9.5) 0.441 −9.9 (−19.9; 0.1) 0.052
10.1 (3.8; 16.5) 0.002 −3.5 (−9.8; 2.8) 0.277 13.6 (4.7; 22.6) 0.003 4.6 (−2.1; 11.3) 0.178 −4.8 (−11.0; 1.5) 0.133 9.4 (0.2; 18.5) 0.044
0.1 (−2.2; 2.4) 0.935 1.8 (−0.5; 4.1) 0.131 −1.7 (−5.0; 1.6) 0.313 2.5 (0.1; 5.0) 0.044 2.1 (−0.2; 4.4) 0.077 0.5 (−2.9; 3.8) 0.787
−0.8 (−1.5; −0.2) 0.013 0.2 (−0.4; 0.9) 0.518 −1.1 (−2.0; −0.1) 0.027 −0.7 (−1.4; 0.0) 0.064 0.3 (−0.4; 0.9) 0.394 −0.9 (−1.9; 0.0) 0.053
−0.5 (−0.9; −0.2) 0.003 0.3 (−0.1; 0.6) 0.124 −0.8 (−1.3; −0.3) 0.001 −0.2 (−0.6; 0.2) 0.285 0.2 (−0.2; 0.5) 0.337 −0.4 (−0.9; 0.1) 0.151
−2.8 (−6.5; 0.8) 0.131 1.7 (−2.0; 5.4) 0.365 −4.6 (−9.8; 0.7) 0.087 0.0 (−3.9; 3.9) 0.983 0.8 (−2.8; 4.4) 0.664 −0.8 (−6.2; 4.5) 0.756
−7.2 (−13.3; −1.2) 0.019 2.4 (−3.5; 8.3) 0.422 −9.7 (−18.1; −1.2) 0.025 −6.6 (−12.7; −0.4) 0.036 −2.5 (−8.3; 3.3) 0.403 −4.1 (−12.6; 4.3) 0.34
−1.4 (−3.8; 1.1) 0.286 1.2 (−1.2; 3.6) 0.319 −2.6 (−6.0; 0.9) 0.144 −0.7 (−3.2; 1.8) 0.585 0.2 (−2.2; 2.6) 0.866 −0.9 (−4.4; 2.6) 0.608
10.9 (6.7; 15.1) <0.001 4.6 (0.4; 8.7) 0.031 6.3 (0.4; 12.3) 0.036 9.0 (4.7; 13.3) <0.001 1.1 (−3.0; 5.1) 0.607 8.0 (2.0; 13.9) 0.008
0.0 (−1.8; 1.8) 0.988 −1.1 (−2.9; 0.6) 0.195 1.1 (−1.4; 3.6) 0.375 0.0 (−1.8; 1.9) 0.968 −1.4 (−3.2; 0.3) 0.105 1.5 (−1.1; 4.0) 0.253
−1.0 (−1.6; −0.4) <0.001 0.2 (−0.4; 0.8) 0.445 −1.3 (−2.1; −0.4) 0.004 −0.8 (−1.4; −0.2) 0.01 0.0 (−0.6; 0.6) 0.999 −0.8 (−1.7; 0.0) 0.062
−0.2 (−0.8; 0.5) 0.58 −0.5 (−1.2; 0.1) 0.095 0.3 (−0.5; 1.2) 0.447 0.4 (−0.2; 1.1) 0.198 0.0 (−0.6; 0.6) 0.979 0.4 (−0.5; 1.3) 0.36
13.4 (9.1; 19.7) <0.001 6.0 (4.0; 9.0) <0.001 2.2 (1.3; 3.9) 0.005
1.6 (1.2; 2.1) 0.002 1.3 (1.0; 1.6) 0.015 1.2 (0.9; 1.8) 0.225
1.1 (0.9; 1.4) 0.233 1.2 (0.9; 1.4) 0.156 1.0 (0.7; 1.3) 0.916

Abbreviations: CGM, continuous glucose monitor; DTSQ, Diabetes Treatment Satisfaction Questionnaire; HbA1c, haemoglobin A1c.
5

CGM high glucose value >180 mg/dL (>10 mmol/L). CGM target glucose value between 71 and 180 mg/dL (4.0–10.0 mmol/L). CGM low glucose value <71 mg/dL(<4 mmol/L).
6 DEJGAARD ET AL.

F I G U R E 1 Estimated levels
(±SEM) by treatment group
during follow-up. A, Haemoglobin
A1c. B, Total daily insulin dose. C,
Body weight. Stars indicate level
of significance test of difference
in baseline corrected change
between treatment groups:
***P <0.001 and *P <0.05

liraglutide had their dose temporarily reduced to 1.2 mg QD shortly treated with liraglutide had been exposed to a mean of 1.7 mg/day,
after escalation of the dose to 1.8 mg QD (range 6–34 days). One including the planned period for up-escalation.
patient who received liraglutide was unable to tolerate 1.8 mg QD Three severe AEs occurred (two in the liraglutide group vs. one in
and completed the trial on 1.2 mg QD. At end-of-treatment, patients the placebo group), including one case of severe hypoglycaemia in a
DEJGAARD ET AL. 7

patient who received placebo. No events of ketoacidosis were HbA1c compared with placebo when adding liraglutide to MDI.9-13
reported. Our population may have obtained a greater benefit of liraglutide due
A summary of AEs is reported in Table 3. to a more advanced insulin regimen at baseline. Furthermore, in the
present study, a small but insignificant increase in HbA1c of 2 mmol/
mol (0.2%) in the placebo group may be of importance for the results
4 | DISCUSSION when estimating the effect of liraglutide on HbA1c as a mean differ-
ence between treatment groups. In the previous studies evaluating
We demonstrated that the GLP-1RA liraglutide 1.8 mg QD as an add- liraglutide treatment in type 1 diabetes, the HbA1c reduction
on to CSII treatment in overweight or obese patients with type 1 dia- obtained with liraglutide has been in the range of 3–8 mmol/mol
betes and non-optimal glycaemic control reduced the HbA1c levels (0.3%–0.8%), which was similar to our findings, but a concomitant
without an increase in events of hypoglycaemia or time spent in reduction in HbA1c in the placebo arm has minimized the effect of
hypoglycaemia. Further, the total daily insulin dose and body weight liraglutide between groups.9-13
were significantly reduced. Liraglutide treatment positively affected In line with previous studies, treatment with a GLP-1RA reduced
patient-reported outcome measures compared with placebo. body weight progressively during the 26 weeks.9-13 The majority of
None of the patients included in the present study had reached patients included in this study were overweight at baseline, which
the recommended goals for glycaemic control with an HbA1c of increased the chance of obtaining a significant reduction in body
approximately 66 mmol/mol (8.1%–8.2%) when randomized. When weight. We obtained a total reduction of 8% of body weight in per-
adding liraglutide 1.8 mg QD to CSII therapy in this population, we sons treated with liraglutide, which is likely to be of clinical
demonstrated a clinically significant improvement in HbA1c of importance,15 as weight loss has been reported to improve quality of
−7.3 mmol/mol (−0.7%) when compared with placebo. This is in con- life and insulin sensitivity, and reduce cardiovascular risk factors in
trast to the majority of previous randomized studies reporting only people with type 1 diabetes.16-18
minor treatment effects of 2–3 mmol/mol (0.2%–0.3%) reduction in Even though patients were included with non-optimal glycaemic
control and significantly improved HbA1c during the study, the total
daily insulin was reduced by 17% when adding liraglutide. This differ-
TABLE 3 Adverse events
ence between groups disappeared when adjusting for body weight,
Liraglutide Placebo though the decrease in insulin may not only contribute to a reduction
1.8 mg (N = 22),
in hypoglycaemic events, but also have importance for the improve-
(N = 22), n (%) n (%)
ments in body weight. Despite a reduction of 10% in basal insulin
Patients with one or more adverse eventa 20 (91) 13 (59)
dose and an increase in insulin sensitivity factors and insulin-to-
≥1 adverse events*
carbohydrate ratios a significant reduction was seen in insulin dose
Nausea 16 (73) 9 (41)
within the first 2 weeks after randomization. This reduction in insulin
Decreased appetite 5 (23) 1 (5)
dose could be the result of the effect on gastric emptying and sup-
Diarrhoea 4 (18) 2 (9)
pression of postprandial glucagon in the early phase, independent of
Vomiting 3 (14) 0 (0)
the reduction in body weight, as the decline in body weight was more
Dizziness 3 (14) 0 (0) protracted. Furthermore, the reduction in both insulin dose and
Constipation 2 (9) 3 (14) bodyweight may be a consequence of the appetite-reducing effect of
Dyspepsia 1 (5) 1 (5) GLP-1 inducing a lower food volume and carbohydrate intake.19 The
Stomach ache 1 (5) 1 (5) direct effect of GLP-1RA on insulin resistance in peripheral tissue is
Fatigue 1 (5) 0 (0) limited and, if present, may be a result of reduction in adipose tissue
Headache 1 (5) 3 (14) in humans.19 Despite a reduction in body weight of 8%, no changes in
Allergic reaction not related to IMP 1 (5) 0 (0) CSII settings for insulin sensitivity factors were found. Concomitantly,

Inflammation in joint 1 (5) 0 (0) only a minor non-significant effect on insulin-to-carbohydrate ratios
was found during the intervention period. This may support the evi-
Pneumonia 1 (5) 0 (0)
dence that the effect of liraglutide on insulin resistance is sparse,
Urinary tract infection 0 (0) 2 (9)
though a direct measure of insulin resistance was not performed.
Epididymitis 0 (0) 1 (5)
Generally, liraglutide 1.8 mg was well tolerated. The most com-
Angina pectoris 1 (5) 0 (0)
mon AEs were gastrointestinal, primarily nausea. In most patients the
≥1 Serious adverse events
gastrointestinal side effects were transient, but five patients had to
Multiple scleroses 1 (5) 0 (0) reduce the liraglutide dose to 1.2 mg QD temporarily and one patient
Breast cancer 1 (5) 0 (0) completed the study on 1.2 mg QD. Notably, patients in the present
Severe hypoglycaemia 0 (0) 1 (5) study were overweight or obese. From previous studies, including
Abbreviations: IMP, investigational medicinal product. lean patients with type 1 diabetes, we have experienced that the
a
Events of hypoglycaemia are described separately. 1.2 mg QD of liraglutide is a more optimal dose than 1.8 mg QD in
8 DEJGAARD ET AL.
relation to minimizing gastrointestinal events in non-obese patients,
without compromising the effect on glycaemic control.11,20 Despite
more AEs in the liraglutide-treated patients, the improvement in treat-
ment satisfaction score increased more with liraglutide compared with
placebo.
As reported in previous trials investigating liraglutide, levels of
plasma amylase and lipase increased during the 6 months of treat-
ment. In trials with longer duration, levels seemed to increase over the
first 6 months of treatment and then remain stable. The increases
seem to be dose-independent. Importantly, the increases are not pre-
12,21,22
dictive for events of subsequent acute pancreatitis.
Compared with the ADJUNCT trials, where an increased number
of symptomatic or confirmed events of hypoglycaemia were reported
for patients treated with liraglutide 1.2 and 1.8 mg QD, we did not
find any difference between groups. This may be due to a less-
intensive treat-to-target regimen with less contacts during the trial
combined with a higher level of total insulin dose used in the
ADJUNCT trials or the fact that this study was not powered for evalu-
9,12
ating events of hypoglycaemia.
The strength of the present study is the double-blinded, placebo-
controlled design only including patients treated with CSII. We chose
liraglutide 1.8 mg, the highest dose approved for the treatment of
type 2 diabetes, to bring about the largest effect on both glycaemic
control and weight loss. The dropout rate was low.
A limitation to the present study is the relatively small number of
participants. In addition, the duration of 26 weeks does not provide
data on long-term efficacy and safety of the treatment and may not
have impact in a lifelong disease unless compliance is optimized.
In conclusion we demonstrated that adding liraglutide 1.8 mg QD
to CSII treatment in a population of overweight or obese persons with
type 1 diabetes and insufficient glycaemic control induced a clinically
relevant improvement in HbA1c and increased the time spent in nor-
moglycaemia with less need of insulin and no elevated risk of
hypoglycaemia compared with placebo. Furthermore, body weight
was significantly reduced. Liraglutide was well tolerated with transient
gastrointestinal AEs that were described during treatment with GLP-
1RAs in patients with type 1 as well as type 2 diabetes.
The clinical use of GLP-1RAs may be limited in the general popu-
lation of persons with type 1 diabetes; however, our results with an
attractive benefit–risk profile suggest that liraglutide may be a promis-
ing adjunct treatment in a subpopulation of obese patients treated
with CSII and non-optimal glycaemic control. Nevertheless, specific
clinical outcomes are still needed to predict the treatment effect in
this group of patients.
ACKNOWLEDGMENTS
The authors thank the staff at the Clinical Research Unit, Steno Diabe-
tes Center Copenhagen and the Department of Endocrinology,
Copenhagen University Hospital Hvidovre for assistance with collect-
ing data and laboratory work. In particular, we are grateful to study
nurse Annette Hougaard and Merete Meldgaard Andersen for an unri-
valled commitment to the study. Finally, we thank the patients for
their participation in this trial.
CONFLIC T OF INT ER E ST
T.F.D. has received research support from Novo Nordisk and
AstraZeneca; and has received lecture fees from Novo Nordisk,
AstraZeneca and Boehringer-Ingelheim. S.S. has served on an advisory
panel for Roche Diagnostics and has consulted for Unomedical.
C.S.F. has received research support and lecture fees from Novo
Nordisk. D.V. is a shareholder in Novo Nordisk. S.M. has served on
advisory panels for Novartis Pharma, Novo Nordisk, Merck Sharp &
Dome, Sanofi-Aventis, AstraZeneca, Johnson & Johnson, Roche Diag-
nostics, Mankind, Boehringer-Ingelheim, Zealand, Eli Lilly and Intarcia
Therapeutics; and has received lecture fees from Novo Nordisk,
Merck Sharp & Dome, Astra-Zeneca, Johnson and Johnson, Roche,
Shering-Ploug, Sanofi-Aventis, Novartis Pharma, Eli Lilly and Bristol-
Meyer Squibb. H.U.A. is a shareholder of Novo Nordisk, has served on
advisory panels for Abbott, Novo Nordisk and AstraZeneca and has
received lecture fees from Nordic Infucare. K.N. is a shareholder of
Novo Nordisk; has received research support from Novo Nordisk,
Roche Diagnostics and Zealand Pharma; has received lecture fees
from Medtronic, Roche Diagnostics, Rubin Medical, Sanofi, Zealand
Pharma, Novo Nordisk and Bayer; and has served on advisory panels
for Medtronic, Abbott and Novo Nordisk.
AUTHOR CONTRIBU TIONS
T.F.D., S.S. and C.S.F. contributed to the study design, data collection
and analysis. S.M., H.U.A. and K.N contributed to the study design
and data collection. D.V. contributed to the data analysis. All authors
were involved in the writing of the manuscript and approved the final
version of the manuscript. T.F.D. is the guarantor of this work and, as
such, had full access to all the data in the study and takes responsibil-
ity for the integrity of the data and the accuracy of the data analysis.
OR CID
Thomas F. Dejgaard https://orcid.org/0000-0002-0097-7052
Signe Schmidt https://orcid.org/0000-0002-6968-6675
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SUPPORTING INF ORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Dejgaard TF, Schmidt S, Frandsen CS,
et al. Liraglutide reduces hyperglycaemia and body weight in
overweight, dysregulated insulin-pump-treated patients with
type 1 diabetes: The Lira Pump trial—a randomized, double-
blinded, placebo-controlled trial. Diabetes Obes Metab. 2019;
1–9. https://doi.org/10.1111/dom.13911