Diabetes Care 1

Liana K. Billings,1,2 Ankur Doshi,3

Efficacy and Safety of IDegLira Didier Gouet,4 Alejandra Oviedo,5

CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL
Helena W. Rodbard,6
Versus Basal-Bolus Insulin Nikolaos Tentolouris,7 Randi Grøn,8
Natalie Halladin,8 and Esteban Jodar9
Therapy in Patients With Type 2
Diabetes Uncontrolled on
Metformin and Basal Insulin;
DUAL VII Randomized Clinical
Trial
https://doi.org/10.2337/dc17-1114

OBJECTIVE
In patients with uncontrolled type 2 diabetes on basal insulin, prandial insulin may be
initiated. We assessed the efficacy and safety of initiating insulin degludec/liraglutide
fixed-ratio combination (IDegLira) versus basal-bolus insulin. 1
NorthShore University HealthSystem, Evanston,
IL
RESEARCH DESIGN AND METHODS 2
University of Chicago Pritzker School of Medi-
A phase 3b trial examined patients with uncontrolled type 2 diabetes on insulin cine, Chicago, IL
3
PrimeCare Medical Group, Houston, TX
glargine (IGlar U100) 20–50 units/day and metformin, randomized to IDegLira or 4
La Rochelle Hospital, La Rochelle, France
IGlar U100 and insulin aspart four or fewer times per day. 5
Santojanni Hospital and Cenudiab, Ciudad
Autonoma de Buenos Aires, Argentina
RESULTS 6
Endocrine and Metabolic Consultants, Rockville,
Glycated hemoglobin (HbA1c) decreased from 8.2% (66 mmol/mol) to 6.7% MD
7
National and Kapodistrian University of Athens,
(50 mmol/mol) with IDegLira, and from 8.2% (67 mmol/mol) to 6.7% (50 mmol/mol) Medical School, Athens, Greece
with basal-bolus (estimated treatment difference [ETD] 20.02% [95% CI 20.16, 8
Novo Nordisk A/S, Søborg, Denmark
0.12]; 20.2 mmol/mol [95% CI 21.7, 1.3]), confirming IDegLira noninferiority versus
9
H. U. QuironSalud Madrid y Ruber Juan Bravo,
Universidad Europea de Madrid, Madrid, Spain
basal-bolus (P < 0.0001). The number of severe or blood glucose–confirmed symptom-
atic hypoglycemia events was lower with IDegLira versus basal-bolus (risk ratio 0.39 Corresponding author: Liana K. Billings, lbillings@
northshore.org.
[95% CI 0.29, 0.51]; rate ratio 0.11 [95% CI 0.08, 0.17]). Body weight decreased with
Received 5 June 2017 and accepted 5 February
IDegLira and increased with basal-bolus (ETD 23.6 kg [95% CI 24.2, 22.9]). Fasting 2018.
plasma glucose reductions were similar; lunch, dinner, and bedtime self-monitored Clinical trial reg. no. NCT02420262, clinicaltrials
plasma glucose measurements were significantly lower with basal-bolus. Sixty-six .gov.
percent of patients on IDegLira versus 67.0% on basal-bolus achieved HbA1c <7.0% This article contains Supplementary Data online
(53 mmol/mol). Total daily insulin dose was lower with IDegLira (40 units) than basal- at http://care.diabetesjournals.org/lookup/
bolus (84 units total; 52 units basal). suppl/doi:10.2337/dc17-1114/-/DC1.
© 2018 by the American Diabetes Association.
CONCLUSIONS Readers may use this article as long as the work
is properly cited, the use is educational and not
In patients with uncontrolled type 2 diabetes on IGlar U100 and metformin, IDegLira
for profit, and the work is not altered. More infor-
treatment elicited HbA1c reductions comparable to basal-bolus, with statistically mation is available at http://www.diabetesjournals
superior lower hypoglycemia rates and weight loss versus weight gain. .org/content/license.
Diabetes Care Publish Ahead of Print, published online February 26, 2018
2 IDegLira vs. Basal-Bolus Insulin: DUAL VII
Progression of type 2 diabetes means ad-
equate blood glucose (BG) control with
basal insulin may deteriorate over time.
By the time basal insulin is initiated, patients
on average have had a type 2 diabetes di-
agnosis for 9.2 years and a glycated hemo-
globin (HbA1c) level of 9.5% (80 mmol/mol)
(1). In one study, only 29% of patients could
maintain HbA1c ,7.0% (53 mmol/mol)
3 years after basal insulin initiation (2).
Current guidelines recommend therapy
intensification if HbA1c targets are not
reached after 3–6 months of basal insulin
(3). However, many patients remain
without therapy intensification (4) due
to concerns over potential increased hy-
poglycemia risk, weight gain, and treat-
ment complexity (5,6).
Glucagon-like peptide-1 receptor ago-
nists (GLP-1RAs) are incretin mimetics
that lower fasting plasma glucose (FPG)
and postprandial glucose via stimulation
of endogenous insulin and inhibition of
glucagon secretion, with weight-reducing
effects through appetite suppression (7).
Using basal insulin with GLP-1RAs is a rec-
ognized therapeutic option after failure
to achieve glycemic control with basal in-
sulin (3). Comparison of basal insulin and
GLP-1RA given in separate injections ver-
sus basal insulin alone showed a sign-
ificantly greater HbA1c reduction and
weight loss with the combination ther-
apy, with significantly more hypoglycemic
events (8). Comparison with basal-bolus
showed noninferior HbA1c reduction with
basal insulin and GLP-1RA loose combina-
tion, and more desirable hypoglycemia
rates and weight management (9). This
evidence supports combination therapies
such as IDegLira, a fixed-ratio combina-
tion of insulin degludec (degludec) and
liraglutide.
IDegLira efficacy and safety were estab-
lished in the DUAL clinical trial program in
patients with uncontrolled type 2 diabetes
on oral antidiabetic drugs (DUAL I, IV, and
VI) (10–12), GLP-1RAs (DUAL III) (13), and
basal insulin (DUAL II and V) (14,15).
DUAL VII assessed IDegLira efficacy and
safety versus basal-bolus.
RESEARCH DESIGN AND METHODS
Trial Design and Participants
DUAL VII was a phase 3b, multinational
(Supplementary Table 1), open-label,
two-arm parallel, randomized trial in pa-
tients with type 2 diabetes conducted at
89 sites in 12 countries from July 2015 to
October 2016. The trial lasted 32 weeks,
with 2-week screening, 26-week treat-
ment, and 4-week follow-up periods. It
was conducted in accordance with the In-
ternational Conference on Harmonization
Good Clinical Practice (16) and the Decla-
ration of Helsinki (17).
Patients included were $18 years old
with type 2 diabetes, HbA1c 7.0–10.0%
(53–86 mmol/mol), BMI #40 kg/m2 ,
and on stable daily doses of insulin glar-
gine 100 units/mL (IGlar U100) 20–50
units and metformin $1,500 mg or max-
imum tolerated dose for .90 days prior
to screening. Exclusion criteria included
treatment with any medication for dia-
betes or obesity other than stated in the
inclusion criteria during 90 calendar days
before screening, anticipated initiation
or change in concomitant medications
known to affect weight or glucose metab-
olism, and renal impairment (estimated
glomerular filtration rate ,60 mL/min/
1.73 m2) (Supplementary Table 2).
A treat-to-target approach ensured op-
timal insulin titration and improved glyce-
mic control in all patients.
Randomization and Masking
Patients were randomized 1:1 using a
centralized allocation via an interactive
voice web response system.
Procedures/Interventions
Patients were randomized to either
IDegLira (insulin degludec 100 units/mL
and liraglutide 3.6 mg/mL, in a 3-mL
prefilled FlexTouch pen for subcutaneous
injection) or IGlar U100 (insulin glargine
100 units/mL solution, in a 3-mL prefilled
Solostar pen for subcutaneous injection)
and insulin aspart (IAsp; 100 units/mL
solution in a 3-mL prefilled FlexPen for
subcutaneous injection). Metformin was
continued at pretrial doses.
IDegLira was administered once daily
at any time, independent of meals, repeated
approximately the same time each day. Pa-
tients were initiated on 16 units (16 units
degludec/0.58 mg liraglutide) and titrated
twice weekly, aiming for a mean prebreak-
fast self-monitored plasma glucose (SMPG)
target range of 4.0–5.0 mmol/L (72–
90 mg/dL) (Supplementary Table 3A).
The maximum dose of IDegLira was 50
units (50 units degludec/1.8 mg liraglutide).
IGlar U100 was administered once daily
according to local labeling and was initi-
ated at a dose equivalent to the pretrial
dose, titrated using the same algorithm as
IDegLira. IAsp was initiated from the day of
Diabetes Care
randomization at a starting dose of 4 units
per main meal (four or fewer times per day)
and titrated twice weekly, aiming for a mean
preprandial and bedtime SMPG target range
of 4.0–6.0 mmol/L (72–108 mg/dL)
(Supplementary Table 3B). The principal
investigator at each study site could ad-
just the titration per clinical judgment.
There were no protocols given to patients
regarding meal size or constituents.
Patients who prematurely discontin-
ued treatment had telephone contacts
every 4 weeks to collect information on
serious adverse events (AEs; death, life-
threatening experience, inpatient hos-
pitalization or prolongation of existing
hospitalization, persistent/significant dis-
ability/incapacity, congenital anomaly,
event that jeopardizes the patient requir-
ing medical/surgical intervention, and
suspicion of transmission of infectious
agents via trial product), major cardiovas-
cular events, and antidiabetic medica-
tion. These patients were also invited
to the week-26 visit for data collection
on these parameters, as well as HbA1c. A
small number of patients completed the
week-26 visit as a telephone contact, with
no HbA1c collected.
Outcome Measures
The primary end point was change in
HbA1c from baseline to week 26 of treat-
ment. Confirmatory secondary end points
included number of treatment-emergent
severe or BG-confirmed symptomatic hy-
poglycemic episodes during 26 weeks of
treatment and change in body weight
from baseline after 26 weeks of treat-
ment. Hypoglycemic events were defined
as either severe according to the Ameri-
can Diabetes Association (ADA) classifica-
tion (requiring assistance of another
person to take corrective actions) (18)
or symptomatic BG-confirmed (,3.1
mmol/L [56 mg/dL] accompanied by gly-
copenic symptoms). Supportive second-
ary efficacy end points included total,
basal, and bolus daily insulin doses; re-
sponders for HbA1c ,7.0% (53 mmol/mol)
and #6.5% (48 mmol/mol) after 26 weeks
of treatment; and proportion of patients
achieving these HbA 1c targets without
severe or BG-confirmed symptomatic hy-
poglycemia in the last 12 weeks and/or
weight gain. Hypoglycemia rates during
the last 12 weeks were included as this
was considered a maintenance period with
more stable insulin doses and comparable
hypoglycemia rates. Other glycemia-related
care.diabetesjournals.org
secondary end points included changes in
FPG and mean difference in the nine-point
SMPG profile.
Supportive secondary safety end points
included number of treatment-emergent
AEs and treatment-emergent nocturnal
severe or BG-confirmed symptomatic
hypoglycemic episodes (severe or BG-
confirmed symptomatic hypoglycemia
occurring between 0001 h and 0559 h
inclusive) (Supplementary Fig. 1) and
changes from baseline in blood pressure,
heart rate, laboratory assessments of bio-
chemistry, hematology, and fasting lipid
profile.
Statistical Analyses
The trial was powered for the primary
objective of confirming noninferiority
with respect to HbA1c change from base-
line, using a one-sided Student t test with
the following assumptions: a mean treat-
ment difference of 0.0%, an SD from
HbA1c change from baseline of 1.0%, a
noninferiority margin of 0.30%, and up
to 15% of randomized patients excluded
from the per protocol analysis set. Sample
size was set to 250 per treatment arm,
ensuring a power of at least 85% for con-
firming the primary objective in the per
protocol analysis set.
All efficacy end points were summa-
rized using the full analysis set (FAS),
and safety end points were summarized
using the safety analysis set (SAS). All sta-
tistical analyses of efficacy and safety end
points were based on the FAS (analysis set
definitions are detailed in Supplementary
Table 4).
For the primary end point, noninferior-
ity was considered confirmed if the upper
bound of the two-sided 95% CI for esti-
mated mean between-treatment differ-
ence in change from baseline in HbA1c
was ,0.30%. All postbaseline HbA1c
on-treatment measurements obtained
at scheduled visits were analyzed using
a linear mixed normal model using an un-
structured residual covariance matrix for
HbA1c measurements within the same pa-
tient. The model included treatment,
visit, and region as fixed factors and base-
line HbA1c as covariate, with interactions
between visit and all factors and covari-
ates included. In order to control the
overall type I error on a 5% level with
regards to confirmatory secondary end
points, a hierarchical testing procedure
was used (Statistical Analyses Detail in
Supplementary Material).
A negative binomial model with a log-
link function and the log of the time pe-
riod in which a hypoglycemic episode is
considered treatment emergent as offset
was used to analyze the number of treat-
ment-emergent severe or BG-confirmed
symptomatic hypoglycemic episodes,
including treatment and region as fixed
factors. Risk of hypoglycemia versus no
hypoglycemia was analyzed using a gen-
eralized linear regression model with a
log link, including treatment and region
as fixed factors.
A mixed model for repeated mea-
surements (MMRM) with an unstruc-
tured covariance matrix was used for
the continuous confirmatory and sup-
portive secondary end points, including
treatment, visit, and region as fixed fac-
tors and corresponding baseline values
as covariates. Interactions between visit
and all factors and the covariate were
also included in the model. Insulin dose
was analyzed using a compound symme-
try covariance matrix and included IGlar
U100 dose at screening as an additional
covariate.
A number of sensitivity analyses, in-
cluding reference-based multiple im-
putation, were performed to assess
the robustness of primary and confirma-
tory secondary analyses (Supplementary
Table 5).
The nine-point SMPG profile was ana-
lyzed using a linear mixed-effect model
fitted to data at week 26. The model in-
cluded treatment, region, time (within
nine-point profile), and interactions be-
tween treatment and time and between
time and region as fixed factors and pa-
tient as a random effect, where measure-
ments within patients were assumed
correlated using a compound symmetry
covariance matrix.
Responder end points were analyzed
using a logistic regression model with
treatment and region as fixed factors
and baseline HbA1c with or without base-
line body weight as covariates. Missing
response data were imputed from the
MMRM analysis of the primary end point
change in HbA1c from baseline with or
without the confirmatory secondary end
point change in body weight. AEs were
summarized descriptively.
RESULTS
Patients
Overall, 672 patients were screened and
506 were randomized, with 99.2% of
Billings and Associates 3
those randomized to IDegLira and 98.0%
of those randomized to basal-bolus
completing the trial. Furthermore, 94.4%
and 91.7% completed 26 weeks of treat-
ment with IDegLira and basal-bolus,
respectively (Fig. 1). Baseline character-
istics were similar between the two arms
(Table 1).
Primary End Point
After 26 weeks of treatment, mean HbA1c
decreased from 8.2% (66 mmol/mol) at
baseline to 6.7% (50 mmol/mol) at end
of trial (EOT) with IDegLira, and from 8.2%
(67 mmol/mol) to 6.7% (50 mmol/mol)
with basal-bolus. The estimated treatment
difference (ETD) was 20.02% (95% CI 20.16,
0.12) (20.2 mmol/mol [95% CI 21.7, 1.3])
(Fig. 2A), confirming noninferiority of
IDegLira versus basal-bolus (P , 0.0001).
In total, 489 patients (244 and 245 in the
IDegLira and basal-bolus arms, respec-
tively) contributed to the primary anal-
ysis. All preplanned sensitivity analyses
were in agreement with the primary
analysis (Supplementary Tables 5 and 6
and Supplementary Fig. 2).
Confirmatory Secondary End Points
During 26 weeks of treatment, 19.8% of
patients on IDegLira experienced one or
more severe or BG-confirmed symptom-
atic hypoglycemic episodes versus 52.6%
with basal-bolus treatment, correspond-
ing to a 61% lower risk with IDegLira com-
pared with basal-bolus (estimated risk
ratio 0.39 [95% CI 0.29, 0.51], P ,
0.0001). Patients on IDegLira experienced
129 episodes in total (rate of 1.07 epi-
sodes per patient year of exposure
[PYE)] versus patients on basal-bolus
who experienced 975 episodes in total
(rate of 8.17 episodes per PYE). This re-
sulted in an 89% lower rate of severe or
BG-confirmed symptomatic hypoglyce-
mic episodes with IDegLira versus basal-
bolus (estimated rate ratio 0.11 [95% CI
0.08, 0.17], P , 0.0001), confirming the
superiority of IDegLira versus basal-bolus.
Figure 2B demonstrates an increasing
divergence in the cumulative hypoglyce-
mia rate from randomization until EOT.
Severe hypoglycemic episodes occurred
in 1.2% of patients on IDegLira through-
out the treatment period (three episodes)
at a rate of 0.03 episodes per PYE, versus
1.6% of patients on basal-bolus (10 epi-
sodes) at a rate of 0.08 episodes per PYE.
There was a 34% lower risk (estimated
risk ratio 0.76 [95% CI 0.17, 3.35],
4 IDegLira vs. Basal-Bolus Insulin: DUAL VII
Figure 1—Patient disposition. Treatment completers are patients who completed the week-26 visit without premature permanent discontinuation of
randomized treatment. Trial completers are treatment completers and patients who completed the week-26 visit after premature permanent discon-
tinuation.
P = 0.7173) and 72% lower rate (esti-
mated rate ratio 0.28 [0.04, 1.98], P =
0.2034) of severe hypoglycemia in IDegLira
compared with basal-bolus. Over 26 weeks
of treatment, observed mean body weight
decreased by 0.9 kg with IDegLira from
87.2 kg and increased with basal-bolus by
2.6 kg from 88.2 kg (ETD 23.6 kg [95%
CI 24.2, 22.9], P , 0.0001) (Fig. 2C), con-
firming the superiority of IDegLira over
basal-bolus.
All preplanned sensitivity analyses, includ-
ing reference-based multiple imputation,
were in agreement with conclusions from
confirmatory analyses (Supplementary
Tables 5 and 6 and Supplementary Fig. 2).
Supportive Secondary End Points
Total daily insulin dose increased to
a mean EOT dose of 40 and 84 units with
IDegLira and basal-bolus, respectively (ETD
244.5 units [95% CI 248.3, 240.7], P ,
Table 1—Baseline characteristics
Characteristic
FAS (n)
Male, n (%)
Age (years)
Weight (kg)
BMI (kg/m2)
Duration of diabetes (years)
HbA1c (%)
HbA1c (mmol/mol)
FPG (mmol/L)
FPG (mg/dL)
Daily insulin dose (units)
Daily metformin dose (mg)
Values are mean (SD) unless otherwise stated.
Diabetes Care
0.0001) (Fig. 2D). Mean basal insulin dose once-daily basal injection (Supplementary
with basal-bolus increased from 34 units Fig. 3) versus the once-daily single injec-
in week 1 to 52 units at EOT versus a tion with IDegLira.
mean EOT dose of 40 units with IDegLira Patients on IDegLira had a lower rate of
(corresponding to 40 units degludec/ nocturnal hypoglycemia compared with
1.44 mg liraglutide) (ETD 212.6 units basal-bolus. During the 26 treatment
[95% CI 214.9, 210.3], P , 0.0001). Total weeks, 4.8% of patients on IDegLira expe-
daily bolus insulin dose in the basal-bolus rienced one or more nocturnal severe or
arm at EOT was 32 units of bolus insulin. BG-confirmed symptomatic hypoglyce-
After 26 weeks of treatment, 86 patients mic episodes (16 episodes) at a rate of
on IDegLira were on the 50-unit maximum 0.13 episodes per PYE, versus 19.4% of
dose, with a mean HbA1c at week 26 of 7.0% patients on basal-bolus (198 episodes)
(53 mmol/mol); 57% of these patients at a rate of 1.66 per PYE. There was a
achieved HbA1c ,7.0% (53 mmol/mol), 75% lower risk and 92% rate reduction
with a mean HbA1c at week 26 of 6.4% in nocturnal hypoglycemia with IDegLira
(46 mmol/mol). Those who did not achieve versus basal-bolus (estimated risk ratio
an HbA1c ,7.0% on 50 units IDegLira 0.25 [95% CI 0.13, 0.45], estimated rate
had a mean HbA1c at week 26 of 7.8% ratio 0.08 [95% CI 0.04, 0.17]; both P ,
(61 mmol/mol). 0.0001). No patients on IDegLira experi-
By week 26, ;90% of patients on enced any nocturnal severe hypoglycemic
basal-bolus reported taking at least three episodes versus one episode in the basal-
insulin injections per day, including the bolus arm.
Similar proportions of patients in each
treatment arm achieved an HbA1c ,7.0%
(53 mmol/mol): 66% in IDegLira and
67% in basal-bolus (Fig. 3). Likewise,
IDegLira IGlar U100 + IAsp
49.6% and 44.6% of patients on IDegLira
252 254 and basal-bolus, respectively, achieved
110 (43.7) 117 (46.1) HbA1c #6.5% (48 mmol/mol; ETDs not
58.6 (9.0) 58.0 (8.6) statistically significant for both targets)
87.2 (16.0) 88.2 (17.2) (Supplementary Fig. 4). More patients
31.7 (4.4) 31.7 (4.5) reached the triple composite HbA1c tar-
13.2 (7.0) 13.3 (6.8) gets (,7.0% [,53 mmol/mol]) without
8.2 (0.8) 8.2 (0.8) hypoglycemic episodes in the last 12
66 (8) 67 (9) weeks of treatment and without weight
8.5 (2.7) 8.3 (2.5) gain on IDegLira versus basal-bolus (odds
153.5 (47.8) 149.3 (45.6) ratio [OR] 10.39 [95% CI 5.76, 18.75], P ,
34 (10.7) 33 (10.4) 0.0001) (Fig. 3). Odds for HbA 1c tar-
2,049 (456.0) 2,091 (458.3) gets ,7.0% (53 mmol/mol) without hy-
poglycemic episodes in 26 weeks of
treatment and without weight gain were
care.diabetesjournals.org Billings and Associates 5

Figure 2—Results for HbA1c (A), severe or BG-confirmed hypoglycemia (B), change in body weight (C), daily total insulin dose (D), FPG (E), and nine-point
SMPG profiles (F). A: Mean observed values with error bars (SEM) based on FAS. B: Mean cumulative frequency based on the SAS. Severe or BG-confirmed
symptomatic is an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value ,3.1 mmol/L (,56 mg/dL) with
symptoms consistent with hypoglycemia. C: Least square mean (LSMean) values with error bars (SE of estimated LSMean) based on FAS, using MMRM.
D: Mean observed values with error bars (SEM) based on the SAS. E: Mean observed values with error bars (SEM) based on FAS. F: Mean observed values with
error bars (SEM) based on FAS. An asterisk represents a statistically significant difference between EOT means in favor of IGlar U100 + IAsp vs. IDegLira.

higher with IDegLira versus basal-bolus
(OR 12.56 [95% CI 6.46, 24.45], P ,
0.0001) (Fig. 3).
The observed mean FPG decreased
with IDegLira by 2.4 mmol/L, and by
1.9 mmol/L with basal-bolus (ETD 20.31
mmol/L [95% CI 20.67, 0.05], P = 0.0936)
(Fig. 2E).
The nine-point SMPG profile decreased
with both treatments at all time points
(Fig. 2F) but to a larger extent with basal-
bolus than with IDegLira. The mean of
the nine-point SMPG decreased from
9.7 to 7.2 mmol/L with IDegLira and
from 9.7 to 6.6 mmol/L with basal-bolus
(ETD 0.57 mmol/L [95% CI 0.31, 0.83],
P , 0.0001; in favor of basal-bolus). Basal-
bolus insulin treatment resulted in sta-
tistically significantly lower postlunch,
dinner, postdinner, and bedtime SMPG
readings (Fig. 2F). The mean prandial in-
crements decreased in both arms at all
three meals but were only statistically sig-
nificantly different in favor of basal-bolus
6 IDegLira vs. Basal-Bolus Insulin: DUAL VII
Figure 3—Patients achieving composite outcomes with HbA1c ,7.0% (53 mmol/mol) at week 26. ORs and P values are based on logistic regression.
*, statistically significant in favor of IDegLira; †, severe or BG-confirmed symptomatic hypoglycemia based on episodes during the last 12 weeks of treatment;
‡, severe or BG-confirmed symptomatic hypoglycemia based on hypoglycemic episodes during a patient’s entire 26 weeks of treatment (post hoc analysis).
at the evening meal (ETD 0.49 mmol/L
[95% CI 0.06, 0.92], P = 0.0261).
Clinical Observations and Laboratory
Values
A greater decrease in mean systolic blood
pressure was observed with IDegLira
(24.5 mmHg) versus basal-bolus (21.2
mmHg) (ETD 23.70 [95% CI 25.68,
21.72], P = 0.0003), but no statistically
significant difference between the two
arms in terms of changes in diastolic
blood pressure. There was a greater dif-
ference in increase in heart rate with
IDegLira (3.5 bpm) versus basal-bolus
(1.3 bpm) (ETD 2.73 [95% CI 1.30, 4.16],
P = 0.0002). Small, but statistically signif-
icant, differences were seen between the
two arms for various lipid profile para-
meters (Supplementary Table 8).
Adverse Events
AEs occurred in similar proportions of pa-
tients in both treatment arms: 59.1% of
IDegLira patients at a rate of 4.1 events
per PYE versus 56.9% of patients on basal-
bolus at a rate of 3.5 events per PYE
(Supplementary Table 7). The majority
of AEs were nonserious and there was
no clustering of events: 13 and 11 serious
AEs with IDegLira and basal-bolus, respec-
tively (Supplementary Table 7). There
were no fatal AEs. The most common AE
with IDegLira was nausea, with 11.1% vs.
1.6% of patients on basal-bolus reporting
one or more events. At all time points, the
reported nausea rate was ,3% in either
treatment arm (Supplementary Fig. 5).
The most common AE on basal-bolus
was nasopharyngitis, with 11.9% vs.
4.8% of patients on IDegLira reporting
one or more events. There was one con-
firmed adjudicated cardiovascular event
in the IDegLira arm, confirmed as unsta-
ble angina pectoris. There was one con-
firmed benign neoplasm (a colorectal
polyp) with IDegLira and no confirmed
neoplasms on basal-bolus. There were
no confirmed events of pancreatitis or
thyroid disease or major cardiovascular
events in the trial.
CONCLUSIONS
This is the only trial thus far that com-
pares a fixed-ratio combination of basal
insulin and GLP-1RA with basal-bolus.
With once-daily versus multiple daily in-
jections, IDegLira was noninferior to
basal-bolus with respect to HbA1c reduc-
tion and statistically superior with respect
to lower hypoglycemia rate and change in
body weight in patients on IGlar U100 and
metformin with uncontrolled BG.
Other trials have investigated combi-
nations of insulin and GLP-1RA given sep-
arately. In the BEGIN: VICTOZA ADD-ON
trial, addition of liraglutide to degludec in
separate injections resulted in a signifi-
cantly greater reduction in HbA1c versus
Diabetes Care
addition of IAsp at one meal to degludec,
with weight loss and a reduced risk of
hypoglycemia (19). Addition of once-
weekly albiglutide to IGlar U100 resulted
in similar HbA1c reductions versus IGlar
U100 and prandial insulin lispro, with
weight loss and a reduced risk of hypo-
glycemia (9). These results are mirrored
in this trial. Furthermore, the fixed com-
bination achieved these outcomes with
only one injection per day (versus five or
fewer in the basal-bolus arm) and lower
rates of nausea, likely attributable to the
ability to slowly titrate the IDegLira dose
in contrast to the separate injections
(9,19).
An insulin-sparing effect was demon-
strated with IDegLira versus basal-bolus.
Patients achieved similar HbA1c reduc-
tions with a mean daily dose of ;13 units
of basal insulin less with IDegLira and
nearly 45 units of total daily insulin less.
Despite being an efficacious glucose-
lowering therapy, basal-bolus treatment
is associated with a higher rate of hypo-
glycemia versus other diabetes therapies
(20). Although resulting in similar HbA1c
reductions, IDegLira was confirmed to
be statistically superior to basal-bolus,
with an 89% lower rate of severe or
BG-confirmed symptomatic hypoglycemic
episodes and 92% lower rate in nocturnal
hypoglycemia. The striking difference in
the cumulative incidence of hypoglycemia
care.diabetesjournals.org
was noted early in the treatment period,
with an immediate split between the
two curves at randomization and continu-
ing divergence toward EOT. This differ-
ence is likely to be explained by the lower
total daily insulin dose with IDegLira,
the glucose-stimulated insulin secretion
promoted by the GLP-1RA component
of IDegLira (7), which reduces the risk
of low BG (21), and the lower rate of hy-
poglycemia with degludec versus IGlar
U100 (22).
Weight gain is another concern when
initiating basal-bolus treatment, and in-
creasing doses of insulin can promote
weight gain (3,6). Here, IDegLira was con-
firmed to be statistically superior to basal-
bolus in terms of change in body weight.
This is likely to be due to the weight-
reducing and insulin-sparing effects of
liraglutide mitigating the risk of weight
gain with insulin (3).
There were no unexpected safety or
tolerability issues identified with IDegLira
in this trial, and the safety profile was as
expected based on results from previous
DUAL and monocomponent trials, includ-
ing the LEADER (Liraglutide Effect and
Action in Diabetes: Evaluation of Cardio-
vascular Outcome ResultsdA Long Term
Evaluation) and DEVOTE (Trial Comparing
Cardiovascular Safety of Insulin Degludec
Versus Insulin Glargine in Patients with
Type 2 Diabetes at High Risk of Cardiovas-
cular Events) cardiovascular outcome tri-
als (23,24).
The main limitation in this trial was its
open-label design, which may have af-
fected reporting of AEs and other results.
However, it was necessary to avoid addi-
tional placebo injections with IDegLira,
which were deemed an unacceptable
burden to patients.
Trial design meant patients treated
with basal-bolus continued IGlar U100,
whereas those treated with IDegLira trans-
ferred from IGlar U100 to degludec as
a basal insulin. The comparison of different
basal insulins may be seen as a limita-
tion as they have different pharmacoki-
netic properties (25). Notably, degludec
has an efficacy similar to IGlar U100 in
terms of HbA1c lowering (24). However,
IGlar U100 was the chosen comparator
because it was the most prescribed basal
insulin at the time of study design.
Additionally, this trial used more strin-
gent titration targets than some cur-
rent guidelines. The titration target
for preprandial SMPG (4.0–6.0 mmol/L
[72–108 mg/dL]) with IAsp was lower
than the ADA-recommended target of
4.4–7.2 mmol/L (80–130 mg/dL) (20).
Thus, higher doses of preprandial insulin
may have been used in this trial, contrib-
uting to the difference in total daily insu-
lin dose, weight, and hypoglycemia at
EOT between arms. Nonetheless, a sim-
ilar significant lowering of nocturnal hy-
poglycemia was observed with IDegLira
versus basal-bolus when fasting treat-
ment targets were lower than ADA-
recommended targets, but there was
no difference in FPG levels at EOT between
treatment arms.
Medication compliance may be higher
in this study than might be expected in
the real world, where compliance de-
creases as the number of insulin injections
increases (26). This trial contains real-
world features, including the choice of
basal comparison, no specific meal plan,
and open-label design. Real-world studies
are warranted to determine if the results
are replicated in clinical practice.
Conclusion
IDegLira provides an efficacious intensifi-
cation option with noninferior glycemic
control versus basal-bolus in patients with
type 2 diabetes on 20–50 units of basal
insulin with no renal impairment and
HbA 1c levels of 7.0–10.0%. Compared
with basal-bolus, IDegLira offers an alter-
native well-tolerated treatment with
fewer injections, doses taken indepen-
dently of meals, lower total daily insulin
dose, reduced monitoring, weight loss,
and reduced rate of hypoglycemic epi-
sodes. This alternative might help over-
come the inertia that currently leaves
many patients with poor glycemic control.
Acknowledgments. The authors thank investi-
gators, research coordinators, and patients in
the trial, as well as Bue F. Ross Agner and Jakob
Langer (both of Novo Nordisk A/S) for their
review and input to the manuscript. The authors
also thank Victoria Stone and Germanicus Hansa-
Wilkinson (Watermeadow Medical, an Ashfield
Company, Oxford, U.K.) for providing medical
writing and editorial support.
Funding and Duality of Interest. This trial was
funded by Novo Nordisk A/S in accordance with
Good Publication Practice (GPP3) guidelines
(http://www.ismpp.org/gpp3). L.K.B. has partic-
ipated in advisory panels for Novo Nordisk and is
on the speakers’ bureau for Novo Nordisk. A.D.
has participated in research trials as a principal
investigator for Novo Nordisk, AstraZeneca, Eli
Lilly and Company, Pfizer, and Sanofi. D.G. has
received research support from Novo Nordisk,
Billings and Associates 7
Eli Lilly and Company, Boehringer Ingelheim,
Medtronic, Johnson & Johnson, and Sanofi. A.O.
has received research support from Novo Nordisk
and is on the speakers’ bureau for Novo Nordisk.
H.W.R. has participated in advisory panels for
AstraZeneca, Boehringer Ingelheim, Eli Lilly and
Company, Janssen, Merck, Novo Nordisk, Sanofi,
and Regeneron; is a consultant for AstraZeneca,
Boehringer Ingelheim, Eli Lilly and Company,
Janssen, Merck, Novo Nordisk, Sanofi, and Re-
generon; has received research support from
AstraZeneca, Bristol-Myers Squibb, Boehringer
Ingelheim, Eli Lilly and Company, Janssen, Lexicon,
Merck, Novo Nordisk, Sanofi, and Regeneron; and
is on the speakers’ bureau for AstraZeneca, Eli Lilly
and Company, Merck, Novo Nordisk, and Sanofi.
N.T. has participated in advisory panels for Merck,
AstraZeneca, Sanofi, Novo Nordisk, ELPEN, Eli Lilly
and Company, Boehringer Ingelheim, and Novar-
tis and has received research support from Merck,
Eli Lilly and Company, Novo Nordisk, Sanofi, Pfizer,
AstraZeneca, Janssen, Cilag, GlaxoSmithKline, and
Novartis. R.G. is an employee of Novo Nordisk.
N.H. is an employee of Novo Nordisk. E.J. has par-
ticipated in advisory panels for Janssen, Eli Lilly
and Company, Merck, and Novo Nordisk; has re-
ceived research support from Janssen, Eli Lilly and
Company, Merck, Novo Nordisk, Pfizer, and Sanofi;
and is on the speakers’ bureau for Janssen, Eli Lilly
and Company, Merck, and Novo Nordisk.
Author Contributions. L.K.B., A.D., D.G., A.O.,
and H.W.R. participated in drafting the manu-
script or revising it critically for important in-
tellectual content. N.T., R.G., N.H., and E.J. made
substantial contributions to conception and de-
sign, and/or acquisition of data, and/or analysis
and interpretation of data and participated in
drafting the manuscript or revising it critically for
important intellectual content. All authors gave
final approval of the version of the manuscript to
be submitted and any revised version. Novo
Nordisk was involved in the trial design and
protocol development, provided logistical sup-
port, and obtained the data, which were evalu-
ated jointly by the authors and the sponsor.
L.K.B. 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 have
been presented orally at the 77th Scientific
Sessions of the ADA, San Diego, CA, 9–13 June
2017, and as a poster at the 53rd Annual Meeting
of the European Association for the Study of Di-
abetes, Lisbon, Portugal, 11–15 September 2017.
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