752315

review-article2018
TAE0010.1177/2042018817752315Therapeutic Advances in Endocrinology and MetabolismW Nuffer, A Guesnier

Therapeutic Advances in Endocrinology and Metabolism Review

A review of the new GLP-1 receptor

Ther Adv Endocrinol
Metab

agonist/basal insulin fixed-ratio

2018, Vol. 9(3) 69­–79

DOI: 10.1177/
https://doi.org/10.1177/2042018817752315
https://doi.org/10.1177/2042018817752315
2042018817752315

combination products © The Author(s), 2018.

Reprints and permissions:
http://www.sagepub.co.uk/
journalsPermissions.nav
Wesley Nuffer  , Ashley Guesnier and Jennifer M. Trujillo

Abstract:  There have been several new treatment approaches established for the
management of hyperglycemia in type 2 diabetes (T2D), with treatment guidelines listing
both glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and basal insulin therapies as
considerations for patients who have failed to control their blood glucose with oral antidiabetic
agents. New studies have highlighted the importance of initiating combination therapy earlier
in the T2D disease process to avoid clinical inertia and prevent the long-term complications
arising from uncontrolled diabetes. Until recently, both GLP-1 RAs and basal insulin therapies
were only available as single agents, but there are now two combination pen devices that
deliver both a GLP-1 RA and basal insulin simultaneously. This article reviews the current
clinical evidence evaluating the use of these combination GLP-1 RA/basal insulin preparations
to treat T2D, presents both potential benefits as well as possible downsides with the use of
these agents, and discusses the current place in therapy these products represent in the
management of T2D.

Keywords:  basal insulin, combination products, GLP-1 agonists, injections, type 2 diabetes

Received: 24 August 2017; revised manuscript accepted: 11 December 2017.

Introduction Current treatment recommendations by the Correspondence to:

Wesley Nuffer
Type 2 diabetes (T2D) is a chronic, progressive American Diabetes Association (ADA) recommend University of Colorado
disease affecting over 400 million people globally a stepwise approach to achieving glycemic control Skaggs School
of Pharmacy and
and over 30 million people in the United States.1 starting with the initiation of metformin and adding Pharmaceutical Sciences,
The disease is a result of multiple pathophysio- therapy every 3 months until glycemic control is 12850 East Montview
Boulevard C238, Aurora,
logic defects including insulin resistance, reduced reached.3 Unfortunately, clinical evidence suggests CO 80045, USA
beta cell function, increased hepatic glucose out- that significant delays in treatment intensification wesley.nuffer@ucdenver.
edu
put, inappropriate glucagon secretion, and are common. Khunti et al. found that the median
Ashley Guesnier
decreased incretin effect.2 Good glycemic control time to add a second oral antihyperglycemic agent Jennifer M. Trujillo
is crucial in order to reduce the risk of long-term in T2D patients with an A1C >7% was 2.9 years.7 University of Colorado
Skaggs School
disease-related complications such as retinopathy Khunti et al. also found that, in patients treated with of Pharmacy and
and kidney disease.3,4 This goal remains difficult basal insulin, the median time from basal insulin Pharmaceutical Sciences,
Aurora, CO, USA
to achieve in a large portion of patients with T2D, initiation to treatment intensification was 4.3 years.8
despite a growing armamentarium of treatment
options. Data from the National Health and These studies highlight the continued need for effec-
Nutrition Examination Survey showed that only tive and durable treatment approaches as well as bet-
57% of people with diabetes achieved a goal A1C ter intensification strategies to achieve and sustain
<7% in 2003–2004.5 Another study showed that glycemic control. A more physiologic approach to
only 52.5% of people with diabetes achieved a treatment in which combination therapy is initiated
goal A1C <7% in 2007–2010.5 A more recent earlier in the disease process to target multiple patho-
study showed that, while the use of antihypergly- physiologic defects may be more appropriate.2,9,10
cemic agents has changed significantly from 2006
to 2013, the proportion of patients achieving an Combining basal insulin with a glucagon-like
A1C <7% declined from 56.4% to 54.2%.6 peptide 1 receptor agonist (GLP-1 RA) has many

journals.sagepub.com/home/tae 69
Therapeutic Advances in Endocrinology and Metabolism 9(3)
potential benefits. Basal insulin is a recommended
treatment option at many stages of T2D and is
effective at lowering fasting plasma glucose
(FPG). The dose can be titrated to the individual
patient’s needs; however, it increases the risk of
hypoglycemia and weight gain. GLP-1 RAs are
also recommended treatment options at multiple
stages of T2D and have complementary mecha-
nisms of action to basal insulin. GLP-1 RA
increases glucose-dependent insulin secretion,
decreases glucose-dependent secretion of gluca-
gon, slows gastric emptying and increases satiety.
Short-acting GLP-1 RAs (exenatide, lixisenatide)
primarily lower post-prandial glucose (PPG) and
longer-acting GLP-1 RAs (albiglutide, dulaglu-
tide, exenatide XR, and liraglutide) lower both
FPG and PPG. GLP-1 RAs are attractive add-on
options to basal insulin because they decrease
weight and have a low risk of hypoglycemia, how-
ever they do cause gastrointestinal (GI) adverse
effects (AEs). Clinical studies have demonstrated
improved glycemic control and low risk of hypo-
glycemia and weight gain with the combination of
basal insulin plus a GLP-1 RA.11
Until recently, basal insulin and GLP-1 RAs had
to be administered separately. Combining basal
insulin with a GLP-1 RA in a single injection may
have additional benefits such as improved adher-
ence. This review will focus on the two recently
approved fixed-ratio basal insulin/GLP-1 RA co-
formulations: insulin glargine (iGlar) U-100/lixi-
senatide (iGlarLixi) and insulin degludec (iDeg)
U-100/liraglutide (iDegLira).
Fixed-ratio basal insulin/GLP-1 RA co-
formulations
iGlarLixi is a fixed-ratio co-formulation of a
once-daily long-acting basal insulin, iGlar (100
units/ml) and a short-acting, once-daily GLP-1
RA, lixisenatide (33 μg/ml; Soliqua 100
units/33 μg) (Figure 1) indicated to improve
glycemic control in adults with T2D inade-
quately controlled on basal insulin (<60 units
daily) or lixisenatide.12 iDegLira is a fixed-ratio
co-formulation of a once-daily long-acting
basal insulin, iDeg (100 units/mL) and a long-
acting, once-daily GLP-1 RA, liraglutide (3.6
mg/ml; Xultophy 100 units/3.6 mg) indicated
to improve glycemic control in adults with
T2D inadequately controlled on basal insulin
(<50 units daily) or liraglutide.13 Both agents
were approved by the Food and Drug
Administration (FDA) in November 2016 and
70 journals.sagepub.com/home/tae
Figure 1.  Example of combination product labeling
on pen injector device.
are available as single injections administered
via disposable pen devices. Doses should be
administered once daily (at the same time each
day with or without food for iDegLira and
within 1 h prior to the first meal of the day for
iGlarLixi) and are titrated based on the basal
insulin component.
Pharmacokinetics and pharmacodynamics
Insulin degludec
iDeg is a basal insulin with an ultra-long duration
of action developed for once-daily administra-
tion. The half-life of iDeg is >25 h in patients
with T1D and T2D, and the drug reaches steady
state within 3 days of administration.13,14 Upon
subcutaneous injection, iDeg forms long, soluble
multi-hexamer chains that result in a soluble
depot in the subcutaneous tissue from which iDeg
monomers gradually separate.15 This results in a
flat and stable pharmacokinetic and pharmacody-
namic profile, allowing for reduced fluctuations
in its glucose-lowering effect across one dosing
interval.16
Insulin glargine
iGlar is a long-acting basal insulin developed for
once daily administration. It is indicated to
improve glycemic control in adults and children
with T1D and adults with T2D.17 The half-life of
iGlar is approximately 12 h in patients in patients
with T1D.18 IGlar was designed to have low
aqueous solubility at neutral pH, but is com-
pletely soluble at pH 4 of its injection solution.
The acidic solution become neutralized upon
subcutaneous injection, leading to the formation
of microprecipitates. This allows for slow release
of small amounts of iGlar and a relatively con-
stant pharmacokinetic and pharmacodynamic
profile over 24 h with no pronounced peak.17
This is also true when given as a combination
product with lixisenatide.

Lixisenatide
Lixisenatide is a synthetic analogue of exendin-4,
with about 50% amino acid sequence homology
to human GLP-1, that acts as a selective GLP-1
receptor agonist.19 Two clinical trials evaluating
the pharmacokinetic effects of lixisenatide showed
the mean half-life to be approximately 3 h when
administered in doses ranging from 5 to 20 µg in
patients with T2D taking oral antidiabetes
agents.20 Lixisenatide concentrations increased in
a dose-dependent manner, reaching peak concen-
trations between 1 and 2 h.20 Once-daily dosing
of lixisenatide has been shown to be effective
despite its relatively short half-life due to its high
affinity for the GLP-1 receptor and inhibition of
gastric emptying.19 Increased doses of lixisenatide
are also correlated with increasing area under the
concentration curve (AUC).20 When lixisenatide
is administered in combination with iGlar, the
Cmax is lower but the AUC is generally compara-
ble with that when lixisenatide is administered
alone.12 Following subcutaneous administration
of iGlarLixi, the median tmax of lixisenatide ranged
from 2.5 to 3.0 h in patients with T2D. There
was a 22–34% decrease in Cmax of lixisenatide
compared with separate simultaneous adminis-
tration of iGlar and lixisenatide, which is not
likely to be clinically significant.12 There are also
no clinically relevant differences in rate of absorp-
tion when administered subcutaneously in the
abdomen, thigh, or arm. In addition, the iGlar-
Lixi ratio has no impact on the pharmacokinetics
of lixisenatide when administered alone versus
when given as Soliqua 100/33.12
Liraglutide
Liraglutide is an incretin mimetic with 97%
amino acid sequence homology to human GLP-
1, that acts as a long-acting, selective GLP-1 ago-
nist.21 This results in a longer half-life of
approximately 13 h and a protracted pharmacoki-
netic profile suitable for once-daily administra-
tion.22 Following subcutaneous injection,
liraglutide demonstrates a relatively slow rate of
absorption with maximum concentrations being
achieved in 8–12 h and absolute bioavailability of
about 55%.21 Liraglutide has a dose–response
relationship with regards to Cmax and AUC,
increasing proportionally over the therapeutic
dose range of 0.6–1.8 mg.21 Exposure to liraglu-
tide concentrations are considered comparable
upon subcutaneous administration in the abdo-
men, thigh, and arm.21 The combination of lira-
glutide with iDeg (Xultophy®) shows similar
journals.sagepub.com/home/tae 71
W Nuffer, A Guesnier et al.
pharmacokinetic and pharmacodynamic profiles
compared with its individual parts.13 No clinically
significant differences have been reported.
Clinical data
iGlarLixi
One phase II study (LixiLan proof-of-concept) as
well as two phase III studies (LixiLan-O and
LixiLan-L) were conducted to evaluate the clini-
cal safety and efficacy of the iGlar U-100/lixisena-
tide combination (iGlarLixi). Specific details
regarding the trial methods and efficacy outcomes
are found in Table 1. Specific adverse event rates
across the trials are listed in Table 2.
The LixiLan proof-of-concept study compared
the efficacy and safety of the combination iGlar-
Lixi versus iGlar once daily in patients with T2D
who were inadequately controlled on metformin
alone.23 A total of 323 subjects with an average
A1C of 8.1%, average age of 57, and an average
body mass index (BMI) of 32.1 kg/m2 were
enrolled in this 24-week trial with a primary end-
point of change in A1C from baseline. Patients
were initiated on iGlarLixi 10 units/5 μg or iGlar
10 units, administered subcutaneously within 1 h
before breakfast and were titrated based on units
of iGlar to achieve a target FPG of 80–100 mg/dl.
Patients taking iGlarLixi had significantly greater
reductions in A1C compared with iGlar (−1.82%
versus −1.64%, p = 0.01) and greater reductions
in 2-hour PPG levels compared with iGlar (−70
mg/dl versus −12 mg/dl, p < 0.0001). Treatment
with iGlarLixi was associated with weight loss
compared with weight gain with iGlar and there
were no significant differences in hypoglycemia
between groups. Rates of nausea and vomiting
were overall low, but higher in patients taking
iGlarLixi compared with iGlar, but discontinua-
tion rates due to GI AEs were low. The authors
concluded that iGlarLixi demonstrated superior
glycemic control with weight loss, no increased
risk of hypoglycemia and a low incidence of nau-
sea and vomiting compared to iGlar alone.
The LixiLan-O study compared iGlarLixi with
iGlar and lixisenatide individually in insulin-naïve
patients with T2D who were inadequately con-
trolled after at least 3 months of treatment with
metformin ± a second oral antidiabetic (OAD)
agent.24 A total of 1170 subjects with an average
A1C of 8.1%, average age of 58, and an average
 Table 1.  Trial methods and efficacy outcomes for iGlarLixi and IDegLira.

Study Mean baseline Background Treatment arms Mean final Baseline Mean A1C Proportion Mean body
characteristics therapy basal insulin A1C (%) change from of patients weight change
dose (units) baseline (%) achieving A1C from baseline
<7% (%) (kg)
Lixi- Age (years) = 56.8 Metformin iGlarLixi (n = 161) 36 8.1 –1.82 84 –1.16
Lan (24 BMI (kg/m2) = 32.1 iGlar (n = 162) 39 8.0 –1.64 78 +0.39
weeks) Duration of T2D
(years) = 6.7
Lixi- Age (years) = 58.4 Metformin ± iGlarLixi (n = 469) 39.8 8.1 –1.6 73.7 –0.3
Lan-O BMI (kg/m2) = 31.8 2nd OAD iGlar (n = 467) 40.3 8.1 –1.3 59.4 +1.1
(30 Duration of T2D Lixisenatide (n = – 8.1 –0.9 33.0 –2.3
weeks) (years) = 8.8 233)
Lixi- Age (years) = 60 Basal insulin ± iGlarLixi (n = 367) 47 8.1 –1.1 54.9 –0.7
Lan-L BMI (kg/m2) = 31.2 up to 2 OADs iGlar (n = 369) 47 8.1 –0.6 29.6 +0.7
(30 Duration of T2D
Therapeutic Advances in Endocrinology and Metabolism 9(3)

weeks) (years) = 12.05

DUAL Age (years) = 55 Metformin ± IDegLira (n = 833) 38 8.3 –1.9 81 –0.5
I (26 BMI (kg/m2) = 31.2 pioglitazone IDeg (n = 413) 53 8.3 –1.4 65 +1.6
weeks) Duration of T2D Liraglutide (n = 414) – 8.3 –1.3 60 –3.0
(years) = 6.9
DUAL Age (years) = 57.5 Basal insulin + IDegLira (n = 199) 45 8.7 –1.9 60 –2.7
II (26 BMI (kg/m2) = 33.7 metformin ± IDeg (n = 199) 45 8.8 –0.9 23 0.0
weeks) Duration of T2D sulfonylurea/
(years) = 10.5 glinides
DUAL Age (years) = 58.4 ±Metformin ± IDegLira (n = 292) 43 7.8 –1.4 75 +2.0
III (26 BMI (kg/m2) = 32.95 pioglitazone ± GLP-1RA (n = 146) – 7.7 –0.3 36 –0.8
weeks) Duration of T2D sulfonylurea
(years) = 10.4
DUAL Age (years) = 59.7 Sulfonylurea ± IDegLira (n = 289) 28 7.9 –1.5 79.2 +0.5
IV (26 BMI (kg/m2) = 31.6 metformin Placebo (n = 146) – 7.9 –0.5 28.8 –1.0
weeks) Duration of T2D
(years) = 9.15
DUAL Age (years) = 58.8 Metformin IDegLira (n = 278) 41 8.4 –1.81 71.6 –1.4
V (26 BMI (kg/m2) = 31.7 IGlar (n = 279) 66 8.2 –1.13 47 +1.8
weeks) Duration of T2D
(years) = 11.5

72 journals.sagepub.com/home/tae
BMI, body mass index; OAD, oral antidiabetic; T2D, type 2 diabetes.
 W Nuffer, A Guesnier et al.

Table 2.  Specific adverse event rates seen across the clinical trials for iGlarLixi and IDegLira.

Study Treatment Nausea Vomiting Diarrhea Hypoglycemia Serious Discontinuation

arms (%) (%) (%) (%) adverse (%)
events (%)
Lixi- iGlarLixi 7.5 2.5 3.1 21.7 5.6 3.7
Lan iGlar 0.0 0.6 3.7 22.8 3.7 0.0
Lix- iGlarLixi 9.6 3.2 9.0 25.6 3.8 2.6
Lan-O iGlar 3.6 1.5 4.3 23.6 4.1 1.9
Lixisenatide 24.0 6.4 9.0 6.4 3.9 9.0
Lixi- iGlarLixi 10.4 3.6 4.4 40.0 5.5 2.7
Lan-L iGlar 0.5 0.5 2.7 42.5 4.9 0.8
DUAL I IDegLira 9.0 4.0 8.0 32.0 2.0 12.0
IDeg 4.0 1.0 5.0 39.0 2.0 12.0
Liraglutide 20.0 8.0 13.0 7.0 3.0 18.0
DUAL II IDegLira 6.5 <5.0 6.5 24 4.0 1.0
IDeg 3.5 0.0 3.5 25 3.6 2.0
DUAL III IDegLira 3.1 NR NR 32.0 3.1 0.3
GLP-1RA 4.1 2.8 2.1 1.4
DUAL IV IDegLira 4.5 2.4 4.2 41.7 4.9 3.1
Placebo 3.4 2.7 4.8 17.1 3.4 1.4
DUAL V IDegLira 9.4 NR NR 28.4 NR NR
IGlar 1.1 49.1  
GLP-1RA, glucagon-like peptide-1 receptor agonists; NR, not reported.

BMI of 32 kg/m2 were enrolled in this 30-week
trial with a primary endpoint of change in A1C
from baseline. Patients on iGlar were initiated on
10 units once daily and titrated to a target FPG of
80–100 mg/dl with a maximum dose of 60 units/
day. Patients on lixisenatide were initiated on 10
μg once daily for 2 weeks and then increased to 20
μg once daily. Patients on iGlarLixi were initiated
on 10 units/5 μg once daily and titrated based on
iGlar units to a target FPG of 80–100 mg/dl with
a maximum dose of 60 units/20 μg, using two
pens with different iGlar:lixisenatide dose ratios
(2:1 and 3:1).
Patients taking iGlarLixi had significantly greater
reductions in A1C compared with iGlar or lixi-
senatide alone (−1.6%, −1.3%, and −0.9%
respectively, p < 0.0001 for both) and signifi-
cantly more patients taking iGlarLixi achieved an
A1C <7% compared with iGlar or lixisenatide
alone (73.7%, 59.4%, 33%, p < 0.0001 for both).
Mean body weight decreased with iGlarLixi and
lixisenatide but increased with iGlar. The rates of
hypoglycemia were similar between the iGlarLixi
and iGlar groups, but lower in the lixisenatide
group. Nausea, vomiting, and diarrhea were the
most common side effects in the iGlariLixi group
but occurred less frequently than in the lixisena-
tide group. Discontinuation rates due to GI AEs
were low, but higher in the lixisenatide group
compared with the iGlarLixi group.
The LixiLan-L study compared iGlarLixi with
iGlar in patients with T2D inadequately con-
trolled on basal insulin ± up to two OADs (met-
formin, sulfonylurea, glinide, SGLT-2 inhibitor,
or DPP4 inhibitor).25 During the 6-week run-in
phase, metformin was continued, other OADs
were discontinued, and patients on other basal
insulins were transitioned to iGlar and all doses
were optimized. A1C decreased during the run-in
phase by 0.4%. Patients with A1C >7%, but
FPG ⩽140 mg/dl, and iGlar dose ⩽50 units were
randomized to iGlar once daily at any time of day
and titrated to a maximum dose of 60 units once
daily or iGlarLixi once daily within 1 h before
breakfast. The iGlarLixi dose was based on the
iGlar dose during the run-in phase. Patients

journals.sagepub.com/home/tae 73
Therapeutic Advances in Endocrinology and Metabolism 9(3)
taking ⩾30 units/day started with iGlarLixi 30
units/10 μg using a 3:1 pen; patients taking <30
units/day started with iGlarLixi 20 units/10 μg
using a 2:1 pen. The dose was titrated based on
iGlar units to a FPG target of 80–100 mg/dl.
Patients taking iGlarLixi had significantly greater
reductions in A1C compared to patients taking
iGlar (−1.1% versus −0.6%, p < 0.0001) and
more patients taking iGlarLixi achieved an A1C
<7% (54.9% versus 29.6%, p < 0.0001). Body
weight decreased in the iGlarLixi group and
increased in the iGlar group (−0.7 kg versus +0.7
kg, p < 0.0001) and hypoglycemia rates were
similar between groups. The rates of GI AEs were
low in both groups, but significantly more com-
mon in the iGlarLixi group compared with the
iGlar group.
IDegLira
There were five phase III clinical trials conducted
on the degludec/liraglutide combination
(IDegLira), coined the DUAL™ (Dual Action of
Liraglutide and iDeg) clinical trial programs.
Specific details regarding these trials are found in
Table 1. Specific adverse event rates across the
trials are listed in Table 2. All of the DUAL trials
utilized ‘dose steps’ terminology for the combina-
tion IDegLira, with each dose step containing 1
unit of IDeg and 0.036 mg of liraglutide.
DUAL I randomly assigned 1663 adult T2D sub-
jects to IDegLira, IDeg or liraglutide on a 2:1:1
ratio.26 The primary endpoint for the trial was
change in hemoglobin A1C after 26 weeks, to
assess noninferiority of IDegLira compared with
iDeg [upper 95% confidence interval (CI) margin
of 0.3%], and superiority of IDegLira compared
with liraglutide (lower 95% CI margin of 0).
Subjects had a mean age of 55, mean A1C of
8.3%, and a mean BMI of 31.2 kg/m2. For the
IDegLira and IDeg groups, dosing started at 10
units of IDeg or 10 dose steps of IDegLira and
was titrated upwards twice a week, with a pre-
breakfast mean glucose target of 72–90 mg/dl.
Patients using liraglutide monotherapy started at
0.6 U and titrated up weekly to achieve the 1.8
mg dosing. IDegLira successfully demonstrated
noninferiority to iDeg (estimated treatment dif-
ference −0.47%, 95% CI −0.58 to −0.36, p <
0.0001) and superiority to liraglutide (treatment
difference −0.64%, 95% CI −0.75 to −0.53, p <
0.0001) after 26 weeks. Weight loss was highest
in the liraglutide group (−3.0 kg), followed by the
74 journals.sagepub.com/home/tae
IDegLira group (−0.5 kg), with the IDeg group
gaining weight (+1.6 kg). The authors noted sim-
ilar rates of adverse events across the three groups,
with the iDeg monotherapy group predictably
having the lowest rates of GI side effects, and the
liraglutide monotherapy having lowest rates of
hypoglycemia. Of note, the IDegLira group
reported lower rates of nausea compared with the
liraglutide group (8.8% compared with 19.7%)
and lower rates of hypoglycemia compared to the
iDeg group (1.8 events per patient year compared
with 2.6 events per patient year).
The DUAL II trial compared the efficacy of the
combination IDegLira with iDeg alone in patients
using basal insulin and metformin with or without
a secretagogue.27 A total of 413 subjects with an
average A1C of 8.8%, average age of 57–58, and
an average BMI of 33.7 kg/m2 were enrolled in
this 26-week trial with a primary endpoint of
change in A1C from baseline. Patients in both
groups started with 16 units of IDeg or 16 dose
steps of IDegLira. Titration occurred twice a
week utilizing a predefined titration algorithm,
with a prebreakfast mean glucose target range of
72–90 mg/dl. The IDegLira group demonstrated
a statistically significant improvement in A1C
compared with the iDeg group (A1C treatment
difference of −1.1%, 95% CI −1.3 to −0.8, p <
0.0001). Rates of hypoglycemia were comparable
between the groups, with 24% in the IDegLira
group and 25% in the iDeg group. Nausea was
reported as low in both groups, at 6.5% in the
IDegLira group and 3.5% in the iDeg group, and
the IDegLira group documented a 2.7 kg weight
loss effect, compared with no weight change in
the iDeg group (p < 0.0001). The authors con-
cluded that IDegLira demonstrated superior gly-
cemic control while maintaining a similar
side-effect profile and providing the additional
benefit of weight loss to subjects.
The third phase III trial with this combination,
the DUAL III, studied the effects of IDegLira in
T2D patients who were on maximum doses of
GLP-1 therapy with concomitant oral diabetes
therapies.28 The primary outcome was change
from baseline A1C intending to establish superi-
ority of the combination IDegLira compared with
maximum dose of GLP-1 therapy in patients with
T2D. Patients’ mean age was 58, mean baseline
A1C was 7.8% for IDegLira and 7.7% for the
GLP-1 group, and mean BMI was 33 kg/m2.
Similar to the DUAL II trial, initial dosing was 16
units or 16 dose steps, with a twice-weekly

titration targeting a mean prebreakfast glycemic
range of 72–90 mg/dl. After 26 weeks, the
IDegLira group successfully demonstrated supe-
riority, with an estimated A1C treatment differ-
ence of −0.94% (95% CI −1.11 to −0.78%, p <
0.001). The authors did note a weight loss differ-
ence that favored the unchanged GLP-1 group,
with the estimated treatment difference of 2.89 kg
(95% CI 2.17–3.62, p < 0.001). With regards to
safety, hypoglycemia rates in the IDegLira group
were 2.82 episodes per patient-year of exposure
(PYE), compared with 0.12 episodes per PYE
with the unchanged GLP-1 group. Nausea was
documented as occurring in 3.1% of patients in
the IDegLira group, compared with 4.1% of
patients in the unchanged GLP-1 group. Two
major adverse cardiovascular events (MACE)
occurred during the 26 weeks, both confirmed to
be a stroke, and both occurring in the IDegLira
treatment group.
DUAL IV examined the effects of the new combi-
nation drug in patients using sulfonylureas as
background therapy, with or without metformin.29
Importantly, this study population was insulin-
naïve. A total of 435 subjects were randomized in
this 26-week trial to IDegLira or placebo in a 2:1
ratio, with the primary outcome of A1C change
from baseline. The study population had an aver-
age A1C of 7.9%, an average age of 59–60 and an
average BMI of 31–32 kg/m2. Patients started
with 10 dose steps and titrated upward similar to
previous trials, with a twice-weekly schedule tar-
geting a mean fasting blood glucose of 72–108
mg/dl. This trial successfully established superi-
ority of IDegLira compared with placebo, with an
estimated treatment difference of 1.02% (95% CI
−1.18 to −0.87, p < 0.001). With regards to
adverse events, nausea was reported in 4.5% of
the treatment group, compared with 3.4% of the
placebo. Patients in the IDegLira group showed a
mean weight gain of 0.5 kg, while patients in the
placebo group had a mean weight loss of −1.0 kg,
demonstrating a treatment difference of 1.48 kg
(95% CI 0.90–2.06, p < 0.001). Hypoglycemia
occurred at a rate of 41.7% of the treatment
group and 17.1% with placebo. Of note, most of
these hypoglycemic episodes were mild to moder-
ate in nature, with only two episodes (0.7%)
being reported as severe with the treatment group,
and zero episodes in placebo.
The final phase III trial evaluating IDegLira was
the DUAL V trial. This 26-week trial assessed the
noninferiority of IDegLira compared with iGlar
journals.sagepub.com/home/tae 75
W Nuffer, A Guesnier et al.
in T2D patients previously using iGlar and met-
formin.30 The primary endpoint was change of
A1C from baseline, with a noninferiority upper
CI margin of 0.3%. A total of 557 patients
enrolled in the trial with an average age of 58.8,
average A1C of 8.4% in the IDegLira group and
8.2% in the iGlar group, and average BMI of 31.7
kg/m2. Patients using glargine alone continued on
the dose they were utilizing prior to enrollment;
patients in the IDegLira group discontinued their
glargine and started IDegLira at 16 dose steps.
Both groups utilized a twice-weekly titration algo-
rithm based on a prebreakfast mean glucose tar-
get of 72–90 mg/dl. The IDegLira group had a
maximum dose of 50 units of iDeg/1.8 mg of lira-
glutide; there was no maximum dose for the iGlar
group. This trial established noninferiority and
met criteria for statistical superiority with
IDegLira, demonstrating an estimated treatment
difference of −0.59% (95% CI −0.74 to −0.45%,
p < 0.01). Patients in the IDegLira group had a
mean weight loss of 1.4 kg, compared with mean
weight gain in the iGlar group of +1.8 kg, with an
estimated treatment difference of −3.20 kg (95%
CI −3.77 to −2.64, p < 0.001). Nausea was
reported at a higher rate with IDegLira (9.4%
compared with 1.1%), although the authors noted
that when evaluating nausea adverse events by
week, only ⩽4% of the IDegLira patients reported
this side effect in any given week interval.
Hypoglycemia rates were reported as 2.23 per
PYE in the IDegLira group, and 5.05 episodes
per PYE in the iGlar group, with an estimated
rate ratio between groups of 0.43 (95% CI 0.30–
0.61, superiority, p < 0.001).
Dosing and administration
Both combination products recommend stopping
both the basal insulin and GLP-1 agonist therapy
prior to starting the combination. For iGlarLixi,
the recommended starting dose is 15 units (15
U/5 μg) for patients previously using 30 units or
less of basal insulin, and 30 units (30 U/10 μg) for
patients using 30–60 units of basal insulin, admin-
istered subcutaneously once daily within an hour
of the first meal.12 The maximum dose is 60 units
(60 U/20 μg). For IDegLira, the recommended
starting dose is 16 units (16 U/0.58 mg) given
subcutaneously once a day. The maximum dose
for this product is 50 units (50 U/1.8 mg).13 Both
products have a suggested titration schedule
based upon average glucose readings and estab-
lished glycemic goals, with LixiLan suggesting
changes of 2–4 units once weekly and IDegLira
Therapeutic Advances in Endocrinology and Metabolism 9(3)
suggesting a 2 unit change every 3–4 days until
glycemic targets are achieved. In both cases, the
number listed in the device window correlates to
the basal insulin units to be delivered.
Place in therapy
The benefits of combining a GLP-1 agonist with
insulin therapy has been well documented, and is
mentioned as one possibility by treatment guide-
lines for the management of hyperglycemia in
T2D from the European Association for the
Study of Diabetes (EASD)/ADA.31 Within the
stepwise therapy approach, patients whose blood
glucose remain elevated despite OAD treatment
often progress to injection therapy with treatment
intensification. This can be challenging to initi-
ate, and is often delayed due to perceived biases
regarding injections and lack of resources to ade-
quately train patients on administration. A com-
bination, once-daily injection may help with this
transition by providing an easy initiation to injec-
tion therapy that does not compromise the effec-
tiveness of either agent. Of note, however, is the
fact that the FDA approved both products for
T2D patients who were inadequately controlled
on either basal insulin or a GLP-1 agonist, sug-
gesting patients should already be using injection
therapy before utilizing these products. While
hypoglycemia does occur with combination
GLP-1/basal insulin treatment, studies suggest
that the rates are comparable, if not slightly bet-
ter, than rates seen with insulin therapy alone.
Utilizing GLP-1 therapy in combination with
basal insulin reduces the overall insulin require-
ment needed to adequately manage patients’ gly-
cemia, likely leading to both less hypoglycemia
episodes and less weight gain. Basal insulins have
also been shown to pose much lower risk of hypo-
glycemia compared with patients using both basal
and bolus insulin, so the use of these products
could help familiarize patients with the process on
injecting medications, and provide good A1C
benefit, without the acute risk of hypoglycemia
seen with basal/bolus regimens. The positive
weight loss effects provided by GLP-1 agonists
will also offset some of the weight gain tradition-
ally seen with insulin therapy, as shown by the
trials presented in this review. Patients titrate the
dose in steps, usually by averaging morning glu-
cose readings, to approach specified glycemic
ranges. There were also lower rates of GI AEs
reported with the combination therapies in clini-
cal trials, possibly because this slow titration,
which starts with very low concentrations of
76 journals.sagepub.com/home/tae
GLP-1 agonist (lower than the monotherapy
titration), may help patients adjust to the medica-
tion better. Adherence is another consideration
with the combination products; studies have
shown that patients’ adherence to insulin therapy
decreases as the number of daily injections
increases.32,33 Delivering two medications with
one daily injection may avoid nonadherence
issues.
There are disadvantages to combination therapies
delivered together. Patients who experience
severe side effects with initiation of a new drug
therapy are often strongly averse to using that
product; in the case of combination products
such as these, a bad initial reaction to the therapy
could condition the patient to avoid both drug
classes, which are among the best therapeutic
tools for managing diabetes. There is also a risk of
medication errors, as patients may forget to dis-
continue their previous treatment, which may be
duplicated in the combination product. Particular
care should be given to counseling patients about
stopping any monotherapy duplicate prior to ini-
tiating treatment with the combination product
(Figure 1). In addition, the pen devices show only
the insulin units in the window, without reference
to the GLP-1 dose, which could lead to confusion
or dosing errors. Again, providing training and
education to patients about the device is key for
them to understand how these medications
should be titrated and dosed. Another potential
disadvantage to the combination products is that
any increases to dosing affect both the GLP-1
component as well as the insulin, with no ability
to vary either individual component. Providers
who may want to continue to increase insulin
while leaving the GLP-1 dose constant would not
be able to do so. There is a maximum amount of
insulin that can be delivered as well (60 units with
the iGlarLixi, 50 units with IDegLira), so T2D
patients with higher insulin resistance that require
greater insulin doses would need individual prod-
ucts for therapy. Cost is always a consideration;
depending on the health plan, specific GLP-1
agonists and specific insulin products may be pre-
ferred over these combination products. Choosing
formulary products may help to save patients
money, even if they have to give multiple injec-
tions instead of just one a day.
There are no trials directly comparing the two
combination GLP-1/basal insulin products.
Indirectly comparing the two, there are a few
notable differences. Lixisenatide has different

pharmacokinetics compared with liraglutide, and
is considered to have greater effects on post-pran-
dial blood glucose and less effects on fasting blood
glucose. The clinical impact of this difference is
debatable; the A1C reductions across the studies
suggest similar effects of approximately 1% to
>1.5% reduction with combination therapy. The
data suggest that IDegLira may have overall
slightly better impacts on A1C reduction across
trials, but it should also be noted that the pre-
specified glycemic targets were also more aggres-
sive in the DUAL trials, which could account for
this difference. Comparing the DUAL V trial
with the LixiLan-L, where both combination
products were compared with the use of iGlar,
both preparations established superiority over
glargine therapy, with IDegLira showing an addi-
tional −0.59% A1C lowering, and iGlarLixi
showing similar reductions of −0.50%. Notably,
IDegLira did demonstrate statistically lower rates
of hypoglycemia, whereas iGlarLixi demonstrated
similar rates of hypoglycemia compared with
iGlar treatment. This could be due to the second
notable difference between products; the iDeg
inclusion within IDegLira, which has been shown
to be more predictable and cause less hypoglyce-
mic events compared with iGlar.34 Overall, how-
ever, it is difficult to draw any definitive
conclusions on the efficacy between the products
without a direct head-to-head comparison.
Finally, it should be noted that recent data have
demonstrated that patients with high cardiovas-
cular risk may receive cardiovascular benefit with
the use of liraglutide monotherapy.35 Recognizing
that these data cannot be extrapolated to the
combination product, it is still encouraging to see
macrovascular benefit with the GLP-1 compo-
nent. Lixisenatide currently has not demonstrated
similar cardiovascular benefit, either by itself or in
combination.
Conclusion
The two new combination products, IDegLira
and iGlarLixi, provide additional options for cli-
nicians and patients that may help ameliorate
some of the side effects seen with insulin therapy
by itself, while still providing clinically robust
A1C improvements. Providing a once-daily
injectable option that contains two effective phar-
macologic agents may help clinicians transition
patients who need treatment intensification more
easily. Providers will be limited in customizing
doses of the individual components with these
products, and there is a risk that a patient who is
journals.sagepub.com/home/tae 77
W Nuffer, A Guesnier et al.
intolerant to the combination therapy may be
averse to using either class of medication in the
future.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
Wesley Nuffer and Ashley Guesnier have no con-
flicts of interest to declare. Jennifer Trujillo has
served as a consultant on the Sanofi ad board.
ORCID iD
Wesley Nuffer https://orcid.org/0000-0002-33
55-4582
References
1. Centers of Disease Control and Prevention.
National diabetes statistics report, 2017, https://
www.cdc.gov/diabetes/pdfs/data/statistics/
national-diabetes-statistics-report.pdf (2017,
accessed 23 August 2017).
2. DeFronzo RA, Eldor R and Abdul-Ghani M.
Pathophysiologic approach to therapy in patients
with newly diagnosed type 2 diabetes. Diabetes
Care 2013; 36(Suppl. 2): S127–138.
3. Marathe PH, Gao HX and Close KL. American
Diabetes Association Standards of Medical Care
in Diabetes 2017. J Diabetes 2017; 9: 320–324.
4. King P, Peacock I and Donnelly R. The UK
prospective diabetes study (UKPDS): clinical and
therapeutic implications for type 2 diabetes. Br J
Clin Pharmacol 1999; 48: 643–648.
5. Stark Casagrande S, Fradkin JE, Saydah SH,
et al. The prevalence of meeting A1C, blood
pressure, and LDL goals among people with
diabetes, 1988–2010. Diabetes Care 2013; 36:
2271–2279.
6. Lipska KJ, Yao X, Herrin J, et al. Trends in drug
utilization, glycemic control, and rates of severe
hypoglycemia, 2006–2013. Diabetes Care 2017;
40: 468–475.
7. Khunti K, Wolden ML, Thorsted BL, et al.
Clinical inertia in people with type 2 diabetes: a
retrospective cohort study of more than 80,000
people. Diabetes Care 2013; 36: 3411–3417.
8. Khunti K, Nikolajsen A, Thorsted BL, et al.
Clinical inertia with regard to intensifying therapy
in people with type 2 diabetes treated with basal
insulin. Diabetes Obes Metab 2016; 18: 401–409.
Therapeutic Advances in Endocrinology and Metabolism 9(3)
9. Schwartz SS, Epstein S, Corkey BE, et al. The
time is right for a new classification system for
diabetes: rationale and implications of the beta-
cell-centric classification schema. Diabetes Care
2016; 39: 179–186.
10. Abdul-Ghani MA, Puckett C, Triplitt C, et al.
Initial combination therapy with metformin,
pioglitazone and exenatide is more effective than
sequential add-on therapy in subjects with new-
onset diabetes. Results from the Efficacy and
Durability of Initial Combination Therapy for
Type 2 Diabetes (EDICT): a randomized trial.
Diabetes Obes Metab 2015; 17: 268–275.
11. Anderson SL and Trujillo JM. Basal insulin use
with GLP-1 receptor agonists. Diabetes Spectr
2016; 29: 152–160.
12. Sanofi-aventis U.S. Soliqua (package insert).
http://products.sanofi.us/Soliqua100–33/
Soliqua100–33.pdf (2016, accessed 23 August
2017).
13. Novo Nordisk. Xultophy (package insert). http://
www.novo-pi.com/xultophy10036.pdf (2016,
accessed 23 August 2017).
14. Haahr H and Heise T. A review of the
pharmacological properties of insulin degludec
and their clinical relevance. Clin Pharmacokinet
2014; 53: 787–800.
15. Jonassen I, Havelund S, Hoeg-Jensen T, et al.
Design of the novel protraction mechanism
of insulin degludec, an ultra-long-acting basal
insulin. Pharm Res 2012; 29: 2104–2114.
16. Heise T, Nosek L, Bottcher SG, et al. Ultra-
long-acting insulin degludec has a flat and
stable glucose-lowering effect in type 2 diabetes.
Diabetes Obes Metab 2012; 14: 944–950.
17. Sanofi-aventis U.S. Lantus (package insert).
http://products.sanofi.us/lantus/lantus.html
(2015, accessed 23 August 2017).
18. Heise T, Tack CJ, Cuddihy R, et al. A new-
generation ultra-long-acting basal insulin with
a bolus boost compared with insulin glargine
in insulin-naive people with type 2 diabetes: a
randomized, controlled trial. Diabetes Care 2011;
34: 669–674.
19. Barnett AH. Lixisenatide: evidence for its
potential use in the treatment of type 2 diabetes.
Core Evid 2011; 6: 67–79.
20. Distiller L and Ruus P. Pharmacokinetics and
pharmacodynamics of a new GLP-1 agonist
AVE0010 in type 2 diabetes patients [abstract].
Diabetes 2008; 57: A154–A155.
21. Novo Nordisk. Victoza (package insert). http://
www.novo-pi.com/victoza.pdf (2010, accessed 23
August 2017).
78 journals.sagepub.com/home/tae
22. Neumiller JJ and Campbell RK. Liraglutide: a
once-daily incretin mimetic for the treatment of
type 2 diabetes mellitus. Ann Pharmacother 2009;
43: 1433–1444.
23. Rosenstock J, Diamant M, Aroda VR, et al.
Efficacy and safety of LixiLan, a titratable fixed-
ratio combination of lixisenatide and insulin
glargine, versus insulin glargine in type 2 diabetes
inadequately controlled on metformin monotherapy:
the LixiLan proof-of-concept randomized trial.
Diabetes Care 2016; 39: 1579–1586.
24. Rosenstock J, Aronson R, Grunberger G, et al.
Benefits of LixiLan, a titratable fixed-ratio
combination of insulin glargine plus lixisenatide,
versus insulin glargine and lixisenatide
monocomponents in type 2 diabetes inadequately
controlled on oral agents: the LixiLan-O
randomized trial. Diabetes Care 2016; 39: 2026–
2035.
25. Aroda VR, Rosenstock J, Wysham C, et al.
Efficacy and Safety of LixiLan, a titratable
fixed-ratio combination of insulin glargine plus
lixisenatide in type 2 diabetes inadequately
controlled on basal insulin and metformin: the
LixiLan-L randomized trial. Diabetes Care 2016;
39: 1972–1980.
26. Gough SC, Bode B, Woo V, et al. Efficacy and
safety of a fixed-ratio combination of insulin
degludec and liraglutide (IDegLira) compared
with its components given alone: results of a
phase 3, open-label, randomised, 26-week, treat-
to-target trial in insulin-naive patients with type
2 diabetes. Lancet Diabetes Endocrinol 2014; 2:
885–893.
27. Buse JB, Vilsboll T, Thurman J, et al.
Contribution of liraglutide in the fixed-ratio
combination of insulin degludec and liraglutide
(IDegLira). Diabetes Care 2014; 37: 2926–2933.
28. Linjawi S, Bode BW, Chaykin LB, et al. The
efficacy of IDegLira (insulin degludec/liraglutide
combination) in adults with type 2 diabetes
inadequately controlled with a GLP-1 receptor
agonist and oral therapy: DUAL III randomized
clinical trial. Diabetes Ther 2017; 8: 101–114.
29. Rodbard HW, Bode BW, Harris SB, et al. Safety
and efficacy of insulin degludec/liraglutide
(IDegLira) added to sulphonylurea alone or to
sulphonylurea and metformin in insulin-naive
people with type 2 diabetes: the DUAL IV trial.
Diabet Med 2017; 34: 189–196.
30. Lingvay I, Perez Manghi F, Garcia-Hernandez
P, et al. Effect of insulin glargine up-titration
vs insulin degludec/liraglutide on glycated
hemoglobin levels in patients with uncontrolled
type 2 diabetes: the DUAL V randomized clinical
trial. JAMA 2016; 315: 898–907.

31. Inzucchi SE, Bergenstal RM, Buse JB, et al.
Management of hyperglycemia in type 2 diabetes,
2015: a patient-centered approach—update to
a position statement of the American Diabetes
Association and the European Association for
the Study of Diabetes. Diabetes Care 2015; 38:
140–149.
32. Peyrot M, Rubin RR, Kruger DF, et al.
Correlates of insulin injection omission. Diabetes
Care 2010; 33: 240–245.
journals.sagepub.com/home/tae 79
W Nuffer, A Guesnier et al.
33. Sarbacker GB and Urteaga EM. Adherence to
insulin therapy. Diabetes Spectr 2016; 29: 166–
170.
34. Marso SP, McGuire DK, Zinman B, et al.
Efficacy and safety of degludec versus glargine
in type 2 diabetes. N Engl J Med 2017; 377:
723–732.
Visit SAGE journals online
35. Maro SP, Daniels GH, Brown-Frandsen K, et al. journals.sagepub.com/
Liraglutide and cardiovascular outcomes in type 2 home/tae
diabetes. N Engl J Med 2016; 375: 1797–1798. SAGE journals