review article

Diabetes, Obesity and Metabolism 15: 301–309, 2013.

© 2012 Blackwell Publishing Ltd

article
review
Insulin degludec: overview of a novel ultra long-acting basal
insulin
S. C. L. Gough1 , S. Harris2 , V. Woo3 & M. Davies4
1 Oxford Centre for Diabetes, Endocrinology and Metabolism and NIHR Oxford Biomedical Research Centre, Oxford, UK
2 Department of Family Medicine/Division of Endocrinology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
3 University of Manitoba, Winnipeg, Manitoba, Canada
4 University of Leicester, Leicester, UK

All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible
and peakless pharmacodynamic (PD) effect that endures over 24 h from once-daily dosing. Insulin degludec is a novel acylated basal insulin with
a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection.
PK/PD studies show that insulin degludec has a very long duration of action, with a half-life exceeding 25 h. Once-daily dosing produces a
steady-state profile characterized by a near-constant effect, which varies little from injection to injection in a given patient. Clinically, insulin
degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once-daily insulin glargine, in both basal+bolus
and basal-only insulin regimens. The constancy of the steady-state profile of insulin degludec also means that day-to-day irregularities at the
time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients.
Keywords: basal insulin, hypoglycaemia, insulin analogue, insulin degludec, insulin glargine, type 1 diabetes, type 2 diabetes

Date submitted 4 October 2012; date of first decision 19 November 2012; date of final acceptance 11 December 2012

Introduction: The Need for a New Basal
Insulin
The concept of a basal insulin can be traced back to the 1950s
when products such as neutral protamine Hagedorn (NPH) and
the Lente and Ultralente insulins were formulated to extend
the duration of glucose-lowering action and thereby reduce
injection frequency for patients. Their use, alongside faster-
acting mealtime insulins, led to the concept of basal+bolus
therapy, which became established as a physiological approach
to insulin replacement therapy [1], with the Diabetes Control
and Complications Trial demonstrating the benefits of multi-
dose insulin regimens [2,3]. This approach remains the
standard of care for many individuals with type 1 diabetes
(T1D) and is being widely adopted for type 2 diabetes (T2D)
as the disease progresses. The 1980s saw the emergence
of continuous subcutaneous insulin infusion (CSII) as an
alternative to multiple injection therapy, but resource, funding
and prescription issues continue to limit its role to a minority
of patients in most countries, although some 40% of patients
with T1D in the USA are estimated to be using it [4]. In the
1990s, the first rapid-acting insulin analogues were developed
with the ability to improve post-prandial glucose control
while reducing the risk of hypoglycaemia in both multiple
injection and CSII therapy [5,6]. Advances in basal insulin
Correspondence to: Prof. Stephen Charles Langford Gough, Oxford Centre for Diabetes,
Endocrinology and Metabolism and NIHR Oxford Biomedical Research Centre, Churchill
Hospital, Headington, Oxford OX3 7JL, UK.
E-mail: stephen.gough@OCDEM.ox.ac.uk
therapy came with the insulin analogues glargine and detemir,
which first entered clinical use in the years 2000 and 2004,
respectively. While NPH insulin is injected as a precipitate,
these analogues achieve protracted absorption through other
mechanisms, described below, meaning they can be injected
as clear solutions. This avoids the risk of incomplete re-
suspension of the formulation before injection and hence
removes a well-recognized source of injection-to-injection
variability in pharmacodynamic (PD) effect [7]. Glargine and
detemir produce more prolonged and less peaked PD responses
than NPH insulin, and both analogues produce lower intra-
patient injection-to-injection variability in glucose-lowering
effect [8,9]. Clinically, this profile generally enables once-daily
dosing and incurs a lower risk of hypoglycaemia overnight
than NPH insulin, as demonstrated in studies with ‘treat-to-
target’ protocols [10–13]. Consequently, the basal analogues
are now widely used for insulin initiation in T2D, added to
oral antidiabetic (OAD) therapy as a simple, well-tolerated
treatment to establish patient confidence in insulin, which can
be intensified as needed [14,15].
Despite the advantages over NPH insulin, clamp study and
clinical data show that the glucose-lowering effect of current
basal insulin analogues tends to wax and wane considerably
over 24 h with once-daily dosing [16]. When dosed at bedtime
or in the evening, as is generally done for titration against
fasting plasma glucose (FPG), a rising kinetic profile can
conspire with variability in absorption rate to increase the
risk of nocturnal hypoglycaemia (albeit that this risk is reduced
versus NPH). This remains a major concern with basal insulins
review article
and is a significant limiting factor in titration. Indeed, fear of
hypoglycaemia can intimidate patients and their caregivers and
frequently leads to delayed insulin initiation and/or tentative
dose titration [17]. A lack of confidence in the setting of FPG
targets will in turn limit the achievement of HbA1c targets.
The daytime waning of effect can also be problematic, such
that some patients, particularly those with T1D, who tend to
use lower doses, require twice daily dosing to avoid afternoon
periods of hyperglycaemia [16]. This is less convenient, and
is also less efficient since twice-daily dosing of a basal insulin
tends to drive up dose consumption disproportionately to
the gain in glycaemic control [15,16,18]. Also, while glargine
and detemir represent an improvement over NPH, there may
still be variability in the total and maximum glucose-lowering
effect from injection to injection [8]. If patients experience
varying FPG readings despite being consistent in their dosing,
behaviour and calorie intake, then this can create confusion
and erode confidence in dose titration.
An improved basal insulin would need to deliver a constant
and predictable level of glucose-lowering effect over 24 h
from an injection schedule not exceeding once daily. The
currently available basal analogues are perceived by many
to have durations of action close to 24 h. However, the
definition of duration of action is rather subjective and is
usually determined according to the criteria used in clamp
studies to define onset and end of action [9]. With little or no
overlap in the absorption (and hence glucose-lowering action)
between one dose and the next, it follows that the dosing
schedule can result in a high plasma peak : trough ratio, with
attendant risk periods for relative hypo- and hyperglycaemia.
Indeed, when dosed in the evening, current basal insulins tend
to reach peak plasma levels close to the pre-breakfast titration
target point, and this will have the effect of maximizing the
peak : trough discrepancy because absorption will subsequently
wane over the rest of the day. An insulin that was absorbed
for >24 h would, with once-daily dosing, reach steady state
after a few days to provide more stable plasma insulin levels
than previously possible. With such a profile, some flexibility
in dose timing would also become possible, because day-to-
day inconsistencies in administration time would have only a
minor impact on the plasma kinetics.
The Unique Mechanism of Protraction of Insulin
Degludec
The traditional approach to prolonging insulin action has been
to increase the apparent molecular mass of the insulin complex
because large molecules are slower to pass through capillary
membranes into the circulation than small ones. Human insulin
naturally self-assembles at high concentrations into hexamers,
each of which incorporates two zinc ions. This is believed to
be an adaptation for efficient storage within β-cell vesicles.
A tolerable injection volume requires that exogenous insulin
products are formulated at concentrations at which insulin
becomes hexameric. Absorption from a subcutaneous depot
is, therefore, naturally protracted due to the time taken for
these hexamers to dissociate into monomers. In the case of
basal insulin development, the effective molecular mass has
302 Gough et al.
DIABETES, OBESITY AND METABOLISM
Figure 1. Chemical structure of insulin degludec. Adapted with
permission from Ref. [21].
been increased further in a number of ways. NPH and the
Lente insulins were formulated as pre-formed protamine- or
zinc-based precipitates. Insulin glargine is engineered to be
soluble in the pharmaceutical formulation, but to precipitate
in the higher pH environment of the subcutaneous depot [19].
Insulin detemir forms a hexamer–dihexamer equilibrium and
is further retained in the injection depot by reversible albumin
binding, with both these properties the result of an acylated
fatty acid side chain [20].
Novel protraction mechanisms might further improve the
kinetic properties of a basal insulin. In the case of insulin
degludec, hexamers link together by contacts involving an
acylated ligand composed of a glutamic acid spacer (attached
to the B29 amino acid residue, with the B30 threonine residue
removed) and a fatty diacid side chain of 16 carbon atoms [21].
The name ‘degludec’ is derived from the chemical name of this
complex (figure 1).
Data from spectroscopy [21], size exclusion chromatography
[21] and electron microscopy studies [22] support the following
hypothesis for the prolonged absorption of degludec:
Phenol is commonly used at low concentration in the
pharmaceutical formulation of insulin products as a stabilizing
excipient. In its presence, degludec adapts a stable dihexameric
state, but phenol rapidly diffuses from the depot following
injection and the hexameric conformation of degludec
immediately changes to allow hexamers to link together as
long chains. These are constructed of hundreds of hexameric
units in length, but they remain soluble [21]. The hexamers
are linked one to another by a single contact between one
of the fatty-acid moieties and the zinc-containing core of a
neighbouring hexamer [21]. Zinc will gradually diffuse from
these complexes – most likely where exposed in the terminal
hexamers at each end of the chain – causing the chains to
shorten as they slowly disassemble to release monomers, which
are readily absorbed (figure 2). The release of monomers
is thought to represent the rate-limiting step in insulin
absorption rather than, for example, blood perfusion of the
depot region [21]. Theoretically, this should result in constancy
of degludec plasma level with an appropriate dose schedule.
Insulin degludec also binds reversibly to plasma albumin. This
property adds little to its duration of action, but is likely to buffer
Volume 15 No. 4 April 2013
DIABETES, OBESITY AND METABOLISM
Figure 2. Schematic representation of insulin degludec protraction
mechanism. Dihexamers in the pharmaceutical formulation assemble into
multi-hexamer chains immediately after subcutaneous injection. These
slowly disassemble with the diffusion of zinc to release a steady supply of
degludec monomers into the circulation. Adapted with permission from
Ref. [21].
the PD consequence of any acute change in absorption rate that
does occur, as described previously for insulin detemir [23].
Receptor Interaction Profile
Another important aspect of the molecular pharmacology of
degludec, given recent concerns over the mitogenic potential
of some insulin analogues, is that of its receptor interaction
profile. A study of binding affinities, involving human insulin-
like growth factor-1 (IGF-1) receptors and recombinant human
insulin receptors (both isoforms, hIR-A and hIR-B) showed
degludec to have similar affinities for hIR-A and hIR-B insulin
receptors (13 and 15% relative to human insulin) with a low
affinity for the IGF-1 receptor (2% relative to human insulin)
[24]. The binding kinetics of degludec to the insulin receptor
did not differ to human insulin. The mitogenicity of degludec
was determined by measuring 3 H-thymidine incorporation
into L6 myoblasts expressing hIRs (L6-hIR), primary human
mammary epithelial cells, and cell lines from human colon and
mammary adenocarcinomas. The metabolic effects of degludec
were determined by lipogenesis in rat adipocytes, glycogen
accumulation in rat hepatocytes and glycogen synthesis in rat
skeletal muscle cells, L6-hIR and mammary adenocarcinoma
cells. These experiments showed degludec to elicit the same
metabolic responses (with equivalent maximal effects) as
human insulin, but with reduced mitogenicity, ranging from 4
to14% relative to human insulin [24]. Thus, insulin degludec
was found to be a full agonist at the insulin receptor,
maintaining the metabolic responses of human insulin, but
with a low IGF-1 receptor binding affinity and hence a
low mitogenic : metabolic potency ratio. The equipotency of
degludec and human insulin with regard to metabolic responses
suggested that degludec would have molar equipotency to
Volume 15 No. 4 April 2013
review article
human insulin in clinical use despite a lower insulin receptor
binding affinity. This expectation has been borne out in
subsequent clamp and clinical studies, described below.
An Ultra-long and Stable
Pharmacokinetic/Pharmacodynamic Profile
The potential for an ultra-long action with constancy of effect
was first observed in a steady-state pharmacokinetic (PK) study
of 12 subjects with T1D who received 5.0 nmol/kg of degludec
once daily for 6 consecutive days [25]. The steady-state PK
profile (indicating the plasma drug concentration at which
absorption over 24 h balances elimination over 24 h) was
smooth and stable across 24 h. Following the completion of the
6-day study period, insulin degludec plasma levels decreased
with a terminal half-life (t 1/2 – the time for the plasma level to
decline by 50% after the final dose) of more than 24 h, with
degludec still detectable after 96 h.
Similar results were reported from a randomized, double-
blind, two-period, crossover trial, in which 66 patients with
T1D received one of three fixed once-daily doses (0.4, 0.6 or
0.8 U/kg) of degludec or glargine for 8 days (with a wash-out
period between treatments), with a 42-h euglycaemic glucose
clamp performed on each final treatment day along with
blood sampling for kinetics over 120 h [22,26]. Degludec again
showed a stable PK profile that increased proportionally with
dose. Serum degludec concentrations were equally distributed
between the first and second 12-h post-dosing periods
(AUC0-12h /AUCtotal = 0.5), whereas for glargine exposure was
higher during the first 12 h (AUC0–12h /AUCtotal = 0.6) [26].
Degludec was still detectable in serum at 120 h following final
dose, whereas glargine tended to become undetectable 36–48
h post-dosing. The mean terminal t 1/2 was 25.4 h for degludec
and 12.5 h for glargine. A similar result was obtained in a
non-comparative clamp study of 49 patients with T2D, where
a terminal t 1/2 of 25.1 h was reported [27]. For comparison,
NPH insulin is reported to have a terminal t 1/2 of 5–10 h
[28]. Steady-state plasma levels of degludec are reached with
once-daily dosing after 2–3 days [29], and it is noteworthy that
the PK profile of degludec is unaffected by hepatic [30] or renal
impairment, including during dialysis [31].
Isoglycaemic clamp studies show that the stable PK profile
of degludec translates into a stable glucose-lowering action.
The PD profile of once-daily degludec in the T1D study was
reported to be flat for the 0.6 and 0.8 U/kg doses over the 42-h
euglycaemic glucose clamp (clamp blood glucose 100 mg/dl)
[22]. At all doses, the glucose-lowering effect of degludec was
still evident at 42 h. The PD effects of once-daily degludec (0.4,
0.6, and 0.8 U/kg) were also investigated in the T2D study [27],
and after 6 days of treatment the glucose-lowering effect of
degludec was found to be evenly distributed between the first
and second 12-h periods for all the three dose levels, reflecting
the PK data (figure 3).
In terms of variability of effect, clamp studies have suggested
that insulin degludec might have substantial clinical advantages.
In a double-blind, parallel-group study, Heise and colleagues
randomized 54 patients with T1D to receive 0.4 U/kg of
degludec or glargine once daily for 12 days [32]. On treatment
doi:10.1111/dom.12052 303
review article
Figure 3. (A) Mean glucose infusion rate profiles with insulin degludec at
steady state following 6 days of once-daily administration in subjects with
type 2 diabetes. (B) Twenty-six-hour mean blood glucose profiles during
these clamp studies. Adapted with permission from Ref. [27].
days 6, 9 and 12 (at steady state) patients underwent 24-h
euglycaemic clamps, with blood glucose fixed at 5.5 mmol/l.
The variability across the three clamp days in the overall glucose
infusion rate (GIR), reflecting the glucose-lowering effect, was
reduced by 75% for degludec compared with glargine (i.e. was
4-fold lower), with respective (AUCGIR 0-24h ) CV values of 20 vs.
82%, p < 0.0001. The respective CV values for the maximum
effect (GIRmax ) were 18 vs. 60%, p < 0.0001. Furthermore, the
metabolic effect of degludec was evenly distributed between
the first and second 12 hours (ratio of AUC-GIR0–12h : AUC-
GIR0–24h ; geometric mean: 0.50 vs. 0.57 with insulin glargine)
and this distribution was also less variable than with glargine
(CV 10 vs. 17%, p < 0.001) [33]. There was a lower day-to-
day variability in the fluctuation around the mean GIR value
across the 24-h clamp period with degludec than glargine,
with CV values of 31 vs. 73%, respectively, p < 0.0001 [32].
Moreover, when the GIR data were divided into values for
sequential 2-h intervals, the lower within-subject variability of
degludec was found to be consistent over time, whereas the
variability of glargine was not only higher but also tended to
increase substantially after 8 h. In terms of overall total glucose-
lowering effect, this study also showed degludec to have equal
molar potency to glargine. Finally, the region of injection has
been shown to have little effect on the overall PD effect of
degludec, with overall PK exposure slightly reduced (by ∼6%)
with administration into the thigh versus the abdomen or
deltoid [34].
304 Gough et al.
DIABETES, OBESITY AND METABOLISM
Clinical Expectations
Collectively, the available PK/PD data support the expectation
that degludec will provide a near constant PD effect of
long duration. This has a number of implications for dosing
and safety. Notably, with once-daily dosing, degludec should
produce a steady-state concentration with a low peak : trough
ratio, which, coupled with low day-to-day variability, raises the
expectation of a very low risk of hypoglycaemia [32].
Another implication of a long t 1/2 and low variability is
that at steady state the PK/PD profile becomes less critically
dependent upon the time at which injections are made each day.
Consequently, there should be greater tolerance for flexibility
in dose timing. This possibility has been clinically tested and is
elaborated in the discussion of clinical data below.
An interesting implication of the novel protraction
mechanism of degludec is that, unlike other basal insulin
analogues, it could be co-formulated with a rapid-acting
analogue. This has not been possible previously because
mixtures of two different insulins are liable to form hybrid
hexamers with unpredictable and/or inappropriate absorption
kinetics. Co-formulation of insulin aspart with insulin degludec
is possible, however, because the hexameric conformational
properties of insulin degludec mean that the two insulins do
not interact [21]. Therefore, the discrete PK/PD profiles of the
two insulin components are preserved, hence this promising
combination product is undergoing clinical testing [35–37].
Another formulation undergoing testing is a double-strength
‘U200’ (200 U/mL) insulin degludec, and this has been
found in a clamp study to have bioequivalence to standard
strength (U100) degludec as well as a similar steady-state
PD profile, suggesting that U100 and U200 degludec could
be used interchangeably in clinical practice [38–40]. A U200
formulation is likely to prove beneficial in T2D where obesity
and insulin resistance frequently require high daily doses,
which are sometimes not possible to administer in a single
injection using available basal insulin products. A prefilled pen
device enables the administration of up to 160 U of the U200
formulation in a single injection [40].
Insulin Degludec in Clinical Use
The evaluation of insulin degludec in the ‘BEGIN®’ studies
represents the largest and most comprehensive phase 3
programme undertaken for an insulin product, with more
than 5500 patients recruited. Further studies are evaluating
the insulin degludec+aspart combination. The BEGIN studies
have collectively evaluated insulin degludec in basal+bolus
therapy for T1D, and as basal+OAD and basal+bolus therapy
in T2D. In most of these studies, insulin glargine has been the
comparator using a treat-to-target protocol. Here, the basal
insulin doses of the comparator groups are titrated to the same
FPG target. This approach is intended to result in a similar level
of achievement for overall blood glucose control, hence the
primary statistical assessment of efficacy is for non-inferiority
of the test compound, based on an a priori difference in HbA1c
of 0.4% (∼4 mmol/mol). In this setting, any between-treatment
differences emerge in other endpoints, such as tolerability and
safety issues, with hypoglycaemia rate being an endpoint of
Volume 15 No. 4 April 2013
DIABETES, OBESITY AND METABOLISM review article
primary interest. As noted below, the phase 2 studies of insulin

units if specified)

60 units 51 units
degludec showed remarkably low incidences of hypoglycaemia,

dose (U/kg, or

IGlar

0.82

1.42

0.60

0.35

0.66
Total insulin
hence a more ambitious FPG titration target (aiming for

Table 1. Reported data concerning HbA1c, fasting blood glucose control and insulin dose in studies comparing insulin degludec with insulin glargine using equal once-daily dosing regimens [40–45].
4.0–4.9 mmol/l) than had previously been used in treat-to-

IDeg vs. IGlar IDeg

target insulin trials was adopted for the phase 3 programme in

0.75

1.46

0.59

0.28

0.62
order to strive for the low HbA1c levels advocated in guidelines.
Results from these studies are currently being published, and

comparison

p = 0.005
available data are here summarized in Tables 1 and 2.

outcome

−3.72∗ −3.39∗ p = 0.02

FPG

−0.54 ns

ns

ns

ns
Basal+Bolus Therapy

−3.3∗
IGlar

−1.4

−2.0
(mmol/l)

n/a
The first clinical data reported for degludec in patients with

FPG
T1D came from a small-scale phase 2 proof-of-concept study

−3.8∗
−1.6

−1.3

−2.3
IDeg
with patients randomized to evening injections of degludec

n/a
or glargine, with insulin aspart given at mealtimes [41].
Insulin degludec and glargine produced similar improvements

n/a 5.7∗
in HbA1c, but the mean rate of confirmed hypoglycaemia

IGlar

7.2∗
9.7∗
6.4∗

9.6∗
6.2∗
9.5
8.9
9.7
8.3
9.2
was 28% lower with degludec than glargine, while nocturnal

FPG (mmol/l)
Baseline Final
hypoglycaemia was reduced by 58% (Table 2). In a large-scale
phase 3 study, patients with T1D were randomized to receive

n/a 5.6∗

IDeg, insulin degludec; IGlar, insulin glargine; n/a, not available (data not provided in currently available publications); ns, not significant.
once-daily insulin degludec or glargine, again with mealtime

IDeg

6.9∗
9.6∗
5.9∗

9.6∗
5.9∗
9.9
8.3
9.1
7.8
9.2
insulin aspart [42]. After 1 year, HbA1c had improved to a
similar extent in both groups at similar total insulin doses; hence

HbA1c outcome

Non-inferiority
−0.39 (–4) Non-inferiority

−1.06 (–12) −1.19 (-13) Non-inferiority

−1.24 (–13) −1.35 (-15) Non-inferiority

Non-inferiority
the primary endpoint of non-inferiority was met for insulin

IDeg vs. IGlar

confirmed

confirmed

confirmed

confirmed

confirmed
comparison
degludec (Table 1). The rate of confirmed (plasma glucose
<3.1 mmol/l) nocturnal hypoglycaemia was significantly 25%
lower with degludec than glargine, while rates of overall

∗Data estimated or calculated herein, that is not reported in source publication, or reported but in different units.
−0.62 (–7) ns
confirmed hypoglycaemia were similar (Table 2). Severe
hypoglycaemic episodes (requiring third-party intervention)

−1.1 (–12) −1.2 (13)

occurred at similar low rates in both treatment groups.
IGlar

n/a
A similar protocol has also been used in a T2D trial
in which once-daily degludec or glargine were given with
(mmol/mol∗)
HbA1c %

−0.57 (–6)

−0.4 (–4)

mealtime insulin aspart, with or without metformin and/or

pioglitazone [43]. After 1 year, degludec and glargine were

−1.3
IDeg

associated with similar HbA1c reductions (Table 1), and an

HbA1c <7.0% (<53 mmol/mol) was achieved by 49 and
HbA1c % (mmol/mol∗)

50%, respectively. Rates of confirmed overall and nocturnal

7.3∗ (56)

7.2∗ (55)

7.0∗ (53)
8.3 (67)
7.6 (62)
7.7 (61)

8.4 (68)

8.2 (66)

hypoglycaemia were significantly lower with degludec than 8.3 (67)

IGlar

n/a

glargine, being reduced, respectively, by 18 and 25%, with n/a

Baseline Final

severe hypoglycaemia similarly rare in both the groups. In

both the T1D and the T2D basal+bolus studies the difference
7.3∗ (56)

7.2∗ (55)

7.1∗ (54)
8.4 (68)
7.8 (62)
7.7 (61)

8.3 (67)

8.2 (66)

8.3 (67)

in nocturnal hypoglycaemia rates became more evident after

(IDeg : IGlar) IDeg

†Study reported in abstract form only at the time of writing.

7.0∗
n/a

about 16–20 weeks, perhaps indicating that this difference is

N randomized

more likely to manifest after initial titration when patients have

1030 (3 : 1)

reached stable doses of basal insulin (figure 4).

118 (1 : 1)

629 (3 : 1)

992 (3 : 1)

435 (2 : 1)

457 (1 : 1)

Basal+OAD Therapy
Preliminary data are available for three studies comparing
+OAD/26-week
T1D/basal+bolus/

T1D/basal+bolus/

T2D/basal+bolus/

T2D/basal+OAD/

(IDeg = U200)/
T2D/basal+OAD
Cohort/regimen/

patients/basal

insulin degludec with glargine for insulin initiation in T2D.

In a year-long trial that randomized previously insulin-naı̈ve
16-week

52-week

52-week

52-week

26-week
T2D Asian

adult patients to once-daily degludec or glargine as addition to

duration

metformin±dipeptidyl peptidase 4 (DPP-4) inhibitor, HbA1c

reduction was non-inferior for degludec, while the FPG
2012 [44]†

2012 [45]†

2012 [40]†

reduction was significantly greater using similar insulin doses

2011 [41]

2012[42]

2012[43]

Bergenstal
Birkeland

Zinmann

(Table 1) [44]. Overall confirmed hypoglycaemia rates were low

Garber

Onishi
Heller
Study

and similar for degludec and glargine, but nocturnal confirmed

hypoglycaemia occurred at a significantly 36% lower rate with

Volume 15 No. 4 April 2013 doi:10.1111/dom.12052 305

 review article DIABETES, OBESITY AND METABOLISM

Risk difference

+38% ns

−86%*
n/a

n/a

n/a

n/a
Severe hypoglycaemia

[0 · 72–2 · 64]

[0.03–0.70]
Rate ratio

1 · 38

0.14
n/a

n/a

n/a

n/a
6 events

1 event
(EPY)

IDeg, insulin degludec; IGlar, insulin glargine; EPY, events per patient per year; n/a, not available (data not provided in currently available publications); ns, not significant.
0.023
IGlar

0.16

0.05

n/a
7 events
Table 2. Reported data concerning hypoglycaemia in studies comparing insulin degludec with insulin glargine using equal once-daily dosing regimens [40–45].

(EPY)

0.003
IDeg

0.21

0.06

n/a
0
difference

−38% ns

−36%ns
−58%*

−25%*

−25%*

−36%*
Risk
Nocturnal hypoglycaemia

[0.25–0.69]

[0.59–0.96]

[0.58–0.99]

[0.42–0.98]

[0.30–1.37]
Rate ratio
0.42

0.75

0.75

0.64

0.64
n/a
(EPY)
IGlar

12.3

0.39

0.28
5.9

1.8

1.2
(EPY)

Figure 4. Cumulative incidences of nocturnal hypoglycaemia with insulin

IDeg

0.25

0.18
5.1

4.4

1.4

0.8

degludec and insulin glargine during 52-week studies of basal+bolus

therapy of (A) Type 1 diabetes (T1D). Adapted with permission from Ref.
difference
−28% ns

−18% ns

−18% ns

−14% ns

[42]. (B) Type 2 diabetes (T2D). Adapted with permission from Ref. [43].
+7% ns

−18%*
Risk

degludec. Severe hypoglycaemia occurred rarely, but with a

significantly 86% lower frequency with degludec (Table 2).
All hypoglycaemia

[0 · 89–1 · 28]
[0.52–1.00]

[0.69–0.99]

[0.64–1.04]

[0.58–1.28]

Qualitatively similar results were reported in a trial of Asian

Rate ratio

adult patients with T2D, who added once-daily degludec or

1 · 07
0.72

0.82

0.82

0.86

glargine to stable OAD therapy [45] (Tables 1 and 2). Here, the
n/a

rate of overall hypoglycaemia was non-significantly lower with

(EPY)

degludec over the full trial period (Table 2), but the difference
IGlar

66.2

40.2

13.6

1.85

1.42
3.7

was statistically significantly lower (by 37%) after 16 weeks of

treatment [relative risk (RR): 0.63 (95% confidence interval:
(EPY)
IDeg

47.9

42.5

11.1

1.52

1.22

0.42; 0.94)].
3.0

The third study of insulin initiation in T2D compared

N randomized

†Study reported in abstract form only at time of writing.

the U200 formulation of insulin degludec with 100 U/ml

(IDeg : IGlar)

1030 (3 : 1)

of insulin glargine [40]. Here, patients combined once-daily

118 (1 : 1)

629 (3 : 1)

992 (3 : 1)

435 (2 : 1)

457 (1 : 1)

basal insulin (initiated at 10 U/day) with metformin ± DPP-

4 inhibitor. HbA1c reductions were again similar with both
insulins (degludec U200 non-inferior to glargine), but mean
FPG reductions were significantly greater with degludec U200
T1D/basal+bolus/

T1D/basal+bolus/

T2D/basal+bolus/

T2D/basal+OAD/

(IDeg = U200)/
patients/basal+

T2D/basal+OAD

(Table 1). Hypoglycaemia rates were numerically, but not

OAD/26-week
Cohort/regimen

statistically significantly, lower with degludec U200 than

16-week

52-week

52-week

52-week

26-week
T2D Asian

glargine (Table 2), and mean daily basal insulin doses (corrected
to total insulin units/kg) were similar (Table 1).

Flexible Dosing of Degludec

Zinmann 2012

2012 [40]†
Garber 2012

Onishi 2012
2011 [41]
Heller 2012

Bergenstal

∗p < 0.05.
Birkeland

With once-daily dosing, the prolonged PK/PD profile of

[44]†

[45]†
[42]

[43]
Study

degludec should mean that consistency in the timing of the

injection becomes less critical, thereby increasing flexibility for

306 Gough et al. Volume 15 No. 4 April 2013

DIABETES, OBESITY AND METABOLISM
the patient. The feasibility of flexible dose timing has been
tested to the extreme in two studies, one in T1D and one in
T2D, with preliminary data reported for each.
In a 26-week trial in T2D [46–48], insulin-naive patients
were randomized to receive either glargine given once daily in
the evening (n = 230), degludec given once daily at a fixed
time with the evening meal (n = 228), or degludec given
once daily in a ‘forced’ flexible dosing regimen (n = 229),
in which a compulsory, rotating morning and evening dosing
schedule was used to create alternating intervals of 8 and 40
h between doses. The basal insulins were added to existing
OAD therapy and titrated to an FPG target <5.0 mmol/l.
Two statistical analyses were carried out: one comparing
fixed-time versus flexible dosing of degludec [46] and the
other (primary analysis) comparing flexible dosing of degludec
versus evening dosing of glargine [46,48]. At baseline, the
overall mean HbA1c was 8.4% (∼68 mmol/mol), and after
26 weeks, the flexible and fixed-time degludec regimens had
reduced HbA1c by 1.3 and 1.1%, respectively (non-significant
difference) (≈14 and 12 mmol/mol). The overall baseline FPG
of 8.9 mmol/l was reduced to 5.8 mmol/l in both degludec
groups. Self-measured 9-point glucose profiles were also
reported to be similar between the two degludec groups, as were
rates of confirmed overall (3.6 episodes/patient-year in both
groups) and nocturnal hypoglycaemia (0.6 episodes/patient-
year in both groups). Glargine reduced HbA1c by 1.3%
(similar to flexible degludec, but the final FPG value with
flexible degludec was lower than with glargine (estimated
treatment difference, ∼0.42 mmol/l, p = 0.04). The overall
and nocturnal confirmed hypoglycaemia rates with glargine
were 3.5 and 0.8 episodes/patient-year, respectively, hence
very similar to the flexible degludec regimen, and insulin
doses were reported to be similar. Severe hypoglycaemia was
equally rare (0.02 events/patient-year) in all three groups. This
study, therefore, shows that flexible administration timing
is possible with degludec in a basal insulin+OAD regimen,
without compromising glycaemic control or tolerability.
A similar protocol was used in a study of T1D, in which
once-daily forced-flexible or fixed-time degludec, or once-daily
fixed-time glargine were given as basal+bolus therapy with
insulin aspart [49,50]. Here, both degludec regimens reduced
HbA1c over 26 weeks from a baseline of 7.7% (∼61 mmol/mol)
by 0.4% [50]. Overall hypoglycaemia rates were similar for
flexible and fixed-time degludec (82.4 vs. 88.3 events/patient-
year, p = NS), with nocturnal hypoglycaemia rates significantly
lower in the flexible regimen (6.2 vs. 9.6, p = 0.0031). Regarding
the comparison with glargine, data have so far only been
reported for a 52-week assessment [49]. After the first 26
weeks, patients (n = 329) randomized to both the fixed and
flexible degludec groups were allocated to ‘free flexible’ use
of degludec whereby dosing at any time of day was allowed
provided dose intervals remained between 8 and 40 h. There
was no significant difference between use of this regimen and
once-daily glargine (given at the same time each day) in overall
glycaemic control, with respective HbA1c reductions (baseline
∼7.7%) of 0.13 and 0.21%. FPG, however, was reduced to
a significantly greater extent [difference, 19.3 mg/dl (∼1.1
mmol/l); p = 0.005] by degludec. The overall hypoglycaemia
Volume 15 No. 4 April 2013
review article
rates were similar (68.1 and 63.4 events/patient-year, p = NS),
but nocturnal hypoglycaemia was reduced by 25% (p = 0.0255)
comparing free flexible degludec to once-daily glargine. In
absolute terms, hypoglycaemia occurred more frequently in this
study than in the other T1D studies (Table 2), perhaps reflecting
differences between cohorts and study design. Nevertheless,
an advantage over glargine in nocturnal hypoglycaemia was
maintained, hence this study demonstrates that degludec can
be administered flexibly at any time of day in a basal+bolus
regimen for T1D without compromising glycaemic control or
increasing the risk of hypoglycaemia.
Clinical Assessment and Conclusions
The available clinical trial reports are consistent in suggesting
that degludec achieves a better balance between glycaemic
control and risk of hypoglycaemia tolerability in clinical use
than the main comparator, insulin glargine. There does not
appear to be any difference between these insulins in terms
of weight gain. In a prospectively planned meta-analysis of
the phase 3 hypoglycaemia data [51], nocturnal hypoglycaemia
in particular was confirmed to be reduced with degludec,
by 38% overall in T2D (RR: 0.62, 0.49; 0.78), by 49% in
previously insulin-naive T2D (RR: 0.51, 0.36; 0.72), and by
25% in T1D (RR: 0.75, 0.60; 0.94). Similar risk reductions
were also reported when only the data from the ‘maintenance
periods’ of the studies were evaluated that is after a stable
dose was established. These findings are of interest because
nocturnal risk better reflects differences between basal insulins
than hypoglycaemia during the daytime, which is influenced
by other factors such as prandial insulin, food intake and
exercise. Nocturnal hypoglycaemia can have serious sequelae,
if severe, and the fear of nocturnal hypoglycaemia can act
as a powerful psychological barrier to treatment adherence
[52]. Therefore, the prospect of basal insulin with a very low
risk for this might prove helpful in addressing clinical inertia
in the setting of both insulin initiation and intensification.
The mechanism by which a hypoglycaemia risk reduction is
mediated requires confirmation, but likely reflects the flat
and stable PD profile of degludec, ultimately derived from its
unique protraction mechanism. There is also some evidence
from a small-scale clamp study that some counter-regulatory
responses to induced hypoglycaemia are relatively enhanced
during treatment with degludec compared with glargine [53].
Again, this possibility merits further study.
There is also evidence from several of the reported
studies [41,47,49,54] that, despite lower rates of nocturnal
hypoglycaemia [55], degludec has tended to result in lower FPG
values yet similar HbA1c outcomes compared with glargine.
Speculatively, it is possible that more frequent hypoglycaemic
episodes and more time spent in hypoglycaemia contributed
to the parity in HbA1c outcomes for glargine, although the
absolute incidences of confirmed episodes were low in the phase
3 studies. A greater understanding of the relationships between
insulin kinetic profiles, nocturnal hypoglycaemia risk and
fasting glucose levels could lead to important considerations
with respect to optimizing clinical usage. It is also possible that
the PK/PD profile of degludec will lead to further consideration
doi:10.1111/dom.12052 307
review article
of how best to titrate dosage and/or whether modifications
might be required regarding treatment approach to post-
prandial hyperglycaemia. In this respect, titration algorithms
need to be developed and tested. The outcomes in the flexible
dosing studies are, however, especially interesting and suggest
that degludec could be used flexibly to facilitate the integration
of insulin therapy with daily activities. Patients can also be
forgetful about insulin dosing times, in which case this flexibility
would be advantageous, but as it is unwise to encourage any
laxity in self-management, cautious communication about the
potential flexibility of degludec will be required. It is, however,
reassuring for the clinician to know that irregular dosing by
their patient is likely to have little clinical consequence, even if
a dose is missed altogether.
In summary, insulin degludec represents a new approach
to basal insulin therapy that extends the achievable balance
between efficacy and tolerability beyond that possible with
current basal insulins. The likely major clinical impact at this
stage seems to be a further reduction of hypoglycaemia risk,
and an ability to exercise greater flexibility in dosing.
Acknowledgements
The authors thank Murray Edmunds and Mark Nelson from
Watermeadow Medical, Witney, UK, for assistance with the
drafting and editing of this article, this work funded by Novo
Nordisk (UK and Canadian offices).
Conflict of Interest
S. G. has received honoraria for lectures and payments to
attend advisory boards for Novo Nordisk, Eli Lilly, Sanofi,
GSK and Boehringer Ingelheim. S. H. has acted as a consultant
and as an advisory board member for Novo Nordisk. V. W.
has acted as advisory board member and speaker and received
clinical trial funding from Novo Nordisk, Sanofi-Aventis and
Lilly. M. D. has acted as consultant, advisory board member
and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly,
Merck Sharp & Dohme, Boehringer Ingelheim and Roche. She
has received grants in support of investigator and investigator
initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis,
Lilly, Pfizer, Merck Sharp & Dohme and GlaxoSmithKline.
S. G., S. H., V. W. and M. D. all contributed to design,
conduct/data collection, analysis and interpretation of data
and to the writing and final approval of this article.
References
1. Lindholm A. New insulins in the treatment of diabetes mellitus. Best Pract
Res Clin Gastroenterol 2002; 16: 475–492.
2. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes
mellitus. The Diabetes Control and Complications Trial Research Group. N
Engl J Med 1993; 329: 977–986.
3. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment
and cardiovascular disease in patients with type 1 diabetes. N Engl J Med
2005; 353: 2643–2653.
4. Pickup J. Insulin pumps. Int J Clin Pract Suppl 2011: 16–19.
308 Gough et al.
DIABETES, OBESITY AND METABOLISM
5. Bode BW. Use of rapid-acting insulin analogues in the treatment of
patients with type 1 and type 2 diabetes mellitus: insulin pump therapy
versus multiple daily injections. Clin Ther 2007; 29(Suppl D): S135–144.
6. Rossetti P, Porcellati F, Fanelli CG, Perriello G, Torlone E, Bolli GB. Superiority
of insulin analogues versus human insulin in the treatment of diabetes
mellitus. Arch Physiol Biochem 2008; 114: 3–10.
7. McAulay V, Frier BM. Insulin analogues and other developments in insulin
therapy for diabetes. Expert Opin Pharmacother 2003; 4: 1141–1156.
8. Heise T, Nosek L, Ronn BB et al. Lower within-subject variability of insulin
detemir in comparison to NPH insulin and insulin glargine in people with
type 1 diabetes. Diabetes 2004; 53: 1614–1620.
9. Heise T, Pieber TR. Towards peakless, reproducible and long-acting insulins.
An assessment of the basal analogues based on isoglycaemic clamp
studies. Diabetes Obes Metab 2007; 9: 648–659.
10. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized
addition of glargine or human NPH insulin to oral therapy of type 2
diabetic patients. Diabetes Care 2003; 26: 3080–3086.
11. Eliaschewitz FG, Calvo C, Valbuena H et al. Therapy in type 2 diabetes:
insulin glargine vs. NPH insulin both in combination with glimepiride. Arch
Med Res 2006; 37: 495–501.
12. Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P.
A 26-week, randomized, parallel, treat-to-target trial comparing insulin
detemir with NPH insulin as add-on therapy to oral glucose-lowering
drugs in insulin-naive people with type 2 diabetes. Diabetes Care 2006;
29: 1269–1274.
13. Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL,
Thorsteinsson B. Comparison of once-daily insulin detemir with NPH
insulin added to a regimen of oral antidiabetic drugs in poorly controlled
type 2 diabetes. Clin Ther 2006; 28: 1569–1581.
14. Riddle MC. The Treat-to-Target Trial and related studies. Endocr Pract 2006;
12(Suppl 1): 71–79.
15. Meneghini L, Liebl A, Abrahamson MJ. Insulin detemir: a historical
perspective on a modern basal insulin analogue. Prim Care Diabetes
2010; 4(Suppl 1): S31–42.
16. DeVries JH, Nattrass M, Pieber TR. Refining basal insulin therapy: what
have we learned in the age of analogues? Diabetes Metab Res Rev 2007;
23: 441–454.
17. Leiter LA, Yale JF, Chiasson JL, Harris SB, Kleinstiver P, Sauriol L. Assessment
of the impact of fear of hypoglycemic episodes on glycemic and
hypoglycemia management. Can J Diabetes 2005; 29: 186–192.
18. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G.
A randomised, 52-week, treat-to-target trial comparing insulin detemir
with insulin glargine when administered as add-on to glucose-lowering
drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008;
51: 408–416.
19. Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356: 443–445.
20. Havelund S, Plum A, Ribel U et al. The mechanism of protraction of insulin
detemir, a long-acting, acylated analog of human insulin. Pharm Res 2004;
21: 1498–1504.
21. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO,
Ribel U. Design of the novel protraction mechanism of insulin degludec,
an ultra-long-acting basal insulin. Pharm Res 2012; 29: 2104–2114.
22. Kurtzhals P, Heise T, Strauss HM et al. Multi-hexamer formation is the
underlying mechanism behind the ultra-long glucose-lowering effect of
insulin degludec. Diabetes 2011; 60(Suppl 1A): LB12.
23. Kurtzhals P. How to achieve a predictable basal insulin? Diabetes Metab
2005; 31: 4S25–4S33.
24. Nishimura E, Sørensn AR, Hansen BF et al. Insulin degludec: a new
ultra-long, basal insulin designed to maintain full metabolic effect
Volume 15 No. 4 April 2013
DIABETES, OBESITY AND METABOLISM
while minimising mitogenic potential. Diabetologia 2010; 53(Suppl 1):
S388–389.
25. Jonassen I, Havelund S, Ribel U et al. Insulin degludec: multi-hexamer
formation is the underlying basis for this new generation ultra-long acting
basal insulin. Diabetologia 2010; 53(Suppl 1): S388.
26. Heise T, Hövelmann U, Nosek L, Bøttcher SG, Granhall C, Haahr H.
Insulin degludec has a two-fold longer half-life and a more consistent
pharmacokinetic profile than insulin glargine. Diabetes 2011; 60(Suppl
1A): LB11.
27. Heise T, Nosek L, Bottcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin
degludec has a flat and stable glucose-lowering effect in type 2 diabetes.
Diabetes Obes Metab 2012; 14: 944–950.
28. NPH insulin summary of product characteristics. Available from URL:
http://www.medicines.org.uk/emc/medicine/3512/SPC/#PHARMACOK
INETIC_PROPS. Accessed 3 January 2013.
29. Heise T, Nosek L, Coester H-V et al. Steady state is reached within two
to three days of once-daily administration of ultra-long-acting insulin
degludec. Diabetes 2012; 61(Suppl 1): A259.
30. Arold G, Kupèová V, Thrane M, Højbjerre M, Haahr HL. Insulin degludec has
similar pharmacokinetic properties in subjects with hepatic impairment
when compared to subjects with normal hepatic function. Diabetes 2012;
61(Suppl 1): A289.
31. Kiss I, Arold G, Bøttcher SG, Thrane M, Haahr HL. Insulin degludec has
similar pharmacokinetic properties in subjects with renal impairment
and subjects with normal renal function. Diabetes 2012; 61(Suppl 1):
A296–297.
32. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin
degludec: four times lower pharmacodynamic variability than insulin
glargine under steady-state conditions in type 1 diabetes. Diabetes Obes
Metab 2012; 14: 859–864.
33. Heise T, Hermanski L, Nosek L et al. Insulin degludec: Less
pharmacodynamic variability than insulin glargine under steady state
conditions. Diabetologia 2010; 53(Suppl 1): S387.
34. Nosek L, Coester H-V, Thomsen HF, Roepstorff C, Haahr HL, Heise T. Glucose-
lowering effect of insulin degludec is independent of subcutaneous
injection region. Diabetes 2012; 61(Suppl 1): A228.
35. 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.
36. Niskanen L, Leiter LA, Franek E et al. Comparison of a soluble co-formulation
of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2
diabetes: a randomised trial. Eur J Endocrinol 2012; 167: 287–294.
37. Hirsch IB, Bode B, Courreges JP et al. Insulin degludec/insulin aspart
administered once daily at any meal, with insulin aspart at other meals
versus a standard basal-bolus regimen in patients with type 1 diabetes: A
26-week, phase 3, randomized, open-label, treat-to-target trial. Diabetes
Care 2012; 35: 2174–2181.
38. Korsatko S, Deller S, Zahiragic S et al. Ultra-long-acting insulin degludec:
two different formulations (U100 and U200) are bioequivalent and show
similar pharmacodynamics. Diabetes 2011; 60(Suppl 1): A624.
39. Heise T, Nosek L, Hövelmann U, Bøttcher SG, Hastrup H, Haahr H. Insulin
degludec 200 U/ml is ultra-long-acting and has a flat and stable glucose-
lowering effect. Diabetes 2012; 61(Suppl 1): A91.
40. Bergenstal R, Bhargava A, Jain R et al. 200 U/mL insulin degludec
improves glycemic control similar to insulin glargine with a low risk
of hypoglycemia in insulin-naı̈ve people with type 2 diabetes. Abstract
presented at American Association of Clinical Endocrinologists 21st annual
scientific Meeting and Clinical Congress. 2012.
Volume 15 No. 4 April 2013
review article
41. Birkeland KI, Home PD, Wendisch U et al. Insulin degludec in type 1
diabetes: a randomized controlled trial of a new-generation ultra-long-
acting insulin compared with insulin glargine. Diabetes Care 2011; 34:
661–665.
42. Heller S, Buse J, Fisher M et al. Insulin degludec, an ultra-longacting basal
insulin, versus insulin glargine in basal-bolus treatment with mealtime
insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3,
randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012;
379: 1489–1497.
43. Garber AJ, King AB, Del Prato S et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment
with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type
2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.
Lancet 2012; 379: 1498–1507.
44. Zinman B, Philis-Tsimikas A, Cariou B et al. Insulin degludec versus
insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year,
randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012;
35: 2464–2471.
45. Onishi Y, Park SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec
improves glycemic control in insulin-naı̈ve patients with type 2 diabetes:
results of a randomized pan-Asian trial. Diabetes 2012; 61(Suppl 1):
A272.
46. Birkeland KI, Raz I, Gough S et al. Insulin degludec in a flexible daily
dosing regimen provides similar glycaemic control without increasing
rates of hypoglycaemia compared to dosing the same time daily in type
2 diabetes. Diabetologia 2011; 54(Suppl 1): S423.
47. Meneghini L, Atkin SL, Bain S et al. Flexible once-daily dosing of insulin
degludec does not compromise glycemic control or safety compared to
insulin glargine given once daily at the same time each day in people
with type 2 diabetes. Diabetes 2011; 60(Suppl 1A): LB10–11.
48. Atkin SL, Bain S, Gough S et al. Insulin degludec does not compromise
efficacy or safety when given in a flexible once-daily dosing regimen
compared to insulin glargine once daily at the same time each day in
type 2 diabetes. Diabetologia 2011; 54(Suppl 1): S53.
49. Mathieu C, Hollander P, Miranda-Palma B et al. Insulin degludec allows for
flexible daily dosing in type 1 diabetes, providing equal glycemic control
with less nocturnal hypoglycemia than insulin glargine over 52 weeks.
Diabetes 2012; 61(Suppl 1): A550.
50. Russell-Jones DL, Hollander P, Miranda-Palma B et al. Altering the time
of day of once-daily dosing of insulin degludec achieves similar glycemic
control and safety compared to dosing the same time of day in people
with type 1 diabetes. Diabetes 2012; 61 (Suppl 1): A91.
51. Ratner RE, Gough S, Mathieu C et al. Prospectively planned meta-analysis
comparing hypoglycemia rates of insulin degludec with those of insulin
glargine. Diabetes 2012; 61( Suppl 1): A101.
52. Unger J, Parkin C. Hypoglycemia in insulin-treated diabetes: a case for
increased vigilance. Postgrad Med 2011; 123: 81–91.
53. Pieber T, Korsatko S, Köhler G et al. Response to induced hypoglycemia in
type 1 diabetes: insulin degludec elicits an enhanced counter-regulatory
hormone response compared to insulin glargine. Diabetes 2011; 60(Suppl
1): A138.
54. Zinman B, Fulcher G, Rao PV et al. Insulin degludec, an ultra-long-acting
basal insulin, once a day or three times a week versus insulin glargine
once a day in patients with type 2 diabetes: a 16-week, randomised,
open-label, phase 2 trial. Lancet 2011; 377: 924–931.
55. Russell-Jones D, Del Prato S, Gall MA, Lassota NL, Diamant M. Insulin
degludec results in consistently lower rates of nocturnal hypoglycemia
despite lower FPG levels compared to insulin glargine in seven trials with
T1DM or T2DM. Diabetes 2012; 61(Suppl 1): A603.
doi:10.1111/dom.12052 309