supplement to Journal of the association of physicians of india • january 2014 • VOL. 62 21
Treating to Target in Type 2 Diabetes : The BEGIN®
Trial Programme
Subhash K Wangnoo1, Subhankar Chowdhury2, PV Rao3
Abstract
Insulin degludec is a new-generation basal insulin with an ultra-long duration of action. The insulin
degludec and insulin degludec/insulin aspart clinical trial programme was truly global, involving
40 different countries and encompassing a multitude of ethnic populations. It is the largest insulin
development clinical trial programme on record – with more than 11,000 patients included worldwide.
It includes two main components: BEGIN® (insulin degludec studied across the spectrum of diabetes)
and BOOST ® (insulin degludec in a fixed-dose combination with insulin aspart). In clinical trials (phase 2
and phase 3a), insulin degludec achieved similar glycaemic control to that seen with insulin glargine in
patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials
examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the
potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL
formulation of insulin degludec is also available for use in patients who require large volumes of basal
insulin. Subcutaneous insulin degludec is generally well tolerated in patients with type 1 or 2 diabetes
and represents a useful advance in the treatment of type 1 or 2 diabetes.
Introduction
T
he clinical trial programme for insulin degludec (IDeg) is the largest reported
insulin development clinical trial programme. It includes two main components:
BEGIN ® [IDeg studied across the spectrum of diabetes] and BOOST ® [IDeg in a fixeddose combination with insulin aspart (IAsp)]. Details of the BEGIN ® clinical trial
programme are presented in this supplement. The BEGIN ® clinical trial programme
(comprising nine trials) involved subjects from 40 countries, encompassing a multitude
of ethnic populations. The use of IDeg in both type 1 and early-to-advanced type 2
diabetes was evaluated.
Prior to the Phase 3 clinical programme, the drug was evaluated in the laboratory
and in Phase 1 pharmacokinetic/pharmacodynamic and Phase 2 programmes.
Extent and Aims of Phase 2/3a Programmes
Two global phase 2 studies were conducted to provide proof of concept and to
explore the efficacy and safety of IDeg in type 1 and type 2 diabetes. 1,2 The promising
results from the phase 2 studies of IDeg laid the foundation for the BEGIN ® phase 3a
study programme, which examined the efficacy and safety of IDeg once daily (OD) in
three trials in type 1 diabetes (T1D) and six trials in type 2 diabetes (T2D) (Figure 1).
1
Dept. of Endocrinology,
Indraprastha Apollo Hospital,
New Delhi; 2Dept. of
Endocrinology, IPGME&R and
SSKM Hospital, Kolkata; 3Dept.
of Endocrinology, Nizam’s
Institute of Medical Sciences,
Hyderabad
The duration of the BEGIN ® phase 3a trials for IDeg trials was from 26 to 52 weeks,
with four trials having extension arms of 26 to 52 weeks. Comparators were insulin
glargine (IGlar) (seven trials), insulin detemir (IDet) (one trial) and sitagliptin (one trial)
(Figure 1). IDeg was studied across the spectrum of diabetes, including T1D and both
early and advanced T2D. The programme included patients from all over the world
(North America, South America, Europe, Africa, Asia and Australia) and encompassed
a number of different ethnic populations. The majority of exposed patients had T2D,
reflecting the large and growing size of this diabetes population. A broad spectrum
of insulin regimens for both T1D and T2D were spanned, including basal–bolus
therapy, basal plus oral therapy, and basal versus oral therapy, and also investigated
22
supplement to Journal of the association of physicians of india • january 2014 • VOL. 62
for non-inferiority or superiority. A noninferiority limit of 0.4%-points was set for
the treatment difference in the phase 3a
trials. Key secondary endpoints included
hypoglycaemia rate, fasting plasma
glucose (FPG), self-monitored plasma
glucose (SMPG) profiles, insulin dose,
body weight and adverse events (AEs).
Some trials also included patient-reported
outcomes such as health-related quality of
life (HRQoL), using the validated Short
Form 36 Health Survey, version 2.
Fig. 1: Overview of the trials included under the BEGIN® programme3-12
α-gluc, alpha glucosidase inhibitor; BB, basal–bolus; BOT, basal–
oral therapy; DPP4, dipeptidyl peptidase-4 inhibitor; IAsp, insulin
aspart; Met, metformin; OADs, oral anti-diabetic drugs; Pio,
pioglitazone; SU, sulphonylurea; T1, type 1 diabetes; T2, type 2
diabetes. List of OADs in each box apply to all arms in each trial.
flexible dosing options. The extent and breadth of the
BEGIN® clinical trial programme provides an excellent
overview of the potential of IDeg in the treatment of
patients with both T1D and T2D compared with other
available insulin treatment regimens. 3-12
Common Principles Applied Across
Protocols
Definitions of hypoglycaemia3-12
All the phase 2 and 3a trials used a
standardised algorithm for reporting
confirmed hypoglycaemia. Hypoglycaemia
was classified as confirmed if a plasma
glucose measurement of < 3.1 mmol/L
(56 mg/dL) was obtained, irrespective of
any symptoms, or if the hypoglycaemia was severe
(i.e. assistance from another person was required).
Nocturnal hypoglycaemic episodes were defined as
those with time of onset between 00h01 and 05h59
inclusively.
Insulin dosing
Trials in T1D3-5
All the trials were done in accordance with the
Declaration of Helsinki 13and Good Clinical Practice
Guidelines. 14 Signed informed consent was obtained
from each participant. The protocol and the consent
form for each trial were reviewed and approved by
the local independent ethics committee or institutional
review board before trial initiation.
If patients had previously used a basal insulin
OD, the same number of units OD were prescribed.
If prior basal therapy was twice daily, the total basal
dose was calculated and administered OD. For IDeg,
this involved a 1:1 transfer to the full calculated dose
(although dose reductions could be considered at
the investigator’s discretion), while the IGlar dose
was reduced by 20–30%, according to the approved
labelling.
Treat-to-target design
Trials in T2D6-12
All of the trials in the phase 3a programme were
conducted as treat-to-target studies, in accordance
with guidance from regulatory authorities such as
the Food and Drug Administration (FDA) in the
USA. The FDA requirement states that the ‘Test and
comparator groups should be treated to similar goals.
Similar degrees of glycaemic control (test non-inferior to
reference) should be achieved so that comparisons among
groups in frequency and severity of hypoglycaemia will
be interpretable in ultimate risk-benefit assessments’. 15
Using a treat-to-target design means that betweentreatment comparisons of the frequency and severity
of hypoglycaemia can be interpreted without being
confounded by different levels of glycaemic control.
Insulin-naïve patients and patients who had not
previously used basal insulin were given a starting
dose of 10 U of IDeg or IGlar. For patients already
using a basal insulin OD, the same number of units
OD was prescribed. If the prior basal insulin was
taken more than OD, total daily basal dose was
calculated. If the subject was randomised to IGlar, it
was recommended to reduce the administered dose
by 20–30%, according to the approved labelling. For
subjects randomised to IDeg, a dose reduction was
to be considered, according to the investigator’s
discretion.
Conduct of the trials
Trial outcome measures/endpoints3-12
In all the phase 3a trials, the primary endpoint was
the difference between treatment groups in the change
in HbA1c from baseline to study end. The difference
between groups in change in HbA1c was analysed
Titration of basal and bolus insulin1-12
In the phase 2 studies of IDeg, the titration
target was an FPG value of 4–6 mmol/L (72–108 mg/
dL). FPG at the end of these trials did not indicate
normoglycaemia, and hypoglycaemia rates were not
increased compared with previous treat-to-target
supplement to Journal of the association of physicians of india • january 2014 • VOL. 62 studies; therefore, a more ambitious target of 3.9–4.9
mmol/L (70–89 mg/dL) was set for phase 3a. It was
considered that, because of the ultra-long duration of
action and flat profile of IDeg, it should be possible
to administer it at any time of the day. Various
administration schedules were used for IDeg OD in
the phase 3a programme: morning, evening, mealtime,
and at any time during the day. Some studies used a
‘forced flexible’ regimen, in which IDeg was injected
at alternating intervals of 8 hours and 40 hours, or
‘Free-Flex’ regimens, in which patients were free
to choose the time of administration, as long as the
interval between injections was 8–40 hours. In all the
trials that used IGlar, it was administered at the same
time every day, according to its approved product
label. Physicians and patients were free to choose
the optimal administration time for IGlar for each
individual.
Pre-specified titration algorithms were used for
basal and bolus insulin. Physicians increased or
reduced doses, or left it unchanged, according to
measured blood glucose values and other relevant
information (e.g. hypoglycaemic episodes, known
lifestyle changes). In most of the trials, the basal
insulin dose was titrated once weekly based on the
mean pre-breakfast plasma glucose from the preceding
3 days. For the majority of trials that included bolus
insulin supplementation, bolus doses were adjusted
based on the mean pre-prandial plasma glucose level
measured prior to the next meal or before bedtime.
Basal insulin was titrated before bolus insulin doses
were adjusted.
Inclusion and exclusion criteria3-12
I n c l u s i o n c r i t e r i a we r e s e t t o e n s u r e t h a t a
representative population was included, and to
include only patients with T1D/T2D (as relevant).
Exclusion criteria aimed to exclude patients with
conditions or using other treatments that could
confound the results, or whose safety could be
compromised by participating in the trial due to
existing co-morbidities, or who were unlikely to be
able to follow the injection regimen adequately.
Key inclusion criteria for the phase 3a trials:
Adults aged >18 years.
• The trials in T1D required patients to have been
diagnosed with it for at least 1 year, and to have
been using basal-bolus therapy for at least 1 year
before screening.
• The trials in T2D required patients to have been
diagnosed with it for at least 6 months.
• The trials in T2D included insulin-naïve or
insulin-experienced users. For each trial, criteria
were set to specify which medications patients
had been using, and the duration of previous use.
23
• HbA1c < 10% in T1D and in the range of 7.0–10.0%
in T2D. The upper limit was imposed to ensure
that patients could control their disease to
a certain extent. For T2D, it was considered
that patients with HbA1c < 7.0% were already
achieving good glycaemic control.
• BMI < 35 (T1D) or 40 kg/m 2 (T2D). An upper limit
of BMI was imposed to exclude individuals with
severe insulin resistance.
Phase 2 Trials – Efficacy and Safety
There were 2 phase trials conducted – one in T1D
and T2D each. Both were clinical exploratory, proofof-concept, 16-week, randomised, controlled, openlabel, three-arm, parallel-group treat-to-target study
comparing two formulations of IDeg to IGlar. IDeg
Group A was of the same molar concentration as IGlar
(600 μmol/L, 1 unit = 6 nmol); IDeg Group B was a
higher strength formulation (900 μmol/L; 1 unit = 9
nmol). 1,2 The higher strength formulation was tested
for its efficacy and safety and to assess whether any
extra benefit can be obtained from it.
Type 1 Diabetes1
There was one phase 2 trial conducted in T1D,
using IDeg in a basal-bolus regimen with IAsp at
mealtimes versus IGlar as comparator. It included
patients with T1D for > 1 year, previously treated
continuously with any insulin regimen. Participants
were randomised 1:1:1 into three groups: IDeg Group
A, IDeg Group B, or IGlar, all given in the evening.
IAsp was administered at mealtimes.
At 16 weeks, mean A1C was comparable for
IDeg (A) (7.8%), IDeg (B) (8.0%), and IGlar (7.6%),
as was FPG (8.3, 8.3 and 8.9 mmol/L, respectively).
Estimated mean rates of confirmed hypoglycaemia
were 28% lower for IDeg (A) and 10% lower for
IDeg (B) compared with IGlar; rates of nocturnal
hypoglycaemia were 58% lower for IDeg(A) and 29%
lower for IDeg(B). At study end, the plasma glucose
levels in the nine-point SMPG profiles were reduced
in all treatment groups and were similar between
groups. Mean total daily insulin dose was similar to
baseline (60 units, 49 units and 51 units vs. 60 units,
59 units and 52 units at baseline respectively).
The overall rates of adverse events (AEs) for
IDeg(A), IDeg(B), and IGlar were 8.7, 6.5, and 9.1
events/patient year. There were no specific patterns
or clustering of the AEs; most were mild or moderate
in severity and judged to have an unlikely relation to
the trial insulin products. No injection-site reactions
were reported. Four serious AEs were reported:
diabetic ketoacidosis (IGlar ), abdominal distension
(IDeg(A)), hypoglycaemic unconsciousness (IDeg(A)),
and hypoglycaemia (IDeg(B)).
24
supplement to Journal of the association of physicians of india • january 2014 • VOL. 62
At the end of the trial, there were no obvious
differences between groups in clinical laboratory
tests, ECG, fundoscopy, vital signs, or physical
examination.
The level of IDeg specific antibodies was close
to, or below, the limit of detection at screening and
remained at the same level at the end of the treatment
period.
Type 2 Diabetes2
There was one phase 2 trial conducted in T2D which
included insulin-naïve patients, diagnosed with T2D
for > 3 months and with HbA1c 7.0–11.0% and BMI
23–42 kg/m 2 . Patients were randomised 1:1:1:1 as
follows: IDeg (900 μmol/L) three times a week; IDeg
Group A; IDeg Group B; IGlar OD. In all the arms,
insulin was dosed in combination with metformin.
At study end, mean HbA1C levels were much the
same across treatment groups, at 7·3%, 7·4%, 7·5%,
and 7·2%, respectively. Estimated mean HbA1C
treatment differences from IDeg by comparison
with IGlar were 0·08% for the three dose per week
schedule, 0·17% for group A, and 0·28% for group B.
Few participants had hypoglycaemia; however, the
proportion of participants who had hypoglycaemia
in IDeg group A was lower than was the proportion
in the IGlar group and the IDeg three times a week
group. The number of adverse events was much the
same across groups; most were mild-to-moderate in
severity with no apparent treatment specific pattern.
Most AEs were mild or moderate in severity, and
there was no apparent treatment-specific pattern.
Only two serious adverse events were reported:
aggravation of a pretrial coronary heart disease in
the three times a week IDeg group and worsening of
paroxysmal atrial fibrillation in IDeg group B; both
events were judged to be unlikely to be related to
trial product.
AEs judged to have possible or probable relation
to insulin were reported for six participants in the
IDeg three times a week group (headache, dermatitis,
pruritic rash, diarrhoea, stomach discomfort, and
peripheral oedema), two participants in IDeg group A
(three events; dizziness, dysgeusia, and palpitations),
five participants in IDeg group B (headache, increased
blood cholesterol, increased weight, pruritus, and
muscle spasms), and two participants in the IGlar
group (headache and increased blood cholesterol).
There were few injection-site reactions. Concentrations
of antibodies specific to IDeg and those cross-reacting
between IDeg and human insulin were negligible.
Based on both these phase two studies, the 900
μmol/L formulation was not developed further, since
it showed no added advantage over the conventional
formulation.
Phase 3a – The BEGIN® trials
There were three phase 3a trials conducted in T1D,
using IDeg in a basal-bolus regimen with IAsp at
mealtimes versus IGlar as comparator in two, and IDet
in one. Both trials versus IGlar had extension periods.
BEGIN® BB T1 long
This was a 52-week, open-label, treat-to-target,
non-inferiority trial comparing IDeg with IGlar,
which included adults with T1D, who were previously
treated with basal-bolus insulin for at least 1 year.
Patients were randomly assigned in a 3:1 ratio to IDeg
OD or IGlar OD 3.
In the 52-week extension period, for the second
year, patients maintained their prior randomisation
(IDeg:IGlar 3:1). The total duration of the trial was 2
years for patients enrolled in both trial periods. 4
BEGIN® flex T15
This was a 26-week, open-label, treat-to-target trial
comparing a forced-flexible dosing regimen of IDeg
(‘IDeg Forced-Flex’) with IDeg OD and IGlar OD. It
included adults with T1D for ≥12 months, previously
treated with any basal–bolus regimen. Subjects were
randomised 1:1:1 as follows: IDeg OD administered
with the evening meal; IDeg Forced-Flex, where
subjects alternated insulin administration timing
between morning and evening to create intervals of
8 to 40 hours between insulin doses; and IGlar OD at
the same time each day. IAsp was used as prandial
insulin in all three treatment groups.
The 26-week extension period, investigated the
long-term safety and efficacy of IDeg in a ‘free flex’
regimen (‘IDeg Free-Flex’) in combination with
meal-time IAsp. For the extension period, patients in
the IDeg Free-Flex arm were free to choose the time
of administration, provided that the interval between
consecutive doses was more than 8 hours and less
than 40 hours. The comparator was IGlar OD. The
total duration of the trial was 52 weeks for patients
enrolled in both trial periods.
There were six phase 3a trials conducted in T2D;
two of which also had extension periods. Duration of
these trials was 26 or 52 weeks.
BEGIN® once-long
This was a 52-week randomised, controlled, openlabel, multinational, treat-to-target trial, comparing
IDeg with IGlar, used in combination with oral antidiabetics (OADs). The study enrolled insulin-naïve
adults diagnosed with T2D for ≥ 6 months, previously
treated with metformin ± a sulphonylurea (SU),
glinide, DPP-4 inhibitor (DPP4-I), or α-glucosidase
inhibitors (AGI), with dosing unchanged for >3
months. Patients were randomised 3:1 to receive IDeg
OD in the evening or IGlar OD at the same time each
supplement to Journal of the association of physicians of india • january 2014 • VOL. 62 day, in combination with metformin ± DPP4-I (other
OADs were discontinued) 6 . The extension period
was for 52 weeks more, making the total duration of
the trial 104 weeks for patients enrolled in both trial
periods. 7
BEGIN® early8
This was a 26-week randomised, controlled, open
label, multinational, treat-to-target trial, comparing
IDeg with the DPP4-I, sitagliptin as add-on to current
OADs. Insulin-naïve patients with T2D for > 6 months
and inadequately controlled with 1–2 OADs were
eligible. Patients were randomised 1:1 to receive IDeg
injected OD (participants could choose the timing as
long as they maintained an interval between 8 and 40
hours between injections), or sitagliptin taken OD. All
patients continued taking their current OADs.
BEGIN® BB T29
This was a 52-week, randomised, open-label,
multinational, treat-to-target trial, comparing IDeg
with IGlar, both administered OD in a basal-bolus
regimen with IAsp as mealtime insulin ± treatment
with metformin, ± pioglitazone. T2D patients with
HbA1c 7.0–10.0% after > 3 months of any insulin
regimen (with or without OADs) were included
and randomised 3:1 to receive IDeg OD at the main
evening meal or IGlar OD at the same time each day,
stratified by previous insulin regimen. IAsp was given
at breakfast, lunch and dinner and could be given at
a fourth meal.
BEGIN® once asia10
This was a 26-week, randomised, controlled, openlabel, multinational, treat-to-target trial comparing
IDeg OD and IGlar OD, both administered with
metformin, SUs, AGIs or glinides. The study enrolled
insulin-naïve patients in Asia with T2D for > 6 months
who were randomised 2:1 to IDeg OD in the evening or
IGlar OD, both as add-on therapy to stable treatment
with >1 OAD(s).
BEGIN® flex11
This was a 26-week randomised, controlled, openlabel, multinational, three-arm, treat to target trial
comparing fixed-flexible dosing of IDeg with IDeg
OD and IGlar OD, with or without OADs. The study
enrolled patients with type 2 diabetes for > 6 months,
and with HbA1c 7.0–11.0% if previously treated with
OADs, or HbA1c 7.0–10.0% if previously treated with
any basal insulin ± OADs. Patients were randomised
1:1:1 to receive either IDeg OD or IGlar OD at the same
time each day, or IDeg in a fixed-flexible regimen
(IDeg OD Flex), with fixed 8- and 40-hour intervals
between injections.
BEGIN® low volume12
This was a 26-week, randomised, controlled, openlabel, multinational, treat-to-target trial comparing
25
IDeg in a more concentrated formulation (200 U/mL)
with IGlar, both administered OD with metformin
with or without a DPP4-I.
Insulin-naïve patients diagnosed with T2D for > 6
months were enrolled and randomised 1:1 to receive
either IDeg 200 U/mL OD with the main evening
meal or IGlar OD at the same time each day. Both
insulins were given in prefilled pen devices and in
combination with metformin ± DPP4-I treatment as
prior to randomisation.
Further details on the phase 3a trials are presented
in the next article in this supplement, by Mithal et al
titled “Preserving glycaemic control – Insights from
BEGIN trials”.
FlexTouch® - New Insulin Delivery Device
for Insulin Degludec
IDeg is available in FlexTouch ® (Novo Nordisk
A/S, Bagsværd, Denmark), a new prefilled disposable
insulin pen and the device used across all trials for
the delivery of IDeg. It has a new injection mechanism
with no push-button extension. Additional features
include an end-of-dose click, a large dose display,
dial-back mechanism, a maximum deliverable dose
of 80 international units (IU), an ergonomic design,
and compatibility with most screw-thread needles. 16
The unique injection mechanism means that a
lower injection force is required when injecting with
FlexTouch ® compared with other prefilled insulin
pens, at all injection speeds tested. 17,18 FlexTouch ® also
showed consistency and accuracy of dose delivery at
minimum, medium and maximum doses (i.e., 1, 40
and 80 U) 19 which should help to minimise glycaemic
variations by reducing under- or over-dosing. 18,19
More than 95% of health care providers (HCPs)
and patients with diabetes rated FlexTouch ® as easy
to use and hold stable, and responded that it was easy
to depress the push-button/plunger and to read the
dose scale. 20
In two preference studies among patients with
diabetes and HCPs, over 80% of respondents preferred
FlexTouch® and found it easier to use than comparator
pens. 21,22
Dosing and Titration Guidelines
Timing23
IDeg should be injected subcutaneously at any time
of the day, preferably at the same time every day.
When administration at the same time of the day is not
possible, IDeg can be dosed flexibly with a minimum
of 8 hours between injections.
Initial dosing and adjustments23
For insulin naïve patients with T2D, recommended
26
supplement to Journal of the association of physicians of india • january 2014 • VOL. 62
initial dose is 10 U which should be adjusted
individually thereafter. In T1D, if switching from
a previous basal insulin used OD, the initial dose
of IDeg can be transferred in a 1:1 ratio for most
patients, followed by individual dose adjustment.
If the previous basal insulin was used twice daily,
or HbA1c < 8.0% at the time of switching, the dose
must be determined individually for each patient.
In T2D, whether using basal, basal-bolus, premix, or
self-mix regimens, IDeg can be transferred in a 1:1
ratio based upon the previous insulin dose, followed
by individual dose adjustment.
Adjustments made weekly, using the mean of the
preceding 3 days’ SMPG, take into account the fact
that it takes IDeg 2–3 days to reach steady state. 24
References
1.
Birkeland K, Home PD, Wendisch U, et al. Insulin degludec in type 1
diabetes: a randomized controlled trial of a new-generation ultralong-acting insulin compared with insulin glargine. Diabetes Care
2011;34:661–5.
2.
Zinman B, Fulcher G, Rao PT, et al. Insulin degludec, an ultra-longacting 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;377:924–31.
3.
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.
4.
Bode BW, Buse JB, Fisher M, et al. Insulin degludec improves glycemic
control with lower nocturnal hypoglycemia risk than insulin glargine:
a 2-year randomized trial in type 1 diabetes. Diabet Med 2013. doi:
10.1111/dme.12243. [Epub ahead of print].
5.
Mathieu C, Hollander P, Miranda-Palma B et al. Efficacy and safety
of insulin degludec in a flexible dosing regimen versus insulin
glargine in patients with type 1 diabetes (BEGIN®: Flex T1): A 26-week
randomized, treat-to-target trial with a 26-week extension. J Clin
Endocrinol Metab 2013;98:1154–62.
6.
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;35:2464-71.
7.
Rodbard H, Zinman B, Cariou B, et al. Reduced nocturnal
hypoglycaemia with insulin degludec as compared to insulin
glargine: results of a 2-year randomised trial in type 2 diabetes.
Diabetologia 2012;55(Suppl.1):S378(Abstract920).
8.
Philis-Tsimikas A, Del Prato S, Satman I et al. Effect of ultra-long-acting
insulin degludec versus sitagliptin addition in patients with type 2
diabetes uncontrolled on oral antidiabetic agents. Diabetes Obesity
Metab 2013;15:760-6.
9.
Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultralongacting 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-totarget non-inferiority trial. Lancet 2012;379:1498–507.
10. Onishi Y, Iwamoto Y, Yoo SJ. Insulin degludec compared with insulin
glargine in insulin-naïve patients with type 2 diabetes: a 26-week,
randomized, controlled, Pan Asian, treat-to-target trial. J Diabetes
Invest 2013;doi:10.1111/jdi.12102. [Epub ahead of print].
11. Meneghini L, Atkin S, Gough S, et al. on behalf of the NN1250-3668
(BEGIN FLEX) Trial Investigators. The efficacy and safety of insulin
degludec given in variable once-daily dosing intervals compared
with insulin glargine and insulin degludec dosed atthe same
time daily: A 26-week, randomized, open-label, parallel-group,
treat-to-target trial in people with type 2 diabetes. Diabetes Care
2013;364:858-64.
12. Gough S, Bhargava A, Jain R. Low volume insulin degludec 200 U/
ml once-daily improves glycemic control similar to insulin glargine
with a low risk of hypoglycemia in insulin-naïve patients with type
2 diabetes: a 26-week, randomized, controlled, multinational,
treat-to-target trial: the BEGIN™ LOW VOLUME trial. Diabetes Care
2013;36:2536-42.
13. World Medical Association. Declaration of Helsinki. Ethical principles
for medical research involving human subjects. J Indian Med Assoc
2009;107:403–5.
14. ICH Harmonised Tripartite Guideline: guideline for good clinical
practice. J Postgrad Med 2001;47:199–203.
15. US Department of Health and Human Services, Food and
Drug Administration Center for Drug Evaluation and Research
(CDER). Guidance for Industry: Diabetes Mellitus: Developing
Drugs and Therapeutic Biologics for Treatment and Prevention.
(Draft guidance), 2008. www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulator yInformation/Guidances/
ucm071624.pdf. Accessed 15 October 2013
16. Bailey T, Campos C. FlexTouch® for the delivery of insulin: technical
attributes and perception among patients and healthcare
professionals. Expert Rev Med Devices 2012;9:209–17.
17. Hemmingsen H, Niemeyer M, Hansen MR, et al. A prefilled insulin pen
with a novel injection mechanism and a lower injection force than
other prefilled insulin pens. Diabetes Technol Ther 2011;13:1207–11.
18. Wielandt JO, Niemeyer M, Hansen MR, et al. An assessment of
dose accuracy and injection force of a novel prefilled insulin pen:
comparison with a widely used prefilled insulin pen. Expert Opin
Drug Deliv 2011;8:1271–6.
19. Wielandt JO, Niemeyer M, Hansen MR, et al. FlexTouch®: a prefilled
insulin pen with a novel injection mechanism with consistent high
accuracy at low- (1 U), medium- (40 U), and high- (80 U) dose settings.
J Diabetes Sci Technol 2011;5:1195–9.
20. Campos C, Lajara R, Deluzio T. Usability and preference assessment
of a new prefilled insulin pen versus vial and syringe in people
with diabetes, physicians and nurses. Expert Opin Pharmacother
2012;13:1837–46.
21. Oyer D, Narendran P, Qvist M, et al. Ease of use and preference of
a new versus widely available prefilled insulin pen assessed by
people with diabetes, physicians and nurses. Expert Opin Drug Deliv
2011;8:1259–69.
22. Bailey T, Thurman J, Niemeyer M, et al. Usability and preference
evaluation of a prefilled insulin pen with a novel injection mechanism
by people with diabetes and healthcare professionals. Curr Med Res
Opin 2011;27:2043–52.
23.Tresiba®. Summary of product characteristics. Available at: http://
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/002498/human_med_001609.jsp&mid=WC0b01ac0580
01d124Accessed October 2013.
24. 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 Abstract 1013.