Insulin Degludec PDF
Insulin Degludec PDF
Insulin degludec (IDeg) once-daily was compared with insulin detemir (IDet)
once- or twice-daily, with prandial insulin aspart in a treat-to-target,
randomized controlled trial in children 1–17 yr with type 1 diabetes, for 26 wk
(n=350), followed by a 26-wk extension (n=280). Participants were
randomized to receive either IDeg once daily at the same time each day or
IDet given once or twice daily according to local labeling. Aspart was titrated
according to a sliding scale or in accordance with an insulin:carbohydrate
ratio and a plasma glucose correction factor. Randomization was
age-stratified: 85 subjects 1–5 yr. (IDeg: 43), 138 6–11 yr (IDeg: 70) and 127
12–17 yr (IDeg: 61) were included. Baseline characteristics were generally
similar between groups overall and within each stratification. Non-inferiority
of IDeg vs. IDet was confirmed for HbA1c at 26 wk; estimated treatment
difference (ETD) 0.15% [−0.03; 0.32]95%CI. At 52wk, HbA1c was 7.9% (IDeg)
vs. 7.8% (IDet), NS; change in mean FPG was −1.29 mmol/L (IDeg) vs.
+1.10 mmol/L (IDet) (ETD −1.62 mmol/L [−2.84; −0.41]95%CI, p=0.0090)
and mean basal insulin dose was 0.38 U/kg (IDeg) vs. 0.55U/kg (IDet). The
majority of IDet treated patients (64%) required twice-daily administration to
achieve glycemic targets. Hypoglycemia rates did not differ significantly
between IDeg and IDet, but confirmed and severe hypoglycemia rates were
numerically higher with IDeg (57.7 vs. 54.1 patient-years of exposure (PYE)
[NS] and 0.51 vs. 0.33, PYE [NS], respectively) although nocturnal
hypoglycemia rates were numerically lower (6.0 vs. 7.6 PYE, NS). Rates of
hyperglycemia with ketosis were significantly lower for IDeg vs. IDet [0.7 vs.
1.1 PYE, treatment ratio 0.41 (0.22; 0.78)95%CI, p=0.0066]. Both treatments
were well tolerated with comparable rates of adverse events. IDeg achieved
equivalent long-term glycemic control, as measured by HbA1c with a
significant FPG reduction at a 30% lower basal insulin dose when compared
with IDet. Rates of hypoglycemia did not differ significantly between the two
treatment groups; however, hyperglycemia with ketosis was significantly
reduced in those treated with IDeg.
Introduction
The Diabetes Control and Complications Trial/
Epidemiology of Diabetes Interventions and Complications
(DCCT/EDIC) study showed conclusively that
good glycemic control delays, and may even prevent,
the development of long-term complications in type
1 diabetes (T1D) (1–5). Management of T1D in children
and adolescents presents particular challenges.
Factors that increase the complexity of treating children
include hormonal changes during normal growth
and development (e.g., rapid growth, pubertal insulin
resistance, psychosocial and cognitive development),
family dynamics (including socioeconomic status, cultural
considerations and parent/caregiver viewpoints)
and the provision and quality of care and support
outside the home, for example at school/college (6).
In recognition of this, the American Diabetes Association
and the International Society for Pediatric and
Adolescent Diabetes (ISPAD) have published specific
guidance for children (7, 8).
Hypoglycemia is one of the main side effects of
insulin therapy and is often viewed as themajor barrier
to achieving good glycemic control by parents and
physicians alike. A number of studies have shown that
hypoglycemia has a detrimental effect on the cognitive
development of young children, and that episodes of
hypoglycemia, particularly nocturnal hypoglycemia,
can be extremely frightening both for children and
their parents/caregivers (9, 10). It can therefore be
tempting to set higher glycemic targets to minimize
hypoglycemia. In addition, fear of hypoglycemia can
lead to reluctance to titrate to appropriate glucose
targets, with resultant hyperglycemia and suboptimal
HbA1c. However, underinsulinization can place
children at-risk of hyperglycemia with ketosis, which,
if left untreated, can progress to diabetic ketoacidosis
(DKA) (11). The risk of DKA in children with
established T1D is up to 10% per patient per year (11).
Children who restrict or omit insulin intentionally, or
unintentionally due to unstable family circumstances or
limited access to supplies, are at greatly increased risk
(12, 13). Basal insulin can help reduce the risk of DKA
by providing a continual background level of insulin.
The long-acting analogs insulin glargine (IGlar) and
insulin detemir (IDet) can provide up to 24-h coverage
when administered once daily (OD) or twice-daily
(BID) in the case of IDet (14, 15). However, because
of their action profile, administration should ideally be
at the same time each day to prevent periods of insulin
insufficiency (14, 15). As children of all ages often have
highly variable daily schedules, a basal regimen that
provides flexibility in dosing time may be beneficial.
Insulin degludec (IDeg), a new basal insulin for
the treatment of T1D and type 2 diabetes (T2D), has
been showed to have an ultra-long duration of action
and low variability in adults, producing a consistent
glucose-lowering activity profile at steady state (16,
17). Pharmacokinetic data have shown that IDeg has
a terminal half-life of approximately 25 h, twice that
of IGlar, and a duration of action of more than 42 h
(18). A phase 3, randomized, controlled trial in adults
with T1D confirmed that IDeg OD effectively reduced
HbA1c and fasting plasma glucose (FPG), with a lower
risk of nocturnal confirmed hypoglycemia than IGlar
(19). Furthermore, studies in adults with T1D and
T2D have shown that the IDeg injection time may be
varied from day to day without compromising efficacy
or safety, offering patients greater convenience and
flexibility, when needed (20, 21).
The objective of this trial was to investigate
the efficacy and safety of IDeg vs. IDet, both in
combination with bolus insulin aspart (IAsp), in
children and adolescents with T1D (Fig. 1).
Materials and methods
Trial conduct
This was a 26-wk, phase 3b, randomized, controlled,
open-label, multinational, parallel-group, treat-totarget
non-inferiority trial with a 26-wk extension,
comparing the efficacy and safety of IDeg administered
OD with that of IDet administered OD or BID, both
in combination with mealtime IAsp. The study was
conducted at 72 sites in 12 countries (Bulgaria, Finland,
France, Germany, Italy, Japan, the Netherlands,
Republic of Macedonia, Russian Federation, South
Africa, UK and USA). Of these, South Africa did not
participate in the 26-wk extension phase as regulatory
approval was not granted. The protocol, protocol
amendments, consent form, child assent form, subject
information sheet and other information provided to
the participants and parents/participants’ legal representatives
were approved by the relevant independent
ethics committees or institutional review boards (written
informed consent was obtained prior to participant
enrolment) and the trial was conducted according
to the Declaration of Helsinki (22) and ICH Good
Clinical Practice (23). In some countries assent from
children themselves (≤17 yr of age, where appropriate)
was required in addition to parental consent. Ongoing
safety surveillance was performed by a blinded internal
Novo Nordisk safety committee and an unblinded
independent Data Monitoring Committee (comprising
pediatric and endocrine experts). This trial is registered
at www.clinicaltrials.gov: NCT01513473.
Children and adolescents (1–17 yr of age) with T1D
who had been receiving insulin treatment (any regimen)
for at least 3 months, without concomitant oral antidiabetic
drugs andwithHbA1clevels of≤11%, were eligible
for inclusion (Fig. S1, Supporting Information).
Randomization
Following screening, eligible participants were randomized
1:1, using a central interactive voice/web
response system, to receive either IDeg (100 U/mL,
Penfill® 3-mL cartridge, Novo Nordisk, Bagsværd,
Denmark) or IDet (100 U/mL, Penfill®3-mL cartridge;
Novo Nordisk). Randomization was also stratified
by age group: 1–5, 6–11 and 12–17 yr, to ensure
an approximately equal distribution of participants
between treatment arms within each age group.
Procedures
To ensure treatment uniformity between clinics,
and to ensure that the patients received optimal
treatment, insulin treatment algorithms were developed
specifying recommended dose adjustments at different
PG levels. Clinical judgment had to be applied to avoid
increased risks for the patients. Thus the investigators
could overrule the guidelines when necessary. Eligible
participants were switched to either IDeg OD or IDet
OD or BID with mealtime IAsp at randomization
(wk 0). Participants switching to IDet received their
dose OD or BID in accordance with local labeling.
Participants switching to IDeg received a single dose
at the same time each day. The total daily insulin
dose was calculated and used to derive the trial bolus
and basal doses using the initiation table provided
(Table S1), aiming for a basal:bolus ratio of between
50:50 and 30:70 with no basal dose reduction, as this
range was generally considered to be appropriate for
children with T1D. For example, if the participant’s
total daily insulin dose prior to the trial was 28U, the
participant would receive a total of 8U of IDeg or
IDet and 20U of insulin aspart at the ratio of 30:70.
The choice of basal:bolus split for each individual was
made at the discretion of the investigator. At 26wk,
for those participants not continuing in the extension
study, basal insulin was switched to neutral protamine
Hagedorn insulin for 7 days to minimize interference
with antibody detection at a follow-up visit performed
1wk later. For those entering the extension study, this
was done at 52 wk.
The overall trial duration was approximately 53 wk,
including two 26-wk treatment periods and one 7-day
basal insulin washout period (Fig. S1).Atreat-to-target
approach was used to optimize glycemic control and