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Insulin degludec reduces severe or blood glucose-confirmed
hypoglycaemia and is noninferior to insulin glargine in reducing HbA1c
in types 1 and 2 diabetes
In the SWITCH 1 and 2 trials, despite similar reductions in haemoglobin A1c, insulin degludec
reduced severe or blood glucose-confirmed symptomatic hypoglycaemia compared to
insulin glargine in both type 1 and 2 diabetes. These outcomes of the randomised, double-
blind, 2 x 32 week, treat-to-target, crossover SWITCH 1 and 2 trials, were reported at the
EASD 2016 meeting.
SWITCH 1, in type 1 diabetes
Wendy Lane, MD, of Mountain
Diabetes and Endocrine Center,
Asheville, North Carolina, explained
that SWITCH 1 compared the num-
ber of severe or blood glucose-con-
firmed, symptomatic hypoglycaemic
episodes in patients with type 1 dia-
betes treated with insulin degludec
U100 versus insulin glargine U100,
both in combination with mealtime
insulin aspart.
Five-hundred one adults with
type 1 diabetes and at least one fac-
tor associated with increased risk of
hypoglycaemia received once-daily
insulin degludec or insulin glargine,
both with mealtime insulin aspart,
for 32 weeks (a 16-week titration
period and a 16-week maintenance
period), followed by crossover to
insulin degludec or insulin glargine.
The primary objective was to con-
firm noninferiority in terms of the
number of severe or blood glucose-
confirmed (<3.1 mmoL/L) symp-
tomatic hypoglycaemic episodes
during the maintenance periods.
Treatment with insulin degludec
resulted in an 11%, significantly
lower rate of severe or blood glu-
cose-confirmed symptomatic hy-
poglycaemia than insulin glargine
in the maintenance period. Severe
or blood glucose-confirmed symp-
tomatic nocturnal hypoglycaemia
(00:01–05:59) was also significantly
reduced by 36% for insulin degludec
versus insulin glargine.
Severe hypoglycaemia was signifi-
cantly reduced, by 35%more with in-
sulin degludec versus insulin glargine.
Significant reductions for all three
hypoglycaemia categories were also
seen for the total treatment periods.
In addition, a significantly lower
proportion of patients taking insulin
degludec experienced severe hypo-
glycaemia during both the mainte-
nance and total treatment periods
than those taking insulin glargine
(P = 0.0016).
Noninferior reduction in hae-
moglobin A1c between insulin de-
gludec versus insulin glargine was
confirmed in both treatment periods
(week 32: 6.95 vs 6.92%; week 64:
6.95 vs 6.97%). The rates of adverse
events were similar for insulin deglu-
dec and insulin glargine.
Dr Lane concluded that in patients
with type 1 diabetes at increased risk
of experiencing severe hypoglycae-
mia, insulin degludec was noninferior
in terms of haemoglobinA reduction
and significantly reduced the rates
and proportions of severe hypogly-
caemia and rates of severe or blood
glucose-confirmed symptomatic
overall and nocturnal hypoglycaemia
versus insulin glargine.
SWITCH 2, in type 2 diabetes
Carol Wysham, MD, of the Rock-
wood Center for Diabetes and En-
docrinology, Spokane, Washington,
explained that SWITCH 2 compared
the same parameters as SWITCH 1.
Aside from the patient population,
SWITCH 2 differed from SWITCH
1 inasmuch as both insulin degludec
U100 and insulin glargine U100 were
given in combination with pretrial
oral antidiabetic drugs.
She said, “The study was per-
formed to compare the relative
risk of hypoglycaemia with insulin
degludec versus insulin glargine in
a population of patients with type
2 diabetes who were at high risk of
hypoglycaemia. This is a popula-
tion that would have been largely
excluded from previous studies.”
A total of 721 adults with type 2
diabetes and at least one factor
associated with increased risk of
hypoglycaemia received once-daily
insulin degludec or insulin glargine
followed by crossover to insulin
degludec or insulin glargine for 32
weeks (a 16-week titration and a
16-week maintenance period). Pa-
tients had been treated with basal
insulin with or without oral antidia-
betic drugs excluding sulphonylurea/
meglitinides.
The primary endpoint was
the number of severe or blood
glucose-confirmed (<3.1 mmoL/L)
symptomatic hypoglycaemic
episodes during the maintenance
periods.
Treatment with insulin degludec
resulted in significantly lower rates
of severe or blood glucose-confirmed
symptomatic hypoglycaemia and
severe or blood glucose-confirmed
symptomatic nocturnal hypogly-
caemia (00:01–05:59) than insulin
glargine in the maintenance and
total treatment periods.
The proportion of patients experi-
encing severe hypoglycaemia in the
maintenance periods was 1.6% for
insulin degludec vs 2.4% for insulin
glargine (difference not significant).
The rate of severe hypoglycaemia
was significantly lower with insulin
degludec than with insulin glargine
in the total treatment period.
Insulin degludec was noninferior
to insulin glargine in haemoglobin
A reduction.
Adverse event rates were similar
with the two agents.
Dr Wysham concluded that, com-
pared with insulin glargine, insulin
degludec resulted in a consistent re-
duction in hypoglycaemia in patients
with type 2 diabetes at increased risk
of hypoglycaemia and was shown to
be noninferior to insulin glargine in
haemoglobin A reduction.
She added, “In clinical practice,
the results give us direction in how
to treat this population at high risk
of morbidity and mortality from hy-
poglycaemia”.
Even in a clinical trial setting, keeping HbA1c at goal
for 3 years is difficult
Maintaining haemoglobin A1c to goal over 3 years in patients with type 2 diabetes has been shown to be a
challenge, even in a clinical trial setting. Reduced haemoglobin A1c and fasting glucose values after 26 weeks
of treatment increases a patient’s likelihood of sustaining a haemoglobin A1c <53 mmol/mol (<7%) over 3 years
with minimal medication changes.
T
his conclusion, based on a retrospec-
tive analysis of DURATION-3, a 3-year,
randomised, open-label trial of exena-
tide versus insulin glargine in type 2 diabetes,
was presented at the EASD 2016 meeting.
M.E. Trautmann, MD, of Diabetes Re-
search, Hamburg, Germany, explained that
long-term haemoglobin A1c control with
minimal medication change is a reasonable
goal for patients with type 2 diabetes. Dr Trau-
tmann and colleagues analysed 3-year data
from the DURATION-3 study retrospectively
to characterise patients who sustained a hae-
moglobin A1c response to goal (<53 mmol/
mol [7%]) over 3 years.
Type 2 diabetic patients taking metformin
± sulfonylurea were randomised to 2 mg sub-
cutaneous exenatide once weekly or insulin
glargine titrated to a fasting glucose level of
4.0–5.5 mmoL/L).
Patients with a sustained response to ther-
apy were defined as achieving haemoglobin
A1c <53 mmol/mol (<7%) at 26 weeks and
maintaining haemoglobinA1c <53 mmol/mol
(<7%) for 80% of remaining visits, includ-
ing one of two visits in the last 6 months.
Thirty-two potential model parameters were
tested iteratively and included if related to
sustained success (P < 0.05).
The intent-to-treat population was com-
posed of 456 patients, of whom 287 (63%)
completed 3 years.
Of the 287 completers, 175 (61%) had a
haemoglobin A1c level <53 mmol/mol (<7%)
at 26 weeks. Of completers who reached the
haemoglobin A1c goal, 84 (48%) demon-
strated sustained control for
≥
80% of visits
over 3 years.
Responders with a sustained haemoglobin
A1c response were a mean age of 57.7 years,
baseline body mass index was 32.2 kg/m
2
.
Fifty-percent were males and 81% were white.
Their mean baseline and week 26 haemoglo-
bin A1c levels were 62 mmol/mol (7.8%) and
44 mmol/mol (6.2%), respectively.
Patients unable to sustain goal response
were a mean age of 58.6 years and had a
baseline body mass index of 32.3 kg/m
2
.
Fifty-three percent were male and 92% were
white. Their mean baseline and week 26
haemoglobin A1c were 65 mmol/mol (8.1%)
and 48 mmol/mol (6.5%), respectively. Among
patients achieving haemoglobinA1c goal con-
sistently, significantly more were treated with
weekly exenatide (n = 53) than with insulin
glargine (n = 31; P = 0.03).
Other factors related to sustained treat-
ment success included haemoglobin A1c
and fasting glucose at 26 weeks. The major-
ity of evaluated factors, including age, weight
loss, waist-to-hip ratio, titre of anti-exenatide
antibodies, and sulfonylurea use, were not
related to sustained response.
Dr Trautmann concluded that the analysis
demonstrated the difficulty of maintaining
haemoglobin A1c to goal over 3 years, even
in a clinical trial setting, and suggested that
lower haemoglobin A1c and fasting glucose
values after 26 weeks of treatment raise a
patient’s likelihood of sustaining haemoglobin
A1c <53 mmol/mol (<7%) over 3 years with
minimal medication changes.
Weekly fixed-dose exenatide supported
long-term glycaemic control to a greater
extent than titrated insulin glargine, though
sustained success was achieved with both
therapies. Greater response to weekly ex-
enatide treatment after 26 weeks raises the
likelihood of sustaining glycaemic control over
3 years.
Courtesy of EASD 2016
Courtesy of EASD 2016
CONFERENCE COVERAGE
EASD 2016
PRACTICEUPDATE ENDOCRINOLOGY
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