Detailed
Information
Hypoglycemia
in the AWARD Studies
Across
the AWARD studies, documented symptomatic hypoglycemia was defined as
a PG ≤70 mg/dL with or without signs or symptoms associated
with hypoglycemia while severe hypoglycemia was defined as a
hypoglycemic event that required the assistance of another person for
treatment. Hypoglycemic events that occurred between bedtime and
waking were designated as nocturnal.1-10
AWARD
Studies in Which Patients Received Dulaglutide Without Concomitant
Treatment With a Sulfonylurea or Insulin
In
the 5 AWARD studies in which dulaglutide was not used concomitantly
with a sulfonylurea or insulin, the duration of the studies ranged
from 24 to 104 weeks. The incidence and mean rate, defined as
episodes/patient/year, of documented symptomatic and severe
hypoglycemia were similar across treatment groups.1-5
Table
1. Incidence and Rate of Documented Symptomatic and Severe
Hypoglycemia Through Final Study Endpoint in AWARD Studies in
Which Patients Received Dulaglutide Without Concomitant Treatment
With a Sulfonylurea or Insulin
Hypoglycemiaa
|
Dulaglutide
1.5
mg
|
Dulaglutide
0.75
mg
|
Comparator
|
Monotherapy
(AWARD-3)1,11,b
|
n=269
|
n=270
|
Metformin
n=268
|
Documented
symptomatic, PG ≤3.9 mmol/L (70 mg/dL)
|
6.3
(0.62)
|
5.9
(0.15)
|
4.9
(0.09)
|
Severe
|
0
(0.0)
|
0
(0.0)
|
0
(0.0)
|
Add-on
to metformin
(AWARD-5)2,11,c
|
n=304
|
n=302
|
Sitagliptin
n=315
|
Documented
symptomatic,
PG ≤3.9 mmol/L (70 mg/dL)
|
10.9
(0.19)
|
6.3
(0.18)
|
5.7
(0.17)
|
Documented
symptomatic,
PG <3mmol/L (54 mg/dL) 11d
|
0.7
|
0.3
|
0
|
Severe
|
0
(0.0)
|
0
(0.0)
|
0
(0.0)
|
Add-on
to metformin
(AWARD-6)3,e
|
n=299
|
NA
|
Liraglutide
n=300
|
Documented
symptomatic,
PG ≤3.9 mmol/L (70 mg/dL)
|
2.7
(0.12)
|
NA
|
2.7
(0.29)
|
Severe
|
0
(0.0)
|
NA
|
0
(0.0)
|
Add-on
to metformin + pioglitazone (AWARD-1)4,11,b
|
n=279
|
n=280
|
Exenatide
Twice Daily
n=276
|
Documented
symptomatic,
PG ≤3.9 mmol/L (70 mg/dL)
|
6.5
(0.19)
|
6.1
(0.14)
|
13.4
(0.75)
|
Documented
symptomatic, PG <3 mmol/L (54 mg/dL) 11d
|
1.4
|
2.1
|
0
|
Severe
|
0
(0.0)
|
0
(0.0)
|
0.7
(0.01)
|
Add-on
to SGLT-2 inhibitorf
± metformin (AWARD-10)5,11,g
|
n=142
|
n=141
|
Placebo
n=140
|
Documented
symptomatic,
PG ≤3.9 mmol/L (70 mg/dL)
|
1.4
(0.16)
|
2.1
(0.15)
|
2.1
(0.12)
|
Documented
symptomatic, PG <3 mmol/L (54 mg/dL)11d
|
0.7
|
0.7
|
0.7
|
Severe
|
0
(0.0)
|
0.7
(0.02)
|
0
(0.0)
|
Abbreviations:
AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes;
N/A = not applicable; PG = plasma glucose; SGLT-2 = sodium-glucose
cotransporter-2.
a
Data presented as percentage of patients (mean rate);
rate = episodes/patient/year. Documented symptomatic hypoglycemia was
defined as a PG ≤70 mg/dL with or without signs or symptoms
associated with hypoglycemia. Severe hypoglycemia was defined as a
hypoglycemic event that required the assistance of another person for
treatment.
b
Endpoint 52 weeks.
c
Endpoint 104 weeks.
d
Data presented as mean rate percentage
e
Endpoint 26 weeks.
f
Canagliflozin, dapagliflozin, or empagliflozin.
g
Endpoint 24 weeks.
Across
the 5 AWARD studies, the incidence of documented symptomatic
hypoglycemia ranged from
1.4%
to 10.9% in the dulaglutide 1.5 mg treatment groups, and
2.1%
to 6.3% in the dulaglutide 0.75 mg treatment groups.1-5,11
Of
the patients treated with dulaglutide, severe hypoglycemia was only
reported in 1 patient of whom received dulaglutide 0.75 mg.5
Hypoglycemia
in the AWARD-11 Study
The
AWARD-11 trial was a phase 3, randomized, double-blind,
active-controlled, parallel-arm study that assessed the efficacy and
safety of dulaglutide 3.0 mg and dulaglutide 4.5 mg compared to
dulaglutide 1.5 mg in patients with inadequately controlled T2DM on
concomitant metformin therapy.12
Patients
were treated for 52 weeks, which included a 12-week dose-escalation
phase (Figure 1).11
Figure
1. Dulaglutide Dose Escalation Design in AWARD-1111
Abbreviations:
AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes;
DBL = data base lock; Dula = dulaglutide.
In
the clinical trial with patients receiving dulaglutide as add-on
therapy to metformin, incidences of hypoglycemia, identified as a
glucose level < 3 mmol/L (< 54 mg/dL), through 36 weeks were
reported in
7
patients, 1.1%, on dulaglutide 1.5 mg
2
patients, 0.3%, on dulaglutide 3 mg, and
7
patients, 1.1%, on dulaglutide 4.5 mg.13
Incidences
of severe hypoglycemia were experienced in
1
patient, 0.2%, on dulaglutide 1.5 mg
no
patients on dulaglutide 3 mg, and
1
patient, 0.2%, on dulaglutide 4.5 mg.13
There
was a consistent pattern of dose-related improvement in HbA1c, BW,
and proportion of patients achieving glycemic target of HbA1c <7%
at 36 and 52 weeks in patients escalated to dulaglutide 3.0 mg and
4.5 mg compared to patients maintained on dulaglutide 1.5 mg.12,14
Hypoglycemia
findings through 52 weeks from the AWARD-11 study is provided in
Table 2.
Table
2. Hypoglycemia Through 52 Weeks in AWARD-1111
Hypoglycemiaa
|
DULA
1.5 mg
(n=612)
|
DULA
3.0 mg
(n=616)
|
DULA
4.5 mg
(n=614)
|
Documented
symptomatic, PG < 3 mmol/L (<54 mg/dL)
|
8
(1.3)
|
2
(0.3)
|
7
(1.1)
|
Severe
|
1
(0.2)
|
0
(0.0)
|
1
(0.2)
|
Abbreviations:
Assessment of Weekly AdministRation of LY2189265 in Diabetes; DULA =
dulaglutide.
a
All values presented as n (%); AEs presented as number
of patients with ≥1 event.
AWARD
Studies in Which Patients Received Dulaglutide and Concomitant
Treatment With a Sulfonylurea or Insulin
In
the 5 AWARD studies in which dulaglutide was used concomitantly with
a sulfonylurea or insulin, the duration of the studies ranged from 24
to 78 weeks.6-10
Overall, the incidence and mean rate of documented symptomatic,
nocturnal, and severe hypoglycemia were lower in patients treated
with dulaglutide 1.5 mg or dulaglutide 0.75 mg compared with those
treated with an active comparator along with a sulfonylurea or
insulin.7,9,10
Across
the 5 AWARD studies, the incidence of documented symptomatic
hypoglycemia ranged from
11.3%
to 80.8% in the dulaglutide 1.5 mg treatment groups, and
39%
to 85.6% in the dulaglutide 0.75 mg treatment groups.6-10
The
incidence of nocturnal hypoglycemia ranged from
6.7%
to 54.3% in the dulaglutide 1.5 mg treatment groups, and
23.2%
to 53.8% in the dulaglutide 0.75 mg treatment groups.6-10
The
incidence of severe hypoglycemia ranged from
0%
to 3.4% in the dulaglutide 1.5 mg treatment groups, and
0%
to 3% in the dulaglutide 0.75 mg treatment groups.6-10
AWARD
Studies With Insulin Glargine as Comparator
Overall,
the incidence and mean rate of documented symptomatic, nocturnal, and
severe hypoglycemia were lower in patients treated with dulaglutide
1.5 mg or dulaglutide 0.75 mg compared with those treated with the
active comparator insulin glargine.7,9,10
Use
of Dulaglutide With Medications Known to Cause Hypoglycemia
The
risk of hypoglycemia is increased when dulaglutide is used in
combination with insulin secretagogues, such as sulfonylureas, or
insulin. Patients may require a lower dose of the sulfonylurea or
insulin to reduce the risk of hypoglycemia in this setting.15
References
1.
Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al.
Efficacy and safety of dulaglutide monotherapy versus metformin in
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2.
Weinstock RS, Guerci B, Umpierrez G, et al. Safety and efficacy of
once-weekly dulaglutide versus sitagliptin after 2 years in
metformin-treated patients with type 2 diabetes (AWARD-5): a
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3.
Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide
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4.
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5.
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https://doi.org/10.1016/S2213-8587(18)30023-8
6.
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evaluate the efficacy and safety of once-weekly dulaglutide added on
to glimepiride in type 2 diabetes (AWARD-8). Diabetes Obes Metab.
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7.
Giorgino F, Benroubi M, Sun JH, et al. Efficacy and safety of
once-weekly dulaglutide versus insulin glargine in patients with type
2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care.
2015;38(12):2241-2249. https://doi.org/10.2337/dc14-1625
8.
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9.
Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus
bedtime insulin glargine, both in combination with prandial insulin
lispro, in patients with type 2 diabetes (AWARD-4): a randomised,
open-label, phase 3, non-inferiority study. Lancet.
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https://doi.org/10.1016/S0140-6736(15)60936-9
10.
Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus
insulin glargine in patients with type 2 diabetes and
moderate-to-severe chronic kidney disease (AWARD-7): a multicentre,
open-label, randomised trial. Lancet Diabetes Endocrinol.
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11.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
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Frias JP, Nevárez Ruiz L, Li YG, et al. Efficacy and safety
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https://doi.org/10.1210/jendso/bvaa046.2057
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Glossary
AWARD
= Assessment of Weekly AdministRation of LY2189265 in Diabetes
BW =
body weight
HbA1c
= glycated hemoglobin
PG =
plasma glucose
T2DM
= type 2 diabetes mellitus