TRESIBA
®
(insulin degludec injection)
8
Table 12: Results at Week 26 in a Trial Comparing TRESIBA
®
at Same and
Alternating Times to Insulin Glargine U-100 in Adult Patients with Type 2
Diabetes Mellitus on OAD(s)*
TRESIBA
®
at the
same time each
day ± OAD(s)*
TRESIBA
®
at
alternating
times ± OAD(s)*
Insulin glargine
U-100 ± OAD(s)*
N
228
229
230
HbA
1c
(%)
Baseline
8.4
8.5
8.4
End of trial
7.3
7.2
7.1
Adjusted mean change from baseline**
-1.03
-1.17
-1.21
Estimated treatment difference [95%CI]
TRESIBA
®
alternating - Insulin glargine U-100
0.04 [-0.12;0.20]
Estimated treatment difference
TRESIBA
®
alternating – TRESIBA
®
same
-0.13
Proportion Achieving HbA
1c
< 7% at
Trial End
40.8%
38.9%
43.9%
FPG (mg/dL)
Baseline
158
162
163
End of trial
105
105
112
Adjusted mean change from baseline
-54.2
-55.0
-47.5
Daily insulin dose
Baseline mean
21 U
19 U
19 U
Mean dose after 26 weeks
45 U
46 U
44 U
*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA
1c
was analyzed using ANOVA with treatment, region,
sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA
1c
as covariates.
In Study G, there were 11.4% subjects for TRESIBA
®
(both same time and alternating times) and 11.7% Insulin
glargine arms for whom data was missing at the time of the HbA
1c
measurement.
Study H: TRESIBA
®
Administered at the Same Time Each Day in Combination with a Rapid-
Acting Insulin Analog at Mealtimes in Adult Patients
The efficacy of TRESIBA
®
was evaluated in a 52-week randomized, open-label, multicenter trial
in 992 patients with type 2 diabetes mellitus inadequately controlled on premix insulin, bolus
insulin alone, basal insulin alone, oral antidiabetic agents (OADs) alone or any combination
thereof. Patients were randomized to TRESIBA
®
once-daily with the main evening meal or insulin
glargine U-100 once-daily according to the approved labeling. Insulin aspart was administered
before each meal in both treatment arms. Up to two of the following oral antidiabetes agents
(metformin or pioglitazone) were used as background therapy in both treatment arms.
The mean age of the trial population was 58.9 years and mean duration of diabetes was 13.5
years. 54.2% were male. 82.9% were White, 9.5% Black or African American. 12.0% were
Hispanic. 12.4% of patients had eGFR<60 mL/min/1.73m
2
. The mean BMI was approximately
32.2 kg/m
2
.
At week 52, the difference in HbA
1c
reduction from baseline between TRESIBA
®
and insulin
glargine U-100 was 0.08% with a 95% confidence interval of [-0.05%; 0.21%] and met the
pre-specified non-inferiority margin (0.4%). See Table 13.
Table 13: Results at Week 52 in a Trial Comparing TRESIBA
®
to Insulin Glargine
U-100 in Adult Patients with Type 2 Diabetes Mellitus Receiving Insulin Aspart at
Mealtimes and OADs*
TRESIBA
®
+ Insulin
aspart ± OAD(s)*
Insulin glargine U-100 +
Insulin aspart ± OAD(s)*
N
744
248
HbA
1c
(%)
Baseline
8.3
8.4
End of trial
7.1
7.1
Adjusted mean change from baseline**
-1.10
-1.18
Estimated treatment difference [95%CI]
TRESIBA
®
- Insulin glargine U-100
0.08 [-0.05;0.21]
Proportion Achieving HbA
1c
< 7% at Trial End
49.5%
50.0%
FPG (mg/dL)
Baseline
166
166
End of trial
122
127
Adjusted mean change from baseline
-40.6
-35.3
Daily basal insulin dose
Baseline mean
42 U
41 U
Mean dose after 52 weeks
74 U
67 U
Daily bolus insulin dose
Baseline mean
33 U
33 U
Mean dose after 52 weeks
70 U
73 U
*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA
1c
was analyzed using ANOVA with treatment, region,
sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA
1c
as covariates.
In Study H, there were 16.1% of subjects in the TRESIBA
®
and 14.5% Insulin glargine arms for whom data was
missing at the time of the HbA
1c
measurement.
Study I: TRESIBA
®
Administered at Any Time Each Day as an Add-on to One or Two of the
Following Oral Agents: Metformin, Sulfonylurea, or Pioglitazone in Adult Patients
The efficacy of TRESIBA
®
was evaluated in a 26-week randomized, open-label, multicenter
trial in 447 patients with type 2 diabetes mellitus inadequately controlled on one or more oral
antidiabetic agent (OADs) at baseline. Patients were randomized to TRESIBA
®
once-daily
at any time of day or sitagliptin once-daily according to the approved labeling. One or two
of the following oral antidiabetes agents (metformin, sulfonylurea or pioglitazone) were also
administered in both treatment arms.
The mean age of the trial population was 55.7 years and mean duration of diabetes was 7.7 years.
58.6% were male. 61.3% were White, 7.6% Black or African American. 21.0% were Hispanic.
6% of patients had eGFR<60 mL/min/1.73m
2
. The mean BMI was approximately 30.4 kg/m
2
.
At the end of 26 weeks, TRESIBA
®
provided greater reduction in mean HbA
1c
compared to
sitagliptin (p < 0.001). See Table 14.
Table 14: Results at Week 26 in a Trial Comparing TRESIBA
®
to Sitagliptin in
Adult Patients with Type 2 Diabetes Mellitus on OADs*
TRESIBA
®
+ OAD(s)*
Sitag OAD(s)*
N
225
222
HbA
1c
(%)
Baseline
8.8
9.0
End of trial
7.2
7.7
Adjusted mean change from baseline**
-1.52
-1.09
Estimated treatment difference [95%CI]
TRESIBA
®
- Sitagliptin
-0.43 [-0.61;-0.24]
1
Proportion Achieving HbA
1c
< 7% at Trial
End
40.9%
27.9%
FPG (mg/dL)
Baseline
170
179
End of trial
112
154
Adjusted mean change from baseline
-61.4
-22.3
Daily insulin dose
Baseline mean
10 U
N/A
Mean dose after 26 weeks
43 U
N/A
*OAD: oral antidiabetic agent
**The change from baseline to end of treatment visit in HbA
1c
was analyzed using ANOVA with treatment, region,
sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA
1c
as covariates.
In Study I, there were 20.9% of subjects in the TRESIBA
®
and 22.5% Sitagliptin arms for whom data was
missing at the time of the HbA
1c
measurement.
1
p <0.001; 1-sided p-value evaluated at 2.5% level for superiority
14.4 Safety Outcomes Trial
DEVOTE (NCT01959529) Cardiovascular Outcomes Trial of TRESIBA
®
Administered Once-Daily
Between Dinner and Bedtime in Combination with Standard of Care in Subjects with Type 2
Diabetes and Atherosclerotic Cardiovascular Disease
DEVOTE was a multi-center, multi-national, randomized, double-blinded, active-controlled,
treat-to-target, event-driven trial. 7,637 patients with inadequately controlled type 2 diabetes and
atherosclerotic cardiovascular disease were randomized to either TRESIBA
®
or insulin glargine
U-100. Each was administered once-daily between dinner and bedtime in addition to standard of
care for diabetes and cardiovascular disease for a median duration of 2 years.
Patients eligible to enter the trial were; 50 years of age or older and had established, stable,
cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA
class II and III heart failure (85% of the enrolled population) or were 60 years of age or older
and had other specified risk factors for cardiovascular disease (15% of the enrolled population).
At baseline, demographic and disease characteristics were balanced between treatment groups.
The mean age of the trial population was 65 years and the mean duration of diabetes was 16.4
years. The population was 62.6% male, 75.6% White 10.9% Black or African American, 10.2%
Asian. 14.9% had Hispanic ethnicity. The mean HbA
1c
was 8.4% and the mean BMI was 33.6 kg/
m
2
. The baseline mean estimated glomerular filtration rate (eGFR) was 68 mL/min/1.73m
2
. 41%
of patients had eGFR 60-90 mL/min/1.73m
2
; 35% of patients had eGFR 30 to 60 mL/min/1.73
m
2
and 3% of patients had eGFR <30 mL/min/1.73 m
2
. Previous history of severe hypoglycemia
was not captured in the trial.
At baseline, patients treated their diabetes with oral antidiabetic drugs (72%) and with an insulin
regimen (84%). Types of insulins included long acting insulin (60%), intermediate acting insulin
(14%) short acting insulin (37%) and premixed insulin (10%). 16% of patients were insulin
naive. The most common background oral antidiabetic drugs used at baseline were metformin
(60%), sulfonylureas (29%) and DPP-4 inhibitors (12%).
During the trial, investigators could modify anti-diabetic and cardiovascular medications to
achieve local standard of care treatment targets for lipids and blood pressure.
Cardiovascular Outcomes
- Patients with T2DM and Atherosclerotic CVD
The incidence of major cardiovascular events with TRESIBA
®
was evaluated in DEVOTE.
Subjects treated with TRESIBA
®
had a similar incidence of major adverse cardiovascular events
(MACE) when compared to those treated with insulin glargine U-100.
The primary endpoint in DEVOTE was time from randomization to the first occurrence of a
3-component major adverse cardiovascular event (MACE): cardiovascular death, non-fatal
myocardial infarction, or non-fatal stroke. The study was designed to exclude a pre-specified risk
margin of 1.3 for the hazard ratio of MACE comparing TRESIBA
®
to insulin glargine U-100. The
primary outcome at end of trial was available for 98.2% of participants in each treatment group.
