Trulicity ® (dulaglutid) injektion

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Trulicity® (dulaglutid): AWARD-11 högre dos

Behandling med 4,5 mg dulaglutid resulterade i signifikant större minskningar av HbA1c, vikt, FBG och andel som uppnådde HbA1c <7,0% jämfört med dulaglutid 1,5 mg.

SE_cFAQ_GLP079_HIGHER_DOSE_AWARD-11
SE_cFAQ_GLP079_HIGHER_DOSE_AWARD-11
en-GB

Detailed Information

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.1,2

The primary endpoint of the AWARD-11 trial was the change from baseline in HbA1c at 36 weeks in patients with inadequately controlled T2DM who were also receiving concomitant metformin therapy.1-4

Data from the AWARD-11 trial suggests that escalation from dulaglutide 1.5 mg to dulaglutide 3 mg or dulaglutide 4.5 mg once-weekly provided clinically relevant, dose-related improvements in glycemic control and BW with an acceptable safety profile.1

Key Inclusion Criteria

Patients included in AWARD-11 

  • were 18 years old or older
  • had a BMI ≥25 kg/m2
  • had T2DM that was being treated with stable doses of metformin ≥1500 mg/day
  • had an HbA1c value of 7.5% to 11% inclusive, and
  • had T2DM for ≥6 month.1,2,4

AWARD-11 baseline demographics and clinical characteristics are presented in AWARD-11 Baseline Demographics and Clinical Characteristics.4

AWARD-11 Baseline Demographics and Clinical Characteristics2,4

Parametera

DULA 1.5 mg
(n=612)

DULA 3.0 mg 
(n=616)

DULA 4.5 mg
(n=614)

Age (y)b

57.8±9.7

56.9±10.2

56.6±10.2

Female, n (%)

314.0 (51.3)

288.0 (46.8)

296.0 (48.2)

Diabetes duration (y)

7.6±5.8

7.6±5.5

7.7±5.8

HbA1c (%) 

8.6±0.9

8.6±1.0

8.6±0.9

FSG, mmol/L (mg/dL)c

10.3±2.9 (185.0±52.0)

10.2± 7.2 (184.0±54.4)

10.2±2.7 (183.4±48.0)

Weight (kg)

95.5±20.2

96.3±20.1

95.4±20.6

BMI (kg/m2)

34.4±6.4

34.3±6.2

34.0±6.2

SBP (mmHg) 

132.1±14.2

131.1±14.1

132.1±14.0

DBP (mmHg)

78.8±9.3

78.4±8.7

79.0±9.0

HR (bpm)

75.6±10.1

75.3±9.5

75.5±10.3

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; BMI = body mass index; DBP = diastolic blood pressure; DULA = dulaglutide; FSG = fasting serum glucose; HbA1c = glycated hemoglobin; HR = heart rate; SBP = systolic blood pressure.

aAll values presented as mean ± SD unless otherwise noted.

b24% of patients included in the study were ≥65 years old.

cmmol/L calculated by dividing mg/dL by 18.

Study Design

In the AWARD-11 trial, 1842 patients were randomized 1:1:1 to receive treatment with

  • dulaglutide 1.5 mg once weekly (n=612)
  • dulaglutide 3.0 mg once weekly (n=616), or
  • dulaglutide 4.5 mg once weekly (n=614).

All 3 treatment groups were also concomitantly treated with metformin.1,2,4

Patients were treated for 52 weeks, which included a 12-week dose-escalation phase (Dulaglutide Dose Escalation in AWARD-11).4

Dulaglutide Dose Escalation in AWARD-114

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; DULA = dulaglutide.

Efficacy Results

Patients enrolled in the AWARD-11 trial that were escalated to dulaglutide 3.0 mg or dulaglutide 4.5 mg were more likely to achieve clinically-relevant composite endpoints.1,4

Primary and secondary efficacy outcomes at 36 and 52 weeks with the efficacy estimand are provided in Primary and Secondary Efficacy Outcomes at 36 and 52 Weeks With Efficacy Estimand in AWARD-11.

Primary and Secondary Efficacy Outcomes at 36 and 52 Weeks With Efficacy Estimand in AWARD-111-3

Parametera

DULA 1.5 mg
(n=612)

DULA 3.0 mg
(n=616)

DULA 4.5 mg
(n=614)

LSM ∆ From Baseline

LSM ∆ From Baseline

LSM Difference (95% CI)

LSM ∆ From Baseline

LSM Difference (95% CI)

36 Weeks 

Change from baseline HbA1c, %

-1.5

-1.7

-0.17 (-0.29, -0.06)b

-1.9

-0.34 (-0.45, -0.22)c

Change from baseline BW, kg

-3.1

-4.0

-0.90 (-1.40, -0.40)d

-4.7

-1.60 (-2.10, -1.10)c

Patients achieving HbA1c target <7.0%, %

57.0

64.7

1.49 (1.12, 1.98)ef

71.5

2.23 (1.65, 3.01)cf

Change from baseline FSG, mmol/L (mg/dL)g

-2.5 (-44.2)

-2.7 (-47.9)

-0.2 (-0.4,0.02) (-3.7 (-7.8, 0.5))

-2.9 (-52.3)

-0.5 (-0.7,-0.2) (-8.1 (-12.3, -3.9))c

52 Weeks

Change from baseline HbA1c, %

-1.5

-1.7

-0.19 (-0.31, -0.07)h

-1.8

-0.31 (-0.43, -0.19)i

Change from baseline BW, kg

-3.5

-4.3

-0.8 (-1.4, -0.2)j

-5.0

-1.6 (-2.2, -1.0)k

Patients achieving HbA1c target <7.0%, %

59.0

65.0

1.41 (1.06, 1.88)lf

72.0

2.0 (1.47, 2.72)mf

Change from baseline FSG, mmol/L (mg/dL)g

-2.4 (-43.1)

-2.7 (-48.7)

 (-5.6 (-9.9, -1.3))n

-2.9 (-52.7)

-0.5 (0.8, 0.3) (-9.6 (-13.9, -5.3))o

Abbreviations: Δ = change; AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; BW = body weight; DULA = dulaglutide; FSG = fasting serum glucose; HbA1c = glycated hemoglobin; LSM = least squares mean.

aMissing values were imputed by treatment using monotone regression multiple imputation method.

bp=.003.

cp<.001.

dp=.001.

ep=.006.

fOdds ratio.

gmmol/L calculated by dividing mg/dL by 18.

hp=.002.

ip<.001.

jp=.006.

kp<.001.

lp=0.02.

mp<.001.

np value < .05 vs dulaglutide 1.5 mg.

op value < .001 vs dulaglutide 1.5 mg.

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.1-3

At both 36 weeks and 52 weeks, there was a pattern of dose-related improvement in FSG.2,4

At the primary 36-week endpoint, the efficacy estimand showed that the secondary efficacy objective of superiority over the 1.5-mg dose for change from baseline in FSG was met only with the dulaglutide 4.5 mg dose. At 52 weeks, the reduction in FSG was significantly greater in both the 3.0 mg and 4.5 mg groups compared to the dulaglutide 1.5 mg group.4

Safety Results

Consistent with the known safety profile of dulaglutide, the most common AEs were related to GI symptoms. The incidence was highest early after dulaglutide initiation and tended to wane over time.1,2,4

The most frequently reported TEAEs in AWARD-11 were GI related (Most Frequently Reported GI TEAEs Reported in AWARD-11).1-4

Most Frequently Reported GI TEAEs Reported in AWARD-111-4

Parameter

DULA 1.5 mg
(n=612)

DULA 3.0 mg
(n=616)

DULA 4.5 mg
(n=614)

Total
(n=1842)

P Valuea

36 weeks

Patients ≥1 TEAE, n (%)

346 (56.5)

351 (57.0)

378 (61.6)

1075 (58.4)

.140

Nausea

82 (13.4)

96 (15.6)

101 (16.4)

279 (15.1)

.305

Diarrhea

43 (7.0)

70 (11.4)

66 (10.7)

179 (9.7)

.018

Vomiting 

34 (5.6)

51 (8.3)

57 (9.3)

142 (7.7)

.036

Dyspepsia

17 (2.8)

31 (5.0)

16 (2.6)

64 (3.5)

.044

52 weeks

Patients ≥1 TEAE, n (%)

380 (62.1)

384 (62.3)

408 (66.4)

1172 (63.6)

.204

Nausea

87 (14.2)

99 (16.1)

106 (17.3)

292 (15.9)

.336

Diarrhea

47 (7.7)

74 (12.0)

71 (11.6)

192 (10.4)

.021

Vomiting

39 (6.4)

56 (9.1)

62 (10.1)

157 (8.5)

.048

Dyspepsia

17 (2.8)

31 (5.0)

17 (2.8)

65 (3.5)

.060

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; DULA = dulaglutide; GI = gastrointestinal; TEAE = treatment emergent adverse event.

aP values for overall treatment effect were computed using Fisher’s Exact test.

Nearly all cases of nausea, vomiting, and diarrhea reported by patients, >95% for each, were mild to moderate in severity.2,4

There were no reported cases of medullary thyroid carcinoma in the AWARD-11 trial.2

All safety findings for the AWARD-11 trial were similar across the elderly patient population, ≥65 years old, when compared to the general patient population.2

Other safety findings through 52 weeks from AWARD-11 can be seen in Adverse Events and Hypoglycemia Through 52 Weeks in AWARD-11.

Adverse Events and Hypoglycemia Through 52 Weeks in AWARD-112,4

Parametera

DULA 1.5 mg
(n=612)

DULA 3.0 mg
(n=616)

DULA 4.5 mg
(n=614)

Patients with ≥1 TEAE

380 (62.1)

384 (62.3)

408 (66.4)

TEAEs ≥5% in any treatment arm

Nausea 

87 (14.2)

99 (16.1)

106 (17.3)

Diarrhea

47 (7.7)

74 (12.0)

71 (11.6)

Vomiting

39 (6.4)

56 (9.1)

62 (10.1)

Nasopharyngitis

28 (4.6)

32 (5.2)

38 (6.2)

Dyspepsia

17 (2.8)

31 (5.0)

17 (2.8)

Serious adverse events

51 (8.3)

42 (6.8)

38 (6.2)

Death

3 (0.5)

4 (0.6)

4 (0.7)

Adjudication confirmed

Acute pancreatitis

1 (0.2)

2 (0.3)

3 (0.5)b

CV events

2 (0.3)

8 (1.3)c

5 (0.8)d

Hypoglycemia

Documented symptomatic (<3 mmol/L)

8 (0.1)

2 (0.0)

7 (0.1)

Severe

1 (0.0)

0 (0.0)

1 (0.0)

Abbreviations: AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; CV = cardiovascular; DULA = dulaglutide; TEAE = treatment emergent adverse event.

aAll values presented as n (%); Adverse events presented as number of patients with ≥ 1 event.

bOne of the confirmed acute pancreatitis cases in the 4.5 mg group was a patient with previously undisclosed history of prior hospitalization for acute pancreatitis.

cTwo of the 8 CV events occurred when patients were taking the 1.5 mg dose.

dOne of the 5 CV events occurred when a patient was taking the 0.75 mg dose

In patients with T2DM and inadequate glycemic control on metformin, escalation from dulaglutide 1.5 mg to dulaglutide 3.0 mg or 4.5 mg once weekly allowed for

  • clinically relevant dose related improvements in glycemic control and BW, and
  • a safety and tolerability profile that is comparable to the 1.5 mg once-weekly dulaglutide dose and that of other GLP-1 RAs.2-4

Escalation to higher dulaglutide doses would allow more patients to achieve and maintain treatment goals while remaining on the same familiar therapy.2,4

References

1Frias JP, Nevárez Ruiz L, Li YG, et al. Efficacy and safety of higher dulaglutide doses (3.0 mg and 4.5 mg) when added to metformin in patients with type 2 diabetes: a phase 3, randomized, double-blind, parallel arm study (AWARD-11). J Endocr Soc. 2020;4(suppl 1):A1036. Endocrine Society abstract OR26-08. https://doi.org/10.1210/jendso/bvaa046.2057

2Frias JP, Bonora E, Ruiz LN, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg vs dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. Published online January 4, 2021. https://doi.org/10.2337/dc20-1473

3Frias JP, Bonora E, Nevarez Ruiz LA, et al. Efficacy and safety of dulaglutide 3mg and 4.5mg vs. dulaglutide 1.5mg: 52-week results from AWARD-11. Diabetes. 2020;69(suppl 1). American Diabetes Association abstract 357-OR. https://doi.org/10.2337/db20-357-OR

4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AE = adverse event

AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes

BMI = body mass index

BW = body weight

CV = cardiovascular

FSG = fasting serum glucose

GI = gastrointestinal

HbA1c = glycated hemoglobin

T2DM = type 2 diabetes mellitus

TEAE = treatment-emergent adverse event

Datum fӧr senaste ӧversyn 2020 M08 27

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