Trulicity ® (dulaglutid) injektion

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Vad visade Trulicity® (dulaglutid) AWARD-11 Högre Dosstudien?

Behandling med veckovis dulaglutid 4,5 mg och 3,0 mg resulterade i dosrelaterade förbättringar av HbA1c, vikt, FSG och andel patienter som uppnådde HbA1c <7,0% jämfört med 1,5 mg dulaglutid.

SE_cFAQ_GLP079_HIGHER_DOSE_AWARD-11
SE_cFAQ_GLP079_HIGHER_DOSE_AWARD-11
en-GB

Summary

  • 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 4.5 mg compared with dulaglutide 1.5 mg in patients on metformin with inadequately controlled Type 2 Diabetes mellitus (T2DM).1,2
  • The primary endpoint of the AWARD-11 trial was the change from baseline in HbA1c at week 36.1-4
  • Escalation from dulaglutide 1.5 mg to dulaglutide 3 mg or 4.5 mg provided clinically relevant, dose-related improvements in glycemic control and weight with an acceptable safety profile.1
  • Escalation to higher dulaglutide doses would allow more patients to achieve and maintain treatment goals while remaining on the same familiar therapy.2,4

What were the Key Inclusion Criteria?

Patients included in AWARD-11 

  • were ≥18 years old 
  • had a body mass index (BMI) ≥25 kg/m2
  • were 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.

What was the Study Design?

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

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

What were the Efficacy Results?

Patients that were escalated to dulaglutide 3.0 mg or 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 weight, 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)c

Change from baseline weight, kg

-3.5

-4.3

-0.8 (-1.4, -0.2)e

-5.0

-1.6 (-2.2, -1.0)c

Patients achieving HbA1c target <7.0%, %

59.0

65.0

1.41 (1.06, 1.88)if

72.0

2.0 (1.47, 2.72)cf

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

-2.4 (-43.1)

-2.7 (-48.7)

 (-5.6 (-9.9, -1.3))j

-2.9 (-52.7)

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

Abbreviations: Δ = change; AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes; 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=0.003.

cp<0.001.

dp=0.001.

ep=0.006.

fOdds ratio.

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

hp=0.002.

ip=0.02.

jp value < 0.05 vs dulaglutide 1.5 mg.

kp value <0.001 vs dulaglutide 1.5 mg.

At 36 and 52 weeks, those patients showed a consistent pattern of dose-related improvement in

  • HbA1c
  • weight, and
  • proportion of patients achieving glycemic target of HbA1c <7%.1-3

Compared with dulaglutide 1.5 mg, dose-related improvement in fasting serum glucose (FGS) from baseline was observed at

  • week 36 with dulaglutide 4.5 mg, and
  • week 52 with dulaglutide 3.0 mg and 4.5 mg.2,4 

What were the Safety Results?

Gastrointestinal (GI) symptoms were the most common adverse events (AEs), which is consistent with the known safety profile of dulaglutide.

The incidence was highest early after dulaglutide initiation and tended to wane over time.1,2,4

The most frequently reported treatment emergent adverse events (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)

0.140

Nausea

82 (13.4)

96 (15.6)

101 (16.4)

279 (15.1)

0.305

Diarrhea

43 (7.0)

70 (11.4)

66 (10.7)

179 (9.7)

0.018

Vomiting 

34 (5.6)

51 (8.3)

57 (9.3)

142 (7.7)

0.036

Dyspepsia

17 (2.8)

31 (5.0)

16 (2.6)

64 (3.5)

0.044

52 weeks

Patients ≥1 TEAE, n (%)

380 (62.1)

384 (62.3)

408 (66.4)

1172 (63.6)

0.204

Nausea

87 (14.2)

99 (16.1)

106 (17.3)

292 (15.9)

0.336

Diarrhea

47 (7.7)

74 (12.0)

71 (11.6)

192 (10.4)

0.021

Vomiting

39 (6.4)

56 (9.1)

62 (10.1)

157 (8.5)

0.048

Dyspepsia

17 (2.8)

31 (5.0)

17 (2.8)

65 (3.5)

0.060

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.

In AWARD-11,

  • more than 95% of reported cases of nausea, vomiting, and diarrhea were mild to moderate in severity.
  • there were no reported cases of medullary thyroid carcinoma, and
  • all safety findings were similar across the elderly patient population (≥65 years old) and the general patient population.2,4

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

cardiovascular (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; 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 weight, 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

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, Nevarez Ruiz L, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. 2021;44(3):765-773. 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.

Datum fӧr senaste ӧversyn 2020 M08 27


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