Trulicity® (dulaglutid): AWARD-11 högre dos

Label information

Dulaglutide is indicated for the treatment of adults with insufficiently controlled T2DM as an adjunct to diet and exercise

• as monotherapy when metformin is considered inappropriate due to intolerance or contraindications, and

• in addition to other medicinal products for the treatment of diabetes.¹

The recommended dose of dulaglutide is 0.75 mg once weekly as monotherapy.¹

The recommended dose of dulaglutide is 1.5 mg once weekly as add-on therapy.¹

For potentially vulnerable populations 0.75 mg once weekly can be considered as a starting dose.¹

For additional glycaemic control,

• the 1.5 mg dose may be increased after at least 4 weeks to 3 mg once weekly

• the 3 mg dose may be increased after at least 4 weeks to 4.5 mg once weekly.

The maximum dose is 4.5 mg once weekly¹

Detailed Information

The AWARD-11 trial was a phase 3, randomized, double-blind, parallel-arm study that assessed the efficacy and safety of investigational dulaglutide doses when added to metformin in patients with T2DM.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.^2-4

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.²

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.^2,4

AWARD-11 baseline demographics and clinical characteristics are presented in Table 1.⁴

Table 1. AWARD-11 Baseline Demographics and Clinical Characteristics⁴

Parametera	DULA 3.0 mg  (n=616)	DULA 4.5 mg (n=614)	DULA 1.5 mg (n=612)
Age (y)b	56.9±10.2	56.6±10.2	57.8±9.7
Female, n (%)	288.0 (46.8)	296.0 (48.2)	314.0 (51.3)
Diabetes duration (y)	7.6±5.5	7.7±5.8	7.6±5.8
HbA1c (%)	8.6±1.0	8.6±0.9	8.6±0.9
FSG, mmol/L (mg/dL)c	10.2±3.0 (184.0±54.4)	10.2±2.7 (183.4±48.0)	10.3±2.9 (185.0±52.0)
Weight (kg)	96.3±20.1	95.4±20.6	95.5±20.2
BMI (kg/m2)	34.3±6.2	34.0±6.2	34.4±6.4
SBP (mmHg)	131.1±14.1	132.1±14.0	132.1±14.2
DBP (mmHg)	78.4±8.7	79.0±9.0	78.8±9.3
HR (bpm)	75.3±9.5	75.5±10.3	75.6±10.1

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.

^a All values presented as mean ± SD unless otherwise noted.

^b 24% of patients included in the study were ≥65 years old.

^c mmol/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.^2,4

Patients were treated for 52 weeks, which included a 12-week dose-escalation phase (Figure 1).⁴

Figure 1. 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.^2,4

Primary and secondary efficacy outcomes at 36 and 52 weeks with the efficacy estimand are provided in  .

Table 2. Primary and Secondary Efficacy Outcomes at 36 and 52 Weeks With Efficacy Estimand^2,3

Parametera	DULA 3.0 mg (n=616)		DULA 4.5 mg (n=614)			DULA 1.5 mg (n=612)
	LSM ∆ From Baseline	LSM Difference (95% CI)		LSM ∆ From Baseline	LSM Difference (95% CI)		LSM ∆ From Baseline
36 Weeks
Change from baseline HbA1c, %	-1.7	-0.17 (-0.29, -0.06)b		-1.9	-0.34 (-0.45, -0.22)c		-1.5
Change from baseline BW, kg	-4.0	-0.90 (-1.40, -0.40)d		-4.7	-1.60 (-2.10, -1.10)c		-3.1
Patients achieving HbA1c target <7.0%, %	64.7	1.49 (1.12, 1.98)ef		71.5	2.23 (1.65, 3.01)cf		57.0
Change from baseline FSG, mmol/L (mg/dL)g	-2.7 (-47.9)	-3.7 (-7.8, 0.5)		-2.9 (-52.3)	-8.1 (-12.3, -3.9)c		-2.5 (-44.2)
52 Weeks
Change from baseline HbA1c, %	-1.7	-0.19 (-0.31, -0.07)h		-1.8	-0.31 (-0.43, -0.19)i		-1.5
Change from baseline BW, kg	-4.3	-0.8 (-1.4, -0.2)j		-5.0	-1.6 (-2.2, -1.0)k		-3.5
Patients achieving HbA1c target <7.0%, %	65.0	1.41 (1.06, 1.88)lf		72.0	2.0 (1.47, 2.72)mf		59.0
Change from baseline FSG, mmol/L (mg/dL)g	-2.7 (-48.7)	-5.6 (-9.9, -1.3)n		-2.9 (-52.7)	-9.6 (-13.9, -5.3)o		-2.4 (-43.1)

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.

^a Missing values were imputed by treatment using monotone regression multiple imputation method.

^b p=.003.

^c p<.001.

^d p=.001.

^e p=.006.

^f Odds ratio.

^g mmol/L calculated by dividing mg/dL by 18.

^h p=.002.

ⁱ p<.001.

^j p=.006.

^k p<.001.

^l p=0.02.

^m p<.001.

ⁿ The p value < .05 vs dulaglutide 1.5 mg.

^o The p 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.^2,3

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

The most frequently reported TEAEs in AWARD-11 were GI in nature ( ).^2-4

Table 3. Most Frequently Reported GI TEAEs Reported in AWARD-11^2-4

Parameter	DULA 3.0 mg (n=616)	DULA 4.5 mg (n=614)	DULA 1.5 mg (n=612)	Total (n=1842)	P Valuea
36 weeks
Patients ≥1 TEAE, n (%)	351 (57.0)	378 (61.6)	346 (56.5)	1075 (58.4)	.140
Nausea	96 (15.6)	101 (16.4)	82 (13.4)	279 (15.1)	.305
Diarrhea	70 (11.4)	66 (10.7)	43 (7.0)	179 (9.7)	.018
Vomiting	51 (8.3)	57 (9.3)	34 (5.6)	142 (7.7)	.036
Dyspepsia	31 (5.0)	16 (2.6)	17 (2.8)	64 (3.5)	.044
52 weeks
Patients ≥1 TEAE, n (%)	384 (62.3)	408 (66.4)	380 (62.1)	1172 (63.6)	.204
Nausea	99 (16.1)	106 (17.3)	87 (14.2)	292 (15.9)	.336
Diarrhea	74 (12.0)	71 (11.6)	47 (7.7)	192 (10.4)	.021
Vomitting	56 (9.1)	62 (10.1)	39 (6.4)	157 (8.5)	.048
Dyspepsia	31 (5.0)	17 (2.8)	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.

^a P 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.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.⁴

Other safety findings through 52 weeks from AWARD-11 can be seen in Table 4.

Table 4. Adverse Events and Hypoglycemia Through 52 Weeks in AWARD-11⁴

Parametera	DULA 3.0 mg (n=616)	DULA 4.5 mg (n=614)	DULA 1.5 mg (n=612)
Patients with ≥1 TEAE	384 (62.3)	408 (66.4)	380 (62.1)
TEAEs ≥5% in any treatment arm
Nausea	99 (16.1)	106 (17.3)	87 (14.2)
Diarrhea	74 (12.0)	71 (11.6)	47 (7.7)
Vomiting	56 (9.1)	62 (10.1)	39 (6.4)
Nasopharyngitis	32 (5.2)	38 (6.2)	28 (4.6)
Dyspepsia	31 (5.0)	17 (2.8)	17 (2.8)
Serious adverse events	42 (6.8)	38 (6.2)	51 (8.3)
Death	4 (0.6)	4 (0.7)	3 (0.5)
Adjudication confirmed
Acute pancreatitis	2 (0.3)	3 (0.5)b	1 (0.2)
CV events	8 (1.3)c	5 (0.8)d	2 (0.3)
Hypoglycemia
Documented symptomatic (<54 mmol/), mg/dLe	2 (0.02), 0.3	7 (0.06), 1.1	8 (0.07), 1.3
Severe	0 (0.0)	1 (0.2)	1 (0.2)

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

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

^b One 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.

^c Two of the 8 CV events occurred when patients were taking the 1.5 mg dose.

^d One of the 5 CV events occurred when a patient was taking the 0.75 mg dose

^e mmol/L calculated by dividing mg/dL by 18.

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

• superior and clinically relevant dose-related improvements in glycemic control and BW at 36 weeks

• reductions in HbA1c and BW that were sustained through 52 weeks of treatment, and

• a safety and tolerability profile that is comparable to the 1.5 mg once-weekly dose and that of other GLP-1 RAs.^3,4

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

References

1. Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Frias 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

3. Frias 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

4. Data 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