A novel, long-acting glucagon-like peptide receptor-agonist: dulaglutide

Figures & data

Figure 1 PRISMA flow diagram.

Abbreviations: PRISMA, preferred reporting items for systematic reviews and meta-analyses; GLP-1, glucagon-like peptide-1.

Table 1 Characteristics of the included studies

Study and country	Interventions	Characteristics of participants	Study duration	Outcomes measured
Wysham et al^Citation23 (AWARD-1) Mexico, Argentina, and USA (multicenter)	Dulaglutide 1.5/0.75 mg; exenatide 10 μg; placebo	Number: 976 Mean age: 55–56 years Sex: 40%–44% female HbA1c (%): dula 1.5, 0.75 mg, exenatide 10 μg placebo: 8.1. BMI (kg/m^2): dula 1.5, 0.75 mg, and placebo: 33; exenatide 10 μg: 34. Ethnicity: Hispanic or Latino (32%–36%); not Hispanic or Latino (64%–68%); American Indian (13%–14%); Asian (1%–4%); black (7%–9%); multiple, 1%; Native Hawaiian (0%–< 1%); white (73%–76%) Diabetes duration: 9 years Previous medication (at screening) (metformin and pioglitazone): 1 OAM, (20%–31%); 2 OAMs (44%–56%)	52 weeks	Primary: HbA1c change at 26 weeks Secondary: HbA1c change at 52 weeks, change in central laboratory FSG, 8-point SMPG profiles, change in body weight, and β-cell function and insulin sensitivity indices (updated HOMA2)
Giorgino et al^Citation21 (abstract) (AWARD-2) Country: N/A	Dulaglutide 1.5 mg; Dulaglutide 0.75 mg; Insulin glargine	Number: 807 Mean age: 57 years Sex: N/A HbA1c(%):8.1 BMI (kg/m^2): N/A Weight (kg): 86.3 Ethnicity: N/A Diabetes duration: N/A Previous medication: maximal dose of metformin and glimepiride	78 weeks	Primary: HbA1c
Nauck et al^Citation22 (AWARD-5) Country: NR	Dulaglutide 1.5 mg; Dulaglutide 0.75 mg; Sitagliptin 100 mg 100 mg; placebo	Number: 1,098 Mean age: 54–55 years Sex: 49%–56% female HbA1c (%): dula 1.5 mg, 8.1 ; dula 0.75 mg, 8.2; sita, 8.1 ; placebo, 8.1 BMI (kg/m^2): dula 1.5 mg, 31; dula 0.75 mg, 31; sita, 31; placebo, 31 Ethnicity: Aboriginal (0%–<1%); black (2%–5%); white (50%–54%); East Asian (16%–17%); Hispanic (17%–22%); Native American (0%–<1%); West Asian (6%–10%) Diabetes duration: 7 years Previous medication: oral glucose-lowering monotherapy or combination therapy (metformin plus other drugs); OAM (93%–94%); one medication class (64%–69%); two or more medication class (24%–30%)	104 weeks	Primary: HbA1c Secondary: body weight, FPG (central laboratory measure), and fasting insulin; B-cell function and insulin sensitivity indices (updated HOMA2) and lipids Others: safety
Dungan et al^Citation20 (AWARD-6) 62 sites in 9 countries (Czech Republic, Germany, Hungary, Mexico, Poland, Romania, Spain, Slovakia, and USA)	Once-weekly dulaglutide 1.5 mg; Once-daily liraglutide 1.8 mg	Number: 599 Mean age: 56.5–56.8 years Sex: 50%–54% female HbA1c (%): dula 1.5 mg and lira 1.8 mg: 8.1 BMI (kg/m^2): dula 1.5 mg, 33.5; lira 1.8 mg, 33.6 Ethnicity: Hispanic or Latino (25%–24%); not Hispanic or Latino (75%-76%) Diabetes duration: 7.1–7.3 years Previous medication: metformin	26 weeks	Primary: HbA1c Secondary: change in fasting plasma serum glucose (evaluated at a central laboratory), seven-point self-monitored plasma glucose profiles, bodyweight BMI, and β-cell function assessed with the homoeostasis model assessment (HOMA2-%B). Others: safety, health-related quality of life with exploratory patients-reported outcome measures

Abbreviations: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; Sita, sitagliptin; Lira, liraglutide; NR, not reported; N/A, not available; HbA_1c, glycated hemoglobin; HOMA, homeostatic model assessment; BMI, body mass index; FPG, fasting plasma glucose; OAM, oral antihyperglycemic medications; FSG, fasting serum glucose; SMPG, self-monitored plasma glucose.

Figure 2 Risk of bias.

Abbreviation: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes.

Figure 3 Mean change in HbA_1c from baseline to follow-up (AWARD 1 and 2).

Notes: (A) AWARD-1: *P<0.001, superiority vs exenatide; **P<0.001, superiority vs placebo; ***P<0.001 vs placebo. (B) AWARD-2: *,** indicate multiplicity adjusted one-sided P<0.001 for noninferiority or superiority vs glargine, respectively.
Abbreviations: LS, least square; HbA_1c, glycated hemoglobin; AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; Exe, exenatide; P, placebo.

Figure 4 Mean change in HbA_1c from baseline to follow-up (AWARD 5 and 6).

Notes: (A) AWARD-5: *P<0.001 vs sitagliptin; **P<0.001, superiority vs placebo; ***P<0.001 vs placebo; ^#P<0.001, superiority vs sitagliptin. (B) AWARD-6: P<0.0001 non inferiority of dulaglutide vs liraglutide.
Abbreviations: LS, least square; HbA_1c, glycated hemoglobin; AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; P, placebo; Sita, sitagliptin; Lira, liraglutide.

Figure 5 Proportion of patients achieving a target HbA_1c level of <7% and ≤6.5% (AWARD 1 and 2).

Notes: (A) AWARD-1: *P<0.001 vs exenatide; **P<0.001 vs placebo; ^#P<0.001 vs exenatide. (B) AWARD-2: * indicated two-sided P<0.05 vs glargine.
Abbreviations: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; HbA_1c, glycated hemoglobin; Dula, dulaglutide; P, placebo; Exe, exenatide; Glar, glargine.

Table 2 Changes in HbA_1c, weight and BMI

Study	HbA1c (change from baseline)	P-value	HbA1c <7% (change from baseline %)	P-value	HbA1c <6.5% (change from baseline)	P-value	Weight change from baseline (kg)	P-value	BMI
Dula 1.5/0.75/exe/placebo
Wysham et al^Citation23 AWARD-1	26 weeks: Dula 1.5: −1.51%, SD 1.002 Dula 0.75: −1.3%, SD 1.003 Exe: −0.99%, SD 0.99 P: −0.46%, SD 0.94 52 weeks: Dula 1.5: −1.36%, SD 1.33 Dula 0.75: −1.07%, SD 1.33 Exe: −0.80%, SD 1.32	26 weeks: Dula 1.5 and 0.75: adjusted one-sided P<0.001 for superiority, vs exe or P, respectively, for HbA1c change only Exe: two-sided P<0.05 vs P 52 weeks: Dula 1.5 and 0.75: adjusted one-sided P<0.001 for superiority, vs Exe for HbA1c change only	26 weeks: Dula 1.5: 218 (78.2) Dula 0.75: 184 (65.8) Exe: 144 (52.3) P: 60 (42.9) 52 weeks: Dula 1.5: 197 (70.8) Dula 0.75: 165 (59.1) Exe: 136 (49.2)	26 weeks: Dula 1.5 and 0.75: two-sided P<0.05 vs P two-sided P<0.05 vs Exe Exe: 2 sided P<0.05 vs P 52 weeks: Dula 1.5 and 0.75: two-sided P<0.05 vs Exe	26 weeks: Dula 1.5: 176 (63) Dula 0.75: 148 (53) Exe: 105 (38) P: 34 (24) 52 weeks: Dula 1.5: 57% Dula 0.75: 48% Exe: 35%	P<0.001 all comparisons Not given	26 weeks: Dula 1.5: −1.30, SD 4.84 Dula 0.75: 0.20, SD 4.85 Exe: −1.07, SD 4.39 P: 1.24, SD 4.39 52 weeks: Dula 1.5: −1.01, SD 6.3 Dula 0.75: 0.54, SD 6.3 Exe: −0.71, SD 6.31	26 weeks: Dula 1.5: two-sided P<0.05 vs P Dula 0.75: two-sided P<0.05 vs Exe and P 52 weeks: Dula 0.75: two-sided P<0.05 vs exe	Not given
Dula 1.5/0.75 mg/glargine
Giorgino et al^Citation21 AwARD-2 (abstract)	52 weeks: Dula 1.5: −1.08%, SD 0.9 Dula 0.75: 0%–0.76%, SD 0.9 Glar: 0.63%, SD 0.9 78 weeks: Dula 1.5: −0.9%, SD 1.1 Dula 0.75: −0.62%, SD 1.1 Glar: −0.59%, SD 1.1	Dula 1.5: adjusted P<0.001 for superiority vs glargine for A1c change Dula 0.75: adjusted P<0.001 for nonsuperiority vs glargine for A1c change	52 weeks: Dula 1.5: 145 (53.2) Dula 0.75: 101 (37.1) Glar: 81 (30.9) 78 weeks: Dula 1.5: 134 (49) Dula 0.75: 93 (34.1) Glar: 80 (30.5)	(Two-sided P<0.05 vs glargine) Two-sided P<0.05 vs glargine	Not given		52 weeks: Dula 1.5: −1.87, SD 3.9 Dula 0.75: −1.33, SD 3.9 Glar: 1.44, SD 3.8 78 weeks: Dula 1.5: −1.96, SD 4.2 Dula 0.75: −1.54, SD 4.2 Glar: +1.28, SD 4.2	Two-sided P<0.05 vs glargine	N/A
Dula 1.5/0.75 mg/sita/placebo
Nauck et al^Citation22 AwARD-5	26 weeks: Dula 1.5: −1.22%, SD 0.87 Dula 0.75: −1.01%, SD 1.04 Sita: −0.61%, SD 0.88 (two-sided P<0.001 vs P) P: 0.03%, SD 0.93 52 weeks: Dula 1.5: −1.1%, SD 1.04 Dula 0.75: −0.87%, SD 1.04 Sita: −0.39%, SD 1.06 104 weeks: Dula 1.5: −1%, SD 1.04 Dula 0.75: −0.71%, SD 1.2 Sita: 0.32%, SD 1.06	26 weeks: Dula 1.5 and 0.75: adjusted one-sided P<0.001 for superiority vs P for A1c change Two-sided P<0.001 vs sita 52 weeks: Dula 1.5 and 0.75: adjusted one-sided P<0.001 for superiority vs Sita for A1c change 104 weeks: Dula 1.5 and 0.75: adjusted one-sided P<0.001 for superiority vs Sita for A1c change only	26 weeks: Dula 1.5: 185 (61) Dula 0.75: 167 (55.2) Sita: 119 (37.8) P: 37 (21) 52 weeks: Dula 1.5: 175 (57.6) Dula 0.75: 147 (48.8) Sita: 104 (33) 104 weeks: Dula 1.5: 165 (54.3) Dula 0.75: 135 (44.8) Sita: 98 (31.1)	26 weeks: Dula 1.5 and 0.75: two-sided P<0.001 vs P Two-sided P<0.001 vs sita 52 weeks: Dula 1.5 and 0.75: two-sided P<0.001 vs sita 104 weeks: Dula 1.5 and 0.75: two-sided P<0.001 vs sita	26 weeks: Dula 1.5: 143 (47) Dula 0.75: 94 (31) Sita: 69 (22) P: 23 (13) 52 weeks: Dula 1.5: 128 (42) Dula 0.75: 88 (29) Sita: 60 (19) 104 weeks: Not given	P<0.001, both comparisons (P<0.001 both dula comparisons; P=0.005 sita comparison) P≤0.001 vs sita, both comparisons	26 weeks: Dula 1.5: −3.04, SD 3.48 ≤Dula 0.75: −2.65, SD 3.47 ≤Sita: −1.39, SD 3.54 ≤P: −1.42, SD 3.5≤52 weeks: ≤Dula 1.5: −3.03, SD 3.83 ≤Dula 0.75: −2.6, SD 3.9≤Sita: −1.53, SD 3.9≤104 weeks:≤Dula 1.5: −2.88, SD 4.3≤Dula 0.75: −2.39, SD 4.5≤Sita: −1.75, SD 4.4	26 weeks: Dula 1.5 and 0.75: two-sided P<0.001 vs P Two-sided P<0.001 vs sita 52 weeks: Dula 1.5 and 0.75: two-sided P<0.001 vs sita 104 weeks: Dula 1.5: two-sided P<0.001 vs sita Dula 0.75: two-sided P=0.054 vs sita	Not given
Dula/lira
Dungan et al^Citation20 (AWARD-6)	26 weeks: Dula: −1.4%, SD 0.86 Lira: −1.36%, SD 0.86	From baseline: <0.0001 From baseline: <0.0001 Difference between groups (95% CI): −0.06% (−0.19 to 0.07) P≤0.0001 (noninferiority of dula vs lira)	26 weeks: Dula: 200/293 (68) Lira: 199/293 (68)	Not given	26 weeks: Dula: 169 (55%) Lira: 149 (51%)		26 weeks: Dula: −2.9, SD 3.88 Lira: −3.61, SD 3.8	From baseline P<0.0001 From baseline P<0.0001 Difference between groups (95% CI): 0.71 (0.17–1.26) P=0.011	Consistent with weight finding
Bain 2014^Citation44 (abstract) post hoc analysis at 26 weeks to determine the influence of baseline HbA1c in the AWARD-1 trial
		Baseline <8.5%	Baseline ≥8.5%	P-value
Dula 1.5 mg		−1.16 (0.07)%	−2.37 (0.10)%	<0.001, all comparisons
Placebo		0.17 (0.10)%	−0.76 (0.16)%
Exenatide 10 µg		−0.64 (0.07)%	−1.86 (0.11)%
Proportion of patients achieving HbA1c targets
		Baseline <8.5%	Baseline ≥8.5%
Dula 1.5 mg
<7%		92%	47%	<0.05, all comparisons
≤6.5		80%	26%
Placebo
<7%		55%	10%
≤6.5		32%	3%
Exe
<7%		65%	21%
≤6.5		50%	9%
Dula 0.75 mg reported significant changes for both baseline groups vs placebo Dula 0.75 mg with exenatide 10 µg in the baseline HbA1c ≥8.5% groups					<0.05, both outcomes, all comparisons Statistically not significant

Abbreviations: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; HbA_1c, glycated hemoglobin; Dula, dulaglutide; P, placebo; Exe, exenatide; Glar, glargine; Sita, sitagliptin; Lira, liraglutide; BMI, body mass index; N/A, not available; SD, standard deviation; CI, confidence interval.

Figure 6 (A) and (B) Proportion of patients achieving a target HbA_1c level of <7% and ≤6.5% (AWARD 5 and 6).

Notes: AWARD-5: *P<0.001 vs sitagliptin and placebo; **P<0.001 vs placebo; ***P<0.001 vs sitagliptin; ^#P<0.05 vs sitagliptin; ^##P<0.001 vs sitagliptin.
Abbreviations: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; HbA_1c, glycated hemoglobin; Dula, dulaglutide; P, placebo; Sita, sitagliptin; Lira, liraglutide.

Figure 7 Mean change in weight (kg) from baseline to follow-up (AWARD 1 and 2).

Notes: (A) AWARD-1: * two-sided P<0.05 vs placebo; ** two-sided P<0.05 vs exenatide. (B) AWARD-2: *two-sided P<0.05 vs glargine.
Abbreviations: LS, least square; AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; Exe, exenatide; P, placebo.

Figure 8 Mean change in weight (kg) from baseline to follow-up (AWARD 5 and 6).

Notes: AWARD-5: *two-sided P<0.001 vs sitagliptin; **two-sided P<0.001 vs placebo.
Abbreviations: LS, least square; AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; P, placebo; Sita, sitagliptin; Lira, liraglutide.

Table 3 Fasting plasma glucose, postprandial plasma glucose, and blood pressure

Study	FPG (change from baseline) mmol/L	P-value	PPG (change from baseline) mmol/L	P-value	SBP (change from baseline) mmHg	P-value	DBP (change from baseline) mmHg	P-value
Dula 1.5/0.75/exe/placebo
Wysham et al^Citation23 AWARD-1	26 weeks: Dula 1.5: −43, SD 33.4 Dula 0.75: −34, SD 33.4 Exe: −24, SD 33.4 P: −5, SD 35 52 weeks: Both dula arms continued with significantly greater changes from baseline in FSG compared with exenatide 10 µg (P<0.001, dula 1.5 mg; P=0.005, dula 0.75 mg)	Mean difference between dula 1.5 mg and 0.75 mg vs exe −18 mg/dL and −10 mg/dL (P<0.001, both comparisons)	Mean eight-point self-monitored plasma glucose (SMPG) profile (mmol/L) at baseline and 26 weeks: dula 1.5 g and dula 0.75 mg were associated with a greater reduction in the mean of all premeal PG compared with placebo and exe (P<0.001, both comparisons) Postprandial PG: all active treatment arms had significantly greater LS mean reductions compared with placebo (P<0.001) Patients receiving dula 1.5 mg had a significantly greater reduction in the mean of all postprandial PG values compared with exenatide 10 µg (P=0.047) 2-hour postprandial PG: patients receiving dula 1.5 mg and exenatide had significantly greater reductions in the mean 2-hour postprandial PG excursions compared with placebo (P=0.003, dula 1.5 mg; P<0.001, exenatide 10 µg), with changes in the exenatide group significantly greater than in the dula groups (P<0.001, both comparisons) 52 weeks: Similar results for active treatment arms (data not shown)	26 weeks: Dula 1.5: 0.11, SD 13.8* Dula 0.75: −0.36, SD 13.7* Exe: 0.06, SD 13.7* P: 3.4, SD 13.4 52 weeks: Dula 1.5: 0.83, SD 14.5 Dula 0.75: 1.62, SD 14.2 Exe: 0.02, SD 14.6	*P<0.05 vs placebo	26 weeks: Dula 1.5: 0.76, SD 9.1 Dula 0.75: 0.56, SD 0.0 Exe: −0.11, SD 9.1 P: 1.25, SD 8.9 52 weeks: Dula 1.5: 0.89, SD 9.5 Dula 0.75: 0.76, SD 0.02 Exe: 0.02, SD 9.6
Dula 1.5/0.75 mg/glargine
Giorgino et al^Citation21 AwARD-2 (abstract)	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Dula 1.5/0.75 mg/sita/placebo
Nauck et al^Citation22 AWARD-5	There was significant reduction in FPG in the first 2 weeks with both dulaglutide doses and with sitagliptin 100 mg and the FPG levels remained stable thereafter, whereas those in the placebo arm showed small and slower reduction in FPG overtime. 52 weeks: Dula 1.5: −26 mg/dL (mean difference) Dula 0.75: −13 mg/dL (mean difference)	52 weeks: <0.001, both comparisons with placebo.	NR	NR	26 weeks: Dula 1.5: −1.7, SD 12.2* Dula 0.75: −1.4, SD 12.1* Sita: −1.9, SD 12.4* P: 1.1, SD 11.9 52 weeks: Dula 1.5: −0.8, SD 12.2 Dula 0.75: −0.5, SD 12.1 Sita: −0.5, SD 12.4	*P<0.05 vs placebo	26 weeks: Dula 1.5: −0.4, SD 6.9 Dula 0.75: −0.2, SD 6.9 Sita: −1.1, SD 7.09 P: 0.7, SD 7.9* 52 weeks: Dula 1.5: 0.3, SD 8.7 Dula 0.75: 0.3, SD 8.6 Sita: −0.2, SD 8.8	*P<0.05 vs placebo
Dula 1.5 mg/lira
Dungan et al^Citation20 (AWARD-6)	26 weeks: Dula: −1.93, SD 2.07 Lira: −1.9, SD 2.07	Reduction from baseline <0.0001 (both groups) Between groups: 0.83	26 weeks: Dula: −2.56, SD 1.55 Lira: −2.43, SD 1.5	From baseline <0.0001 (both groups) Between groups: 0.26	Dula: −3.36, SD 12.1 Lira: −2.82, SD 12.1	0.60	Dula: −0.22, SD 6.9 Lira: −0.31, SD 6.9	0.88

Note:

* P<0.05.

Abbreviations: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; P, placebo; Exe, exenatide; Sita, sitagliptin; Lira, liraglutide; N/A, not available; SD, standard deviation; NR, not reported; FPG, fasting plasma glucose; FSG, fasting serum glucose; SMPG, self-monitored plasma glucose; DBP, diastolic blood pressure; SBP, systolic blood pressure; PPG, postprandial glucose; PG, plasma glucose; LS, least square.

Table 4 Adverse events, withdrawals, and hypoglycemia

Study	Discontinuation due to adverse events, n (%)	At least one treatment-emergent adverse event, n (%)	Gastrointestinal events, n (%)				Serious adverse events, n (%)	Pancreatitis, n (%)	Positive immunogenicity	Deaths, n (%)	Mild/moderate/overall hypos, n (%)	Severe hypos, n (%)
			Nausea	Vomiting	Diarrhea	Other gastrointestinal events
Dula 1.5/0.75/Exe/P
Wysham et al^Citation23 AWARD-1	26 weeks: 8 (3)/4 (1)/9 (3)/3 (2) 52 weeks: 9 (3)/4 (1)/10 (4)	26 weeks: 215 (77)/199 (71)/198 (72)/104 (74) 52 weeks: 226 (81)/220 (79)/221 (80)	26 weeks: 78 (28)*/45 (16)**,***/71 (26)*/8 (6) 52 weeks: 81 (29)/47 (17)**/77 (28)	26 weeks: 47 (17)**,*/17 (6)**,***/30 (11)*/2 (1) 52 weeks: 47 (17)/17 (6)**/33 (12)	26 weeks: 31 (11)/22 (8)/16 (6)/8 (6) 52 weeks: 36 (13)/26 (9)/21 (8)	26 weeks: Dyspepsia: 22 (8)***/5 (2)**/19 (7)4 (3) Constipation: 12 (4)/5 (2)/5 (2)/2 (1) Flatulence: 14 (5)/3 (1)/6 (2)/3 (2) 52 weeks: Dyspepsia: 23 (8)/6 (2)**/20 (7) Constipation: 16 (6)/5 (2)/5 (2) Flatulence: 16 (6)/3 (1)/7 (3)	26 weeks: 12 (4)/15 (5)/15 (5)12 (9) 52 weeks: 18 (7)/22 (8)/27 (10)	NR	Anti-drug antibodies 26 weeks (1.5/0.75/exe/P): antibodies: 4(1.4)/2(0.7)/12 (4.3) 2 (1.4) 52 weeks: (1.5/0.75/exe): 5 (1.8)/3 (1.1)/14 (5.1)	26 weeks: 1 (0.4)/1 (0.4)/0 (0)/0 (0) 52 weeks: 1 (0.4)/1 (0.4)/0 (0)	26 weeks: dula 1.5/0.75/exe/P: 29 (10.4)/30(10.7)/44 (15.9)/50 (3.5) Mean 1 year adjusted rates of total hypoglycemia 0.45/1.10/1.47/0.37 events/patient/year 52 weeks: rates and incidence of total hypoglycemia remained lower for dulaglutide 1.5 mg compared to exenatide 10 µg	Exe: 2 None in dulaglutide groups
Dula 1.5/0.75 mg/glargine
Giorgino et al^Citation21 AWARD-2	NR	NR	42 (15.4)/21 (7.7)/4 (1.5)	NR	29 (10.6)/25 (9.2)/15 (5.7)	NR	NR	NR	NR	NR	78 weeks symptomatic hypoglycemia (≤70 mg/dL) event/patient/year) 1.7/1/7/3 (P≤0.002 both)	Severe hypoglycemia was minimal with dula and glargine
Dula 1.5/0.75/sita/P
Nauck et al^Citation22 AWARD-5	26 weeks: 21 (7)/12 (4)/14 (4)/24 (14) 52 weeks: 33 (11)/23 (8)/30 (10)	26 weeks: 208 (68)****/204 (68)****/185 (59)/111 (63) 52 weeks: 233 (77)/231 (77)/219 (70)	26 weeks: 51 (17)#,*/38 (13)#,***/14 (4)/7 (4) 52 weeks: 53 (17)#/42 (14)#/16 (5)	26 weeks: 36 (12)#,*/22 (7)****,*/6 (2)/1 (1) 52 weeks: 39 (13)#/23 (8)****/7 (2)	26 weeks: 39 (13)#,***/27 (9)#/8 (3)***/11 (6) 52 weeks: 44 (15)#/30 (10)#/9 (3)	26 weeks: Abdominal pain: 13 (4)/11 (4)6 (2)/3 (2) Dyspepsia: 13 (4)/14 (5)/8 (3)/2 (1) Abdominal distension: 12 (4)/12 (4)/3 (1)/1 (1) 52 weeks: Abdominal pain: 18 (6)/12 (4)/10 (3) Dyspepsia: 14 (5)/18 (6)/9 (3) Abdominal distension: 12 (4)/14 (5)/3 (1)	26 weeks: 17 (6)/10 (3)/11 (4)/6 (3) 52 weeks: 26 (9)/16 (5)/17 (5)	Acute pancreatitis: Dula/Sita/P: 0/2/1	26 weeks: dula anti-drug antibodies (1.5/0.75/sita/P): 2 (<1)/6 (2)/1 (<1)/0(0) 52 weeks: (1.5/0.75/sita): 2(<1)/7(2)/2(<1)	26 weeks: 1 (<1)/0 (0)/0 (0)/0 (0) 52 weeks: 1 (<1)/0 (0)/2 (<1)	26 weeks: NR 52 weeks: Mean (SD) 1 year adjusted rates (events/patient/year) Dula 1.5: 0.4, SD 1.6 Dula 0.75: 0.3, SD 2.6 Sita: 0.1, SD 1.1	There were no severe hypoglycemic events reported
Dula 1.5 mg/lira
Dungan et al^Citation20 AWARD-6	18 (6)/18 (6) P=0.99	185 (62)/189/63 P=0.78	61 (20)/54 (18) P=0.46	21 (7)/25 (8) P=0.55	36 (12)/36 (12) P=0.995	Dyspepsia: 24 (8)/18 (6), P=0.33 Constipation: 11 (4)/17 (6), P=0.25	5 (2)/11 (4) P=0.13	No cases of pancreatic cancer or adjudicated pancreatitis	3 (1%) patient developed TE antibodies to dulaglutide. Liraglutide group was not assessed. None of these patient developed hypersensitivity reactions	0	Dula/lira: 26 (9)/17 (6) Overall rate (events/patient/year): Mean event rate of 0.34 (Se 1.44) events/patient/year for dula compared with 0.52 (3.01) for lira	None in all groups

Notes:

# P<0.001 versus sitagliptin;

* P<0.001 versus placebo;

** P<0.05 versus exenatide 10;

*** P<0.05 versus placebo;

**** P<0.05 versus sitagliptin.

Abbreviations: AWARD, Assessment of Weekly Administration of Dulaglutide in Diabetes; Dula, dulaglutide; P, placebo; Exe, exenatide; Sita, sitagliptin; Lira, liraglutide; SD, standard deviation; NR, not reported; TE, treatment-emergent; SE, standard error of the mean.

Table S1 Search strategy: MEDLINE

1.	Exp glucagon-like peptides/
2.	(Glucagon like peptide* or GLP-1).tw.
3.	(Dulaglutide or LY2189265 or GLP-1 Fc).tw.
4.	1 or 2 or 3
5.	(Random* or blind* or placebo or trial).tw.
6.	Randomized controlled trial.pt.
7.	Random$.tw.
8.	5 or 6 or 7
9.	Diabetes mellitus, type 2/
10.	Type 2 diabetes mellitus.tw.
11.	9 or 10
12.	4 and 8 and 11
13.	Limit 12 to (English language and humans and year = “2005–current”)

Note: The above search strategy was adopted for other databases.

WyshamCBlevinsTArakakiREfficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1)Diabetes Care20143782159 216724879836

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GiorginoFBenroubiMSunJHZimmermannAGPechtnerVEfficacy and safety of once-weekly dulaglutide vs insulin glargine in combination with metformin and glimepiride in type 2 diabetes patients (AWARD-2)Diabetes201463A87

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NauckMWeinstockRSUmpierrezGEGuerciBSkrivanekZMilicevicZEfficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5)Diabetes Care20143782149 215824742660

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