Glycemic control, weight-loss effects, and safety of cotadutide in individuals with type 2 diabetes: A systematic review and meta-analysis

Table 1 Characteristics of the randomized controlled trials and trial participants with type 2 diabetes evaluated in this meta-analysis, mean ± SD/median (interquartile range)

Ref.	Trial ID	Country	Phase of the trial	Major inclusion criteria	Trial arms (sample size, n)	Age (years)	Male (%)	Weight (kg)	BMI kg/m2	HbA1c (%)	Trial duration
Ambery et al[8]	NCT02548585	Germany	Phase 2a	Age: 18-65 years; HbA1c: 6.5%-8.5%; BMI: 27-40 kg/m2	MEDI0382 up to 200 μg (n = 25)	57.7 ± 6.0	52	95.9 ± 18.9	32.0 ± 4.4	7.2 ± 0.6	41 days
					Placebo (n = 26)	56.0 ± 7.2	58	99.9 ± 15.1	33.4 ± 3.4	7.3 ± 0.7
Asano et al[9]	NCT03645421	Japan	Phase 2a	Age: ≥20 years; HbA1c: 7%-10.5%; BMI: 24-40 kg/m2	Cotadutide 100 μg (n = 15)	56.7 ± 10.7	53	77.08 ± 14.21	28.82 ± 4.70	7.71 ± 0.44	48 days
					Cotadutide 200 μg (n = 15)	58.7 ± 11.3	87	73.05 ± 8.29	26.42 ± 1.81	8.2 ± 0.82
					Cotadutide 300 μg (n = 15)	57.5 ± 9.2	87	76.68 ± 9.97	26.99 ± 2.32	7.77 ± 0.85
					Placebo (n = 16)	60.0 ± 8.6	81	78.33 ± 12.8	28.53 ± 4.15	8.15 ± 0.90
Asano et al[10]	NCT04208620	Japan	Phase 1	Age: 20-74 years; HbA1c: 6.5%-8.5%; BMI: 25-35 kg/m2	Cotadutide 600 μg or HCTD (n = 12)	58.5 (34-69)	58.3	77.05 (62.3-84.8)	27.185 (25.21-34.71)	7.41 ± 0.67	10 weeks (70 days)
					Placebo (n = 4)	60.0 (46-63)	75.0	79.50 (69.8-80.5)	28.045 (26.17-32.12)	7.95 ± 0.45
Golubic et al[11]	NCT03596177	United Kingdom	Phase 2a	Age: 30-75 years; HbA1c: ≤ 8%; BMI: 28-40 kg/m2	Cotadutide 200 μg (n = 19)	59.5 ± 8.4	94.7	99.3 ± 10.8	32.2 ± 2.2	53 (5) mmol/mol	42 days
					Placebo (n = 9)	62.2 ± 7.2	77.8	101.4 ± 16.0	34.5 ± 2.8	50 (4) mmol/mol
Nahra et al[12]	NCT03235050	Eight countries	Phase 2b	Age: ≥18 years; HbA1c: 7%-10.5%; BMI: ≥ 25 kg/m2	Cotadutide 100 μg (n = 256)	57.6 ± 9.9	43	99.0 ± 20.3	35.0 ± 5.7	8.1 ± 0.9	54 weeks (378 days)
					Cotadutide 200 μg (n = 256)	57.3 ± 9.9	43	98.1 ± 20.2	34.9 ± 5.4	8.2 ± 1.0
					Cotadutide 300 μg (n = 256)	56.3 ± 10.2	50	100.8 ± 19.6	35.2 ± 5.4	8.1 ± 1.1
					Liraglutide 18 mg (n = 110)	55.5 ± 9.8	46	102.1 ± 22.7	35.4 ± 6.1	8.1 ± 1.0
					Placebo (n = 112)	57.3 ± 9.5	51	98.1 ± 19.8	34.2 ± 5.1	8.2 ± 1.1
Parker et al[13]	NCT03244800	Germany	Phase 2b	Age: ≥ 18 years; HbA1c: 6.5%-8.5%; BMI: 27-40 kg/m2	Cohort 1: Cotadutide 300 μg (n = 26)	58.7 ± 8.5	73	95.6 ± 17.2	31.5 ± 3.5	7.26 ± 0.58	49 days
					Cohort 1: Placebo (n = 13)	60.2 ± 5.6	69	93.8 ± 21.0	31.6 ± 3.8	7.19 ± 0.52
Parker et al[14]	NCT03550378	United Kingdom	Phase 2a	Age: 18-84 years; HbA1c: 6.5%-10.5%; BMI: 25-45 kg/m2; CKD (eGFR 30-59 mL/minute/1.73 m2)	Cotadutide 300 μg (n = 21)	71.1 ± 7.4	57.1	94.7 ± 17.6	32.4 ± 4.1	7.85 ± 0.7	32 days
					Placebo (n = 20)	70.9 ± 4.7	45	91.6 ± 15.8	32.9 ± 5.5	7.88 ± 1.3
Parker et al[15]	NCT03555994	Sweden and Netherlands	Phase 2a (Part A)	Age: ≥ 18 years; HbA1c: ≤ 8%; BMI: 27-40 kg/m2	Cotadutide 300 μg (n = 12)	65.8 ± 7.3	58	96.2 ± 7.7	31.8 ± 3.0	6.5 ± 0.6	28 days
					Placebo (n = 9)	69.3 ± 5.7	67	99.6 ± 20.1	32.7 ± 4.8	6.3 ± 0.7
			Phase 2a (Part B)	Similar to part A	Cotadutide 300 μg (n = 9)	61.8 ± 7.5	67	94.0 ± 14.6	31.9 ± 4.0	6.8 ± 0.66	35 days
					Placebo (n = 11)	64.0 ± 10.7	82	93.4 ± 11.8	30.08 ± 4.0	7.1 ± 0.63
					Liraglutide 1.8 mg (n = 10)	65.2 ± 9.1	60	91.5 ± 10.1	30.2 ± 2.3	6.8 ± 0.73
Selvarajah et al[16]	NCT04515849	Multiple countries	Phase 2b	Age: 18-79 years; HbA1c: 6.5%-12.5%; BMI: ≥ 25 kg/m2 (≥ 23 kg/m2 in Japan); CKD (eGFR 20-90 mL/minute/1.73 m2, UACR > 50 mg/mL)	Cotadutide 100 μg (n = 52)	67.2 ± 7.3	82.7	93.79 ± 19.94	32.15 ± 5.22	8 ± 1.07	14 weeks (98 days)
					Cotadutide 300 μg (n = 49)	65.7 ± 8.8	93.9	94.01 ± 18.79	32.26 ± 5.76	7.91 ± 1.1
					Cotadutide 600 μg (n = 51)	66.1 ± 7.4	80.4	93.69 ± 22.66	32.14 ± 5.65	8.1 ± 1.12
					Placebo (n = 51)	69.5 ± 7.3	74.5	93.15 ± 19.28	32.33 ± 6.05	7.84 ± 0.81
					Semaglutide 1 mg (n = 45)	67.0 ± 7.3	73.3	97.52 ± 19.45	34.41 ± 6.54	8.04 ± 1.18

HbA1c: Glycated hemoglobin; BMI: Body mass index; CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate; UACR: Urinary albumin-to-creatinine ratio; HCTD: Highest clinically tolerated dose.

Table 2 Comparison of the safety outcomes in the cotadutide group vs the placebo control group

Outcome variables (categorical)	Cotadutide dose	Number of studies reporting the outcome	Number of participants with outcome/participants analyzed		Pooled effect size, RR (95%CI)	I2 (%)	P value
			Cotadutide	PCG
TEAEs	All doses	9	739/931	175/269	1.20 (1.07-1.35)	24	0.002
	100 μg/day	3	124/170	114/179	1.13 (0.99-1.29)	0	0.08
	200 μg/day	4	252/314	103/161	1.21 (0.98-1.49)	50	0.07
	300 μg/day	6	313/387	146/232	1.26 (1.12-1.41)	6	0.0001
	600 μg/day	2	50/60	40/55	1.46 (0.51-4.22)	50	0.48
TRAEs	All doses	5	418/697	57/185	1.96 (1.50-2.56)	26	< 0.00001
	200 μg/day	3	184/299	42/145	1.97 (1.21-3.20)	67	0.007
	300 μg/day	3	188/298	39/152	2.40 (1.82-3.15)	0	< 0.00001
Serious AEs	All doses	9	84/931	20/269	0.99 (0.62-1.58)	0	0.97
	100 μg/day	3	17/170	17/179	1.06 (0.56-2.00)	0	0.86
	200 μg/day	4	35/314	13/161	1.18 (0.65-2.14)	0	0.59
	300 μg/day	6	27/387	19/232	0.81 (0.46-1.43)	0	0.47
	600 μg/day	2	5/60	5/55	1.06 (0.33-3.44)	NA	0.92
Discontinuation of the study drug due to AEs	All doses	7	134/880	10/230	2.54 (1.39-4.64)	0	0.002
	100 μg/day	3	15/170	9/179	1.31 (0.22-7.83)	71	0.76
	200 μg/day	3	47/289	5/135	3.75 (1.65-8.56)	0	0.002
	300 μg/day	5	62/361	10/219	2.40 (0.92-6.29)	27	0.08
	600 μg/day	2	10/60	4/55	2.66 (0.89-7.90)	NA	0.08
Any GI AEs	All doses	4	380/675	47/155	1.86 (1.45-2.38)	0	< 0.00001
	200 μg/day	2	167/281	44/138	1.81 (1.25-2.60)	44	0.001
	300 μg/day	2	163/282	33/125	2.17 (1.60-2.96)	0	< 0.00001
Abdominal distension	All doses	5	10/264	0/133	2.73 (0.69-10.77)	0	0.15
	100 μg/day	2	1/67	0/67	2.94 (0.12-70.61)	NA	0.51
	200 μg/day	2	6/40	0/42	13.50 (0.80-227.75)	NA	0.07
	300 μg/day	4	3/106	0/107	2.76 (0.45-16.72)	0	0.27
Abdominal pain	All doses	7	11/308	4/153	1.18 (0.45-3.13)	0	0.73
	100 μg/day	2	0/67	1/67	0.33 (0.01-7.85)	NA	0.49
	200 μg/day	3	3/58	2/49	0.87 (0.16-4.92)	0	0.88
	300 μg/day	5	6/132	2/120	1.67 (0.49-5.71)	0	0.42
Dyspepsia	All doses	8	82/886	6/253	3.46 (1.71-7.02)	0	0.0006
	100 μg/day	2	8/155	2/163	3.67 (0.91-14.77)	0	0.07
	200 μg/day	3	27/299	3/145	4.22 (1.41-12.63)	0	0.01
	300 μg/day	5	46/372	5/216	4.07 (1.81-9.15)	0	0.0007
	600 μg/day	2	1/60	0/55	1.15 (0.06-23.88)	NA	0.93
GERD	All doses	6	9/282	0/140	2.12 (0.46-9.78)	0	0.33
	100 μg/day	2	1/67	0/67	2.94 (0.12-70.61)	NA	0.51
	200 μg/day	3	1/58	0/49	1.26 (0.06-27.82)	NA	0.88
	300 μg/day	4	4/106	0/107	3.66 (0.61-21.81)	0	0.15
Nausea	All doses	9	312/931	28/269	3.13 (2.21-4.45)	0	< 0.00001
	100 μg/day	3	31/170	15/179	2.22 (1.25-3.95)	0	0.007
	200 μg/day	4	118/314	20/161	3.05 (1.98-4.68)	0	< 0.00001
	300 μg/day	6	142/387	21/232	3.47 (2.29-5.27)	0	< 0.00001
	600 μg/day	2	21/60	2/55	6.82 (1.93-24.13)	0	0.003
Vomiting	All doses	9	154/931	9/269	3.84 (2.13-6.91)	0	< 0.00001
	100 μg/day	3	15/170	6/179	2.45 (0.99-6.05)	0	0.05
	200 μg/day	4	68/314	6/161	4.55 (2.14-9.68)	0	< 0.0001
	300 μg/day	6	63/387	8/232	3.88 (2.00-7.55)	0	< 0.0001
	600 μg/day	2	8/60	1/55	4.13 (0.75-22.66)	0	0.10
Eructation	All doses	6	39/854	2/229	2.74 (0.89-8.41)	0	0.08
	100 μg/day	2	2/152	1/163	1.41 (0.09-22.80)	38	0.81
	200 μg/day	3	21/299	1/145	5.13 (1.20-21.99)	0	0.03
	300 μg/day	4	16/352	1/196	2.79 (0.62-12.48)	0	0.18
Constipation	All doses	8	55/914	7/249	2.26 (1.16-4.40)	0	0.02
	100 μg/day	3	4/170	4/179	0.99 (0.26-3.83)	0	0.99
	200 μg/day	4	19/314	5/161	2.20 (0.88-5.51)	0	0.09
	300 μg/day	5	24/366	4/212	2.74 (1.06 -7.13)	0	0.04
	600 μg/day	2	8/64	2/55	2.25 (0.55-9.27)	0	0.26
Diarrhea	All doses	8	117/905	22/256	1.16 (0.61-2.19)	26	0.65
	100 μg/day	3	18/170	12/179	1.58 (0.79-3.14)	0	0.19
	200 μg/day	4	57/314	17/161	1.14 (0.38-3.39)	64	0.81
	300 μg/day	5	38/361	15/219	1.37 (0.65-2.86)	11	0.41
	600 μg/day	2	4/60	2/55	1.47 (0.32-6.67)	0	0.62
Flatulence	All doses	5	9/242	2/117	1.49 (0.43-5.18)	0	0.53
	200 μg/day	2	1/43	1/33	0.67 (0.07-6.10)	0	0.72
	300 μg/day	3	5/96	1/84	2.45 (0.50-12.08)	0	0.27
Decreased appetite	All doses	8	70/919	5/265	3.81 (1.80-8.06)	0	0.0005
	100 μg/day	3	3/170	2/179	1.34 (0.14-13.05)	31	0.80
	200 μg/day	4	25/314	1/161	6.39 (1.79-22.84)	0	0.004
	300 μg/day	6	37/387	5/232	3.57 (1.56-8.20)	0	0.003
Fatigue	All doses	4	19/224	4/110	2.34 (0.92-5.95)	0	0.07
	300 μg/day	3	10/96	4/84	1.72 (0.58-5.15)	4	0.33
Dizziness	All doses	8	51/920	11/265	1.51 (0.80-2.87)	0	0.20
	100 μg/day	3	5/167	4/179	1.36 (0.37-4.98)	0	0.64
	200 μg/day	4	17/314	8/161	1.19 (0.52-2.74)	0	0.68
	300 μg/day	6	27/388	6/232	2.40 (1.07-5.37)	0	0.03
Headache	All doses	8	64/887	14/253	1.59 (0.91-2.77)	0	0.11
	100 μg/day	2	4/152	4/163	1.08 (0.28-4.25)	0	0.91
	200 μg/day	3	26/299	7/145	1.75 (0.48-6.33)	58	0.40
	300 μg/day	5	30/373	10/216	1.60 (0.81-3.17)	0	0.18
	600 μg/day	2	4/63	1/55	2.14 (0.36-12.92)	0	0.41
Hypoglycemia	All doses	4	35/223	11/110	1.16 (0.64-2.09)	0	0.63
	300 μg/day	3	13/95	11/84	1.11 (0.53-2.33)	0	0.77

TEAE: Treatment-emergent adverse events; TRAE: Treatment-related adverse events; AE: Adverse events; GI: Gastrointestinal; GERD: Gastroesophageal reflux disease; PCG: Placebo control group; NA: Not applicable; RR: Risk ratio; CI: Confidence interval.

Table 3 Comparison of the safety outcomes in the cotadutide group vs the active control group

Outcome variables (categorical)	Cotadutide dose	Number of studies reporting the outcome	No. of participants with outcome/participants analyzed		Pooled effect size, RR (95%CI)	I2 (%)	P value
			Cotadutide	ACG
TEAEs	All doses	3	610/772	115/165	1.07 (0.83-1.36)	77	0.62
	100 μg/day	2	118/155	107/155	1.05 (0.84-1.31)	67	0.65
	300 μg/day	3	251/313	115/165	1.07 (0.81-1.41)	76	0.63
TRAEs	All doses	2	356/621	32/120	1.71 (0.77-3.80)	84	0.19
	300 μg/day	2	162/265	32/120	1.76 (0.75-4.14)	86	0.19
Serious AEs	All doses	3	80/772	12/165	1.34 (0.75-2.41)	0	0.32
	100 μg/day	2	17/155	12/155	1.42 (0.70-2.87)	0	0.33
	300 μg/day	3	25/313	12/165	1.10 (0.57-2.15)	0	0.78
Discontinuation of the study drug due to AEs	All doses	3	121/772	9/165	2.26 (0.15-34.46)	91	0.56
	100 μg/day	2	15/155	9/155	1.30 (0.05-37.17)	90	0.88
	300 μg/day	3	57/313	9/165	1.80 (0.04-73.66)	92	0.76
Abdominal pain	All doses	2	3/161	1/55	0.89 (0.09-8.33)	0	0.92
	300 μg/day	2	1/58	1/55	0.92 (0.06-14.25)	NA	0.95
Dyspepsia	All doses	3	610/772	115/165	1.07 (0.83-1.36)	77	0.62
	100 μg/day	2	118/155	107/155	1.05 (0.84-1.31)	67	0.65
	300 μg/day	3	251/313	115/165	1.07 (0.81-1.41)	76	0.63
GERD	All doses	2	6/161	4/55	0.65 (0.16-2.58)	0	0.54
	300 μg/day	2	2/58	4/55	0.60 (0.12-2.96)	0	0.53
Nausea	All doses	3	243/772	29/165	1.64 (0.57-4.70)	82	0.35
	100 μg/day	2	29/155	28/155	0.86 (0.27-2.79)	79	0.80
	300 μg/day	3	116/313	29/165	1.72 (0.47-6.37)	82	0.41
Vomiting	All doses	3	116/772	10/165	1.61 (0.26-9.97)	81	0.61
	100 μg/day	2	12/155	9/155	1.04 (0.08-13.28)	85	0.97
	300 μg/day	3	46/313	10/165	1.38 (0.17-11.19)	79	0.76
Eructation	All doses	2	28/764	1/155	1.09 (0.01-101.81)	78	0.97
	100 μg/day	2	2/155	1/155	1.31 (0.07-23.51)	42	0.85
	300 μg/day	2	12/305	1/155	1.97 (0.06-64.31)	63	0.70
Constipation	All doses	3	34/772	6/165	1.47 (0.60-3.60)	0	0.39
	100 μg/day	2	3/155	4/155	0.70 (0.16-3.12)	0	0.64
	300 μg/day	3	17/313	6/165	1.59 (0.60-4.19)	0	0.35
Diarrhea	All doses	3	102/772	10/165	1.70 (0.34-8.51)	77	0.52
	100 μg/day	2	17/155	10/155	1.42 (0.23-8.97)	81	0.71
	300 μg/day	3	33/313	10/165	1.59 (0.47-5.35)	50	0.45
Decreased appetite	All doses	3	36/772	11/165	0.67 (0.09-5.23)	73	0.70
	100 μg/day	2	3/155	9/155	0.44 (0.01-27.33)	81	0.69
	300 μg/day	3	16/313	11/165	0.70 (0.07-6.61)	71	0.76
Fatigue	All doses	2	7/161	2/55	2.03 (0.45-9.09)	0	0.35
	300 μg/day	2	3/58	2/55	1.39 (0.15-13.21)	34	0.78
Dizziness	All doses	3	38/773	3/165	1.98 (0.41-9.46)	26	0.39
	100 μg/day	2	5/152	1/155	2.78 (0.26-30.23)	30	0.40
	300 μg/day	3	20/314	3/165	2.63 (0.46-15.08)	38	0.28
Headache	All doses	3	43/773	3/165	1.72 (0.33-8.96)	37	0.52
	100 μg/day	2	4/152	2/155	1.59 (0.10-26.25)	55	0.75
	300 μg/day	3	21/314	3/165	1.85 (0.23-14.77)	48	0.56

TEAE: Treatment-emergent adverse events; TRAE: Treatment-related adverse events; AE: Adverse events; GI: Gastrointestinal; GERD: Gastroesophageal reflux disease; ACG: Active control group; NA: Not applicable; RR: Risk ratio; CI: Confidence interval.