Network meta-analysis

Percent body weight change

Type 2 diabetes (adults); background therapy: one or more non insulin glucose lowering drugs

weeks 20 to 40 (target week 26)Not stated by the trialsEach dose separatelyMean difference

Randomized trials

Treatments

1,768

Participants

Trial arms

In plain language

Across 5 trials with 1,768 participants, 0 of 7 treatments had a clearly better result than placebo on percent body weight change, and for 7 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 1.0 mg subcutaneous once weekly: mean difference -4.36 percentage points (95% credible interval -9.35 to 1.01).

Lower values favor the treatment. "Clearly" means the 95% credible interval excludes no difference. These are averages across trials; they do not say how any one person will respond. Not medical advice.

Network of trials

Each circle is a treatment; each line joins treatments that were randomized against each other in at least one trial.

Node area shows participants; line width shows trials comparing two treatments directly. Blue: GLP-1 receptor agonist containing treatments; grey: comparators. Hover over or tab to a node or line for details.

Effects compared with Placebo

Mean difference in percentage points. Lower values favor the treatment.

Versus Placebo. Blue: Bayesian random effects posterior median with 95% credible interval (thick) and 95% prediction interval (dashed). Amber diamond: frequentist estimate with 95% confidence interval. Hover over or tab to a row for its values.

Effects of each treatment versus Placebo
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	-4.36 (-9.35 to 1.01)	-11.67 to 3.22	-4.40 (-5.31 to -3.49)	Unclear
Cotadutide 300 ug subcutaneous once daily COTA_SC_300UG_QD	-3.26 (-7.86 to 2.71)	-10.12 to 5.21	-3.42 (-4.43 to -2.40)	Unclear
Exenatide extended release 2 mg subcutaneous once weekly EXENER_SC_2MG_QW	-2.62 (-8.41 to 3.52)	-10.60 to 5.34	-2.70 (-5.99 to 0.59)	Unclear
Cotadutide 200 ug subcutaneous once daily COTA_SC_200UG_QD	-2.60 (-7.09 to 3.01)	-9.62 to 5.86	-2.76 (-3.77 to -1.74)	Unclear
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	-2.59 (-6.52 to 2.44)	-8.96 to 5.18	-2.90 (-4.08 to -1.71)	Unclear
Cotadutide 100 ug subcutaneous once daily COTA_SC_100UG_QD	-1.90 (-6.85 to 3.63)	-9.15 to 6.53	-2.05 (-3.28 to -0.81)	Unclear
Liraglutide 1.2 mg subcutaneous once daily LIRA_SC_1p2MG_QD	-0.26 (-6.98 to 7.12)	-9.24 to 9.33	-0.30 (-1.48 to 0.88)	Unclear

Ranking

How likely each treatment is to be among the best. Rankings ignore the size of differences and their certainty, so read them with the effects above.

League table

Every treatment against every other: mean difference of the row treatment versus the column treatment, posterior median and 95% credible interval. Green: row clearly better; red: row clearly worse.

Every treatment in a row compared with every treatment in a column
Row versus column	PLACEBO	SEMA_SC_1p0MG_QW	COTA_SC_300UG_QD	EXENER_SC_2MG_QW	COTA_SC_200UG_QD	LIRA_SC_1p8MG_QD	COTA_SC_100UG_QD	LIRA_SC_1p2MG_QD
PLACEBO	PLACEBO	4.36 -1.01 to 9.35	3.26 -2.71 to 7.86	2.62 -3.52 to 8.41	2.60 -3.01 to 7.09	2.59 -2.44 to 6.52	1.90 -3.63 to 6.85	0.26 -7.12 to 6.98
SEMA_SC_1p0MG_QW	-4.36 -9.35 to 1.01	SEMA_SC_1p0MG_QW	-1.11 -8.69 to 5.77	-1.70 -9.47 to 6.21	-1.79 -9.33 to 5.33	-1.74 -8.77 to 4.63	-2.49 -9.87 to 4.88	-4.11 -9.57 to 1.19
COTA_SC_300UG_QD	-3.26 -7.86 to 2.71	1.11 -5.77 to 8.69	COTA_SC_300UG_QD	-0.54 -8.08 to 8.03	-0.67 -6.14 to 4.78	-0.64 -5.99 to 4.45	-1.35 -6.78 to 4.32	-2.99 -11.28 to 6.01
EXENER_SC_2MG_QW	-2.62 -8.41 to 3.52	1.70 -6.21 to 9.47	0.54 -8.03 to 8.08	EXENER_SC_2MG_QW	-0.11 -8.55 to 7.26	-0.12 -8.16 to 6.56	-0.77 -9.00 to 6.64	-2.44 -11.78 to 6.68
COTA_SC_200UG_QD	-2.60 -7.09 to 3.01	1.79 -5.33 to 9.33	0.67 -4.78 to 6.14	0.11 -7.26 to 8.55	COTA_SC_200UG_QD	0.05 -5.30 to 5.24	-0.71 -6.10 to 4.85	-2.36 -10.66 to 6.42
LIRA_SC_1p8MG_QD	-2.59 -6.52 to 2.44	1.74 -4.63 to 8.77	0.64 -4.45 to 5.99	0.12 -6.56 to 8.16	-0.05 -5.24 to 5.30	LIRA_SC_1p8MG_QD	-0.75 -5.72 to 4.74	-2.38 -10.21 to 6.15
COTA_SC_100UG_QD	-1.90 -6.85 to 3.63	2.49 -4.88 to 9.87	1.35 -4.32 to 6.78	0.77 -6.64 to 9.00	0.71 -4.85 to 6.10	0.75 -4.74 to 5.72	COTA_SC_100UG_QD	-1.63 -10.25 to 7.13
LIRA_SC_1p2MG_QD	-0.26 -6.98 to 7.12	4.11 -1.19 to 9.57	2.99 -6.01 to 11.28	2.44 -6.68 to 11.78	2.36 -6.42 to 10.66	2.38 -6.15 to 10.21	1.63 -7.13 to 10.25	LIRA_SC_1p2MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 1.634 (95% CrI 0.086 to 5.896)
Residual deviance: 12.6 for 13 data points
DIC: 25.0 (pD 12.4)
Largest R-hat: 1.001
Smallest ESS: bulk 1,878, tail 3,318
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 35^2); PR03 N(0, 17.5^2); PR07 half normal(0, 3.5^2) on tau

Frequentist check (netmeta)

Method: inverse variance, REML, MD
Tau: 0.000
I squared: 0%
Q (total): 0.61 on 1 df, P = 0.436
Q (between designs): 0.61, P = 0.436

Inconsistency

Do trials comparing two treatments directly agree with the indirect evidence through other treatments?

No comparison here has both direct and indirect evidence, so inconsistency cannot be checked by node splitting; the between designs Q above is the global check.

Small study effects

A comparison adjusted funnel plot: each point is one trial comparison, centered on its own network estimate. Asymmetry can signal that small trials with unfavorable results are missing.

Fewer than ten trial comparisons, too few to judge funnel plot asymmetry.

Baseline characteristics of the trials

The baseline value of each effect modifier or prognostic factor that applies here, per trial: mean or percent over arms, weighted by the number randomized. A note under a value names a stand in (a median for a mean, 100 minus the male share, Asian subgroup rows, an all Asian site list); "not reported" means no source of the trial prints it.

Baseline effect modifiers and prognostic factors per trial
Trial	Baseline BMI or body weight (kg/m2) effect modifier, prognostic factor; 3 of 5	Sex (percent female) effect modifier, prognostic factor; 5 of 5	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 3 of 5	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 2 of 5	Treatment duration (weeks) effect modifier; 5 of 5	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 5 of 5
NCT03235050 S000257	not reported	53.72	0.72	not reported	54	not_reported
SUSTAIN 9 S000483	31.9	41.72	23.51	95.2	30	not_reported
SUSTAIN 10 S000584	body weight 96.9 kg	43.33	1.39	92.4	30	not_reported
EXENDA S000796	31.34	33.35	not reported	not reported	24	not_reported
S002969 S002969	36.76 median	77.78	not reported	not reported	26	standard

Comparability of the trials

Checked across designs (the set of treatments each trial compares) for eligibility, outcome definition and assessment, and the baseline factors above. Flags point to possible intransitivity; notes describe variation that is not tied to design.

FlagBaseline, Baseline BMI or body weight: not reported by 2 of 5 trials
FlagBaseline, Baseline BMI or body weight: design means range from 31.3 (EXENER_SC_2MG_QW vs PLACEBO) to 36.8 (LIRA_SC_1p8MG_QD vs PLACEBO) kg/m2; threshold 3
FlagBaseline, Sex: design means range from 33.3 (EXENER_SC_2MG_QW vs PLACEBO) to 77.8 (LIRA_SC_1p8MG_QD vs PLACEBO) percent female; threshold 15
FlagBaseline, Asian ancestry or region: not reported by 2 of 5 trials
FlagBaseline, Kidney function (eGFR): not reported by 3 of 5 trials
FlagBaseline, Treatment duration: design means range from 24.0 (EXENER_SC_2MG_QW vs PLACEBO) to 54.0 (COTA_SC_100UG_QD vs COTA_SC_200UG_QD vs COTA_SC_300UG_QD vs LIRA_SC_1p8MG_QD vs PLACEBO) weeks; threshold 26
NoteOutcome assessment, time point: selected time points span 24 to 30 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 3, modified_itt 1, randomized 1
NoteRisk of bias, blinding: mixed: double_blind 4, open_label 1
NoteData handling, input conversions: median_converted 2

Comparability items per trial
Trial	time weeks	analysis set	definition	instrument	adjudicated	proportion method	intercurrent events (discontinuation)	intercurrent events (rescue)	blinding	funding	start year	Eligibility
NCT03235050	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	age 18 or older; BMI 25 or higher; HbA1c 7.0 to 10.5 percent; on metformin
SUSTAIN 9	30	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	adults 18 or older (20 in Japan); HbA1c 7.0 to 10.5 percent; stable SGLT2i with or without metformin or SU
SUSTAIN 10	30	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2017	adults with T2D, HbA1c 7.0 to 11.0 percent on 1 to 3 oral drugs
EXENDA	24	randomized	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2017	age 18 to 75; BMI 25 or more; HbA1c 6.5 to 11 percent; metformin 1000 mg or more
S002969	26.07	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2018	age 18 to 70; BMI 30 to 50; HbA1c 48 to below 97 mmol/mol; T2DM under 10 years; undergoing LAGB

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the mean difference on the analysis scale against the trial's first row. Flags mark converted, combined or approximated inputs.

Trial data entering this analysis
Trial	Arm	Treatment	Week	Data	Value	SE	Events / N	Flags	Source
NCT03235050	A1	PLACEBO	26	arm, percent_change	-1.140	0.434	112		registry:outcomes
NCT03235050	A2	LIRA_SC_1p8MG_QD	26	arm, percent_change	-4.120	0.436	110		registry:outcomes
NCT03235050	A3	COTA_SC_100UG_QD	26	arm, percent_change	-3.230	0.462	100		registry:outcomes
NCT03235050	A4	COTA_SC_200UG_QD	26	arm, percent_change	-3.940	0.288	256		registry:outcomes
NCT03235050	A5	COTA_SC_300UG_QD	26	arm, percent_change	-4.600	0.288	256		registry:outcomes
SUSTAIN 9	A1	SEMA_SC_1p0MG_QW	30	arm, percent_change	-5.400	0.391	151		registry:outcomes
SUSTAIN 9	A2	PLACEBO	30	arm, percent_change	-1.000	0.252	151		registry:outcomes
SUSTAIN 10	A1	SEMA_SC_1p0MG_QW	30	arm, percent_change	-6.100	0.288	290		registry:outcomes
SUSTAIN 10	A2	LIRA_SC_1p2MG_QD	30	arm, percent_change	-2.000	0.248	287		registry:outcomes
EXENDA	A1	EXENER_SC_2MG_QW	24	arm, percent_change	-7.500	1.050	16		R0025594:Supplement S3
EXENDA	A2	PLACEBO	24	arm, percent_change	-4.800	1.310	14		R0025594:Supplement S3
S002969	A1	LIRA_SC_1p8MG_QD	26.07	arm, percent_change	-3.253	2.014	12	median_converted	R0010852:Table 2
S002969	A2	PLACEBO	26.07	arm, percent_change	-2.980	2.763	13	median_converted	R0010852:Table 2

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