Network meta-analysis

Weight loss of 10 percent or more

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 separatelyOdds ratio

Randomized trials

Treatments

1,655

Participants

213

Events

In plain language

Across 4 trials with 1,655 participants, 5 of 7 treatments had a clearly better result than placebo on weight loss of 10 percent or more, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for Polyethylene glycol loxenatide 400 µg injection once weekly: odds ratio 17.75 (95% credible interval 3.46 to 71.92).

Higher 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

Odds ratio. Higher values favor the treatment.

Versus Placebo, log scale. 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 OR (95% CrI)	95% prediction interval	Frequentist OR (95% CI)	Verdict
Polyethylene glycol loxenatide 400 µg injection once weekly PEGLOX_SC_400UG_QW	17.75 (3.46 to 71.92)	2.46 to 93.45	23.36 (6.74 to 80.98)	Better
Polyethylene glycol loxenatide 300 µg injection once weekly PEGLOX_SC_300UG_QW	10.71 (2.27 to 42.21)	1.57 to 54.61	13.96 (4.37 to 44.57)	Better
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	8.52 (1.92 to 38.91)	1.30 to 51.11	11.74 (2.67 to 51.56)	Better
Cotadutide 200 ug subcutaneous once daily COTA_SC_200UG_QD	6.86 (1.44 to 36.34)	1.00 to 47.19	13.63 (1.83 to 101)	Better
Cotadutide 300 ug subcutaneous once daily COTA_SC_300UG_QD	6.60 (1.40 to 36.11)	0.99 to 47.48	13.09 (1.76 to 97.55)	Better
Cotadutide 100 ug subcutaneous once daily COTA_SC_100UG_QD	3.99 (0.69 to 23.60)	0.53 to 29.57	8.35 (1.01 to 69.14)	Unclear
Liraglutide 1.2 mg subcutaneous once daily LIRA_SC_1p2MG_QD	1.65 (0.25 to 9.52)	0.18 to 12.87	2.38 (0.48 to 11.88)	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: odds ratio 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	PEGLOX_SC_400UG_QW	PEGLOX_SC_300UG_QW	SEMA_SC_1p0MG_QW	COTA_SC_200UG_QD	COTA_SC_300UG_QD	COTA_SC_100UG_QD	LIRA_SC_1p2MG_QD
PLACEBO	PLACEBO	0.06 0.01 to 0.29	0.09 0.02 to 0.44	0.12 0.03 to 0.52	0.15 0.03 to 0.70	0.15 0.03 to 0.71	0.25 0.04 to 1.44	0.61 0.11 to 4.02
PEGLOX_SC_400UG_QW	17.75 3.46 to 71.92	PEGLOX_SC_400UG_QW	1.65 0.37 to 7.13	2.10 0.23 to 15.64	2.50 0.27 to 21.35	2.67 0.27 to 20.86	4.38 0.41 to 39.10	10.85 0.98 to 102
PEGLOX_SC_300UG_QW	10.71 2.27 to 42.21	0.61 0.14 to 2.70	PEGLOX_SC_300UG_QW	1.26 0.17 to 8.69	1.55 0.17 to 12.01	1.60 0.18 to 12.73	2.65 0.27 to 24.07	6.56 0.65 to 57.99
SEMA_SC_1p0MG_QW	8.52 1.92 to 38.91	0.48 0.06 to 4.29	0.79 0.12 to 5.99	SEMA_SC_1p0MG_QW	1.23 0.14 to 10.93	1.29 0.14 to 10.59	2.15 0.21 to 19.76	5.20 1.64 to 16.43
COTA_SC_200UG_QD	6.86 1.44 to 36.34	0.40 0.05 to 3.71	0.65 0.08 to 5.87	0.81 0.09 to 7.29	COTA_SC_200UG_QD	1.04 0.33 to 3.26	1.70 0.47 to 6.58	4.25 0.40 to 47.20
COTA_SC_300UG_QD	6.60 1.40 to 36.11	0.37 0.05 to 3.69	0.63 0.08 to 5.55	0.77 0.09 to 7.19	0.96 0.31 to 3.05	COTA_SC_300UG_QD	1.66 0.45 to 6.42	4.06 0.38 to 48.12
COTA_SC_100UG_QD	3.99 0.69 to 23.60	0.23 0.03 to 2.42	0.38 0.04 to 3.66	0.47 0.05 to 4.74	0.59 0.15 to 2.12	0.60 0.16 to 2.20	COTA_SC_100UG_QD	2.45 0.20 to 30.54
LIRA_SC_1p2MG_QD	1.65 0.25 to 9.52	0.09 0.01 to 1.02	0.15 0.02 to 1.54	0.19 0.06 to 0.61	0.24 0.02 to 2.53	0.25 0.02 to 2.62	0.41 0.03 to 4.96	LIRA_SC_1p2MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.319 (95% CrI 0.073 to 1.308), log scale
Residual deviance: 11.0 for 11 data points
DIC: 20.9 (pD 9.9)
Largest R-hat: 1.001
Smallest ESS: bulk 3,241, tail 2,869
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.29, 1.53^2) on tau^2 (General physical health indicators, pharm vs placebo control)

Frequentist check (netmeta)

Method: inverse variance, REML, OR
Tau: 0.000
I squared: 0%
Q (total): 0.00 on 8.88178419700125e-16 df, P = 0.000
Q (between designs): 0.00

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; 2 of 4	Sex (percent female) effect modifier, prognostic factor; 4 of 4	Treatment duration (weeks) effect modifier; 4 of 4	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 4 of 4
NCT03235050 S000257	not reported	53.72	54	not_reported
SUSTAIN 9 S000483	31.9	41.72	30	not_reported
SUSTAIN 10 S000584	body weight 96.9 kg	43.33	30	not_reported
S002928 S002928	53.83 median	32.37	24	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 4 trials
FlagBaseline, Baseline BMI or body weight: design means range from 31.9 (PLACEBO vs SEMA_SC_1p0MG_QW) to 53.8 (PEGLOX_SC_300UG_QW vs PEGLOX_SC_400UG_QW vs PLACEBO) kg/m2; threshold 3
FlagBaseline, Sex: design means range from 32.4 (PEGLOX_SC_300UG_QW vs PEGLOX_SC_400UG_QW vs PLACEBO) to 53.7 (COTA_SC_100UG_QD vs COTA_SC_200UG_QD vs COTA_SC_300UG_QD vs PLACEBO) percent female; threshold 15
FlagBaseline, Treatment duration: design means range from 24.0 (PEGLOX_SC_300UG_QW vs PEGLOX_SC_400UG_QW vs PLACEBO) to 54.0 (COTA_SC_100UG_QD vs COTA_SC_200UG_QD vs COTA_SC_300UG_QD vs PLACEBO) weeks; threshold 26
NoteOutcome assessment, time point: selected time points span 24 to 30 weeks
NoteOutcome assessment, analysis set: mixed: completers 1, full_analysis 3
NoteOutcome assessment, definition: mixed: HbA1c below 7 percent at week 24 1, not stated 3
NoteOutcome assessment, proportion method: mixed: not stated 1, not_stated 2, observed 1
NoteRisk of bias, blinding: mixed: double_blind 2, open_label 1, single_blind 1
NoteRisk of bias, funding: mixed: industry 3, non_industry 1
NoteData handling, input conversions: count_from_percent 7

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	observed	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
S002928	24	completers	HbA1c below 7 percent at week 24	not stated	not stated	not_stated	not stated	not stated	single_blind	non_industry	2022	age 18 to 65; BMI 50 or more; type 2 diabetes

Trial data

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

Trial data entering this analysis
Trial	Arm	Treatment	Week	Data	Events / N	Flags	Source
NCT03235050	A1	PLACEBO	26	arm, responders	1 / 112		registry:outcomes
NCT03235050	A3	COTA_SC_100UG_QD	26	arm, responders	7 / 100		registry:outcomes
NCT03235050	A4	COTA_SC_200UG_QD	26	arm, responders	28 / 256		registry:outcomes
NCT03235050	A5	COTA_SC_300UG_QD	26	arm, responders	27 / 256		registry:outcomes
SUSTAIN 9	A1	SEMA_SC_1p0MG_QW	30	arm, responders	19 / 121	count_from_percent	registry:outcomes
SUSTAIN 9	A2	PLACEBO	30	arm, responders	2 / 128	count_from_percent	registry:outcomes
SUSTAIN 10	A1	SEMA_SC_1p0MG_QW	30	arm, responders	55 / 290	count_from_percent	registry:outcomes
SUSTAIN 10	A2	LIRA_SC_1p2MG_QD	30	arm, responders	13 / 287	count_from_percent	registry:outcomes
S002928	A1	PLACEBO	24	arm, responders	6 / 35	count_from_percent	R0007034:Results
S002928	A2	PEGLOX_SC_300UG_QW	24	arm, responders	26 / 35	count_from_percent	R0007034:Results
S002928	A3	PEGLOX_SC_400UG_QW	24	arm, responders	29 / 35	count_from_percent	R0007034:Results

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