Network meta-analysis

Body weight change in kilograms (diabetes)

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

weeks 36 to 64 (target week 52)Treatment policyEach dose separatelyMean differenceSeparate part 3 of a disconnected network

Randomized trials

Treatments

961

Participants

Trial arms

In plain language

Across 4 trials with 961 participants, 0 of 4 treatments had a clearly better result than semaglutide 1.0 mg subcutaneous once weekly on body weight change in kilograms (diabetes), and for 4 the evidence could not tell them apart from semaglutide 1.0 mg subcutaneous once weekly. The most favorable estimate was for Semaglutide 8 mg injection once weekly: mean difference -1.82 kg (95% credible interval -8.52 to 5.12).

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 Semaglutide 1.0 mg subcutaneous once weekly

Mean difference in kg. Lower values favor the treatment.

Versus Semaglutide 1.0 mg subcutaneous once weekly. 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 Semaglutide 1.0 mg subcutaneous once weekly
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict
Semaglutide 8 mg injection once weekly SEMA_SC_8MG_QW	-1.82 (-8.52 to 5.12)	-10.24 to 6.40	-1.90 (-4.60 to 0.80)	Unclear
Semaglutide 2.0 mg subcutaneous once weekly SEMA_SC_2p0MG_QW	-0.99 (-5.58 to 3.80)	-7.83 to 5.94	-1.00 (-1.75 to -0.25)	Unclear
Exenatide extended release 2 mg subcutaneous once weekly EXENER_SC_2MG_QW	2.97 (-2.04 to 7.65)	-4.33 to 9.77	3.04 (2.29 to 3.79)	Unclear
Insulin icodec and semaglutide (IcoSema) subcutaneous once weekly titrated ICOSEMA_SC_TIT_QW	4.49 (-0.53 to 9.13)	-2.89 to 11.31	4.54 (3.85 to 5.24)	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	SEMA_SC_1p0MG_QW	SEMA_SC_8MG_QW	SEMA_SC_2p0MG_QW	EXENER_SC_2MG_QW	ICOSEMA_SC_TIT_QW
SEMA_SC_1p0MG_QW	SEMA_SC_1p0MG_QW	1.82 -5.12 to 8.52	0.99 -3.80 to 5.58	-2.97 -7.65 to 2.04	-4.49 -9.13 to 0.53
SEMA_SC_8MG_QW	-1.82 -8.52 to 5.12	SEMA_SC_8MG_QW	-0.82 -6.12 to 4.95	-4.76 -12.90 to 4.11	-6.31 -14.46 to 2.58
SEMA_SC_2p0MG_QW	-0.99 -5.58 to 3.80	0.82 -4.95 to 6.12	SEMA_SC_2p0MG_QW	-3.97 -10.63 to 2.92	-5.48 -12.02 to 1.51
EXENER_SC_2MG_QW	2.97 -2.04 to 7.65	4.76 -4.11 to 12.90	3.97 -2.92 to 10.63	EXENER_SC_2MG_QW	-1.51 -8.22 to 5.24
ICOSEMA_SC_TIT_QW	4.49 -0.53 to 9.13	6.31 -2.58 to 14.46	5.48 -1.51 to 12.02	1.51 -5.24 to 8.22	ICOSEMA_SC_TIT_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 1.543 (95% CrI 0.064 to 5.275)
Residual deviance: 5.0 for 5 data points
DIC: 10.1 (pD 5.0)
Largest R-hat: 1.002
Smallest ESS: bulk 1,784, tail 2,516
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 25^2); PR03 N(0, 12.5^2); PR07 half normal(0, 2.5^2) on tau

Frequentist check (netmeta)

Method: inverse variance, REML, MD
Tau: 0.000
Q (total): 0.00 on 0 df
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; 4 of 4	Sex (percent female) effect modifier, prognostic factor; 4 of 4	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 4 of 4	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 3 of 4	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 1 of 4	Treatment duration (weeks) effect modifier; 4 of 4	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 4 of 4
COMBINE 2 S000155	31.11	41.87	S1	27.65	not reported	52	not_reported
SUSTAIN™ 3 S000329	33.8	44.53	S1	not reported	not reported	56	not_reported
SUSTAIN FORTE S001353	34.6	41.42	S1	7.18	93.4	40	not_reported
NCT05486065 S001555	37.65	48.69	S1	1.49	not reported	40	not_reported

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: design means range from 31.1 (ICOSEMA_SC_TIT_QW vs SEMA_SC_1p0MG_QW) to 37.7 (SEMA_SC_2p0MG_QW vs SEMA_SC_8MG_QW) kg/m2; threshold 3
FlagBaseline, Asian ancestry or region: not reported by 1 of 4 trials
FlagBaseline, Kidney function (eGFR): not reported by 3 of 4 trials
NoteOutcome assessment, time point: selected time points span 40 to 56 weeks
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 3, treatment_policy 1
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 3, treatment_policy 1
NoteRisk of bias, blinding: mixed: double_blind 2, open_label 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
COMBINE 2	52	full_analysis	not stated	not stated	not stated	not stated	treatment_policy	treatment_policy	open_label	industry	2022	adults T2D on GLP-1 RA with or without oral drugs; HbA1c 7.0 to 10.0 percent
SUSTAIN™ 3	56	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	open_label	industry	2013	age 18 or older; T2D on stable 1 to 2 oral drugs; HbA1c 7.0 to 10.5 percent; eGFR 60 or more
SUSTAIN FORTE	40	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2019	T2D on metformin with or without SU; HbA1c 8.0 to 10.0 percent; duration at least 6 months
NCT05486065	40	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2022	age 18 to 64; HbA1c 7.0 to 10.5; BMI 27 or more; on metformin

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	Source
COMBINE 2	A1	ICOSEMA_SC_TIT_QW	52	contrast, md	4.540	0.355		R0005851:Table 2
COMBINE 2	A2	SEMA_SC_1p0MG_QW	52	contrast, md				R0005851:Table 2
SUSTAIN™ 3	A1	SEMA_SC_1p0MG_QW	56	contrast, md	-3.040	0.380		R0020680:Supplement Figure S3B
SUSTAIN™ 3	A2	EXENER_SC_2MG_QW	56	contrast, md				R0020680:Supplement Figure S3B
SUSTAIN FORTE	A1	SEMA_SC_1p0MG_QW	40	arm, change	-5.700	0.269	481	registry:outcomes
SUSTAIN FORTE	A2	SEMA_SC_2p0MG_QW	40	arm, change	-6.700	0.269	480	registry:outcomes
NCT05486065	A1	SEMA_SC_2p0MG_QW	40	contrast, md				R0005510:Figure 2
NCT05486065	A2	SEMA_SC_8MG_QW	40	contrast, md	-0.900	1.327		R0005510:Figure 2

Rerun this analysis yourself

Remove treatments or trials and refit the frequentist and Bayesian models in your browser, with the same methods as the published analysis.

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