Network meta-analysis

Body weight change in kilograms (diabetes)

Type 2 diabetes (adults); background therapy: no glucose lowering drug (lifestyle only)

weeks 20 to 36 (target week 26)Hypothetical (as if everyone stayed on treatment)Each dose separatelyMean differenceConvergence criteria not all met

Randomized trials

Treatments

2,448

Participants

Trial arms

In plain language

Across 4 trials with 2,448 participants, 2 of 7 treatments had a clearly better result than placebo on body weight change in kilograms (diabetes), and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide 14 mg oral once daily (original tablet): mean difference -2.36 kg (95% credible interval -3.39 to -1.37).

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 kg. 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 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	-2.36 (-3.39 to -1.37)	-3.93 to -0.69	-2.37 (-2.95 to -1.78)	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	-1.14 (-2.21 to -0.14)	-2.75 to 0.54	-1.15 (-1.71 to -0.58)	Better
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	-0.32 (-2.42 to 1.63)	-2.65 to 2.02	-0.32 (-1.24 to 0.60)	Unclear
Metformin METFORMIN	-0.27 (-2.33 to 1.72)	-2.57 to 2.17	-0.25 (-1.17 to 0.67)	Unclear
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	-0.09 (-1.13 to 0.87)	-1.67 to 1.56	-0.10 (-0.63 to 0.44)	Unclear
Liraglutide 0.9 mg injection once daily LIRA_SC_0p9MG_QD	0.26 (-1.19 to 1.72)	-1.76 to 2.12	0.27 (-0.42 to 0.96)	Unclear
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	0.59 (-0.83 to 2.00)	-1.32 to 2.46	0.61 (-0.02 to 1.24)	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	PLACEBO	SEMA_PO_14MG_QD	SEMA_PO_7MG_QD	DULA_SC_1p5MG_QW	METFORMIN	SEMA_PO_3MG_QD	LIRA_SC_0p9MG_QD	DULA_SC_0p75MG_QW
PLACEBO	PLACEBO	2.36 1.37 to 3.39	1.14 0.14 to 2.21	0.32 -1.63 to 2.42	0.27 -1.72 to 2.33	0.09 -0.87 to 1.13	-0.26 -1.72 to 1.19	-0.59 -2.00 to 0.83
SEMA_PO_14MG_QD	-2.36 -3.39 to -1.37	SEMA_PO_14MG_QD	-1.22 -2.29 to -0.14	-2.03 -4.21 to 0.21	-2.09 -4.39 to 0.12	-2.27 -3.29 to -1.21	-2.62 -4.37 to -0.85	-2.96 -4.68 to -1.24
SEMA_PO_7MG_QD	-1.14 -2.21 to -0.14	1.22 0.14 to 2.29	SEMA_PO_7MG_QD	-0.81 -3.07 to 1.45	-0.88 -3.04 to 1.29	-1.05 -2.10 to 0.02	-1.41 -3.15 to 0.34	-1.75 -3.48 to 0.05
DULA_SC_1p5MG_QW	-0.32 -2.42 to 1.63	2.03 -0.21 to 4.21	0.81 -1.45 to 3.07	DULA_SC_1p5MG_QW	-0.06 -1.46 to 1.30	-0.24 -2.43 to 2.01	-0.58 -2.48 to 1.29	-0.93 -2.28 to 0.48
METFORMIN	-0.27 -2.33 to 1.72	2.09 -0.12 to 4.39	0.88 -1.29 to 3.04	0.06 -1.30 to 1.46	METFORMIN	-0.17 -2.30 to 2.08	-0.53 -2.44 to 1.43	-0.86 -2.25 to 0.56
SEMA_PO_3MG_QD	-0.09 -1.13 to 0.87	2.27 1.21 to 3.29	1.05 -0.02 to 2.10	0.24 -2.01 to 2.43	0.17 -2.08 to 2.30	SEMA_PO_3MG_QD	-0.36 -2.09 to 1.37	-0.69 -2.41 to 0.91
LIRA_SC_0p9MG_QD	0.26 -1.19 to 1.72	2.62 0.85 to 4.37	1.41 -0.34 to 3.15	0.58 -1.29 to 2.48	0.53 -1.43 to 2.44	0.36 -1.37 to 2.09	LIRA_SC_0p9MG_QD	-0.33 -1.74 to 1.01
DULA_SC_0p75MG_QW	0.59 -0.83 to 2.00	2.96 1.24 to 4.68	1.75 -0.05 to 3.48	0.93 -0.48 to 2.28	0.86 -0.56 to 2.25	0.69 -0.91 to 2.41	0.33 -1.01 to 1.74	DULA_SC_0p75MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.298 (95% CrI 0.012 to 1.738)
Residual deviance: 12.9 for 14 data points
DIC: 25.2 (pD 12.3)
Largest R-hat: 1.004
Smallest ESS: bulk 1,236, tail 1,232
Divergent transitions: 1
Convergence: Not all met; read with caution
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
I squared: 0%
Q (total): 1.47 on 3 df, P = 0.689
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; 3 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; 4 of 4	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 2 of 4	Treatment duration (weeks) effect modifier; 4 of 4	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 4 of 4
NCT01558271 S000837	25.51	19	S0	98.98	72.35 median	52	not_reported
PIONEER 1 S001741	not reported	49.22	S0	17.21	not reported	26	not_reported
NCT01126580 S001786	33.26	56.26	S0	7.56	not reported	52	not_reported
PIONEER 11 S001791	28.2	36.27	S0	74.85	102.5	26	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: not reported by 1 of 4 trials
FlagBaseline, Baseline BMI or body weight: design means range from 25.5 (DULA_SC_0p75MG_QW vs LIRA_SC_0p9MG_QD vs PLACEBO) to 33.3 (DULA_SC_0p75MG_QW vs DULA_SC_1p5MG_QW vs METFORMIN) kg/m2; threshold 3
FlagBaseline, Sex: design means range from 19.0 (DULA_SC_0p75MG_QW vs LIRA_SC_0p9MG_QD vs PLACEBO) to 56.3 (DULA_SC_0p75MG_QW vs DULA_SC_1p5MG_QW vs METFORMIN) percent female; threshold 15
FlagBaseline, Asian ancestry or region: design means range from 7.6 (DULA_SC_0p75MG_QW vs DULA_SC_1p5MG_QW vs METFORMIN) to 99.0 (DULA_SC_0p75MG_QW vs LIRA_SC_0p9MG_QD vs PLACEBO) percent Asian; threshold 30
FlagBaseline, Kidney function (eGFR): not reported by 2 of 4 trials
FlagBaseline, Kidney function (eGFR): design means range from 72.3 (DULA_SC_0p75MG_QW vs LIRA_SC_0p9MG_QD vs PLACEBO) to 102.5 (PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) mL/min/1.73 m2; threshold 15
NoteOutcome assessment, analysis set: mixed: full_analysis 2, modified_itt 2
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 1, not stated 3
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 1, not stated 3

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
NCT01558271	26	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2012	Japanese; age 20 or more; BMI 18.5 to 35; HbA1c 7.0 to 10.0 percent; OAM naive or OAM stopped
PIONEER 1	26	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2016	adults with type 2 diabetes on diet and exercise only; HbA1c 7.0 to 9.5 percent
NCT01126580	26	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2010	type 2 diabetes on diet and exercise or one oral drug; registry gives no ranges
PIONEER 11	26	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2019	age 18 or older; HbA1c 7.0 to 10.0 percent at screening, 7.0 to 9.5 at randomization; no glucose lowering drugs; eGFR 60 or more

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
NCT01558271	A1	DULA_SC_0p75MG_QW	26	arm, change	-0.020	0.140	280	registry:outcomes
NCT01558271	A2	LIRA_SC_0p9MG_QD	26	arm, change	-0.360	0.200	136	registry:outcomes
NCT01558271	A3	PLACEBO	26	arm, change	-0.630	0.290	70	registry:outcomes
PIONEER 1	A1	SEMA_PO_3MG_QD	26	arm, change	-1.800	0.249	175	registry:outcomes
PIONEER 1	A2	SEMA_PO_7MG_QD	26	arm, change	-2.800	0.302	175	registry:outcomes
PIONEER 1	A3	SEMA_PO_14MG_QD	26	arm, change	-4.300	0.317	175	registry:outcomes
PIONEER 1	A4	PLACEBO	26	arm, change	-1.600	0.270	178	registry:outcomes
NCT01126580	A1	DULA_SC_1p5MG_QW	26	arm, change	-2.290	0.240	267	registry:outcomes
NCT01126580	A2	DULA_SC_0p75MG_QW	26	arm, change	-1.360	0.240	269	registry:outcomes
NCT01126580	A3	METFORMIN	26	arm, change	-2.220	0.240	267	registry:outcomes
PIONEER 11	A1	SEMA_PO_3MG_QD	26	arm, change	-1.100	0.308	115	registry:outcomes
PIONEER 11	A2	SEMA_PO_7MG_QD	26	arm, change	-2.200	0.312	119	registry:outcomes
PIONEER 11	A3	SEMA_PO_14MG_QD	26	arm, change	-3.100	0.344	116	registry:outcomes
PIONEER 11	A4	PLACEBO	26	arm, change	-1.100	0.262	106	registry:outcomes

Rerun this analysis yourself

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