Network meta-analysis

Body weight change in kilograms (diabetes)

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

weeks 20 to 36 (target week 26)Treatment policyEach dose separatelyMean differenceConvergence criteria not all met

Randomized trials

Treatments

3,799

Participants

Trial arms

In plain language

Across 7 trials with 3,799 participants, 7 of 9 treatments had a clearly better result than placebo on body weight change in kilograms (diabetes), and for 2 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 -3.59 kg (95% credible interval -4.41 to -2.73).

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	-3.59 (-4.41 to -2.73)	-4.77 to -2.34	-3.62 (-4.23 to -3.01)	Better
Semaglutide 0.5 mg subcutaneous once weekly SEMA_SC_0p5MG_QW	-3.24 (-4.57 to -1.72)	-4.82 to -1.48	-3.28 (-4.19 to -2.36)	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	-2.46 (-3.42 to -1.37)	-3.72 to -1.08	-2.50 (-3.21 to -1.80)	Better
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	-2.40 (-3.42 to -1.42)	-3.76 to -1.09	-2.41 (-3.09 to -1.73)	Better
Efsubaglutide alfa 3 mg injection once weekly EFSUBA_SC_3MG_QW	-1.81 (-3.08 to -0.51)	-3.26 to -0.29	-1.82 (-2.81 to -0.83)	Better
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	-1.54 (-2.51 to -0.48)	-2.82 to -0.12	-1.56 (-2.26 to -0.86)	Better
Dulaglutide 1.5 mg subcutaneous once weekly DULA_SC_1p5MG_QW	-1.18 (-2.25 to -0.09)	-2.49 to 0.20	-1.19 (-2.00 to -0.39)	Better
Dulaglutide 0.75 mg subcutaneous once weekly DULA_SC_0p75MG_QW	-0.86 (-1.73 to 0.04)	-2.05 to 0.43	-0.89 (-1.54 to -0.23)	Unclear
Sitagliptin SITAGLIPTIN	-0.84 (-1.82 to 0.27)	-2.12 to 0.62	-0.87 (-1.56 to -0.18)	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_SC_0p5MG_QW	SEMA_PO_7MG_QD	LIRA_SC_1p8MG_QD	EFSUBA_SC_3MG_QW	SEMA_PO_3MG_QD	DULA_SC_1p5MG_QW	DULA_SC_0p75MG_QW	SITAGLIPTIN
PLACEBO	PLACEBO	3.59 2.73 to 4.41	3.24 1.72 to 4.57	2.46 1.37 to 3.42	2.40 1.42 to 3.42	1.81 0.51 to 3.08	1.54 0.48 to 2.51	1.18 0.09 to 2.25	0.86 -0.04 to 1.73	0.84 -0.27 to 1.82
SEMA_PO_14MG_QD	-3.59 -4.41 to -2.73	SEMA_PO_14MG_QD	-0.35 -1.57 to 0.78	-1.13 -1.85 to -0.48	-1.19 -2.10 to -0.22	-1.79 -3.31 to -0.26	-2.06 -2.73 to -1.40	-2.42 -3.58 to -1.17	-2.74 -3.54 to -1.90	-2.75 -3.42 to -2.15
SEMA_SC_0p5MG_QW	-3.24 -4.57 to -1.72	0.35 -0.78 to 1.57	SEMA_SC_0p5MG_QW	-0.76 -2.02 to 0.48	-0.84 -2.29 to 0.76	-1.43 -3.31 to 0.57	-1.70 -2.91 to -0.45	-2.07 -3.61 to -0.33	-2.38 -3.70 to -0.91	-2.41 -3.37 to -1.35
SEMA_PO_7MG_QD	-2.46 -3.42 to -1.37	1.13 0.48 to 1.85	0.76 -0.48 to 2.02	SEMA_PO_7MG_QD	-0.06 -1.18 to 1.14	-0.67 -2.27 to 1.01	-0.93 -1.62 to -0.17	-1.30 -2.52 to 0.08	-1.61 -2.47 to -0.64	-1.64 -2.40 to -0.83
LIRA_SC_1p8MG_QD	-2.40 -3.42 to -1.42	1.19 0.22 to 2.10	0.84 -0.76 to 2.29	0.06 -1.14 to 1.18	LIRA_SC_1p8MG_QD	-0.60 -2.24 to 0.96	-0.87 -2.06 to 0.23	-1.23 -2.63 to 0.20	-1.54 -2.73 to -0.43	-1.56 -2.79 to -0.45
EFSUBA_SC_3MG_QW	-1.81 -3.08 to -0.51	1.79 0.26 to 3.31	1.43 -0.57 to 3.31	0.67 -1.01 to 2.27	0.60 -0.96 to 2.24	EFSUBA_SC_3MG_QW	-0.27 -1.97 to 1.35	-0.62 -2.31 to 1.05	-0.95 -2.54 to 0.57	-0.97 -2.66 to 0.62
SEMA_PO_3MG_QD	-1.54 -2.51 to -0.48	2.06 1.40 to 2.73	1.70 0.45 to 2.91	0.93 0.17 to 1.62	0.87 -0.23 to 2.06	0.27 -1.35 to 1.97	SEMA_PO_3MG_QD	-0.36 -1.62 to 0.99	-0.67 -1.57 to 0.25	-0.70 -1.46 to 0.04
DULA_SC_1p5MG_QW	-1.18 -2.25 to -0.09	2.42 1.17 to 3.58	2.07 0.33 to 3.61	1.30 -0.08 to 2.52	1.23 -0.20 to 2.63	0.62 -1.05 to 2.31	0.36 -0.99 to 1.62	DULA_SC_1p5MG_QW	-0.32 -1.42 to 0.72	-0.34 -1.72 to 0.92
DULA_SC_0p75MG_QW	-0.86 -1.73 to 0.04	2.74 1.90 to 3.54	2.38 0.91 to 3.70	1.61 0.64 to 2.47	1.54 0.43 to 2.73	0.95 -0.57 to 2.54	0.67 -0.25 to 1.57	0.32 -0.72 to 1.42	DULA_SC_0p75MG_QW	-0.02 -1.03 to 0.90
SITAGLIPTIN	-0.84 -1.82 to 0.27	2.75 2.15 to 3.42	2.41 1.35 to 3.37	1.64 0.83 to 2.40	1.56 0.45 to 2.79	0.97 -0.62 to 2.66	0.70 -0.04 to 1.46	0.34 -0.92 to 1.72	0.02 -0.90 to 1.03	SITAGLIPTIN

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.243 (95% CrI 0.013 to 1.069)
Residual deviance: 17.4 for 18 data points
DIC: 33.3 (pD 15.9)
Largest R-hat: 1.004
Smallest ESS: bulk 1,388, tail 1,568
Divergent transitions: 2
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: 0.097
I squared: 7%
Q (total): 4.31 on 4 df, P = 0.366
Q (between designs): 4.31, P = 0.366

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; 6 of 7	Sex (percent female) effect modifier, prognostic factor; 7 of 7	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 7 of 7	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 6 of 7	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 4 of 7	Treatment duration (weeks) effect modifier; 7 of 7	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 7 of 7
PIONEER 4 S000133	32.94	48	S1	13.4	95.8	52	not_reported
PIONEER 10 S000234	26.26	25.74	S1	100	96.57	52	not_reported
AWARD-10 S000305	32.68	49.99	S1	not reported	not reported	24	not_reported
PIONEER 12 S000522	28.58	41.7	S1	75.22	103.5	26	not_reported
SUSTAIN S001311	27.8	42.5	S1	85.03	109.33 median	30	not_reported
NCT04998032 S002121	26.84	46.97	S1	100 region: all sites in Asia	not reported	24	not_reported
PIONEER 3 S002267	not reported	47.16	S1	13.14	not reported	78	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 26.3 (DULA_SC_0p75MG_QW vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) to 32.9 (LIRA_SC_1p8MG_QD vs PLACEBO vs SEMA_PO_14MG_QD) kg/m2; threshold 3
FlagBaseline, Sex: design means range from 25.7 (DULA_SC_0p75MG_QW vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) to 50.0 (DULA_SC_0p75MG_QW vs DULA_SC_1p5MG_QW vs PLACEBO) percent female; threshold 15
FlagBaseline, Asian ancestry or region: design means range from 13.1 (SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD vs SITAGLIPTIN) to 100.0 (DULA_SC_0p75MG_QW vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) percent Asian; threshold 30
FlagBaseline, Kidney function (eGFR): not reported by 3 of 7 trials
FlagBaseline, Treatment duration: design means range from 24.0 (DULA_SC_0p75MG_QW vs DULA_SC_1p5MG_QW vs PLACEBO) to 78.0 (SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD vs SITAGLIPTIN) weeks; threshold 26
NoteOutcome assessment, time point: selected time points span 24 to 30 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 5, modified_itt 2
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 2, not stated 2, treatment_policy 3
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 3, not stated 1, treatment_policy 3
NoteRisk of bias, blinding: mixed: double_blind 6, single_blind 1

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
PIONEER 4	26	full_analysis	not stated	not stated	not stated	not stated	treatment_policy	treatment_policy	double_blind	industry	2016	Age 18 or older; T2D on metformin with or without SGLT2i; HbA1c 7.0 to 9.5 percent; eGFR 60 or more
PIONEER 10	26	full_analysis	not stated	not stated	not stated	not stated	treatment_policy	treatment_policy	single_blind	industry	2017	Japanese adults 20 or older; T2D; HbA1c 7.0 to 10.5 percent on one oral glucose lowering drug
AWARD-10	24	modified_itt	not stated	not stated	not stated	not stated	not stated	hypothetical	double_blind	industry	2015	T2D; HbA1c 7.0 to 9.5 percent; BMI 45 or lower; SGLT2i with or without metformin
PIONEER 12	26	full_analysis	not stated	not stated	not stated	not stated	treatment_policy	treatment_policy	double_blind	industry	2019	adults with type 2 diabetes on metformin, HbA1c 7.0 to 10.5 percent
SUSTAIN	30	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2017	Adults 18 or older, HbA1c 7.0 to 10.5 percent on metformin monotherapy, eGFR 60 or more
NCT04998032	24	modified_itt	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2021	age 18 to 75; metformin monotherapy; HbA1c 7.5 to 10.5 at randomization; BMI 18.5 to 40; eGFR 60 or higher
PIONEER 3	26	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2016	adults with T2D; HbA1c 7.0 to 10.5 percent; metformin with or without sulfonylurea

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
PIONEER 4	A1	SEMA_PO_14MG_QD	26	arm, change	-4.400	0.200	285	R0015836:Results
PIONEER 4	A2	LIRA_SC_1p8MG_QD	26	arm, change	-3.100	0.200	284	R0015836:Results
PIONEER 4	A3	PLACEBO	26	arm, change	-0.500	0.300	142	R0015836:Results
PIONEER 10	A1	SEMA_PO_3MG_QD	26	arm, change	-0.200	0.300	131	R0018421:Figure 3C
PIONEER 10	A2	SEMA_PO_7MG_QD	26	arm, change	-1.000	0.300	132	R0018421:Figure 3C
PIONEER 10	A3	SEMA_PO_14MG_QD	26	arm, change	-2.200	0.200	130	R0018421:Figure 3C
PIONEER 10	A4	DULA_SC_0p75MG_QW	26	arm, change	0.300	0.300	65	R0018421:Figure 3C
AWARD-10	A1	DULA_SC_1p5MG_QW	24	arm, change	-3.100	0.300	142	registry:outcomes
AWARD-10	A2	DULA_SC_0p75MG_QW	24	arm, change	-2.600	0.300	141	registry:outcomes
AWARD-10	A3	PLACEBO	24	arm, change	-2.100	0.300	140	registry:outcomes
PIONEER 12	A3	SEMA_PO_14MG_QD	26	contrast, md	-3.000	0.255		R0019776:Figure 4
PIONEER 12	A4	SITAGLIPTIN	26	contrast, md				R0019776:Figure 4
SUSTAIN	A1	SEMA_SC_0p5MG_QW	30	contrast, md	-2.410	0.288		R0014802:Supplement Figure S6
SUSTAIN	A3	SITAGLIPTIN	30	contrast, md				R0014802:Supplement Figure S6
NCT04998032	A1	EFSUBA_SC_3MG_QW	24	arm, change	-2.740	0.332	171	R0006975:Table 2
NCT04998032	A2	PLACEBO	24	arm, change	-0.920	0.370	173	R0006975:Table 2
PIONEER 3	A1	SEMA_PO_3MG_QD	26	arm, change	-1.200	0.148	466	registry:outcomes
PIONEER 3	A2	SEMA_PO_7MG_QD	26	arm, change	-2.200	0.181	465	registry:outcomes
PIONEER 3	A3	SEMA_PO_14MG_QD	26	arm, change	-3.100	0.176	465	registry:outcomes
PIONEER 3	A4	SITAGLIPTIN	26	arm, change	-0.600	0.148	467	registry:outcomes

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