Network meta-analysis

HbA1c change

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

weeks 20 to 36 (target week 26)Treatment policyDoses of a drug pooledMean difference

Randomized trials

Treatments

1,503

Participants

Trial arms

In plain language

Across 5 trials with 1,503 participants, 1 of 4 treatments had a clearly better result than placebo on HbA1c change, and for 3 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide tablet: mean difference -3.15 percentage points (95% credible interval -5.21 to -1.18).

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 tablet SEMA_PO	-3.15 (-5.21 to -1.18)	-7.39 to 1.11	-4.91 (-12.66 to 2.84)	Better
Liraglutide injection LIRA_SC	-1.47 (-4.30 to 1.34)	-6.06 to 3.17	-2.92 (-15.12 to 9.27)	Unclear
Safiglipron (HRS-7535) tablet SAFIGL_PO	-0.83 (-3.75 to 2.09)	-5.53 to 4.02	-1.29 (-14.64 to 12.06)	Unclear
Visepegenatide injection VISEPE_SC	-0.51 (-3.34 to 2.48)	-5.36 to 4.35	-0.73 (-14.08 to 12.62)	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	LIRA_SC	SAFIGL_PO	VISEPE_SC
PLACEBO	PLACEBO	3.15 1.18 to 5.21	1.47 -1.34 to 4.30	0.83 -2.09 to 3.75	0.51 -2.48 to 3.34
SEMA_PO	-3.15 -5.21 to -1.18	SEMA_PO	-1.70 -4.74 to 1.39	-2.34 -5.83 to 1.00	-2.65 -6.29 to 0.81
LIRA_SC	-1.47 -4.30 to 1.34	1.70 -1.39 to 4.74	LIRA_SC	-0.64 -4.59 to 3.43	-0.96 -5.08 to 3.15
SAFIGL_PO	-0.83 -3.75 to 2.09	2.34 -1.00 to 5.83	0.64 -3.43 to 4.59	SAFIGL_PO	-0.31 -4.45 to 3.68
VISEPE_SC	-0.51 -3.34 to 2.48	2.65 -0.81 to 6.29	0.96 -3.15 to 5.08	0.31 -3.68 to 4.45	VISEPE_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 1.844 (95% CrI 1.338 to 2.444)
Residual deviance: 16.4 for 10 data points
DIC: 26.4 (pD 9.9)
Largest R-hat: 1.002
Smallest ESS: bulk 4,223, tail 4,944
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 5^2); PR03 N(0, 2.5^2); PR07 half normal(0, 0.5^2) on tau

Frequentist check (netmeta)

Method: inverse variance, REML, MD
Tau: 6.810
I squared: 98%
Q (total): 89.01 on 2 df, P = 0.000
Q (between designs): 0.08, P = 0.771

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 HbA1c (percent) effect modifier, prognostic factor; 4 of 5	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 5 of 5	Diabetes duration (years) effect modifier, prognostic factor; 4 of 5	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 5 of 5	Age (years) prognostic factor; 5 of 5	Treatment duration (weeks) effect modifier; 5 of 5
OUTSTAND-1 S000213	7.95	S0	1.52 median	100	49.41	52
PB119 S000217	8.5	S0	2.18	96.36 Asian subgroup rows	50.35	24
PIONEER 1 S001741	not reported	S0	not reported	17.21	54.75	26
PIONEER 11 S001791	7.95	S0	2.2	74.85	52.5	26
PIONEER 9 S001943	8.2	S0	7.6	100	59.4	52

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 HbA1c: design means range from 8.0 (PLACEBO vs SEMA_PO) to 8.5 (PLACEBO vs VISEPE_SC) percent; threshold 0.5
FlagBaseline, Diabetes duration: design means range from 1.5 (PLACEBO vs SAFIGL_PO) to 7.6 (LIRA_SC vs PLACEBO vs SEMA_PO) years; threshold 3
FlagBaseline, Asian ancestry or region: design means range from 46.0 (PLACEBO vs SEMA_PO) to 100.0 (LIRA_SC vs PLACEBO vs SEMA_PO) percent Asian; threshold 30
FlagBaseline, Treatment duration: design means range from 24.0 (PLACEBO vs VISEPE_SC) to 52.0 (LIRA_SC vs PLACEBO vs SEMA_PO) weeks; threshold 26
FlagHeterogeneity, tau above threshold: tau 1.84 exceeds the outcome threshold 0.3; the flags of this network are candidate explanations
NoteOutcome assessment, time point: selected time points span 24 to 32 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 4, randomized 1
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 3, treatment_policy 2
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 3, treatment_policy 2
NoteData handling, input conversions: arms_combined 3

Comparability items per trial
Trial	definition	time weeks	analysis set	instrument	adjudicated	proportion method	intercurrent events (discontinuation)	intercurrent events (rescue)	blinding	funding	start year	Eligibility
OUTSTAND-1	not stated	32	randomized	not stated	not stated	not stated	treatment_policy	treatment_policy	double_blind	industry	2024	age 18 to 75; HbA1c 7.0 to 10.0 percent; BMI 19.0 to 40.0; diet and exercise only
PB119	not stated	24	full_analysis	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2020	age 18 to 75; HbA1c 7.5 to 11.0 at screening and 7.0 to 10.5 at randomization; BMI 18.5 to 40; eGFR 60 or more; drug naive
PIONEER 1	not stated	26	full_analysis	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
PIONEER 11	not stated	26	full_analysis	not stated	not stated	not stated	treatment_policy	treatment_policy	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
PIONEER 9	not stated	26	full_analysis	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2017	Japanese adults 20 y or older; HbA1c 6.5 to 9.5 on one oral drug washed out, or 7.0 to 10.0 on diet and exercise

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
OUTSTAND-1	A1+A2+A3	SAFIGL_PO	32	arm, change	-1.472	0.064	212	arms_combined	R0011607:Table 2
OUTSTAND-1	A4	PLACEBO	32	arm, change	-0.180	0.115	72		R0011607:Table 2
PB119	A1	VISEPE_SC	24	arm, change	-1.360	0.082	137		R0011471:Table 2
PB119	A2	PLACEBO	24	arm, change	-0.630	0.084	136		R0011471:Table 2
PIONEER 1	A1+A2+A3	SEMA_PO	26	arm, change	-1.233	0.048	525	arms_combined	registry:outcomes
PIONEER 1	A4	PLACEBO	26	arm, change	-0.300	0.090	178		registry:outcomes
PIONEER 11	A2	SEMA_PO	26	contrast, md	-13.000	1.276			R0019663:Figure 2
PIONEER 11	A4	PLACEBO	26	contrast, md					R0019663:Figure 2
PIONEER 9	A1+A2+A3	SEMA_PO	26	arm, change	-1.465	0.072	146	arms_combined	registry:outcomes
PIONEER 9	A4	LIRA_SC	26	arm, change	-1.400	0.159	48		registry:outcomes
PIONEER 9	A5	PLACEBO	26	arm, change	-0.400	0.143	49		registry:outcomes

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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