Network meta-analysis

HbA1c change

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 difference

Randomized trials

Treatments

1,672

Participants

Trial arms

In plain language

Across 4 trials with 1,672 participants, 5 of 5 treatments had a clearly better result than placebo on HbA1c change. The most favorable estimate was for Semaglutide 14 mg oral once daily (original tablet): mean difference -1.39 percentage points (95% credible interval -1.59 to -1.19).

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 14 mg oral once daily (original tablet) SEMA_PO_14MG_QD	-1.39 (-1.59 to -1.19)	-1.71 to -1.06	-1.40 (-1.59 to -1.21)	Better
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	-1.27 (-1.47 to -1.08)	-1.62 to -0.96	-1.28 (-1.47 to -1.09)	Better
Liraglutide 0.9 mg injection once daily LIRA_SC_0p9MG_QD	-1.10 (-1.49 to -0.70)	-1.55 to -0.64	-1.10 (-1.49 to -0.71)	Better
Semaglutide 3 mg oral once daily (original tablet) SEMA_PO_3MG_QD	-0.80 (-1.00 to -0.60)	-1.12 to -0.48	-0.80 (-0.99 to -0.61)	Better
Visepegenatide 150 µg injection once weekly VISEPE_SC_150UG_QW	-0.73 (-1.07 to -0.39)	-1.15 to -0.31	-0.74 (-1.06 to -0.42)	Better

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	LIRA_SC_0p9MG_QD	SEMA_PO_3MG_QD	VISEPE_SC_150UG_QW
PLACEBO	PLACEBO	1.39 1.19 to 1.59	1.27 1.08 to 1.47	1.10 0.70 to 1.49	0.80 0.60 to 1.00	0.73 0.39 to 1.07
SEMA_PO_14MG_QD	-1.39 -1.59 to -1.19	SEMA_PO_14MG_QD	-0.12 -0.31 to 0.09	-0.30 -0.69 to 0.10	-0.59 -0.79 to -0.39	-0.66 -1.05 to -0.27
SEMA_PO_7MG_QD	-1.27 -1.47 to -1.08	0.12 -0.09 to 0.31	SEMA_PO_7MG_QD	-0.18 -0.59 to 0.22	-0.47 -0.68 to -0.28	-0.54 -0.93 to -0.15
LIRA_SC_0p9MG_QD	-1.10 -1.49 to -0.70	0.30 -0.10 to 0.69	0.18 -0.22 to 0.59	LIRA_SC_0p9MG_QD	-0.29 -0.70 to 0.11	-0.37 -0.87 to 0.16
SEMA_PO_3MG_QD	-0.80 -1.00 to -0.60	0.59 0.39 to 0.79	0.47 0.28 to 0.68	0.29 -0.11 to 0.70	SEMA_PO_3MG_QD	-0.07 -0.47 to 0.34
VISEPE_SC_150UG_QW	-0.73 -1.07 to -0.39	0.66 0.27 to 1.05	0.54 0.15 to 0.93	0.37 -0.16 to 0.87	0.07 -0.34 to 0.47	VISEPE_SC_150UG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.079 (95% CrI 0.003 to 0.283)
Residual deviance: 14.4 for 15 data points
DIC: 25.7 (pD 11.3)
Largest R-hat: 1.002
Smallest ESS: bulk 1,965, tail 3,049
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: 0.109
I squared: 10%
Q (total): 6.64 on 6 df, P = 0.355
Q (between designs): 3.05, P = 0.385

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; 3 of 4	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 4 of 4	Diabetes duration (years) effect modifier, prognostic factor; 3 of 4	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 4 of 4	Age (years) prognostic factor; 4 of 4	Treatment duration (weeks) effect modifier; 4 of 4
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: not reported by 1 of 4 trials
FlagBaseline, Baseline HbA1c: design means range from 8.0 (PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) to 8.5 (PLACEBO vs VISEPE_SC_150UG_QW) percent; threshold 0.5
FlagBaseline, Diabetes duration: not reported by 1 of 4 trials
FlagBaseline, Diabetes duration: design means range from 2.2 (PLACEBO vs VISEPE_SC_150UG_QW) to 7.6 (LIRA_SC_0p9MG_QD vs PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) years; threshold 3
FlagBaseline, Asian ancestry or region: design means range from 46.0 (PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) to 100.0 (LIRA_SC_0p9MG_QD vs PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) percent Asian; threshold 30
FlagBaseline, Treatment duration: design means range from 24.0 (PLACEBO vs VISEPE_SC_150UG_QW) to 52.0 (LIRA_SC_0p9MG_QD vs PLACEBO vs SEMA_PO_14MG_QD vs SEMA_PO_3MG_QD vs SEMA_PO_7MG_QD) weeks; threshold 26
NoteOutcome assessment, time point: selected time points span 24 to 26 weeks
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 3, not stated 1
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 3, not stated 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
PB119	24	full_analysis	not stated	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	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
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
PIONEER 9	26	full_analysis	not stated	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	Source
PB119	A1	VISEPE_SC_150UG_QW	24	arm, change	-1.370	0.084	137	R0011471:Table 2
PB119	A2	PLACEBO	24	arm, change	-0.630	0.092	136	R0011471:Table 2
PIONEER 1	A1	SEMA_PO_3MG_QD	26	arm, change	-0.900	0.091	175	registry:outcomes
PIONEER 1	A2	SEMA_PO_7MG_QD	26	arm, change	-1.400	0.068	175	registry:outcomes
PIONEER 1	A3	SEMA_PO_14MG_QD	26	arm, change	-1.600	0.076	175	registry:outcomes
PIONEER 1	A4	PLACEBO	26	arm, change	-0.300	0.090	178	registry:outcomes
PIONEER 11	A1	SEMA_PO_3MG_QD	26	arm, change	-1.100	0.066	114	registry:outcomes
PIONEER 11	A2	SEMA_PO_7MG_QD	26	arm, change	-1.500	0.074	117	registry:outcomes
PIONEER 11	A3	SEMA_PO_14MG_QD	26	arm, change	-1.600	0.093	116	registry:outcomes
PIONEER 11	A4	PLACEBO	26	arm, change	-0.200	0.087	106	registry:outcomes
PIONEER 9	A1	SEMA_PO_3MG_QD	26	arm, change	-1.100	0.114	49	registry:outcomes
PIONEER 9	A2	SEMA_PO_7MG_QD	26	arm, change	-1.700	0.114	49	registry:outcomes
PIONEER 9	A3	SEMA_PO_14MG_QD	26	arm, change	-1.700	0.115	48	registry:outcomes
PIONEER 9	A4	LIRA_SC_0p9MG_QD	26	arm, change	-1.400	0.159	48	registry:outcomes
PIONEER 9	A5	PLACEBO	26	arm, change	-0.200	0.100	49	registry:outcomes

Rerun this analysis yourself

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