Network meta-analysis

Percent body weight change

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

weeks 40 to 104 (target week 68)Hypothetical (as if everyone stayed on treatment)Each dose separatelyMean difference

Randomized trials

Treatments

1,335

Participants

Trial arms

In plain language

Across 2 trials with 1,335 participants, 0 of 4 treatments had a clearly better result than semaglutide 14 mg oral once daily (original tablet) on percent body weight change, and for 4 the evidence could not tell them apart from semaglutide 14 mg oral once daily (original tablet). The most favorable estimate was for Orforglipron 36 mg oral once daily: mean difference -3.81 percentage points (95% credible interval -10.22 to 3.44).

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 14 mg oral once daily (original tablet)

Mean difference in percentage points. Lower values favor the treatment.

Versus Semaglutide 14 mg oral once daily (original tablet). 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 14 mg oral once daily (original tablet)
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict
Orforglipron 36 mg oral once daily ORFO_PO_36MG_QD	-3.81 (-10.22 to 3.44)	-13.00 to 6.34	-3.90 (-4.88 to -2.92)	Unclear
Orforglipron 12 mg oral once daily ORFO_PO_12MG_QD	-1.39 (-8.30 to 5.60)	-11.46 to 8.53	-1.40 (-2.29 to -0.51)	Unclear
Semaglutide 7 mg oral once daily (original tablet) SEMA_PO_7MG_QD	1.61 (-5.19 to 8.69)	-8.17 to 11.59	1.60 (0.81 to 2.39)	Unclear
Liraglutide 1.8 mg subcutaneous once daily LIRA_SC_1p8MG_QD	2.15 (-5.15 to 9.07)	-7.92 to 11.85	2.20 (1.30 to 3.10)	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_PO_14MG_QD	ORFO_PO_36MG_QD	ORFO_PO_12MG_QD	SEMA_PO_7MG_QD	LIRA_SC_1p8MG_QD
SEMA_PO_14MG_QD	SEMA_PO_14MG_QD	3.81 -3.44 to 10.22	1.39 -5.60 to 8.30	-1.61 -8.69 to 5.19	-2.15 -9.07 to 5.15
ORFO_PO_36MG_QD	-3.81 -10.22 to 3.44	ORFO_PO_36MG_QD	-2.44 -9.07 to 4.82	-5.44 -12.10 to 2.10	-5.96 -15.15 to 4.82
ORFO_PO_12MG_QD	-1.39 -8.30 to 5.60	2.44 -4.82 to 9.07	ORFO_PO_12MG_QD	-2.98 -9.95 to 4.27	-3.53 -13.41 to 6.74
SEMA_PO_7MG_QD	1.61 -5.19 to 8.69	5.44 -2.10 to 12.10	2.98 -4.27 to 9.95	SEMA_PO_7MG_QD	-0.53 -10.46 to 10.01
LIRA_SC_1p8MG_QD	2.15 -5.15 to 9.07	5.96 -4.82 to 15.15	3.53 -6.74 to 13.41	0.53 -10.01 to 10.46	LIRA_SC_1p8MG_QD

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 2.201 (95% CrI 0.108 to 7.495)
Residual deviance: 4.9 for 5 data points
DIC: 9.8 (pD 4.9)
Largest R-hat: 1.002
Smallest ESS: bulk 1,986, tail 2,500
Divergent transitions: 0
Convergence: All criteria met
Priors: PR01 N(0, 35^2); PR03 N(0, 17.5^2); PR07 half normal(0, 3.5^2) 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; 2 of 2	Sex (percent female) effect modifier, prognostic factor; 2 of 2	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 2 of 2	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 2 of 2	Treatment duration (weeks) effect modifier; 2 of 2	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 2 of 2
PIONEER 4 S000133	32.94	48	13.4	95.8	52	not_reported
ACHIEVE-3 S000438	35.1	48.59	11.9	90.6	52	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.

FlagOutcome assessment, analysis set: confounded with design: full_analysis 1, modified_itt 1
FlagRisk of bias, blinding: confounded with design: double_blind 1, open_label 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	52	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	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
ACHIEVE-3	52	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	open_label	industry	2023	adults T2D on metformin; HbA1c 7.0 to 10.5 percent

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	52	contrast, md	-2.200	0.459		R0015836:Supplement Table S3
PIONEER 4	A2	LIRA_SC_1p8MG_QD	52	contrast, md				R0015836:Supplement Table S3
ACHIEVE-3	A1	ORFO_PO_12MG_QD	52	arm, percent_change	-6.700	0.340	331	registry:outcomes
ACHIEVE-3	A2	ORFO_PO_36MG_QD	52	arm, percent_change	-9.200	0.400	323	registry:outcomes
ACHIEVE-3	A3	SEMA_PO_7MG_QD	52	arm, percent_change	-3.700	0.270	325	registry:outcomes
ACHIEVE-3	A4	SEMA_PO_14MG_QD	52	arm, percent_change	-5.300	0.300	356	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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