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)Doses of a drug pooledMean difference

Randomized trials

Treatments

1,335

Participants

Trial arms

In plain language

Across 5 trials with 1,335 participants, 0 of 5 treatments had a clearly better result than semaglutide tablet on percent body weight change, and for 5 the evidence could not tell them apart from semaglutide tablet. The most favorable estimate was for orforglipron tablet: mean difference -3.35 percentage points (95% credible interval -9.83 to 3.53).

Orforglipron tablet: not convincingly different from semaglutide tablet (certainty pending).
Empagliflozin: not convincingly different from semaglutide tablet (certainty pending).
Liraglutide injection: not convincingly different from semaglutide tablet (certainty pending).
Sitagliptin: not convincingly different from semaglutide tablet (certainty pending).
Dulaglutide injection: not convincingly different from semaglutide tablet (certainty pending).

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 tablet

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

Versus Semaglutide 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 tablet
Treatment	Bayesian MD (95% CrI)	95% prediction interval	Frequentist MD (95% CI)	Verdict	Confidence
Orforglipron tablet ORFO_PO	-3.35 (-9.83 to 3.53)	-12.82 to 6.04	-3.40 (-4.06 to -2.74)	Unclear	pending
Empagliflozin EMPAGLIFLOZIN	0.97 (-5.61 to 7.53)	-8.47 to 10.61	1.00 (0.20 to 1.80)	Unclear	pending
Liraglutide injection LIRA_SC	2.16 (-4.67 to 8.80)	-7.46 to 11.88	2.20 (1.30 to 3.10)	Unclear	pending
Sitagliptin SITAGLIPTIN	2.48 (-4.35 to 9.04)	-7.05 to 12.20	2.50 (0.95 to 4.05)	Unclear	pending
Dulaglutide injection DULA_SC	2.94 (-3.84 to 9.24)	-6.84 to 12.09	3.00 (1.60 to 4.40)	Unclear	pending

Confidence in the results

How much each comparison can be trusted, rated with CINeMA in six domains and summarized with GRADE.

Ratings follow the protocol's numeric rules from risk of bias and indirectness judgments made by language model reviewers (amendment A028); no human has verified them yet. Reporting bias (ROB-MEN): some concerns.

Confidence in each comparison with Semaglutide tablet
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Dulaglutide injection versus Semaglutide tablet	pending	some	pending	major	none	some	pending
Empagliflozin versus Semaglutide tablet	pending	some	pending	major	none	some	pending
Liraglutide injection versus Semaglutide tablet	pending	some	pending	major	none	some	pending
Orforglipron tablet versus Semaglutide tablet	pending	some	pending	major	none	some	pending
Sitagliptin versus Semaglutide tablet	pending	some	pending	major	none	some	pending

Every other comparison (10)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Dulaglutide injection versus Empagliflozin	pending	some	pending	major	none	some	pending
Dulaglutide injection versus Liraglutide injection	pending	some	pending	major	none	some	pending
Empagliflozin versus Liraglutide injection	pending	some	pending	major	none	some	pending
Dulaglutide injection versus Orforglipron tablet	pending	some	pending	major	none	some	pending
Empagliflozin versus Orforglipron tablet	pending	some	pending	major	none	some	pending
Liraglutide injection versus Orforglipron tablet	pending	some	pending	major	none	some	pending
Dulaglutide injection versus Sitagliptin	pending	some	pending	major	none	some	pending
Empagliflozin versus Sitagliptin	pending	some	pending	major	none	some	pending
Liraglutide injection versus Sitagliptin	pending	some	pending	major	none	some	pending
Orforglipron tablet versus Sitagliptin	pending	some	pending	major	none	some	pending

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.

Rank probabilities

Probability of each rank for each treatment
Treatment	Rank 1	Rank 2	Rank 3	Rank 4	Rank 5	Rank 6	Mean rank
ORFO_PO	80%	9%	5%	3%	2%	1%	1.4
SEMA_PO	3%	53%	29%	12%	3%		2.6
EMPAGLIFLOZIN	7%	17%	34%	19%	13%	10%	3.4
LIRA_SC	4%	8%	13%	27%	27%	21%	4.3
SITAGLIPTIN	4%	7%	11%	22%	28%	28%	4.5
DULA_SC	3%	5%	8%	17%	27%	40%	4.8

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	ORFO_PO	EMPAGLIFLOZIN	LIRA_SC	SITAGLIPTIN	DULA_SC
SEMA_PO	SEMA_PO	3.35 -3.53 to 9.83	-0.97 -7.53 to 5.61	-2.16 -8.80 to 4.67	-2.48 -9.04 to 4.35	-2.94 -9.24 to 3.84
ORFO_PO	-3.35 -9.83 to 3.53	ORFO_PO	-4.35 -13.34 to 4.98	-5.52 -14.53 to 3.88	-5.82 -14.92 to 3.88	-6.31 -15.09 to 3.52
EMPAGLIFLOZIN	0.97 -5.61 to 7.53	4.35 -4.98 to 13.34	EMPAGLIFLOZIN	-1.20 -10.62 to 7.93	-1.46 -10.88 to 7.95	-1.96 -11.26 to 7.58
LIRA_SC	2.16 -4.67 to 8.80	5.52 -3.88 to 14.53	1.20 -7.93 to 10.62	LIRA_SC	-0.29 -9.61 to 9.23	-0.78 -9.68 to 8.45
SITAGLIPTIN	2.48 -4.35 to 9.04	5.82 -3.88 to 14.92	1.46 -7.95 to 10.88	0.29 -9.23 to 9.61	SITAGLIPTIN	-0.50 -9.54 to 8.74
DULA_SC	2.94 -3.84 to 9.24	6.31 -3.52 to 15.09	1.96 -7.58 to 11.26	0.78 -8.45 to 9.68	0.50 -8.74 to 9.54	DULA_SC

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 2.109 (95% CrI 0.102 to 7.150)
Residual deviance: 6.1 for 6 data points
DIC: 12.1 (pD 6.1)
Largest R-hat: 1.001
Smallest ESS: bulk 1,791, tail 2,671
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.

Contribution of direct evidence

Percent contribution of each direct comparison (columns) to each network estimate (rows), from netcontrib.

Contribution of direct comparisons to network estimates
Network estimate	DULA_SC:SEMA_PO	EMPAGLIFLOZIN:SEMA_PO	LIRA_SC:SEMA_PO	ORFO_PO:SEMA_PO	SEMA_PO:SITAGLIPTIN
DULA_SC:SEMA_PO	100
EMPAGLIFLOZIN:SEMA_PO		100
LIRA_SC:SEMA_PO			100
ORFO_PO:SEMA_PO				100
SEMA_PO:SITAGLIPTIN					100

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; 5 of 5	Sex (percent female) effect modifier, prognostic factor; 5 of 5	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 5 of 5	Kidney function (eGFR) (mL/min/1.73 m2) prognostic factor, effect modifier; 5 of 5	Treatment duration (weeks) effect modifier; 5 of 5	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 5 of 5
PIONEER 4 S000133	32.94	48	13.4	95.8	52	not_reported
PIONEER 10 S000234	26.26	25.74	100	96.57	52	not_reported
PIONEER 2 S000251	32.85	49.39	5.96	95.5	52	not_reported
ACHIEVE-3 S000438	35.1	48.59	11.9	90.6	52	not_reported
PIONEER 7 S001153	31.19	43.45	15.08	94.36	104	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 vs SEMA_PO) to 35.1 (ORFO_PO vs SEMA_PO) kg/m2; threshold 3
FlagBaseline, Sex: design means range from 25.7 (DULA_SC vs SEMA_PO) to 49.4 (EMPAGLIFLOZIN vs SEMA_PO) percent female; threshold 15
FlagBaseline, Asian ancestry or region: design means range from 6.0 (EMPAGLIFLOZIN vs SEMA_PO) to 100.0 (DULA_SC vs SEMA_PO) percent Asian; threshold 30
FlagBaseline, Treatment duration: design means range from 52.0 (DULA_SC vs SEMA_PO) to 104.0 (SEMA_PO vs SITAGLIPTIN) weeks; threshold 26
NoteOutcome assessment, analysis set: mixed: full_analysis 3, modified_itt 1, randomized 1
NoteOutcome assessment, intercurrent events (discontinuation): mixed: hypothetical 4, not stated 1
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 4, not stated 1
NoteRisk of bias, blinding: mixed: double_blind 1, open_label 2, single_blind 2
NoteData handling, input conversions: arms_combined 2

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
PIONEER 10	52	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	single_blind	industry	2017	Japanese adults 20 or older; T2D; HbA1c 7.0 to 10.5 percent on one oral glucose lowering drug
PIONEER 2	52	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	single_blind	industry	2016	type 2 diabetes on metformin; HbA1c 7.0 to 10.5 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
PIONEER 7	52	randomized	not stated	not stated	not stated	not stated	not stated	not stated	open_label	industry	2016	age 18 or more; HbA1c 7.5 to 9.5 percent; one or two oral glucose lowering drugs

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
PIONEER 4	A1	SEMA_PO	52	contrast, md	-2.200	0.459			R0015836:Supplement Table S3
PIONEER 4	A2	LIRA_SC	52	contrast, md					R0015836:Supplement Table S3
PIONEER 10	A2	SEMA_PO	52	contrast, md	-3.000	0.714			R0018421:Supplement Table S5
PIONEER 10	A4	DULA_SC	52	contrast, md					R0018421:Supplement Table S5
PIONEER 2	A1	SEMA_PO	52	contrast, md	-1.000	0.408			R0018256:Supplement Table S3
PIONEER 2	A2	EMPAGLIFLOZIN	52	contrast, md					R0018256:Supplement Table S3
ACHIEVE-3	A1+A2	ORFO_PO	52	arm, percent_change	-7.935	0.266	654	arms_combined	registry:outcomes
ACHIEVE-3	A3+A4	SEMA_PO	52	arm, percent_change	-4.536	0.205	681	arms_combined	registry:outcomes
PIONEER 7	A3	SEMA_PO	52	contrast, md	-2.500	0.791			R0023369:Supplement Table S10
PIONEER 7	A4	SITAGLIPTIN	52	contrast, md					R0023369:Supplement Table S10

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