Network meta-analysis

HbA1c change

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

weeks 64 to 130 (target week 104)Hypothetical (as if everyone stayed on treatment)Each dose separatelyMean differenceSeparate part 2 of a disconnected network

Randomized trials

Treatments

891

Participants

Trial arms

In plain language

Across 2 trials with 891 participants, 3 of 3 treatments had a clearly better result than placebo on HbA1c change. The most favorable estimate was for tirzepatide 15 mg subcutaneous once weekly: mean difference -2.01 percentage points (95% credible interval -2.85 to -0.82).

Tirzepatide 15 mg subcutaneous once weekly: better than placebo but not among the most effective (certainty pending).
Tirzepatide 10 mg subcutaneous once weekly: better than placebo but not among the most effective (certainty pending).
Semaglutide 2.4 mg subcutaneous once weekly: better than placebo but not among the most effective (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 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	Confidence
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	-2.01 (-2.85 to -0.82)	-3.32 to -0.35	-2.06 (-2.24 to -1.88)	Better	pending
Tirzepatide 10 mg subcutaneous once weekly TIRZ_SC_10MG_QW	-1.93 (-2.78 to -0.77)	-3.25 to -0.24	-1.98 (-2.16 to -1.80)	Better	pending
Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_2p4MG_QW	-1.48 (-2.43 to -0.36)	-2.89 to 0.20	-1.50 (-1.65 to -1.35)	Better	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 Placebo
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Semaglutide 2.4 mg subcutaneous once weekly versus Placebo	pending	some	pending	none	some	some	pending
Tirzepatide 10 mg subcutaneous once weekly versus Placebo	pending	some	pending	none	some	some	pending
Tirzepatide 15 mg subcutaneous once weekly versus Placebo	pending	some	pending	none	none	some	pending

Every other comparison (3)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Semaglutide 2.4 mg subcutaneous once weekly versus Tirzepatide 10 mg subcutaneous once weekly	pending	some	pending	major	none	some	pending
Semaglutide 2.4 mg subcutaneous once weekly versus Tirzepatide 15 mg subcutaneous once weekly	pending	some	pending	major	none	some	pending
Tirzepatide 10 mg subcutaneous once weekly versus Tirzepatide 15 mg subcutaneous once weekly	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	Mean rank
TIRZ_SC_15MG_QW	56%	34%	10%		1.5
TIRZ_SC_10MG_QW	33%	54%	13%		1.8
SEMA_SC_2p4MG_QW	11%	13%	76%	1%	2.7
PLACEBO			2%	98%	4.0

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	TIRZ_SC_15MG_QW	TIRZ_SC_10MG_QW	SEMA_SC_2p4MG_QW
PLACEBO	PLACEBO	2.01 0.82 to 2.85	1.93 0.77 to 2.78	1.48 0.36 to 2.43
TIRZ_SC_15MG_QW	-2.01 -2.85 to -0.82	TIRZ_SC_15MG_QW	-0.08 -1.09 to 0.92	-0.53 -1.87 to 0.96
TIRZ_SC_10MG_QW	-1.93 -2.78 to -0.77	0.08 -0.92 to 1.09	TIRZ_SC_10MG_QW	-0.45 -1.82 to 1.04
SEMA_SC_2p4MG_QW	-1.48 -2.43 to -0.36	0.53 -0.96 to 1.87	0.45 -1.04 to 1.82	SEMA_SC_2p4MG_QW

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.325 (95% CrI 0.014 to 1.109)
Residual deviance: 4.0 for 4 data points
DIC: 8.0 (pD 4.0)
Largest R-hat: 1.001
Smallest ESS: bulk 2,071, tail 2,418
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: 0.000
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	PLACEBO:SEMA_SC_2p4MG_QW	PLACEBO:TIRZ_SC_10MG_QW:TIRZ_SC_15MG_QW
PLACEBO:SEMA_SC_2p4MG_QW	100
PLACEBO:TIRZ_SC_10MG_QW		100
PLACEBO:TIRZ_SC_15MG_QW		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 HbA1c (percent) effect modifier, prognostic factor; 2 of 2	Background glucose lowering therapy (stratum S0 to S4) effect modifier, prognostic factor; 2 of 2	Diabetes duration (years) effect modifier, prognostic factor; 2 of 2	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 2 of 2	Age (years) prognostic factor; 2 of 2	Treatment duration (weeks) effect modifier; 2 of 2
SURMOUNT-2 S001712	8.02	S1	8.53	13.33	54.2	72
STEP 2 S001740	8.1	S1	8.03	26.2	55.33	68

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
FlagHeterogeneity, tau above threshold: tau 0.32 exceeds the outcome threshold 0.3; the flags of this network are candidate explanations
NoteOutcome assessment, time point: selected time points span 68 to 72 weeks

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
SURMOUNT-2	72	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2021	age 18 or older; BMI 27 or more; type 2 diabetes with HbA1c 7 to 10 percent on diet or oral drugs
STEP 2	68	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2018	age 18 or older; BMI 27 or more; HbA1c 7 to 10 percent; T2D on diet or up to 3 oral agents

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
SURMOUNT-2	A1	TIRZ_SC_10MG_QW	72	arm, change	-2.140	0.060	301	R0008662:Supplement Table S2
SURMOUNT-2	A2	TIRZ_SC_15MG_QW	72	arm, change	-2.220	0.060	300	R0008662:Supplement Table S2
SURMOUNT-2	A3	PLACEBO	72	arm, change	-0.160	0.070	290	R0008662:Supplement Table S2
STEP 2	A2	SEMA_SC_2p4MG_QW	68	contrast, md	-1.500	0.077		R0020858:Results
STEP 2	A3	PLACEBO	68	contrast, md				R0020858:Results

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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