Network meta-analysis

Gallbladder and biliary disease

Overweight or obesity without diabetes (adults)

longest follow-upRecorded harmsDoses of a drug pooledHazard ratio (from event counts)

Randomized trials

Treatments

3,790

Participants

Events

In plain language

Across 6 trials with 3,790 participants, 0 of 5 treatments had a clearly better result than placebo on gallbladder and biliary disease, 1 a clearly worse one, and for 4 the evidence could not tell them apart from placebo. The most favorable estimate was for Mazdutide injection: hazard ratio (from event counts) 0.43 (95% credible interval 0.00 to 31.24).

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

Hazard ratio (from event counts). Lower values favor the treatment.

Versus Placebo, log scale. 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 HR (95% CrI)	95% prediction interval	Verdict
Mazdutide injection MAZD_SC	0.43 (0.00 to 31.24)	0.00 to 32.30	Unclear
Liraglutide injection LIRA_SC	1.95 (0.10 to 38.66)	0.09 to 45.36	Unclear
Vk2735 sc VK2735_SC	2.27 (0.13 to 80.58)	0.12 to 93.93	Unclear
Semaglutide injection SEMA_SC	2.38 (1.09 to 5.39)	0.73 to 7.87	Worse
Cagrilintide OTHER_ACTIVE_cagrilintide	3.45 (0.37 to 62.57)	0.32 to 68.53	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: hazard ratio (from event counts) 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	MAZD_SC	LIRA_SC	VK2735_SC	SEMA_SC	OTHER_ACTIVE_cagrilintide
PLACEBO	PLACEBO	2.35 0.03 to 219	0.51 0.03 to 10.25	0.44 0.01 to 7.41	0.42 0.19 to 0.92	0.29 0.02 to 2.70
MAZD_SC	0.43 0.00 to 31.24	MAZD_SC	0.22 0.00 to 43.18	0.17 0.00 to 38.98	0.17 0.00 to 13.77	0.11 0.00 to 15.84
LIRA_SC	1.95 0.10 to 38.66	4.56 0.02 to 1099	LIRA_SC	0.80 0.01 to 54.40	0.82 0.04 to 17.37	0.57 0.03 to 4.55
VK2735_SC	2.27 0.13 to 80.58	5.97 0.03 to 1685	1.25 0.02 to 121	VK2735_SC	0.98 0.05 to 35.83	0.64 0.01 to 46.48
SEMA_SC	2.38 1.09 to 5.39	5.72 0.07 to 579	1.23 0.06 to 27.32	1.03 0.03 to 20.06	SEMA_SC	0.68 0.04 to 7.29
OTHER_ACTIVE_cagrilintide	3.45 0.37 to 62.57	8.82 0.06 to 1737	1.74 0.22 to 32.55	1.56 0.02 to 85.12	1.47 0.14 to 28.31	OTHER_ACTIVE_cagrilintide

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.303 (95% CrI 0.077 to 1.000), log scale
Residual deviance: 10.1 for 13 data points
DIC: 17.7 (pD 7.6)
Largest R-hat: 1.001
Smallest ESS: bulk 4,739, tail 4,501
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-1.87, 1.52^2) on tau^2 (Adverse events, pharm vs placebo control)

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.

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.

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.

NoteOutcome assessment, time point: selected time points span 19 to 111 weeks
NoteOutcome assessment, intercurrent events (discontinuation): mixed: not stated 5, while_on_treatment 1
NoteOutcome assessment, intercurrent events (rescue): mixed: not stated 5, treatment_policy 1
NoteData handling, input conversions: arms_combined 3

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
STEP 1	75	safety	not stated	not stated	not stated	not stated	while_on_treatment	treatment_policy	double_blind	industry	2018	adults; BMI 30 or more, or 27 or more with a weight related condition; no diabetes; HbA1c below 6.5 percent
STEP 5	111	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2018	age 18 or older; BMI 30 or more, or 27 or more with comorbidity; no diabetes; HbA1c below 6.5 percent
VENTURE	19	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2023	age over 18; BMI 30 or more, or 27 or more with comorbidity; BMI 50 or less; no diabetes
STEP 3	68	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2018	BMI 30 or more, or 27 with comorbidity; no type 2 diabetes
NCT03856047	26	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2019	age 18 or older; BMI 30 or more, or 27 or more with hypertension or dyslipidemia; no diabetes
NCT05623839	27	safety	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2022	age 18 to 70; BMI 27 to 50; HbA1c below 6.5 percent; no diabetes

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the hazard ratio (from event counts) on the analysis scale (log) against the trial's first row. Flags mark converted, combined or approximated inputs.

Trial data entering this analysis
Trial	Arm	Treatment	Week	Data	Events / N	Flags	Source
STEP 1	A1	SEMA_SC	75	arm, events	34 / 1,306		R0023399:Table 3
STEP 1	A2	PLACEBO	75	arm, events	8 / 655		R0023399:Table 3
STEP 5	A1	SEMA_SC	111	arm, events	4 / 152		R0021896:Table 3
STEP 5	A2	PLACEBO	111	arm, events	2 / 152		R0021896:Table 3
VENTURE	A1	PLACEBO	19	arm, events	0 / 35		R0011224:Table 3
VENTURE	A2+A3+A4+A5	VK2735_SC	19	arm, events	2 / 141	arms_combined	R0011224:Table 3
STEP 3	A1	SEMA_SC	68	arm, events	20 / 407		R0013578:Table 1
STEP 3	A2	PLACEBO	68	arm, events	3 / 204		R0013578:Table 1
NCT03856047	A1+A2+A3+A4+A5	OTHER_ACTIVE_cagrilintide	26	arm, events	6 / 506	arms_combined	R0017871:Table 3
NCT03856047	A6	LIRA_SC	26	arm, events	1 / 99		R0017871:Table 3
NCT03856047	A7	PLACEBO	26	arm, events	0 / 101		R0017871:Table 3
NCT05623839	A1	PLACEBO	27	arm, events	0 / 8		R0013210:Supplement Table S2
NCT05623839	A2+A3	MAZD_SC	27	arm, events	0 / 24	arms_combined	R0013210:Supplement Table S2

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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