Network meta-analysis

Percent body weight change

Overweight or obesity without diabetes (adults)

weeks 40 to 104 (target week 68)Hypothetical (as if everyone stayed on treatment)Doses of a drug pooledMean difference

Randomized trials

Treatments

7,143

Participants

Trial arms

In plain language

Across 6 trials with 7,143 participants, 4 of 4 treatments had a clearly better result than placebo on percent body weight change. The most favorable estimate was for Tirzepatide injection: mean difference -20.43 percentage points (95% credible interval -25.14 to -14.86).

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
Tirzepatide injection TIRZ_SC	-20.43 (-25.14 to -14.86)	-29.25 to -10.15	-20.89 (-25.12 to -16.66)	Better
Retatrutide injection RETA_SC	-15.35 (-22.79 to -6.79)	-26.27 to -3.25	-15.95 (-22.78 to -9.12)	Better
Semaglutide injection SEMA_SC	-13.97 (-19.48 to -6.92)	-23.31 to -3.00	-14.44 (-19.60 to -9.28)	Better
Orforglipron tablet ORFO_PO	-8.56 (-15.85 to -0.83)	-19.56 to 2.94	-8.95 (-15.53 to -2.37)	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	TIRZ_SC	RETA_SC	SEMA_SC	ORFO_PO
PLACEBO	PLACEBO	20.43 14.86 to 25.14	15.35 6.79 to 22.79	13.97 6.92 to 19.48	8.56 0.83 to 15.85
TIRZ_SC	-20.43 -25.14 to -14.86	TIRZ_SC	-5.06 -14.68 to 4.79	-6.48 -13.12 to -0.34	-11.88 -20.84 to -2.38
RETA_SC	-15.35 -22.79 to -6.79	5.06 -4.79 to 14.68	RETA_SC	-1.40 -11.97 to 8.57	-6.75 -17.94 to 4.08
SEMA_SC	-13.97 -19.48 to -6.92	6.48 0.34 to 13.12	1.40 -8.57 to 11.97	SEMA_SC	-5.33 -14.90 to 4.79
ORFO_PO	-8.56 -15.85 to -0.83	11.88 2.38 to 20.84	6.75 -4.08 to 17.94	5.33 -4.79 to 14.90	ORFO_PO

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 3.392 (95% CrI 1.624 to 7.303)
Residual deviance: 11.1 for 11 data points
DIC: 22.1 (pD 11.0)
Largest R-hat: 1.001
Smallest ESS: bulk 3,107, tail 3,413
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: 3.343
I squared: 96%
Q (total): 52.34 on 2 df, P = 0.000
Q (between designs): 2.50, P = 0.114

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; 6 of 6	Type 2 diabetes share in weight trials (percent of participants) effect modifier; 6 of 6	Sex (percent female) effect modifier, prognostic factor; 6 of 6	Asian ancestry or region (percent Asian) effect modifier, prognostic factor; 6 of 6	Treatment duration (weeks) effect modifier; 6 of 6	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 6 of 6
SURMOUNT-5 S000093	39.4	0 population codes	64.65	2.4	72	standard
STEP 1 S000144	37.87	0 population codes	74.07	13.33	68	standard
SURMOUNT-1 S001077	37.94	0 population codes	67.75	10.87	72	standard
NCT04881760 S001653	37.34	0 population codes	48.22	1.18	48	standard
ATTAIN-1 S001722	37	0 population codes	64.25	28.27	72	not_reported
SURMOUNT-3 S002157	35.9	0 population codes	62.9	0.7	72	standard

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, Sex: design means range from 48.2 (PLACEBO vs RETA_SC) to 74.1 (PLACEBO vs SEMA_SC) percent female; threshold 15
FlagHeterogeneity, tau above threshold: tau 3.39 exceeds the outcome threshold 2.5; the flags of this network are candidate explanations
NoteOutcome assessment, time point: selected time points span 48 to 72 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 1, modified_itt 3, other 1, randomized 1
NoteOutcome assessment, definition: mixed: not stated 5, percent change in body weight from randomization 1
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 1, not stated 5
NoteRisk of bias, blinding: mixed: double_blind 5, open_label 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
SURMOUNT-5	72	other	not stated	not stated	not stated	not stated	hypothetical	not stated	open_label	industry	2023	adults; BMI 30 or more, or 27 with complication; no diabetes
STEP 1	68	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	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
SURMOUNT-1	72	modified_itt	not stated	not stated	not stated	not stated	hypothetical	not stated	double_blind	industry	2019	age 18 or older; BMI 30 or more, or 27 or more with a weight related complication; no diabetes
NCT04881760	48	modified_itt	not stated	not stated	not stated	not stated	hypothetical	not stated	double_blind	industry	2021	18 to 75 years; BMI 30 or more, or 27 to less than 30 with weight related complication; no type 2 diabetes
ATTAIN-1	72	randomized	not stated	not stated	not stated	not stated	hypothetical	not stated	double_blind	industry	2023	adults BMI 30 or more, or 27 or more with a weight related complication, without diabetes
SURMOUNT-3	72	modified_itt	percent change in body weight from randomization	not stated	not stated	not stated	hypothetical	not stated	double_blind	industry	2021	age 18 or older; BMI 30 or more, or 27 or more with comorbidity; no diabetes; at least 5 percent loss in lead in

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
SURMOUNT-5	A1	TIRZ_SC	72	arm, percent_change	-21.800	0.600	367		registry:outcomes
SURMOUNT-5	A2	SEMA_SC	72	arm, percent_change	-15.400	0.600	373		registry:outcomes
STEP 1	A1	SEMA_SC	68	contrast, md	-14.400	0.459			R0023399:Results
STEP 1	A2	PLACEBO	68	contrast, md					R0023399:Results
SURMOUNT-1	A1	PLACEBO	72	arm, percent_change	-2.400	0.400	635		registry:outcomes
SURMOUNT-1	A2+A3+A4	TIRZ_SC	72	arm, percent_change	-19.974	0.234	1,877	arms_combined	registry:outcomes
NCT04881760	A1	PLACEBO	48	arm, percent_change	-2.110	0.730	68		registry:outcomes
NCT04881760	A2+A3+A4+A5+A6+A7	RETA_SC	48	arm, percent_change	-18.063	0.655	267	arms_combined	registry:outcomes
ATTAIN-1	A1	PLACEBO	72	arm, percent_change	-0.870	0.247	949		registry:outcomes
ATTAIN-1	A2+A3+A4	ORFO_PO	72	arm, percent_change	-9.821	0.197	2,178	arms_combined	registry:outcomes
SURMOUNT-3	A1	TIRZ_SC	72	arm, percent_change	-21.100	0.600	227		R0007405:Results
SURMOUNT-3	A2	PLACEBO	72	arm, percent_change	3.300	0.600	202		R0007405: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.

Open in the NMA lab