Network meta-analysis

Weight loss of 5 percent or more

Overweight or obesity without diabetes (adults)

weeks 40 to 104 (target week 68)Not stated by the trialsEach dose separatelyOdds ratio

Randomized trials

Treatments

2,402

Participants

1,588

Events

In plain language

Across 8 trials with 2,402 participants, 9 of 11 treatments had a clearly better result than placebo on weight loss of 5 percent or more, and for 2 the evidence could not tell them apart from placebo. The most favorable estimate was for Semaglutide and bimagrumab 2.4 to 10 mg injection once weekly: odds ratio 83.10 (95% credible interval 9.31 to 1718).

Higher 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

Odds ratio. Higher 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 OR (95% CrI)	95% prediction interval	Verdict
Semaglutide and bimagrumab 2.4 to 10 mg injection once weekly BIMASEMA_SC_2p4-10MG_QW	83.10 (9.31 to 1718)	7.58 to 1868	Better
Semaglutide and bimagrumab 2.4 to 30 mg injection once weekly BIMASEMA_SC_2p4-30MG_QW	32.49 (5.57 to 274)	4.08 to 323	Better
Semaglutide and bimagrumab 1.0 to 30 mg injection once weekly BIMASEMA_SC_1p0-30MG_QW	32.35 (5.38 to 276)	3.81 to 338	Better
Semaglutide and bimagrumab 1.0 to 10 mg injection once weekly BIMASEMA_SC_1p0-10MG_QW	30.77 (5.38 to 265)	4.24 to 300	Better
Tirzepatide 15 mg subcutaneous once weekly TIRZ_SC_15MG_QW	23.72 (5.73 to 90.52)	4.35 to 117	Better
Tirzepatide 10 mg subcutaneous once weekly TIRZ_SC_10MG_QW	20.28 (5.12 to 72.05)	3.78 to 92.85	Better
Semaglutide 2.4 mg subcutaneous once weekly SEMA_SC_2p4MG_QW	19.68 (10.75 to 29.70)	6.00 to 52.32	Better
Semaglutide 50 mg oral once daily (higher dose oral program) SEMA_PO_50MG_QD	14.90 (4.85 to 37.90)	3.40 to 55.48	Better
Semaglutide 1.7 mg injection once weekly SEMA_SC_1p7MG_QW	9.74 (3.33 to 23.90)	2.22 to 33.79	Better
Semaglutide 1.0 mg subcutaneous once weekly SEMA_SC_1p0MG_QW	2.89 (0.73 to 8.78)	0.51 to 12.02	Unclear
Bimagrumab OTHER_ACTIVE_bimagrumab	2.69 (0.73 to 7.85)	0.50 to 10.55	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: odds ratio 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	BIMASEMA_SC_2p4-10MG_QW	BIMASEMA_SC_2p4-30MG_QW	BIMASEMA_SC_1p0-30MG_QW	BIMASEMA_SC_1p0-10MG_QW	TIRZ_SC_15MG_QW	TIRZ_SC_10MG_QW	SEMA_SC_2p4MG_QW	SEMA_PO_50MG_QD	SEMA_SC_1p7MG_QW	SEMA_SC_1p0MG_QW	OTHER_ACTIVE_bimagrumab
PLACEBO	PLACEBO	0.01 0.00 to 0.11	0.03 0.00 to 0.18	0.03 0.00 to 0.19	0.03 0.00 to 0.19	0.04 0.01 to 0.17	0.05 0.01 to 0.20	0.05 0.03 to 0.09	0.07 0.03 to 0.21	0.10 0.04 to 0.30	0.35 0.11 to 1.37	0.37 0.13 to 1.37
BIMASEMA_SC_2p4-10MG_QW	83.10 9.31 to 1718	BIMASEMA_SC_2p4-10MG_QW	2.58 0.14 to 72.63	2.55 0.14 to 74.79	2.65 0.14 to 73.23	3.61 0.29 to 98.02	4.11 0.34 to 110	4.27 0.49 to 88.81	5.70 0.55 to 134	8.63 0.83 to 201	29.37 3.46 to 680	31.46 3.42 to 744
BIMASEMA_SC_2p4-30MG_QW	32.49 5.57 to 274	0.39 0.01 to 6.91	BIMASEMA_SC_2p4-30MG_QW	1.00 0.07 to 12.84	1.04 0.08 to 14.03	1.43 0.15 to 16.29	1.64 0.19 to 19.49	1.67 0.30 to 14.52	2.23 0.29 to 23.06	3.45 0.47 to 35.01	11.56 1.92 to 106	12.09 2.17 to 116
BIMASEMA_SC_1p0-30MG_QW	32.35 5.38 to 276	0.39 0.01 to 7.03	1.00 0.08 to 13.65	BIMASEMA_SC_1p0-30MG_QW	1.04 0.07 to 13.61	1.39 0.14 to 16.97	1.64 0.18 to 19.11	1.69 0.30 to 14.79	2.26 0.28 to 23.46	3.43 0.47 to 34.88	11.45 1.90 to 111	12.48 2.06 to 122
BIMASEMA_SC_1p0-10MG_QW	30.77 5.38 to 265	0.38 0.01 to 7.25	0.96 0.07 to 12.06	0.96 0.07 to 13.60	BIMASEMA_SC_1p0-10MG_QW	1.36 0.15 to 15.77	1.56 0.18 to 18.02	1.59 0.29 to 13.40	2.15 0.30 to 22.19	3.28 0.45 to 31.61	10.95 1.78 to 112	11.87 2.00 to 112
TIRZ_SC_15MG_QW	23.72 5.73 to 90.52	0.28 0.01 to 3.50	0.70 0.06 to 6.46	0.72 0.06 to 7.01	0.73 0.06 to 6.63	TIRZ_SC_15MG_QW	1.16 0.26 to 5.20	1.21 0.28 to 5.23	1.63 0.32 to 8.59	2.47 0.49 to 12.70	8.32 1.44 to 53.61	8.86 1.55 to 57.21
TIRZ_SC_10MG_QW	20.28 5.12 to 72.05	0.24 0.01 to 2.98	0.61 0.05 to 5.21	0.61 0.05 to 5.42	0.64 0.06 to 5.57	0.86 0.19 to 3.80	TIRZ_SC_10MG_QW	1.04 0.27 to 4.28	1.39 0.27 to 7.00	2.08 0.40 to 10.51	7.13 1.30 to 43.32	7.67 1.38 to 45.06
SEMA_SC_2p4MG_QW	19.68 10.75 to 29.70	0.23 0.01 to 2.03	0.60 0.07 to 3.35	0.59 0.07 to 3.32	0.63 0.07 to 3.51	0.82 0.19 to 3.61	0.96 0.23 to 3.75	SEMA_SC_2p4MG_QW	1.33 0.43 to 4.09	2.03 0.76 to 5.45	6.79 2.12 to 24.54	7.26 2.43 to 25.33
SEMA_PO_50MG_QD	14.90 4.85 to 37.90	0.18 0.01 to 1.83	0.45 0.04 to 3.40	0.44 0.04 to 3.54	0.47 0.05 to 3.32	0.61 0.12 to 3.13	0.72 0.14 to 3.68	0.75 0.24 to 2.31	SEMA_PO_50MG_QD	1.52 0.38 to 6.11	5.12 1.19 to 27.26	5.52 1.30 to 26.68
SEMA_SC_1p7MG_QW	9.74 3.33 to 23.90	0.12 0.00 to 1.20	0.29 0.03 to 2.11	0.29 0.03 to 2.15	0.31 0.03 to 2.22	0.41 0.08 to 2.05	0.48 0.10 to 2.48	0.49 0.18 to 1.32	0.66 0.16 to 2.64	SEMA_SC_1p7MG_QW	3.37 0.81 to 16.59	3.57 0.89 to 16.84
SEMA_SC_1p0MG_QW	2.89 0.73 to 8.78	0.03 0.00 to 0.29	0.09 0.01 to 0.52	0.09 0.01 to 0.53	0.09 0.01 to 0.56	0.12 0.02 to 0.69	0.14 0.02 to 0.77	0.15 0.04 to 0.47	0.20 0.04 to 0.84	0.30 0.06 to 1.24	SEMA_SC_1p0MG_QW	1.08 0.30 to 3.72
OTHER_ACTIVE_bimagrumab	2.69 0.73 to 7.85	0.03 0.00 to 0.29	0.08 0.01 to 0.46	0.08 0.01 to 0.49	0.08 0.01 to 0.50	0.11 0.02 to 0.64	0.13 0.02 to 0.73	0.14 0.04 to 0.41	0.18 0.04 to 0.77	0.28 0.06 to 1.12	0.93 0.27 to 3.34	OTHER_ACTIVE_bimagrumab

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 0.375 (95% CrI 0.151 to 0.994), log scale
Residual deviance: 22.8 for 23 data points
DIC: 41.7 (pD 18.9)
Largest R-hat: 1.002
Smallest ESS: bulk 2,116, tail 2,489
Divergent transitions: 0
Convergence: All criteria met
Priors: PR02 N(0, 5^2); PR05 N(0, 2.5^2); PR09 log normal(-2.53, 1.58^2) on tau^2 (General physical health indicators, pharm vs pharm)

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.

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; 4 of 8	Type 2 diabetes share in weight trials (percent of participants) effect modifier; 8 of 8	Sex (percent female) effect modifier, prognostic factor; 8 of 8	Treatment duration (weeks) effect modifier; 8 of 8	Lifestyle co-intervention intensity (none standard intensive) effect modifier, prognostic factor; 8 of 8
STEP 1 S000144	37.87	0 population codes	74.07	68	standard
STEP 5 S000214	38.55	0 population codes	77.6	104	standard
NCT05616013 S000715	37.3	0 population codes	57.37	48	standard
STEP 10 S000832	39.9	0 population codes	71.01	52	not_reported
SURMOUNT-CN S001086	body weight 91.8 kg	0 population codes	49.05	52	standard
STEP7 S001288	not reported	0 population codes	45.33	44	standard
OASIS 1 S001472	not reported	0 population codes	72.71	68	not_reported
STEP 6 S002102	not reported	0 population codes	36.91	68	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: not reported by 4 of 8 trials
FlagBaseline, Sex: design means range from 36.9 (PLACEBO vs SEMA_SC_1p7MG_QW vs SEMA_SC_2p4MG_QW) to 72.7 (PLACEBO vs SEMA_PO_50MG_QD) percent female; threshold 15
NoteOutcome assessment, time point: selected time points span 44 to 68 weeks
NoteOutcome assessment, analysis set: mixed: completers 1, full_analysis 6, modified_itt 1
NoteOutcome assessment, proportion method: mixed: not stated 6, not_stated 1, observed 1
NoteRisk of bias, blinding: mixed: double_blind 7, open_label 1
NoteData handling, input conversions: arms_combined 1, count_from_percent 11

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	68	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	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	52	full_analysis	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
NCT05616013	48	completers	not stated	not stated	not stated	observed	not stated	not stated	open_label	industry	2022	adults 18 to 80; BMI 30 or more, or 27 or more with comorbidity; no diabetes (HbA1c below 6.5 percent); weight below 150 kg
STEP 10	52	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2021	Adults with obesity and prediabetes; diabetes excluded
SURMOUNT-CN	52	modified_itt	not stated	not stated	not stated	not_stated	not stated	not stated	double_blind	industry	2021	Chinese adults; BMI 28 or more, or 24 or more with a weight related comorbidity; no diabetes
STEP7	44	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2020	age 18 or older; BMI 30 or more, or 27 or more with a weight related comorbidity including T2D
OASIS 1	68	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2021	overweight or obesity
STEP 6	68	full_analysis	not stated	not stated	not stated	not stated	not stated	not stated	double_blind	industry	2019

Trial data

What each trial contributes. Arm rows give the arm value with its standard error, or events over participants; contrast rows give the odds ratio 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	Value	SE	Events / N	Flags	Source
STEP 1	A1	SEMA_SC_2p4MG_QW	68	contrast, or	3.612	0.142			registry:outcomes
STEP 1	A2	PLACEBO	68	contrast, or					registry:outcomes
STEP 5	A1	SEMA_SC_2p4MG_QW	52	arm, responders			132 / 149		registry:outcomes
STEP 5	A2	PLACEBO	52	arm, responders			38 / 129		registry:outcomes
NCT05616013	A1	PLACEBO	48	arm, responders			14 / 35	count_from_percent	registry:outcomes
NCT05616013	A2+A3	OTHER_ACTIVE_bimagrumab	48	arm, responders			49 / 68	count_from_percent;arms_combined	registry:outcomes
NCT05616013	A4	SEMA_SC_1p0MG_QW	48	arm, responders			33 / 45	count_from_percent	registry:outcomes
NCT05616013	A5	SEMA_SC_2p4MG_QW	48	arm, responders			47 / 51	count_from_percent	registry:outcomes
NCT05616013	A6	BIMASEMA_SC_1p0-10MG_QW	48	arm, responders			40 / 41	count_from_percent	registry:outcomes
NCT05616013	A7	BIMASEMA_SC_2p4-10MG_QW	48	arm, responders			40 / 40	count_from_percent	registry:outcomes
NCT05616013	A8	BIMASEMA_SC_1p0-30MG_QW	48	arm, responders			42 / 43	count_from_percent	registry:outcomes
NCT05616013	A9	BIMASEMA_SC_2p4-30MG_QW	48	arm, responders			42 / 43	count_from_percent	registry:outcomes
STEP 10	A1	SEMA_SC_2p4MG_QW	52	arm, responders			111 / 129		registry:outcomes
STEP 10	A2	PLACEBO	52	arm, responders			17 / 66		registry:outcomes
SURMOUNT-CN	A1	TIRZ_SC_10MG_QW	52	arm, responders			64 / 70	count_from_percent	registry:outcomes
SURMOUNT-CN	A2	TIRZ_SC_15MG_QW	52	arm, responders			63 / 68	count_from_percent	registry:outcomes
SURMOUNT-CN	A3	PLACEBO	52	arm, responders			20 / 68	count_from_percent	registry:outcomes
STEP7	A1	SEMA_SC_2p4MG_QW	44	arm, responders			203 / 238		registry:outcomes
STEP7	A2	PLACEBO	44	arm, responders			36 / 116		registry:outcomes
OASIS 1	A1	SEMA_PO_50MG_QD	68	arm, responders			269 / 317		registry:outcomes
OASIS 1	A2	PLACEBO	68	arm, responders			76 / 295		registry:outcomes
STEP 6	A1	SEMA_SC_1p7MG_QW	68	arm, responders			71 / 98		registry:outcomes
STEP 6	A2	SEMA_SC_2p4MG_QW	68	arm, responders			160 / 193		registry:outcomes
STEP 6	A3	PLACEBO	68	arm, responders			21 / 100		registry:outcomes

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