Network meta-analysis

Percent body weight change

Overweight or obesity without diabetes (adults)

weeks 20 to 40 (target week 26)Hypothetical (as if everyone stayed on treatment)Doses of a drug pooledMean difference

Randomized trials

Treatments

2,471

Participants

Trial arms

In plain language

Across 8 trials with 2,471 participants, 3 of 8 treatments had a clearly better result than placebo on percent body weight change, and for 5 the evidence could not tell them apart from placebo. The most favorable estimate was for retatrutide injection: mean difference -11.83 percentage points (95% credible interval -17.95 to -4.35).

Retatrutide injection: better than placebo but not among the most effective (certainty pending).
Tirzepatide injection: better than placebo but not among the most effective (certainty pending).
Alenig po: better than placebo but not among the most effective (certainty pending).
Liraglutide injection: not convincingly different from placebo (certainty pending).
Cagrilintide: not convincingly different from placebo (certainty pending).
Loti po: not convincingly different from placebo (certainty pending).
HRS-7535 tablet: not convincingly different from placebo (certainty pending).
Standard care or no added treatment: not convincingly different from placebo (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
Retatrutide injection RETA_SC	-11.83 (-17.95 to -4.35)	-20.78 to -1.69	-12.11 (-16.80 to -7.41)	Better	pending
Tirzepatide injection TIRZ_SC	-11.24 (-17.63 to -4.83)	-20.67 to -1.63	-11.37 (-15.98 to -6.77)	Better	pending
Alenig po ALENIG_PO	-9.69 (-16.53 to -2.35)	-19.07 to 0.89	-9.97 (-14.98 to -4.96)	Better	pending
Liraglutide injection LIRA_SC	-5.86 (-12.25 to 1.37)	-15.01 to 4.00	-6.00 (-10.80 to -1.20)	Unclear	pending
Cagrilintide OTHER_ACTIVE_cagrilintide	-5.38 (-11.42 to 1.55)	-14.23 to 4.72	-5.49 (-10.17 to -0.80)	Unclear	pending
Loti po LOTI_PO	-4.30 (-10.63 to 2.53)	-13.50 to 5.31	-4.44 (-9.14 to 0.25)	Unclear	pending
HRS-7535 tablet HRS7535_PO	-3.80 (-10.59 to 3.35)	-13.48 to 6.55	-3.90 (-8.86 to 1.06)	Unclear	pending
Standard care or no added treatment STANDARD_CARE	3.90 (-4.08 to 11.59)	-6.32 to 14.31	3.81 (-1.94 to 9.55)	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 Placebo
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Alenig po versus Placebo	pending	some	pending	some	none	some	pending
HRS-7535 tablet versus Placebo	pending	some	pending	major	none	some	pending
Liraglutide injection versus Placebo	pending	some	pending	some	some	some	pending
Loti po versus Placebo	pending	some	pending	major	none	some	pending
Cagrilintide versus Placebo	pending	some	pending	some	some	some	pending
Retatrutide injection versus Placebo	pending	some	pending	none	some	some	pending
Standard care or no added treatment versus Placebo	pending	some	pending	major	none	some	pending
Tirzepatide injection versus Placebo	pending	some	pending	none	some	some	pending

Every other comparison (28)

Confidence in the other comparisons
Comparison	Within study bias	Reporting bias	Indirectness	Imprecision	Heterogeneity	Incoherence	Confidence
Alenig po versus HRS-7535 tablet	pending	some	pending	major	none	some	pending
Alenig po versus Liraglutide injection	pending	some	pending	major	none	some	pending
HRS-7535 tablet versus Liraglutide injection	pending	some	pending	major	none	some	pending
Alenig po versus Loti po	pending	some	pending	major	none	some	pending
HRS-7535 tablet versus Loti po	pending	some	pending	major	none	some	pending
Liraglutide injection versus Loti po	pending	some	pending	major	none	some	pending
Alenig po versus Cagrilintide	pending	some	pending	major	none	some	pending
HRS-7535 tablet versus Cagrilintide	pending	some	pending	major	none	some	pending
Liraglutide injection versus Cagrilintide	pending	some	pending	major	none	some	pending
Loti po versus Cagrilintide	pending	some	pending	major	none	some	pending
Alenig po versus Retatrutide injection	pending	some	pending	major	none	some	pending
HRS-7535 tablet versus Retatrutide injection	pending	some	pending	some	some	some	pending
Liraglutide injection versus Retatrutide injection	pending	some	pending	major	none	some	pending
Loti po versus Retatrutide injection	pending	some	pending	some	some	some	pending
Cagrilintide versus Retatrutide injection	pending	some	pending	major	none	some	pending
Alenig po versus Standard care or no added treatment	pending	some	pending	some	none	some	pending
HRS-7535 tablet versus Standard care or no added treatment	pending	some	pending	major	none	some	pending
Liraglutide injection versus Standard care or no added treatment	pending	some	pending	some	some	some	pending
Loti po versus Standard care or no added treatment	pending	some	pending	some	some	some	pending
Cagrilintide versus Standard care or no added treatment	pending	some	pending	some	some	some	pending
Retatrutide injection versus Standard care or no added treatment	pending	some	pending	none	none	some	pending
Alenig po versus Tirzepatide injection	pending	some	pending	major	none	some	pending
HRS-7535 tablet versus Tirzepatide injection	pending	some	pending	some	some	some	pending
Liraglutide injection versus Tirzepatide injection	pending	some	pending	major	none	some	pending
Loti po versus Tirzepatide injection	pending	some	pending	some	some	some	pending
Cagrilintide versus Tirzepatide injection	pending	some	pending	major	none	some	pending
Retatrutide injection versus Tirzepatide injection	pending	some	pending	major	none	some	pending
Standard care or no added treatment versus Tirzepatide injection	pending	some	pending	none	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	Rank 7	Rank 8	Rank 9	Mean rank
RETA_SC	48%	28%	14%	5%	2%	1%	1%			1.9
TIRZ_SC	32%	38%	20%	5%	3%	1%				2.2
ALENIG_PO	15%	22%	41%	10%	6%	3%	1%	1%		2.9
LIRA_SC	2%	4%	8%	32%	26%	16%	9%	3%	1%	4.8
OTHER_ACTIVE_cagrilintide	1%	3%	7%	21%	31%	21%	12%	3%	1%	5.1
LOTI_PO	1%	2%	5%	15%	16%	28%	25%	5%	2%	5.7
HRS7535_PO	1%	2%	5%	11%	14%	24%	34%	6%	3%	5.9
PLACEBO					1%	3%	14%	74%	8%	7.8
STANDARD_CARE				1%	1%	2%	3%	8%	85%	8.7

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	RETA_SC	TIRZ_SC	ALENIG_PO	LIRA_SC	OTHER_ACTIVE_cagrilintide	LOTI_PO	HRS7535_PO	STANDARD_CARE
PLACEBO	PLACEBO	11.83 4.35 to 17.95	11.24 4.83 to 17.63	9.69 2.35 to 16.53	5.86 -1.37 to 12.25	5.38 -1.55 to 11.42	4.30 -2.53 to 10.63	3.80 -3.35 to 10.59	-3.90 -11.59 to 4.08
RETA_SC	-11.83 -17.95 to -4.35	RETA_SC	-0.63 -9.18 to 9.11	-2.10 -11.94 to 7.78	-6.03 -15.27 to 4.15	-6.51 -15.90 to 3.03	-7.51 -16.57 to 2.10	-8.04 -17.10 to 2.11	-15.80 -25.10 to -4.91
TIRZ_SC	-11.24 -17.63 to -4.83	0.63 -9.11 to 9.18	TIRZ_SC	-1.51 -11.20 to 7.25	-5.37 -14.52 to 3.50	-5.89 -15.15 to 2.89	-6.96 -16.12 to 2.16	-7.45 -16.98 to 1.76	-15.14 -19.97 to -9.96
ALENIG_PO	-9.69 -16.53 to -2.35	2.10 -7.78 to 11.94	1.51 -7.25 to 11.20	ALENIG_PO	-3.82 -13.95 to 5.70	-4.37 -14.03 to 4.89	-5.44 -14.78 to 4.19	-5.92 -15.62 to 4.34	-13.63 -23.40 to -2.47
LIRA_SC	-5.86 -12.25 to 1.37	6.03 -4.15 to 15.27	5.37 -3.50 to 14.52	3.82 -5.70 to 13.95	LIRA_SC	-0.46 -7.58 to 6.14	-1.54 -11.17 to 8.00	-2.06 -11.11 to 7.98	-9.76 -19.45 to 0.87
OTHER_ACTIVE_cagrilintide	-5.38 -11.42 to 1.55	6.51 -3.03 to 15.90	5.89 -2.89 to 15.15	4.37 -4.89 to 14.03	0.46 -6.14 to 7.58	OTHER_ACTIVE_cagrilintide	-1.04 -10.31 to 8.26	-1.58 -10.93 to 8.42	-9.29 -18.55 to 0.76
LOTI_PO	-4.30 -10.63 to 2.53	7.51 -2.10 to 16.57	6.96 -2.16 to 16.12	5.44 -4.19 to 14.78	1.54 -8.00 to 11.17	1.04 -8.26 to 10.31	LOTI_PO	-0.50 -9.92 to 9.32	-8.21 -17.83 to 2.19
HRS7535_PO	-3.80 -10.59 to 3.35	8.04 -2.11 to 17.10	7.45 -1.76 to 16.98	5.92 -4.34 to 15.62	2.06 -7.98 to 11.11	1.58 -8.42 to 10.93	0.50 -9.32 to 9.92	HRS7535_PO	-7.75 -18.10 to 3.31
STANDARD_CARE	3.90 -4.08 to 11.59	15.80 4.91 to 25.10	15.14 9.96 to 19.97	13.63 2.47 to 23.40	9.76 -0.87 to 19.45	9.29 -0.76 to 18.55	8.21 -2.19 to 17.83	7.75 -3.31 to 18.10	STANDARD_CARE

Heterogeneity, fit and convergence

Bayesian random effects (primary)

Heterogeneity (tau): 2.486 (95% CrI 0.439 to 6.755)
Residual deviance: 16.3 for 16 data points
DIC: 32.3 (pD 16.0)
Largest R-hat: 1.002
Smallest ESS: bulk 1,849, tail 2,830
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: 2.296
I squared: 86%
Q (total): 7.18 on 1 df, P = 0.007
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.

Heterogeneity within designs (decomp.design)
Design	Q	df	P
STANDARD_CARE:TIRZ_SC	7.18	1	0.007

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.

Comparisons ordered as ALENIG_PO, HRS7535_PO, LIRA_SC, LOTI_PO, OTHER_ACTIVE_cagrilintide, RETA_SC, STANDARD_CARE, TIRZ_SC, PLACEBO; the shaded triangle is where 95% of points would fall without small study effects. Egger type test P = 0.848.

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	ALENIG_PO:PLACEBO	HRS7535_PO:PLACEBO	LIRA_SC:OTHER_ACTIVE_cagrilintide:PLACEBO	LOTI_PO:PLACEBO	PLACEBO:RETA_SC	PLACEBO:TIRZ_SC	STANDARD_CARE:TIRZ_SC
ALENIG_PO:PLACEBO	100
HRS7535_PO:PLACEBO		100
LIRA_SC:PLACEBO			100
LOTI_PO:PLACEBO				100
OTHER_ACTIVE_cagrilintide:PLACEBO			100
PLACEBO:RETA_SC					100
PLACEBO:STANDARD_CARE						50	50
PLACEBO:TIRZ_SC						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; 8 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	Asian ancestry or region (percent Asian) 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
TOGETHER-PsO S000032	39.25	10.9	44.9	3.31	52	standard
SURMOUNT-OSA S000156	38.89	0 population codes	30.28	17.09	52	standard
NCT05579977 S000448	35.44	100 population codes	52.05	13.22	32	not_reported
ACCESS S000899	39.46	0 population codes	54.35	1.74	36	not_reported
NCT03856047 S001532	37.83	0 population codes	61.75	13.03	26	standard
NCT04881760 S001653	37.34	0 population codes	48.22	1.18	48	standard
TOGETHER-PsA S001889	37.64	11.1	69.76	2.21	52	standard
NCT06250946 S002275	32.5	0 population codes	48.49	100 region: all sites in Asia	36	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, Baseline BMI or body weight: design means range from 32.5 (HRS7535_PO vs PLACEBO) to 39.5 (ALENIG_PO vs PLACEBO) kg/m2; threshold 3
FlagBaseline, Type 2 diabetes share in weight trials: design means range from 0.0 (ALENIG_PO vs PLACEBO) to 100.0 (LOTI_PO vs PLACEBO) percent of participants; threshold 20
FlagBaseline, Sex: design means range from 30.3 (PLACEBO vs TIRZ_SC) to 61.7 (LIRA_SC vs OTHER_ACTIVE_cagrilintide vs PLACEBO) percent female; threshold 15
FlagBaseline, Asian ancestry or region: design means range from 1.2 (PLACEBO vs RETA_SC) to 100.0 (HRS7535_PO vs PLACEBO) percent Asian; threshold 30
NoteOutcome assessment, time point: selected time points span 20 to 36 weeks
NoteOutcome assessment, analysis set: mixed: full_analysis 2, modified_itt 5, randomized 1
NoteOutcome assessment, intercurrent events (rescue): mixed: hypothetical 4, not stated 4
NoteRisk of bias, blinding: mixed: double_blind 6, open_label 1, single_blind 1
NoteData handling, input conversions: arms_combined 7, n_randomized 4

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
TOGETHER-PsO	36	modified_itt	not stated	not stated	not stated	not stated	hypothetical	not stated	open_label	industry	2024	adults; moderate to severe plaque psoriasis; PASI 12 or more; BMI 30 or more, or 27 to 30 with comorbidity
SURMOUNT-OSA	24	modified_itt	not stated	not stated	not stated	not stated	hypothetical	not stated	double_blind	industry	2022	adults; AHI 15 or more; BMI 30 or more (27 in Japan); no diabetes
NCT05579977	20	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2022	age 18 to 75; T2D cohort on metformin, HbA1c 7.0 to 10.0, BMI 23 or more; obesity cohort BMI 30 or more without diabetes
ACCESS	36	full_analysis	not stated	not stated	not stated	not stated	hypothetical	not stated	double_blind	industry	2024	age 18 to 79; BMI 30 or more, or 27 or more with comorbidity; HbA1c below 6.5 percent; weight above 80 kg; no diabetes
NCT03856047	26	full_analysis	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2019	age 18 or older; BMI 30 or more, or 27 or more with hypertension or dyslipidemia; no diabetes
NCT04881760	24	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
TOGETHER-PsA	36	modified_itt	not stated	not stated	not stated	not stated	hypothetical	hypothetical	single_blind	industry	2024	age 18 to 80; active psoriatic arthritis; BMI 30 or more, or 27 to 30 with a weight related comorbidity
NCT06250946	26	randomized	not stated	not stated	not stated	not stated	hypothetical	hypothetical	double_blind	industry	2024	age 18 to 65; BMI 28 to 40; no diabetes, HbA1c below 6.5 percent

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
TOGETHER-PsO	A1	STANDARD_CARE	36	arm, percent_change	-1.200	0.600	136		R0014237:Table 2
TOGETHER-PsO	A2	TIRZ_SC	36	arm, percent_change	-14.600	0.770	138		R0014237:Table 2
SURMOUNT-OSA	A1+A3	TIRZ_SC	24	arm, percent_change	-13.672	0.350	234	n_randomized;arms_combined	R0011011:Table 2
SURMOUNT-OSA	A2+A4	PLACEBO	24	arm, percent_change	-2.300	0.360	235	n_randomized;arms_combined	R0011011:Table 2
NCT05579977	A10+A11+A12+A13+A9	LOTI_PO	20	arm, percent_change	-6.284	0.301	178	arms_combined	R0004106:Supplement Table S2
NCT05579977	A8	PLACEBO	20	arm, percent_change	-1.840	0.614	45		R0004106:Supplement Table S2
ACCESS	A1+A2+A3	ALENIG_PO	36	arm, percent_change	-10.768	0.572	173	arms_combined	R0000892:Results
ACCESS	A4	PLACEBO	36	arm, percent_change	-0.800	0.969	56		R0000892:Results
NCT03856047	A1+A2+A3+A4+A5	OTHER_ACTIVE_cagrilintide	26	arm, percent_change	-8.487	0.288	506	arms_combined	R0017871:Table 2
NCT03856047	A6	LIRA_SC	26	arm, percent_change	-9.000	0.600	99		R0017871:Table 2
NCT03856047	A7	PLACEBO	26	arm, percent_change	-3.000	0.600	101		R0017871:Table 2
NCT04881760	A1	PLACEBO	24	arm, percent_change	-1.550	0.540	68		registry:outcomes
NCT04881760	A2+A3+A4+A5+A6+A7	RETA_SC	24	arm, percent_change	-13.657	0.412	267	arms_combined	registry:outcomes
TOGETHER-PsA	A1	STANDARD_CARE	36	contrast, md					R0018951:Table 2
TOGETHER-PsA	A2	TIRZ_SC	36	contrast, md	-16.900	0.867			R0018951:Table 2
NCT06250946	A1	PLACEBO	26	arm, percent_change	-2.500	0.941	46	n_randomized	R0001289:Table 2
NCT06250946	A2+A3+A4+A5	HRS7535_PO	26	arm, percent_change	-6.401	0.498	189	n_randomized;arms_combined	R0001289:Table 2

Rerun this analysis yourself

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